U.S. patent application number 12/276610 was filed with the patent office on 2009-05-21 for extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt.
Invention is credited to Rolf-Stefan Brickl, Thomas Friedl.
Application Number | 20090130197 12/276610 |
Document ID | / |
Family ID | 34926162 |
Filed Date | 2009-05-21 |
United States Patent
Application |
20090130197 |
Kind Code |
A1 |
Friedl; Thomas ; et
al. |
May 21, 2009 |
EXTENDED RELEASE PELLET FORMULATION CONTAINING PRAMIPEXOLE OR A
PHARMACEUTICALLY ACCEPTABLE SALT
Abstract
An extended release pellet comprising an active ingredient
selected from pramipexole and the pharmaceutically acceptable salts
thereof, and at least one release-modifying excipient.
Inventors: |
Friedl; Thomas;
(Ochsenhausen, DE) ; Brickl; Rolf-Stefan;
(Warthausen, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY RD, P O BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
34926162 |
Appl. No.: |
12/276610 |
Filed: |
November 24, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11202689 |
Aug 12, 2005 |
|
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12276610 |
|
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Current U.S.
Class: |
424/452 ;
424/484; 424/489; 424/490; 424/494; 424/495; 424/497; 514/367 |
Current CPC
Class: |
A61P 25/16 20180101;
A61K 9/5078 20130101; A61P 25/00 20180101 |
Class at
Publication: |
424/452 ;
424/489; 514/367; 424/484; 424/490; 424/495; 424/494; 424/497 |
International
Class: |
A61K 9/52 20060101
A61K009/52; A61K 9/14 20060101 A61K009/14; A61P 25/16 20060101
A61P025/16; A61K 31/428 20060101 A61K031/428 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 13, 2004 |
EP |
04019249.4 |
Claims
1. An extended release pellet comprising pramipexole or a
pharmaceutically acceptable salt thereof, and at least one
release-modifying excipient.
2. The extended release pellet according to claim 1, wherein the
pramipexole or the pharmaceutically acceptable salt thereof is
embedded within a matrix formed by at least one release-modifying
excipient.
3. The extended release pellet according to claim 1, wherein at
least one of the release-modifying excipients is a lipid, wax, or
water-insoluble polymer.
4. The extended release pellet according to claim 1, comprising a
core and a coating, wherein at least one release-modifying
excipient is incorporated in the coating.
5. The extended release pellet according to claim 4, wherein the
pramipexole or the pharmaceutically acceptable salt thereof is
incorporated in the core.
6. The extended release pellet according to claim 4, wherein the
coating comprises at least a first layer and a second layer
surrounding the first layer, wherein the first layer comprises the
pramipexole or the pharmaceutically acceptable salt thereof, and
wherein the second layer comprises at least one release-modifying
excipient.
7. The extended release pellet according to claim 6, wherein at
least one release-modifying excipient is ethyl cellulose, cellulose
acetate, polyvinylacetate, polyacrylate, polymethacrylate, or
ammonio methacrylate copolymer.
8. The extended release pellet according to claim 7, wherein the
second layer further comprises at least one water-soluble
excipient.
9. The extended release pellet according to claim 8, wherein at
least one water-soluble excipient is hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and
polyethylene glycol.
10. The extended release pellet according to claim 7, wherein the
second layer further comprises an enteric coating polymer.
11. The extended release pellet according to claim 8, wherein
enteric coating polymer is methacrylic acid copolymers type A and
B.
12. The extended release pellet according to claim 10, wherein the
second layer comprises from about 10 to about 85 wt.-% of the
enteric coating polymer and from about 15 to about 75 wt.-% of the
water-insoluble polymer.
13. The extended release pellet according to claim 6, wherein the
core comprises a saccharide.
14. The extended release pellet according to claim 13, wherein the
saccharide is saccharose, starch, cellulose, or a cellulose
derivative.
15. The extended release pellet according to claim 14, wherein the
saccharide is microcrystalline cellulose.
16. An extended release pellet comprising: (1) an inert pellet
core; (2) a first layer comprising pramipexole or a
pharmaceutically acceptable salt thereof; and (3) a second layer
provided on the first layer, the second layer being an extended
release coating comprising: (a) at least one water-insoluble
polymer and optionally a pore former, the resulting pellet having a
pH-independent in vitro release characteristic, or (b) a mixture of
a pH-dependent enteric-coating polymer and a pH-independently water
swelling polymer, wherein the extended release pellet has a close
to zero order in vitro release characteristic at acidic pH values
up to pH 6.8, an accelerated release above pH 6.8, and a more
accelerated release above pH 7.3.
17. The extended release pellet according to claim 16, wherein the
first layer further comprises one or more wet binders and further
excipients.
18. The extended release pellet according to claim 16, wherein the
inert pellet core comprises polysaccharides, cellulose, a cellulose
derivative, starch, and/or waxes.
19. The extended release pellet according to claim 16, wherein the
inert pellet core comprises saccharose and/or microcrystalline
cellulose.
20. The extended release pellet according to claim 16, wherein the
water-insoluble polymer is ethyl cellulose, cellulose acetate,
polyvinylacetate, or polyacrylates and derivatives thereof.
21. The extended release pellet according to claim 16, wherein the
pH-dependent enteric-coating polymer is an anionic carboxylic
acrylic polymer soluble above a pH value of 5.5.
22. The extended release pellet according to claim 21, wherein the
pH-dependent enteric-coating polymer is soluble above a pH value of
7.0.
23. The extended release pellet according to claim 21, wherein the
pH-dependent enteric-coating polymer is a partly methyl esterified
methacrylic acid polymer.
24. The extended release pellet according to claim 16, wherein the
pH-independently water swelling polymer is a quaternary ammonium
substituted acrylic polymer.
25. The extended release pellet according to claim 24, wherein the
quaternary ammonium substituted acrylic polymer has an ammonium
substitution of about 5 to about 10 percent by weight.
26. The extended release pellet according to claim 16, wherein the
pH-dependent enteric-coating polymer is present in an amount of 10
to 85% by weight of the coating and the pH-independently water
swelling polymer is present in an amount of 15 to 75% by weight of
the coating.
27. The extended release pellet according to claim 21, wherein the
pH-dependent enteric-coating polymer is present in an amount of 10
to 85% by weight of the coating and the pH-independently water
swelling polymer is present in an amount of 15 to 75% by weight of
the coating.
28. The extended release pellet according to claim 24, wherein the
pH-dependent enteric-coating polymer is present in an amount of 10
to 85% by weight of the coating and the pH-independently water
swelling polymer is present in an amount of 15 to 75% by weight of
the coating.
29. The extended release pellet according to claim 16, comprising:
(1) an inert pellet core; (2) a first layer comprising pramipexole
or a pharmaceutically acceptable salt thereof; and (3) a second
layer provided on the first layer, the second layer being an
extended release coating comprising a mixture of: (i) a
pH-dependent enteric-coating polymer, (ii) a pH-independently water
swelling polymer, and (iii) a pore-forming component, wherein the
extended release pellet has a close to zero order in vitro release
characteristic at acidic pH values up to pH 6.8, an accelerated
release above pH 6.8, and a more accelerated release above pH
7.3.
30. The extended release pellet according to claim 29, wherein the
pore-forming component is hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, polyvinylpyrrolidone, or polyethylene glycol.
31. An extended release pellet comprising pramipexole or a
pharmaceutically acceptable salt thereof prepared by wet or melt
extrusion or melt granulation using excipients achieving extended
release without a further diffusion membrane.
32. A method of manufacturing extended release pellets, the method
comprising the steps of: (1) providing an inert starter pellet
core; (2) applying a solution or dispersion of a first coating
composition comprising pramipexole or a pharmaceutically acceptable
salt thereof, at least a binder, and optionally excipient(s) onto
the inert starter pellet core, wherein the pramipexole or a
pharmaceutically acceptable salt thereof is used as unmilled
material dissolved/dispersed in a solvent together with the
binder(s) and optional excipient(s), and subsequently drying the
first coated pellet; (3) applying a solution or dispersion of a
second coating composition as functional coating composition onto
the first coated pellet obtained in step (2), wherein the coating
composition comprises (a) at least one water-insoluble polymer and
optionally a pore former or (b) a mixture of a pH-dependent
enteric-coating polymer and a pH-independently water swelling
polymer, and optional excipient(s), and a solvent, and subsequently
drying the obtained extended release pellet.
33. The method according to claim 32, further comprising performing
manual screening after step (2) and/or step (3) in order to remove
agglomerates.
34. The method according to claim 32, wherein the applying the
first coating composition of step (2) is done by spraying the
solution or dispersion of the first coating composition onto the
inert starter pellet core.
35. The method according to claim 32, wherein the applying the
second coating composition of step (3) is done by spraying the
solution or dispersion of the second coating composition onto the
first coated pellet.
36. A capsule containing extended release pellets according to
claim 1.
37. A capsule containing extended release pellets according to
claim 16.
38. The capsule according to claim 36, wherein the capsule contains
an amount of extended release pellets sufficient to provide an
effective daily dose of pramipexole or a pharmaceutically
acceptable salt thereof.
39. The capsule according to claim 37, wherein the capsule contains
an amount of extended release pellets sufficient to provide an
effective daily dose of pramipexole or a pharmaceutically
acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] This application claims priority to European Application No.
04019249.4 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
pellet 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:
##STR00001##
[0005] The salt form commonly used is pramipexole dihydrochloride
monohydrate (molecular formula C.sub.10H.sub.12Cl.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 is 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) 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 dosage form
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 controlled release pharmaceutical 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 pregclatinized 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; said core being substantially enclosed in a coating
that constitutes about 2% to about 7% of the weight of the tablet,
said 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, said
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 a modified 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. All
examples are directed to tablets and not to coated pellets.
[0016] Absorption profile in vivo with matrix systems is frequently
highly variable due to differences in gastrointestinal transit
times. Multiparticle extended release formulations such as pellets
distribute in the gastrointestinal tract and therefore show reduced
variability in rate and extent of absorption. Furthermore different
dose strengths can be achieved easily by filling different amounts
of the same extended release pellet type into capsules. As
reproducible absorption is mandatory with pramipexole and there is
a wide range of therapeutic dose strengths, these properties offer
considerable advantages of pramipexole extended release pellets
over the predescribed examples mentioned above.
[0017] Therefore, it is an object of the present invention to
provide an extended release pellet formulation of pramipexole or a
pharmaceutically acceptable salt thereof which may be filled in a
capsule and is suitable for once-daily oral administration. It is a
further object to provide a pellet formulation comprising
pramipexole or a pharmaceutically acceptable salt thereof which may
be filled in a capsule and is suitable to provide a day-long
therapeutic effect and will allow patients to treat their symptoms
with a single daily dose, and makes it possible to adjust the
release profile of the active ingredient according to a selected
release profile dependent or independent from the pH1 value.
Furthermore, a method of manufacturing the pellet formulation shall
be provided.
DESCRIPTION OF THE INVENTION
[0018] 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 pellets and
two alternative formulation principles allow different release rate
types dependent or independent from the pH value.
[0019] One embodiment of the present invention relates to an
extended release pellet comprising an active ingredient selected
from pramipexole and the pharmaceutically acceptable salts thereof,
and at least one release-modifying excipient.
[0020] Preferably the invention relates to an extended release
pellet, wherein the active ingredient is embedded within a matrix
formed by the at least one release-modifying excipient, which is
preferably selected from the group of lipids, waxes, and
water-insoluble polymers.
[0021] Also preferred is an extended release pellet comprising a
core and a coating, wherein at least one release-modifying
excipient is incorporated in the coating.
[0022] Also preferred is an extended release pellet, wherein the
active ingredient is incorporated in the core.
[0023] Also preferred is an extended release pellet, wherein the
coating comprises at least a first layer and a second layer
surrounding the first layer, wherein the first layer comprises the
active ingredient, and wherein the second layer comprises at least
one release-modifying excipient, preferably selected from ethyl
cellulose, cellulose acetate, polyvinylacetate, polyacrylates,
polymethacrylates, and ammonio methacrylate copolymer.
[0024] Most preferred is an extended release pellet, wherein the
second layer further comprises at least one water-soluble
excipient, preferably selected from hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and
polyethylene glycol.
[0025] Particularly preferred is an extended release pellet,
wherein the second layer further comprises an enteric-coating
polymer, preferably selected from methacrylic acid copolymers type
A and B.
[0026] Particularly preferred is an extended release pellet,
wherein the second layer comprises from about 10 to about 85 wt.-%
of the enteric-coating polymer and from about 15 to about 75 wt.-%
of the water-insoluble polymer.
[0027] More particularly preferred is an extended release pellet,
wherein the core comprises a saccharide, such as saccharose,
starch, cellulose, and a cellulose derivative, preferably
microcrystalline cellulose.
[0028] In a further embodiment the present invention relates to an
extended release pellet formulation comprising: [0029] an inert
pellet core; [0030] a first layer being an active ingredient layer
comprising pramipexole or a pharmaceutically acceptable salt
thereof and optionally one or more wet binders and other
excipients; and [0031] a second layer provided on the first layer,
the second layer being an extended release coating comprising:
[0032] (a) at least one water-insoluble polymer and optionally a
pore former, the resulting pellet having a pH-independent in vitro
release characteristic, or [0033] (b) a mixture of a pH-dependent
enteric-coating polymer and a pH-independently water swelling
polymer, the resulting pellet having a close to zero order in vitro
release characteristic at acidic pH values up to pH 6.8, an
accelerated release above pH 6.8 and a more accelerated release
above pH 7.3.
[0034] The expression "layer" should be understood in its broadest
sense also including a coating or a film or any kind of (partly or
fully) surrounding material used in the pharmaceutical sector and
having a defined thickness.
[0035] Instead of using an inert pellet core and a first layer of
active principle, pellets can also be formed by extrusion of active
principle together with excipients in a wet extrusion or melt
extrusion process.
[0036] The extended release formulations (a) and (b) 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 pellets. The two formulation principles have different release
rate types 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.
[0037] 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.
[0038] 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
dosage form is used synonymously with prolonged action, sustained
release, or modified release dosage form. Preferably the extended
release dosage form allows at least a two-fold 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 a prompt
drug-releasing, conventional solid dosage form).
[0039] According to the teaching of the present invention two types
of extended release pellet formulations are available showing
different in vitro release characteristics. The two types have the
same structure, i.e., an inert pellet core and a first and a second
layer applied thereon in this order, the first layer represents the
active ingredient layer comprising pramipexole or a
pharmaceutically acceptable salt thereof and optionally a binder
and further excipients, the second layer represents a functional
coating either comprising a water-insoluble polymer with a pore
former or a mixture of an enteric-coating polymer, i.e., which is
resistant against gastric juice, and a nondissolving water swelling
polymer.
[0040] According to the present invention under "formulation (a)"
is understood the pellet formulation having the second layer as
above-defined under (a) and under "formulation (b)" is understood
the pellet formulation having the second layer as above-defined
under (b) whereas the inert pellet core and first layer
compositions of formulation (a) and (b) will be the same.
[0041] The extended release pellet formulation (a) of the present
invention applies a water-insoluble polymer preferably with a pore
former in the second layer leading to an exponential (1.sup.st
order) in vitro release characteristic, which is widely independent
of the pH value. The extended release pellet formulation (b) of the
present invention applies a mixture of a pH-dependent
enteric-coating polymer and a pH-independently water swelling
polymer, the resulting layer having a close to zero order in vitro
release characteristic over a broad period of time at acidic pH
values up to pH 6.8, an accelerated release above pH 6.8 and an
more accelerated release above pH 7.3. In addition to the close to
zero order release for the main portion of drug, the latter is
furthermore characterized by a certain lag time until drug release
becomes substantial and, after the main portion of drug is
released, by a flattening of the release profile until an asymptote
is reached. This results in a sigmoid profile, i.e., an S-shaped
dissolution profile.
[0042] A close to zero order in vitro release characteristic
indicates a curve which has a virtually constant ascending
slope.
[0043] The inert pellet core present in both alternate pellet
formulations (a) and (b) of the present invention comprises
saccharides, preferably polysaccharides, cellulose or a cellulose
derivative, starch, and/or waxes. It is preferred if the core
consists of or essentially consists of a saccharide, preferably
polysaccharide, or cellulose, particularly preferred saccharose or
microcrystalline cellulose. Most preferred is microcrystalline
cellulose. The size of the cores may be sieve fractions between 0.1
and 3.0 mm, preferably between 0.5 and 1.5 mm.
[0044] In case the inert pellet core consists or essentially
consists of microcrystalline cellulose it has been found that the
thickness of the second layer applied thereon may be decreased to a
great extent compared to the use of other core materials, e.g., if
the core is composed of saccharose. Therefore, the amount of
release controlling polymeric agents and overall spray volumes as
well as process times to apply the coating dispersions or solutions
may be reduced significantly while the release profile for the
active ingredient may be maintained. The related advantages are
reducing the amount of excipient and solvent materials used,
reducing the process times and the embodiment is cost-saving.
[0045] 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 latter can be excipients, the presence of which
does not affect the essential nature of the formulation.
[0046] According to pellet formulations (a) and (b) of the present
invention there is provided a first layer or coating on the inert
core pellet comprising pramipexole or a pharmaceutically acceptable
salt thereof and optionally one or more binders and further
excipients. The first layer or coating normally has a thickness of
0.5 to 25 .mu.m, preferably 1 to 5 .mu.m.
[0047] As active ingredient pramipexole or a pharmaceutically
acceptable salt thereof may be present 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 preferred embodiment, e.g., 0.750
mg pramipexole dihydrochloride monohydrate, corresponding to 0.524
mg anhydrous base, is used in the extended release capsule or
tablet formulation according to the present invention taking into
account that all pellets which are filled in a capsule or
compressed into a tablet are to give the desired dose strengths.
Preferably the extended release pellets are filled into hard
capsules, but also compressing of the pellets together with further
excipients into tablets is possible.
[0048] However, any other amount of active ingredient suitable for
treatment may be used with the only proviso that the amount of
pramipexole or salt, that is the whole number of pellets being
present in one capsule, is sufficient to provide a daily dose in
one to a small plurality, for example one to about 4, of capsules
to be administered at one time. Preferably the full daily dose is
delivered in a single capsule. An amount of pramipexole salt,
expressed as pramipexole dihydrochloride monohydrate equivalent, of
about 0.1 to about 10 mg per capsule, 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 capsule is present. Specific dosage
amounts per capsule, 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 said condition, and
the patient being treated.
[0049] The binder(s) present in the first layer may be any suitable
wet binder(s) as used in the pharmaceutical sector. Examples are
hydrophilic polymers which may swell and glue upon contact with
water. The viscosity of the polymers preferably ranges from 1 to
1,000 mPas (apparent viscosity of a 2% aqueous solution at
20.degree. C.). Examples of such polymers are alkylcelluloses, such
as, methyl cellulose; hydroxyalkylcelluloses, for example,
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose and hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses,
such as, hydroxyethyl methyl cellulose and hydroxypropyl methyl
cellulose; carboxyalkylcelluloses, such as, carboxymethylcellulose;
alkali metal salts of carboxyalkylcelluloses, such as, sodium
carboxymethylcellulose; carboxyalkylalkylcelluloses, such as,
carboxymethyl ethyl cellulose; carboxyalkylcellulose esters; other
natural, semisynthetic, or synthetic polysaccharides, such as,
alginic acid, alkali metal and ammonium salts thereof,
carrageenans, galactomannans, tragacanth, agar-agar, gum arabicum,
guar gum, xanthan gum, starches, pectins, such as sodium
carboxymethylamylopectin, chitin derivates such as chitosan,
polyfructans, inulin; polyacrylic acids and the salts thereof;
polymethacrylic acids and the salts thereof, 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.
[0050] Preferable binders are polysaccharides, in particular
cellulose derivatives and more preferred cellulose ether
derivatives. A most preferred cellulose ether derivative is
hydroxypropyl cellulose.
[0051] Different viscosity grades of hydroxypropyl cellulose and
hydroxypropyl methylcellulose are commercially available.
Hydroxypropyl methyl cellulose preferably used as a wet binder in
the present invention has a viscosity grade ranging from about 3
mPas to about 1,000 mPas, in particular ranging from about 3 mPas
to about 20 mPas and preferably a viscosity grade of about 4 mPas
to about 18 mPas (apparent viscosity of a 2% aqueous solution at
20.degree. C.), e.g., hypromellose 2910 (DOW, Antwerp,
Belgium).
[0052] Hydroxypropyl cellulose having a viscosity lower than 1,500
mPas (apparent viscosity of 1% aqueous solution at 20.degree. C.)
is preferred, in particular hydroxypropyl cellulose having a
viscosity in the range from about 75 to about 150 mPas (5% aqueous
solution), preferably from 300 to 600 mPas (10% aqueous solution),
e.g., KLUCEL.RTM. EFO (Hercules, Wilmington, USA).
[0053] Preferably, the amount of binder in the first layer of the
pellet formulations (a) and (b) of the present invention ranges
from 0 to about 30% by weight, preferably from about 10 to about
20% by weight. Also, a combination of binders may be used.
[0054] According to a preferred embodiment of the present invention
the first layer of the extended release pellet formulation of
alternatives (a) and (b) comprises or consists of hydroxypropyl
cellulose, pramipexole or a pharmaceutically acceptable salt
thereof and excipients. The amount of hydroxypropyl cellulose is
preferably in the range from 1 to 30, particularly preferred from 5
to 25, most preferred from 10 to 20% by weight. The amount of
excipients is preferably in the range from 1 to 40, particularly
preferred from 2 to 25, most preferred from 5 to 15% by weight.
[0055] Beside pramipexole or a salt thereof, and the binder(s), the
first layer or coating of both formulations (a) and (b) of the
present invention may also optionally comprise excipients, i.e.,
pharmaceutically acceptable formulating agents, in order to promote
the manufacture and coating properties of the preparation. These
formulating agents comprise, for example, glidants, antiadherents,
binding agents, granulating agents, anti-caking agents, and
lubricants. Other conventional excipients known in the art can also
be included.
[0056] A glidant and antiadherent can be used to improve the
manufacturing during the spray process and to prevent sticking and
picking of the pellets to each other. Suitable glidants include
colloidal silicon dioxide, magnesium trisilicate, powdered
cellulose, starch, talc, tribasic calcium phosphate and the like.
In a preferred embodiment, talc is included as a
glidant/antiadherent in an amount up to about 25%, preferably about
5% to about 15%, by weight of the first layer.
[0057] According to the present invention waxes, lipids, and
water-insoluble polymers may be used as release modifying
agents.
[0058] Suitable waxes include compounds that are chemically defined
as esters of fatty acids and fatty alcohols or sterols, as well as
derivatives and functional analogues thereof. Usually, the chain
length of the fatty acid moiety is at least about 8 carbon atoms,
and more typically at least about 12 carbon atoms. Waxes are
plastic solids at room temperature, but very often have a
moderately low melting point, such as below about 80.degree.
C.-100.degree. C. Waxes are usually somewhat more brittle than
solid fats, and less greasy. More recently, also compounds which
are chemically different from this definition but similar in their
properties have been referred to as waxes. These waxes or
functional analogues may also be used according to the present
invention. Examples of potentially suitable waxes and wax analogues
include white and yellow beeswax, carnauba wax, microcrystalline
wax, spermaceti wax, candellila wax, saturated fatty acid esters,
sugar cane wax, paraffin wax, castor wax, and wax mixtures such as
nonionic or anionic emulsifying wax, cetyl esters wax, and lanolin.
Among the presently preferred waxes are beeswax, carnauba wax,
saturated fatty acid esters, and microcrystalline wax.
[0059] Suitable lipids include lipophilic compounds or mixtures of
natural or synthetic origin that have similar properties as
glycerides and other natural lipids, such as phospholipids,
sphingolipids, ceramides, sterols, steroids, and carotenoids.
Lipids may be solid or liquid at room temperature, and may be
viscous in their liquid state. Preferably, a lipid used to carry
out the invention is solid at room temperature, even though a
liquid lipid may also be used in mixtures, such as in a mixture
with a solid lipid or wax. Examples of lipids which may be found
useful include mono-, di-, and glycerides of saturated or
unsaturated fatty acids, such as--optionally hydrated or partially
hydrated--vegetable oils (e.g., peanut, castor, coconut,
cottonseed, palm, or soybean), edible fat, hard fat, glyceryl
behenate, glyceryl stearate, glyceryl palmitate; fatty acids such
as stearic acid, behenic acid, palmitic acid, oleic acid, lauric
acid, myristic acid, arachidic acid, linolenic acid, linoleic acid,
arachidonic acid, and erucic acid; fatty alcohols such as those
corresponding to the previously mentioned fatty acids, in
particular cetyl alcohol, stearyl alcohol, oleyl alcohol, and
palmityl alcohol; glycerides, fatty acids, or fatty alcohols which
are modified with sorbitan or polyoxyethylene; and phospholipids
such as lecithin or phosphatidylcholine. Particularly suitable
lipids are solid or at least partially hydrated triglycerides
including edible fat, hard fat, hydrated peanut-, castor-,
coconut-, cottonseed-, palm-, and soybean oil, glyceryl behenate,
glyceryl stearate, glyceryl palmitate, stearic acid, behenic acid,
and palmitic acid.
[0060] Suitable water-insoluble polymers may comprise the
water-insoluble polymers as defined below for the formulations
according to the present invention.
[0061] Among the optional formulating agents that further may be
comprised in the pellet formulation there may be mentioned agents
such as polyvidone; starch; acacia gum; gelatin; seaweed
derivatives, e.g., alginic acid, sodium and calcium alginate;
cellulose, preferably microcrystalline cellulose, cellulose
derivatives, e.g., ethyl cellulose, hydroxypropyl methyl cellulose,
having useful binding and granulating properties.
[0062] According to the pellet formulation (a) of the present
invention the second layer is provided on the first layer, the
second layer, a functional layer, being an extended release coating
or film coating comprising at least one water-insoluble polymer and
preferably a pore former, the resulting pellet having an
pH-independent in vitro release characteristic. Therefore, the
second layer is a non soluble diffusion lacquer with pores leading
to an exponential (1.sup.st order) release profile of the pellet
formulation (a) which has practically a pH-independent in vitro
release characteristic. A release characteristic which is
pH-independent indicates that the release characteristic is
virtually the same in different pH media.
[0063] The water-insoluble polymer according to the present
invention is defined as a polymer having a water solubility which
is lower than 1 part soluble in 1,000, preferably lower than about
1 part soluble in 10,000 parts of solvent.
[0064] The release-controlling second layer, coating or film
according to pellet formulation (a) comprises one or more
hydrophobic or water-insoluble polymers such as cellulosic polymers
e.g., methyl cellulose, ethyl cellulose, hydroxyethyl cellulose,
cellulose esters such as cellulose acetate, polyvinyl acetate,
polymers and copolymers of acrylic acid and methacrylic acid and
esters thereof, such as ammonio methacrylate copolymer, type B, and
the like. Particularly preferred is ethyl cellulose.
[0065] The hydrophobic or water-insoluble component, preferably
ethylcellulose, typically constitutes about 1% to about 25%,
preferably about 3% to about 10%, by weight of the pellet as a
whole, provided that microcrystalline cellulose pellets are used as
described above. In case sugar pellets are used higher amounts of
ethylcellulose can become necessary.
[0066] The second layer can contain one or more pore formers, such
as more water soluble polymers, like hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, and highly water soluble polymers,
like polyvinyl pyrrolidone and polyethylene glycol, or other water
soluble excipients, such as lactose and mannitol. Particularly
preferred pore formers are polyethylene glycols (e.g., Macrogol
6000). The amount of pore former is suitably up to 40 percent by
weight of the layer, coating or film, preferably up to 25% by
weight. Pore formers like polyethylene glycols also serve as
plasticizers, i.e., the function of such excipients either as
plasticizer and/or pore former can not be clearly
differentiated.
[0067] The second layer can optionally contain additional
pharmaceutically acceptable excipients as mentioned above,
preferably used are plasticizers, dyes and antiadherents.
Particularly preferred plasticizers are polyethylene glycols (e.g.,
Macrogol 6000), triacetin, and triethylcitrate. The amount of
plasticizer is suitably up to 25 percent by weight of the layer,
coating or film. Anti-adherents, such as talc and magnesium
stearate can be used.
[0068] The extended release pellet formulation according to
formulation (a) is pH-independent. Therefore, the disadvantage that
food related dose-dumping which 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 a controlled release profile and in
particular has to avoid dose-dumping regardless whether the patient
is in fasted or fed conditions.
[0069] Therefore, the oral extended release formulation (a)
according to the present invention retains 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.
[0070] The alternate pellet formulation (b) has the same structure
with regard to the inert pellet core and first layer composition as
defined for formulation (a) but a different second layer or
functional film coating composition. Thus, the second layer of
formulation (b) comprises or essentially consists of a mixture of a
pH-dependent enteric-coating polymer and a pH-independently water
swelling polymer, the resulting pellet having a close to zero order
in vitro release characteristic at acidic pH values up to pH 6.8,
an accelerated release above pH 6.8 and a more accelerated release
above pH 7.3.
[0071] The pH-dependent enteric-coating polymer is preferably an
anionic polymer, more preferably an anionic carboxylic acrylic
polymer soluble above a pH value of 5.5, preferably above a pH
value of 7.0. By an anionic polymer is meant a polymer containing
anionic groups after dissociation depending on pH. For the purpose
of this invention such polymer should be soluble above pH 5.5,
preferably above pH 7.0. Preferably the anionic carboxylic acrylic
polymer is selected from partly methyl esterified methacrylic acid
polymers. Suitable partly methyl esterified methacrylic acid
polymers are sold under the names EUDRAGIT.RTM. L and EUDRAGIT.RTM.
S, preferably used are EUDRAGIT.RTM. S1100 and L100.
[0072] The water-insoluble, pH-independent swelling polymer is
preferably selected from quaternary ammonium substituted acrylic
polymers. Such polymers are sold under the names EUDRAGIT.RTM. RS
and EUDRAGIT.RTM. RL having an ammonium substitution of about 5 and
about 10 percent by weight, respectively. Preferably EUDRAGIT.RTM.
RS 100 is used.
[0073] It is especially preferred if the layer or film coating
comprises the enteric-coating polymer such as the anionic
carboxylic acrylic polymer in an amount of 10 to 85 percent by
weight of the layer or coating and the water-insoluble,
pH-independent swelling polymer, selected from quaternary ammonium
substituted acrylic polymers, in an amount of 15 to 75 percent by
weight of the layer or coating. Depending on the amount and ratio
of polymers processed in the preparation, the release profile can
be tuned with regard to the release rate, that is the time to,
e.g., reach a level of 50% of drug dissolved, and with regard to
the extent of pH dependency. In general, an excess of the anionic
carboxylic acrylic polymer, e.g., EUDRAGIT.RTM. S 100, over the
quaternary ammonium substituted acrylic polymers is required to
achieve the desired accelerated dissolution characteristic at a pH
above 6.8,
[0074] The second layer, coating or film normally has a thickness
of 5 to 80 .mu.m, preferably 20 to 60 .mu.m.
[0075] The second functional layer according to formulation (b) of
the present invention takes advantage of the fact that the time of
passage through the small intestine is rather constant, said time
is about 2 to 5 hours. According to the invention the change of pH
from acid to about neutral at the pylorus is employed as a trigger
mechanism changing the physical condition of the layer and finally
causing the accelerated release of the active substance. Therefore
the formulation releases a major part of its drug contents in the
small intestine, and in the lower part of the intestinal system
preferentially in the large intestine, i.e., the colon. With a
layer or coating according to formulation (b) the release of
pramipexole or a pharmaceutically acceptable salt thereof can be
accelerated in the lower parts of the intestine, that is under
conditions of higher physiological pH, thereby reducing the loss in
bioavailability and increase in variability typically observed with
pH independent release systems in situations of shorter
gastrointestinal transit times
[0076] According to a preferred embodiment of the present invention
a pore-forming component may be present in the second layer or film
coating of formulation (b). The pore-forming component may be
selected from the group consisting of water soluble polymers, such
as polyethylene glycols, polyvinyl pyrrolidone, and cellulose
derivatives, such as hydroxypropyl cellulose and hydroxypropyl
methyl cellulose, preferably hydroxypropyl cellulose. The
pore-forming component is typically present in an amount of about
1% to about 25%, preferably about 2% to about 10%, by weight of the
polymer mixture in the second layer.
[0077] A particular preferred pore-forming component is
hydroxypropyl cellulose having a viscosity in the range from about
150 to about 700 mPas, preferably from 200 to 600 mPas, e.g.,
selected from the KLUCEL.RTM. series such as KLUCEL.RTM. EF or LF
(Hercules, Wilmington, USA).
[0078] The polymer pore-forming component forms diffusion pores and
leads to an accelerated hydration and an altering of the
rebuffering characteristics of the layer or film coating with a
change from acid to alkaline medium and results in an accelerated
penetrability of the layer or coating for the active ingredient
pramipexole or its salt in the pH range >7.3
[0079] Therefore, the presence of a pore-forming component provides
the further advantage that the release characteristic is
accelerated and occurs more rapid, i.e., the effects of the second
layer are enhanced significantly.
[0080] According to a preferred embodiment an extended release
pellet formulation has the following composition:
Inert Pellet Core
[0081] 90 to 100% by weight of saccharose or microcrystalline
cellulose; and 0 to 10% by weight of excipient(s)
First Layer
[0082] 50 to 100% by weight of pramipexole or a salt thereof; 0 to
30% by weight of binder(s); and 0 to 50% by weight of
excipient(s)
Second Layer
[0083] 50 to 99% by weight of water-insoluble polymer(s); and 1 to
50% by weight of excipient(s) or a mixture of:
[0084] 10 to 85% by weight of a pH-dependent enteric-coating
polymer; 15 to 75% by weight of a pH-independently water swelling
polymer; and 1 to 50% by weight of excipient(s).
[0085] The first and second layers or coatings should be applied at
as uniform a thickness as possible to provide optimum control of
release rate of the pramipexole or pramipexole salt.
[0086] If pellets are formed by extrusion, the following
compositions are most suitable:
Wet Extrusion
[0087] Microcrystalline cellulose, powdered cellulose or starch is
mixed with pramipexole in ratios delivering the necessary amount of
drug in a suitable number of pellets with regard to reproducibility
of filling and acceptable capsule size. Extrusion is achieved by
addition of water only or of water containing binders such as
povidone or methyl cellulose, hydroxypropyl cellulose. In order to
achieve the desired release rates, other excipients such as
lactose, microcrystalline cellulose, starch, etc., can be
added.
Melt Extrusion
[0088] Melt extrusion is achieved either by hydrophilic or
lipophilic compounds with melting points between 40.degree. C. and
120.degree. C. Suitable examples are polyethylene glycol
2000-10000, poloxamer 188, carnauba wax, hydrogenated castor oil,
stearyl alcohol, cetyl alcohol and mixtures thereof. In order to
achieve the desired release rates, other excipients such as
lactose, microcrystalline cellulose, starch, etc., can be
added.
[0089] These pellets are then coated by retarding lacquers as
described for the pellets consisting of inert starters with drug
layers sprayed onto them.
[0090] Some excipients are suitable also to achieve extruded
pellets with suitable extended release even without retarding
lacquers. These are, e.g., carnauba wax, hydrogenated castor oil
and mixtures thereof for lipophilic pellets or carbopol, anionic
carboxylic acrylic polymer, e.g., partly methyl esterified
methacrylic acid polymers. Suitable partly methyl esterified
methacrylic acid polymers are sold under the names EUDRAGIT.RTM. L
and EUDRAGIT.RTM. S, preferably used are EUDRAGIT.RTM. S100 and
L100.
[0091] The extended release pellets can be of sizes between 0.2 and
3 mm in diameter, preferably between 0.5 to 1.5 mm, most preferred
between 0.7 and 1.0 mm. According to the present invention the
pellets are preferably filled in hard capsules. The extended
release capsules can be of any size and shape and color, e.g., for
a 0.75 mg dose strengths preferably a size 3 capsule can be used.
The capsule shell is usually made from hydroxypropyl methyl
cellulose (so-called HPMC or vegetable capsules) or gelatin. The
capsules according to the present invention are usually filled with
pellets, for example, more than 150 extended release pellets. Each
pellet is built up of an inert (starter) core pellet, an active
ingredient layer and an extended or slow release film coating. In
one capsule, the amount of pramipexole or the pharmaceutically
acceptable salt thereof contained in the pellets may preferably be
sufficient to provide a daily dose administered at one time.
[0092] Alternatively the extended release pellets can be admixed
with fillers and binders, such as microcrystalline cellulose,
carrageenans, and alginates and disintegrants, such as sodium
starch glycolate, sodium carboxymethyl cellulose (croscarmellose),
further excipients, like glidants and lubricants, and be compressed
into tablets.
[0093] The present invention is further directed to the use of the
extended release pellet formulation or capsule according to the
present invention for preparing a medical composition for the
treatment of Parkinson's Disease and complications or disorders
associated therewith.
[0094] According to the present invention it is also provided a
method of manufacturing the extended release pellet formulation
comprising the steps of [0095] (1) providing an inert starter
pellet core; [0096] (2) applying a solution or dispersion of a
first coating composition comprising pramipexole or a
pharmaceutically acceptable salt thereof, optionally a binder and
further excipient(s) onto the inert starter pellet core, preferably
by spraying the solution/dispersion of the coating composition onto
the inert starter pellet core, wherein the active ingredient in
form of pramipexole or a pharmaceutically acceptable salt thereof
is used as unmilled or milled material, dissolved/dispersed in a
solvent together with the optional binder(s) and excipient(s) and
sprayed onto the inert starter pellet core and subsequently drying
the obtained active ingredient pellet; and [0097] (3) applying a
solution or dispersion of a second coating composition as
functional coating composition onto the active ingredient pellet
obtained in step (2), preferably by spraying the coating
solution/dispersion onto the active ingredient pellet wherein the
coating composition comprises (a) at least one water-insoluble
polymer or (b) a mixture of a pH-dependent enteric-coating polymer
and a pH-independently water swelling polymer, and optional
excipient(s), and a solvent and subsequently drying the obtained
extended release pellet (ER pellet).
[0098] Optionally a manual screening after process step (2) and/or
process step (3) may be performed in order to remove
agglomerates.
[0099] The solvents employed according to the process of the
invention are solvents having a sufficient volatility to evaporate
under the conditions of application, leaving a layer of the solute
on the surface of the core or body or pellet prepared. Organic
solvents such as alcohols, hydrocarbons and esters may be used as
well as derivatives thereof, such as chlorinated hydrocarbons.
Particularly preferred are alcohol such as ethanol or alcohol/water
mixtures. The process of applying the coating may be carried out in
an apparatus normally used in the pharmaceutical industry for
coating of solid pharmaceutical preparations, preferably in a fluid
bed apparatus. The process is normally carried out at 25.degree. C.
to 35.degree. C. product temperature, however, temperature and
pressure conditions may be varied within broad limits. In a fluid
bed spraying process, the temperature of the inlet air is suitably
about 20.degree. C. to 60.degree. C.
[0100] The obtained extended release pellets are filled in suitable
capsules and the capsules 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. The capsules are for example filled into High
Density Polyethylene (HDPE) bottles. The bottles are closed tightly
with screw caps and appropriately labeled. All packaging and
labeling activities are performed according to cGMP
regulations.
BRIEF DESCRIPTION OF THE DRAWINGS
[0101] FIG. 1 is a flow diagram illustrating process step (1) of a
preferred embodiment of the manufacturing process according to the
present invention wherein the first layer is applied on inert
starter core pellets;
[0102] FIG. 2 is a flow diagram illustrating process step (2) of a
preferred embodiment of the manufacturing process according to the
present invention wherein the second layer is applied on the first
layer of the pellets;
[0103] FIG. 3 is a flow diagram illustrating process step (3) of a
preferred embodiment of the manufacturing process according to the
present invention wherein the pellets are filled in capsules;
[0104] FIG. 4 is a graph illustrating the dissolution profiles of a
pellet formulation according to the present invention wherein the
second layer is a diffusion lacquer composed of ethyl cellulose
(formulation (a)) in 3 different pH media;
[0105] FIG. 5 is a graph illustrating the dissolution profiles of a
pellet formulation according to the present invention wherein the
second layer is a mixture of EUDRAGIT.RTM. S 100 and EUDRAGIT.RTM.
RS 100 (formulation (b)) in 4 different pH media; and
[0106] FIG. 6 is a graph illustrating the dissolution profiles of a
pellet formulation according to the present invention wherein the
second layer is as defined in FIG. 5, but a pore-forming component
is additionally present (formulation (b)+pore-forming component) in
3 different pH media.
[0107] Referring to FIGS. 1 and 2 a preferred embodiment of the
manufacturing process is illustrated with reference to a flow
diagram wherein the manufacture of the pellet formulations D, E, F,
G, H of Examples 1 to 5 is exemplarily shown. The figures show the
detailed process steps of the manufacturing process of the active
ingredient pellets (first layer; FIG. 1) and of the slow or
extended release pellets (second or functional layer; FIG. 2) and
the in process controls performed. FIG. 3 shows the filling of
capsules with the obtained pellets.
[0108] The manufacturing process described applies to all types of
pramipexole extended release pellets and capsules, for example the
formulations D, E, F, G, H of Examples 1 to 5, yet there are
differences in the qualitative and quantitative composition in some
process steps.
Process Step (1)--Inert Starter Pellet Core:
[0109] In the present embodiment microcrystalline cellulose pellets
(Cellets 700) are used which represent the starting material for
the subsequent coating step.
Process Step (2)--Active Ingredient Pellets (First Coating):
[0110] For all types of formulations the same active ingredient
pellets with a drug load of 1% (10 mg/g) can serve as starting
material for the functional film-coating. Yet also other drug loads
in the active ingredient pellets are suitable.
[0111] According to the present flow chart in FIG. 1, the active
ingredient pellets are manufactured by spray-layering of an aqueous
solution of pramipexole dihydrochloride monohydrate (active
ingredient), unmilled quality, together with hydroxypropyl
cellulose (binder) and talc (excipient) onto the surface of
microcrystalline cellulose pellets (core, Cellets 700) in a bottom
spray fluid bed equipment. Light protection of the spray suspension
is normally required. After the spraying is completed, the pellets
are dried at 35.degree. C. for 1 hour in a tray dryer. After
drying, the pellets are manually screened through a 1.12 mm mesh
size screen in order to remove agglomerates.
[0112] The in process controls used are: active ingredient assay
and loss on drying.
Process Step (3)--Functional Film Coating (Second Coating):
[0113] Depending on the type of formulation (D-H) coating
suspensions consisting of methacrylic acid copolymer (type B
USP/NF)) and ammonio methacrylate copolymer (type B USP/NF)), or
ethyl cellulose, and excipients selected from talc, triacetin or
triethylcitrate and hydroxypropyl cellulose or macrogol 6000, are
sprayed onto the active ingredient pellets in a bottom spray fluid
bed equipment. The solvent used is according to the described
embodiment either Ethanol 96% or an Ethanol 96% mixture with water.
After the spraying is completed the extended or slow release
pellets are dried at 40.degree. C. for 12 to 48 hours in a tray
dryer. After drying, the pellets are manually screened through a
1.12 mm mesh size screen in order to remove agglomerates.
[0114] The in process controls used are: active ingredient assay
and loss on drying.
Process Step (4)--Capsule Filling (at the Example of 0.75 mg Dose
Strength):
[0115] An appropriate amount of dried and screened pellets are
filled into vegetable capsules (HPMC capsules) or gelatin capsules
of size 3 to give the desired dose strengths using a suitable
intermittent motion capsule filling machine. The appropriate amount
is calculated from the assay result found for the respective batch
of slow or extended release pellets.
[0116] The in process controls used are: average mass of empty
capsules, mass of filled capsule, and length of closed capsule.
[0117] Referring to FIG. 4, it represents a graph illustrating the
release profiles of a pellet formulation according to the present
invention. The pellet contains an inert pellet core, a first layer
comprising pramipexole hydrochloride monohydrate and binder and a
second layer which represents a diffusion lacquer composed of ethyl
cellulose. The detailed composition of the pellet is given in
Example 4. The pellet meets the requirements as defined in the
abovementioned formulation (a) according to the present invention.
The release characteristics of the pellet formulation in 3
different pH media are shown, i.e., in simulated gastric juice,
n=3, in 0.05 M phosphate buffer, pH=6.8, n=3 and in acetate buffer,
pH=4.5, n=3 (n . . . represents the number of units tested). The
value percent of released active ingredient is plotted against the
time (hours).
[0118] FIG. 4 clearly shows that said pellet formulation has a
release characteristic being independent from the pH value.
[0119] FIG. 5 represents a graph illustrating the release profiles
of a pellet formulation according to the present invention. The
detailed composition of the pellet is given in Example 2. The
pellet formulation has a second layer in accordance with
formulation (b) which is composed of a pH-dependent enteric-coating
polymer and a pH-independently water swelling polymer
(EUDRAGIT.RTM.D S100/EUDRAGIT.RTM. RS 100). The release
characteristics of the pellet formulation in 4 different pH media
are shown, i.e., in acetate buffer, pH=4.5, n=3, in 0.05 M
phosphate buffer, pH=7.5, n=2, in 0.05 M phosphate buffer, pH 6.8,
n=3, and in simulated gastric juice, pH=1.3, n=3. The value percent
of released active ingredient is plotted against the time
(hours).
[0120] FIG. 5 clearly shows that the pellet formulation has a
release characteristic being dependent from the pH value, i.e., the
resulting pellet shows a close to zero order in vitro release
characteristic at acidic pH values up to pH 6.8, and an accelerated
release at pH 7.5.
[0121] FIG. 6 represents a graph illustrating the release profiles
of a pellet formulation according to the present invention. The
detailed composition of the pellet is given in Example 5. The
pellet formulation has a second layer in accordance with
formulation (b) which is composed of a pH-dependent enteric-coating
polymer and a pH-independently water swelling polymer
(EUDRAGIT.RTM. S310/EUDRAGIT.RTM. RS 100) and contains additionally
a pore-forming component (KLUCEL.RTM. EF) and a plasticizer
(triethylcitrate). The release characteristics of the pellet
formulation in 3 different pH media are shown, i.e., in 0.05 M
phosphate buffer, pH=6.8, n=3, in 0.05 M phosphate buffer, pH=6.3,
n=3, and in 0.05 M phosphate buffer, pH=7.3, n 3. The value percent
of released active ingredient is plotted against the time
(hours).
[0122] FIG. 6 clearly shows that the pellet formulation has a
release characteristic being dependent from the pH value. The
presence of a pore-forming component and the use of a different
plasticizer increases and accelerates the effects significantly,
compared with the pellet formulation without pore-forming component
as shown in FIG. 5.
[0123] The advantages of the present invention are manifold:
[0124] According to the present invention two types of extended
release pellets containing pramipexole or a pharmaceutically
acceptable salt thereof are available showing different in vitro
release profiles. The two types have the same structure, i.e., an
inert starter pellet core and a first layer or coating and second
layer or functional film coating provided on the core in this
order. The core and first layer or coating are identical and the
second layer or coating allows to tune the releasing characteristic
as desired.
[0125] According to formulation (a) of the present invention at
least one water-insoluble polymer is present in the second layer,
the resulting pellet having a pH-independent in vitro release
characteristic.
[0126] According to formulation (b) of the present invention the
second layer comprises a mixture of a pH-dependent enteric-coating
polymer and a pH-independently water swelling polymer, the
resulting pellet having a close to zero order in vitro release
characteristic at acidic pH values up to pH 6.8, an accelerated
release above pH 6.8 and a more accelerated release above pH 7.3.
In the latter case (formulation (b)) the additional presence of a
pore-forming component has the significant effect that the release
characteristic is enhanced and accelerated compared with the same
formulation without a pore-forming component.
[0127] Therefore, with a layer or coating according to formulation
(b) the extent of release of pramipexole or a pharmaceutically
acceptable salt thereof can become more independent of
gastrointestinal transit and hence dwell time of the dosage form in
the intestine.
[0128] It is therefore possible to select a tailor-made release
characteristic for patient's needs, symptoms and clinical picture
observed, a desired release with a reduced inter- and
intraindividual variability of bioavailability.
[0129] In case the inert pellet core consists or essentially
consists of microcrystalline cellulose, the thickness of the second
layer and the amount of release controlling excipients applied
thereon may be decreased to a great extent compared to the use of
other core materials, e.g., if the core is composed of
saccharose.
[0130] 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 pellets
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 pellet formulations provide a daily dose administered at
one time. The amount that constitutes a therapeutically effective
amount varies according to the condition being treated, the
severity of said condition, and the patient being treated.
[0131] It is further provided a manufacturing process which applies
to all types of pramipexole extended release pellets and
capsules.
[0132] 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
[0133] In the following Examples cap and body white opaque
hydroxypropyl methyl cellulose capsules of size 3 are used, filled
with extended release pellets. The complete capsules are intended
to be administered orally, and shall not be opened before use. The
pramipexole pellets in the Examples contain 0.75 mg of pramipexole
dihydrochloride monohydrate, corresponding to 0.524 mg of
pramipexole free, anhydrous base.
Example 1
[0134] One embodiment of the qualitative and quantitative
composition of pramipexole extended release pellets according to
the present invention (Formulation D) is shown in Table 1.
TABLE-US-00001 TABLE 1 Qualitative and Quantitative Composition of
Pramipexole Extended Release (ER) Capsule (Formulation D) mg per mg
per 0.75 mg 0.75 mg Reference to Ingredient capsule capsule
Function Standards ER Pellets consisting of: 88.458 Pramipexole
dihydrochloride 0.750 Active ingredient Company monohydrate
standard Microcrystalline cellulose pellets 73.980 Non-pareille
carrier Ph.Eur./NF (Cellets 700) pellet Hydroxypropyl cellulose
0.150 Wet binder Ph.Eur./NF (KLUCEL .RTM. EF) Talc 0.495 Glidant
Ph.Eur./USP Methacrylic acid copolymer, 7.500 Functional coating
Ph.Eur./NF Type B (EUDRAGIT .RTM. S 100) Ammonio methacrylate 3.750
Functional coating Ph.Eur./NF copolymer, Type B (EUDRAGIT .RTM. RS
100) Triacetin 1.833 Plasticizer Ph.Eur./USP Ethanol (96%) 173.333*
Solvent Ph.Eur. Purified water 30.000* Solvent Ph.Eur./USP HPMC
capsule, size 3 46.000 Shell Company Standard Total 134.458 88.458
*removed during processing (does not appear in the final
product)
Example 2
[0135] One embodiment of the qualitative and quantitative
composition of pramipexole extended release pellets according to
the present invention Formulation B) is shown in Table 2.
TABLE-US-00002 TABLE 2 Qualitative and Quantitative Composition of
Pramipexole ER Capsule (Formulation E) mg per mg per 0.75 mg 0.75
mg Reference to Ingredient capsule capsule Function Standards ER
Pellets consisting of: 91.600 Pramipexole dihydrochloride 0.750
Active ingredient Corporate monohydrate standard Microcrystalline
cellulose pellets 73.980 Non-pareille carrier Ph.Eur/NF (Cellets
700) pellet Hydroxypropyl cellulose 0.150 Wet binder Ph.Eur./NF
(KLUCEL .RTM. EF) Talc 0.578 Glidant Ph.Eur./USP Methacrylic acid
copolymer, 9.250 Functional coating Ph.Eur./NF Type B (EUDRAGIT
.RTM. S 100) Ammonio methacrylate 4.625 Functional coating
Ph.Eur./NF copolymer, Type B (EUDRAGIT .RTM. RS 100) Triacetin
2.267 Plasticizer Ph.Eur./USP Ethanol (96%) 214.167* Solvent
Ph.Eur. Purified water 30.000* Solvent Ph.Eur./USP HPMC capsule,
size 3 46.000 Shell Company Standard Total 137.600 91.600 *removed
during processing (does not appear in the final product)
Example 3
[0136] One embodiment of the qualitative and quantitative
composition of pramipexole extended release pellets according to
the present invention (Formulation F) is shown in Table 3.
TABLE-US-00003 TABLE 3 Qualitative and Quantitative Composition of
Pramipexole ER Capsule (Formulation F) mg per mg per 0.75 mg 0.75
mg Reference to Ingredient capsule capsule Function Standards ER
Pellets consisting of: 80.063 Pramipexole dihydrochloride 0.750
Active ingredient Corporate monohydrate standard Microcrystalline
cellulose pellets 73.980 Non-pareille carrier Ph.Eur/NF (Cellets
700) pellet Hydroxypropyl cellulose 0.150 Wet binder Ph.Eur./NF
(KLUCEL .RTM. EF) Talc 0.495 Glidant Ph.Eur./USP Ethyl cellulose
(N14) 3.750 Functional coating Ph.Eur./NF Macrogol 6000 0.938
Plasticizer Ph.Eur./USP Ethanol (96%) 49.167* Solvent Ph.Eur.
Purified water 32.583* Solvent Ph.Eur./USP HPMC capsule, size 3
46.000 Shell Company Standard Total 126.063 80.063 *removed during
processing (does not appear in the final product)
Example 4
[0137] One embodiment of the qualitative and quantitative
composition of pramipexole extended release pellets according to
the present invention (Formulation G) is shown in Table 4.
TABLE-US-00004 TABLE 4 Qualitative and Quantitative Composition of
Pramipexole ER Capsule (Formulation G) mg per mg per 0.75 mg 0.75
mg Reference to Ingredient capsule capsule Function Standards ER
Pellets consisting of: 82.088 Pramipexole dihydrochloride 0.750
Active ingredient Corporate monohydrate standard Microcrystalline
cellulose pellets 73.980 Non-pareille carrier Ph.Eur/NF (Cellets
700) pellet Hydroxypropyl cellulose 0.150 Wet binder Ph.Eur./NF
(KLUCEL .RTM. EF) Talc 0.645 Glidant Ph.Eur./USP Ethyl cellulose
(N14) 5.250 Functional coating Ph.Eur./NF Macrogol 6000 1.313
Plasticizer Ph.Eur./USP Ethanol (96%) 68.333* Solvent Ph.Eur.
Purified water 33.667* Solvent Ph.Eur./USP HPMC capsule, size 3
46.000 Shell Company Standard Total 128.088 82.088 *removed during
processing (does not appear in the final product)
Example 5
[0138] One embodiment of the qualitative and quantitative
composition of pramipexole extended release pellets according to
the present invention (Formulation H) is shown in Table 5.
TABLE-US-00005 TABLE 5 Qualitative and Quantitative Composition of
Pramipexole ER Capsule (Formulation H) mg per mg per 0.75 mg 0.75
mg Reference to Ingredient capsule capsule Function Standards ER
Pellets consisting of: 93.668 Pramipexole dihydrochloride 0.750
Active ingredient Corporate monohydrate standard Microcrystalline
cellulose 73.980 Non-pareille Ph.Eur/NF pellets (Cellets 700)
carrier pellet Hydroxypropyl cellulose 0.630 Wet binder/pore
Ph.Eur./NF (KLUCEL .RTM. EF) former Talc 1.995 Glidant Ph.Eur./USP
Methacrylic acid copolymer, 9.000 Functional Ph.Eur./NF Type B
(EUDRAGIT .RTM. S 100) coating Ammonio methacrylate 4.500
Functional Ph.Eur./NF copolymer, Type B coating (EUDRAGIT .RTM. RS
100) Triethylcitrate 2.813 Plasticizer Ph.Eur./NF Ethanol (96%)
250.200* Solvent Ph.Eur. Purified water 30.000* Solvent Ph.Eur./USP
HPMC capsule, size 3 46.000 Shell Company Standard Total 139.668
93.668 *removed during processing (does not appear in the final
product)
Example 6
[0139] The batch formula for the two pramipexole extended release
pellet formulations of Example 1 and 2 (Formulations D and E) is
shown in Table 6. The batch size for the active ingredient layering
is 1 kg, the batch size for the functional slow release
film-coating of the active pellets is 530.748 g (Formulation D) and
549.600 g (Formulation E), corresponding to a theoretical batch
size of 6000 capsules each.
TABLE-US-00006 TABLE 6 Composition Per Batch of Pramipexole ER
Capsules (Formulation D and Formulation E) Grams Grams per batch
per batch Ingredient (formulation D) (formulation E) Active
ingredient layering suspension: Pramipexole dihydrochloride 10.000
10.000 monohydrate Hydroxypropyl cellulose 2.000 2.000 Talc 1.600
1.600 Purified water 400.000* 400.000* 13.600** 13.600** Active
ingredient layering: Active ingredient layering suspension 13.600**
13.600** Microcrystalline cellulose pellets 986.400 986.400 Active
pellets 1000.000 1000.000 ER coating suspension: Methacrylic Acid
Copolymer, Type B 45.000 55.500 Ammonio Methacrylate 22.500 27.750
Copolymer, Type B Triacetin 10.998 13.602 Talc 2.250 2.748 Ethanol
(96%) 1039.998* 1285.002* 80.748** 99.600** Functional
film-coating: Active pellets 450.000 450.000 ER coating suspension
80.748** 99.600** Extended release pellets 530.748 549.600
Encapsulation: Extended release pellets 530.748 549.600 Capsule
shell 276.000 276.000 Total Weight 806.748 825.600 Number of
capsules (actual depending 6000 6000 on assay of pellets and yield)
*removed during processing (does not appear in the final product)
**dry matter
Example 7
[0140] The batch formula for the two pramipexole capsule
formulations of Example 3 and 4 (Formulations F and G) is shown in
Table 7. The batch size for the active ingredient layering is 1 kg,
the batch size for the functional slow release film-coating of the
active pellets is 480.378 g (Formulation F) and 492.528 g
(Formulation G), corresponding to a theoretical batch size of 6000
capsules each.
TABLE-US-00007 TABLE 7 Composition Per Batch of Pramipexole ER
Capsules (Formulation F and Formulation G) Grams per batch Grams
per batch Ingredient (Formulation F) (Formulation G) Active
ingredient layering suspension: Pramipexole 10.000 10.000
dihydrochloride monohydrate Hydroxypropyl cellulose 2.000 2.000
Talc 1.600 1.600 Purified water 400.000* 400.000* 13.600** 13.600**
Active ingredient layering: Active ingredient layering 13.600**
13.600** suspension Microcrystalline cellulose pellets 986.400
986.400 Active pellets 1000.000 1000.000 ER coating suspension:
Ethyl cellulose (N14) 22.500 31.500 Macrogol 6000 5.628 7.878 Talc
2.250 3.150 Purified water 15.498* 22.002* Ethanol (96%) 295.002*
409.998* 30.378** 42.528** Functional film-coating: Active pellets
450.000 450.000 ER coating suspension 30.378** 42.528** Slow
release pellets 480.378 492.528 Encapsulation: Slow release pellets
480.378 492.528 Capsule shell 276.000 276.000 Total Weight 756.378
768.528 Number of capsules (actual 6000 6000 depending on assay of
pellets and yield) *removed during processing (does not appear in
the final product) **dry matter
Example 8
[0141] The batch formula for the pramipexole pellet formulation of
Example 5 (Formulation H) is shown in Table 8. The batch size for
the active ingredient layering is 1 kg, the batch size for the
functional slow release film-coating of the active pellets is
562.008 g, corresponding to a theoretical batch size of 6000
capsules each.
TABLE-US-00008 TABLE 8 Composition Per Batch of Pramipexole ER
Capsules (Formulation H) Grams per batch Ingredient (Formulation H)
Active ingredient layering suspension: Pramipexole dihydrochloride
monohydrate 10.000 Hydroxypropyl cellulose 2.000 Talc 1.600
Purified water 400.000* 13.600** Active ingredient layering: Active
ingredient layering suspension 13.600** Microcrystalline cellulose
pellets 986.400 Active pellets 1000.000 ER coating suspension:
Methacrylic Acid Copolymer, Type B 54.000 Ammonio Methacrylate
Copolymer, Type B 27.000 Hydroxypropyl cellulose 2.880 Triethyl
citrate 16.878 Talc 11.250 Ethanol (96%) 1501.200* 112.008**
Functional film-coating: Active pellets 450.000 ER coating
suspension 112.008** Extended release pellets 562.008
Encapsulation: Slow release pellets 562.008 Capsule shell 276.000
Total Weight 838.008 Number of capsules (actual depending 6000 on
assay of pellets and yield) *removed during processing (does not
appear in the final product) **dry matter
Example 9
Pellets Prepared by Wet Extrusion
[0142] In order to achieve adequate content uniformity, 9 g of
microcrystalline cellulose is mixed with 1 g of pramipexole. Then
this mixture is mixed with 90 g of microcrystalline cellulose. The
mixture is extruded in a twin screw extruder with an adequate
amount of water (or binder solution), diameter of dye is 0.7 mm.
The resulting extrudates are rounded in a spheronizer at 400 rpm.
After drying pellets are sieved, the fraction of 0.8-1.1 mm is used
for retardation as described in the previous examples. Table 9
provides some further examples of wet extrusion
TABLE-US-00009 TABLE 9 Further Examples for Wet Extrusion Example
Pramipexole Microcrystalline No. [g] cellulose [g] Binder [g] 9 1
69 0 9a 0.5 99.5 0 99b 2 98 0 99c 1 98 1 (povidone K25) 99d 1 98 1
(hydroxypropyl cellulose) 99e 0.5 98.5 1 (methyl cellulose)
Example 10
Pellets Prepared by Melt Extrusion with Hydrophilic Excipients
[0143] In order to achieve adequate content uniformity, 9 g of
polyethylene glycol 6000 (PEG) is mixed with 1 g of pramipexole.
Then this mixture is mixed with 50 g of PEG 6000 and 40 g of
poloxamer 188. The mixture is extruded in a twin screw extruder at
54.degree. C., diameter of dye is 0.7 mm using a face cut
granulator to achieve pieces of about 1 mm. These are rounded in a
spheronizer at 400 rpm and 41.degree. C. The pellets are sieved,
the fraction of 0.8-1.1 mm is used for retardation as described in
the previous examples. Table 10 provides some further examples of
melt extrusion
TABLE-US-00010 TABLE 10 Examples for Melt Extrusion Example
Pramipexole PEG Poloxamer No. [g] 6000 [g] 188 [g] 10 1 59 40 10a
0.5 59.5 40 10b 2 58 40 10c 0.5 69 30
Example 11
Pellets Prepared by Melt Extrusion with Hydrophobic Excipients
[0144] In order to achieve adequate content uniformity, 9 g of
stearyl alcohol is mixed with 1 g of pramipexole. Then this mixture
is mixed with 90 g of stearyl alcohol. The mixture is extruded in a
twin screw extruder at 51.degree. C., diameter of dye is 0.7 mm
using a face cut granulator to achieve pieces of about 1 mm. These
are rounded in a spheronizer at 400 rpm and 41.degree. C. The
pellets are sieved, the fraction of 0.8-1.1 mm is used for
retardation as described in the previous examples. Table 11
provides some further examples of melt extrusion.
TABLE-US-00011 TABLE 11 Further Examples for Melt Extrusion Example
Pramipexole Stearyl Cetyl No. [g] alcohol [g] alcohol [g] 11 1 99 0
10a 0.5 59.5 40 10b 2 58 40 10c 0.5 49 50
Example 12
Extended Release Pellets Prepared by Wet Extrusion
[0145] In order to achieve adequate content uniformity, 9 g of
microcrystalline cellulose is mixed with 1 g of pramipexole. Then
this mixture is mixed with 60 g of microcrystalline cellulose and
30 g of carbomer 971P. The mixture is extruded in a twin screw
extruder with an adequate amount of water (or binder solution),
diameter of dye is 0.7 mm. The resulting extrudates are rounded in
a spheronizer at 400 rpm. After drying, pellets are sieved, the
fraction of 0.8-1.1 mm is filled into capsules. Table 12 provides
some further examples of wet extrusion
TABLE-US-00012 TABLE 12 Further Examples for Extended Release
Pellets Prepared by Wet Extrusion Example Microcrystalline Extended
release No. Pramipexole [g] cellulose [g] excipient [g] 12 1 69 30
carbomer 971P 12a 0.5 69.5 30 carbomer 971P 12b 2 68 30 carbomer
971P 12c 1 69 30 EUDRAGIT .RTM. S 12d 1 58 40 EUDRAGIT .RTM. S 12e
1 44 30 EUDRAGIT .RTM. S 25 carbomer 971P
Example 13
Extended Release Pellets Prepared by Melt Extrusion
[0146] In order to achieve adequate content uniformity, 9 g of
hydrogenated castor oil is mixed with 1 g of pramipexole. Then this
mixture is mixed with 60 g of hydrogenated castor oil and 30 g of
carnauba wax. The mixture is extruded in a twin screw extruder with
an adequate amount of water (or binder solution), diameter of dye
is 0.7 mm. The resulting extrudates are rounded in a spheronizer at
400 rpm. Pellets are sieved, the fraction of 0.8-1.1 mm is filled
into capsules. Table 13 provides some further examples of melt
extrusion
TABLE-US-00013 TABLE 13 Further Examples for Extended Release
Pellets Prepared by Melt Extrusion Example hydrogenated carnauba
No. Pramipexole [g] castor oil [g] wax [g] 13 1 69 30 13a 0.5 69.5
30 13b 2 68 30 13c 1 59 40 13d 1 78 21 12e 1 83 16
Example 14
Extended Release Pellets Prepared by Hot Melt Granulation/Melt
Pelletization
[0147] In this process, agglomeration of active ingredient with
excipients is promoted by the addition of low melting point,
lipophilic binders, such as waxes, fats, fatty acids, fatty acid
alcohols, and more water soluble polymers, such as poloxamers or
polyethylene glycols. The binder is usually added to the other
components as a powder. The binder is liquefied by heat generated
either by friction during the mixing phase or by a heating jacket.
Excipients suitable are, e.g., lactose, microcrystalline cellulose,
and dibasic calcium phosphate. After melting and granulation of the
mass, the resulting mass is either cooled down, screened and
processed into tablets together with further excipients or,
spheronized into pellets, which can be coated in addition, and
filled into capsules
TABLE-US-00014 TABLE 14 Examples for Extended Release Pellets
Prepared by Hot Melt Granulation/Melt Pelletization Pramipexole
carnauba Example No. [%] Lactose Stearyl alcohol [%] wax [%] 14 0.9
74.1 15 10 14a 1.4 58.6 15 25 14b 0.9 79.1 15 5
* * * * *