U.S. patent application number 14/209823 was filed with the patent office on 2015-01-22 for controlled release pharmaceutical compositions comprising a fumaric acid ester.
This patent application is currently assigned to Forward Pharma A/S. The applicant listed for this patent is Forward Pharma A/S. Invention is credited to Bernd W. MUELLER, Henrik NILSSON, Joseph R. ROBINSON, Florian SCHOENHARTING.
Application Number | 20150024049 14/209823 |
Document ID | / |
Family ID | 50726313 |
Filed Date | 2015-01-22 |
United States Patent
Application |
20150024049 |
Kind Code |
A1 |
NILSSON; Henrik ; et
al. |
January 22, 2015 |
CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING A FUMARIC
ACID ESTER
Abstract
The present invention relates to controlled release
pharmaceutical compositions comprising fumaric acid ester(s) as
active substance(s). The compositions are suitable for use in the
treatment of e.g. psoriasis or other hyperproliferative,
inflammatory or autoimmune disorders and are designated to release
the fumaric acid ester in a controlled manner so that local high
concentrations of the active substance within the gastrointestinal
tract upon oral administration can be avoided and, thereby,
enabling a reduction in gastro-intestinal related side effects.
Inventors: |
NILSSON; Henrik;
(Copenhagen, DK) ; SCHOENHARTING; Florian;
(Copenhagen, DK) ; MUELLER; Bernd W.; (Flintbek,
DE) ; ROBINSON; Joseph R.; (Madison, WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Forward Pharma A/S |
Copenhagen K |
|
DK |
|
|
Assignee: |
Forward Pharma A/S
Copenhagen K
DK
|
Family ID: |
50726313 |
Appl. No.: |
14/209823 |
Filed: |
March 13, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11576871 |
Jan 30, 2009 |
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PCT/DK2005/000648 |
Oct 7, 2005 |
|
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14209823 |
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60691513 |
Jun 16, 2005 |
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Current U.S.
Class: |
424/482 ;
514/547; 560/190 |
Current CPC
Class: |
A61K 9/2081 20130101;
A61K 9/2013 20130101; A61K 9/2866 20130101; A61P 43/00 20180101;
A61K 9/2054 20130101; A61K 9/5047 20130101; A61K 31/22 20130101;
A61P 5/14 20180101; A61P 1/04 20180101; A61P 37/00 20180101; A61K
31/215 20130101; A61P 37/02 20180101; A61K 9/2077 20130101; A61K
9/48 20130101; A61P 25/00 20180101; A61K 31/225 20130101; A61K
9/2031 20130101; A61K 45/06 20130101; A61K 9/0053 20130101; A61P
29/00 20180101; A61P 37/06 20180101; A61K 9/167 20130101; A61P
35/00 20180101; A61P 17/06 20180101; A61K 9/2853 20130101; A61K
9/5042 20130101; A61K 9/28 20130101; A61K 9/2846 20130101; A61K
31/225 20130101; A61P 1/16 20180101; A61K 9/5084 20130101; A61P
7/06 20180101; A61K 9/14 20130101; A61P 17/00 20180101; A61K 9/20
20130101; A61P 19/02 20180101; A61K 2300/00 20130101; A61P 3/10
20180101; A61K 9/4808 20130101; A61K 9/4891 20130101; A61K 9/2027
20130101; A61K 9/50 20130101; A61P 25/04 20180101 |
Class at
Publication: |
424/482 ;
560/190; 514/547 |
International
Class: |
A61K 31/225 20060101
A61K031/225; A61K 9/28 20060101 A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 8, 2004 |
DK |
PA 2004 01546 |
Nov 10, 2004 |
DK |
PA 2004 01736 |
Feb 11, 2005 |
DK |
PA 2005 00211 |
Mar 23, 2005 |
DK |
PA 2005 00419 |
Claims
1. A pharmaceutical composition comprising as an active substance
one or more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid, or a
pharmaceutically acceptable salt thereof, which--upon oral
administration and in comparison to that obtained after oral
administration of Fumaderm.RTM. tablets in an equivalent
dosage--gives a reduction in GI related side effects.
2-45. (canceled)
46. A kit comprising: (a) a first unit dosage form consisting
essentially of about 120 mg of dimethylfumarate and one or more
pharmaceutically acceptable excipients, wherein the
dimethylfumarate is formulated for delayed release; and (b) a
second unit dosage form consisting essentially of about 240 mg of
dimethylfumarate and one or more pharmaceutically acceptable
excipients, wherein the dimethylfumarate is formulated for delayed
release.
47. The kit of claim 46, wherein the first unit dosage form is in
the form of a capsule or a tablet.
48. The kit of claim 47, wherein the capsule is a hard gelatin
capsule.
49. The kit of claim 47, wherein the first unit dosage form
comprises microtablets.
50. The kit of claim 49, wherein the microtablets are surrounded by
an enteric coating.
51. The kit of claim 47, wherein the first unit dosage form
comprises pellets.
52. The kit of claim 47, wherein the kit comprises fourteen
capsules of the first unit dosage form.
53. The kit of claim 50, wherein the kit consists of fourteen
capsules of the first unit dosage form.
54. The kit of claim 46, wherein the pharmaceutically acceptable
excipients in the first unit dosage comprise one or more of the
following: micro crystalline cellulose, cross-linked sodium
carboxymethylcellulose, talc, silica colloidal silicon dioxide,
magnesium stearate, or a surfactant having an HLB value above
8.
55. The kit of claim 54, wherein the first unit dosage form
comprises from about 1 to about 60% micro crystalline
cellulose.
56. The kit of claim 54, wherein the first unit dosage form
comprises from about 0.2 to about 3% magnesium stearate.
57. The kit of claim 54, wherein the first unit dosage form
comprises from about 0.2 to about 4% silica.
58. The kit of claim 54, wherein the first unit dosage form
comprises cross-linked sodium carboxymethylcellulose.
59. The kit of claim 54, wherein the first unit dosage form
comprises a surfactant having an HLB value above 8.
60. The kit of claim 46, wherein the second unit dosage form is in
the form of a capsule or a tablet.
61. The kit of claim 60, wherein the capsule is a hard gelatin
capsule.
62. The kit of claim 60, wherein the second unit dosage form
comprises microtablets.
63. The kit of claim 62, wherein the microtablets are surrounded by
an enteric coating.
64. The kit of claim 60, wherein the second unit dosage form
comprises pellets.
65. The kit of claim 60, wherein the kit comprises fourteen
capsules of the second unit dosage form.
66. The kit of claim 46, wherein the pharmaceutically acceptable
excipients in the second unit dosage form comprise at least one of
the following excipients micro crystalline cellulose, cross-linked
sodium carboxymethylcellulose, talc, silica colloidal silicon
dioxide, magnesium stearate, or a surfactant having an HLB value
above 8.
67. The kit of claim 66, wherein the second dosage unit comprises
from about 1 to about 60% micro crystalline cellulose.
68. The kit of claim 66, wherein the second dosage unit comprises
from about 0.2 to about 3% magnesium stearate.
69. The kit of claim 66, wherein the second dosage unit comprises
from about 0.2 to about 4% silica.
70. The kit of claim 66, wherein the second unit dosage comprises
cross-linked sodium carboxymethylcellulose.
71. The kit of claim 66, wherein the second dosage unit comprises a
surfactant having an HLB value above 8.
72. The kit of claim 46, wherein said first dosage unit and said
second dosage unit are produced using dimethylfumarate micro
crystals.
73. The kit of claim 72, wherein said micro crystals are surrounded
by an enteric coating.
74. The kit of claim 72, wherein said first unit dosage form and
said second unit dosage form are produced using dimethylfumarate
micro crystals between 315 and 710 microns, which are subsequently
coated with a layer containing an enteric coating polymer.
75. The kit of claim 46, further comprising a label containing
instructions for an oral dosage regimen of (i) and (ii).
Description
FIELD OF THE INVENTION
[0001] The present invention relates to controlled release
pharmaceutical compositions comprising a fumaric acid ester as an
active substance. The compositions are suitable for use in the
treatment of e.g. psoriasis or other hyperproliferative,
inflammatory or autoimmune disorders and are designed to release
the fumaric acid ester in a controlled manner so that local high
concentrations of the active substance within the gastrointestinal
tract upon oral administration can be avoided and, thereby,
enabling a reduction in gastro-intestinal related side-effects.
BACKGROUND OF THE INVENTION
[0002] Fumaric acid esters, i.e. dimethylfumarate in combination
with ethylhydrogenfumarat have been used in the treatment of
psoriasis for many years. The combination is marketed under the
tradename Fumaderm.RTM.. It is in the form of tablets intended for
oral use and it is available in two different dosage strengths
(Fumaderm.RTM. initial and Fumaderm.RTM.):
TABLE-US-00001 Fumaderm .RTM. Initial Fumaderm .RTM.
Dimethylfumarate 30 mg 120 mg Ethylhydrogenfumarate, 67 mg 87 mg
calcium salt Ethylhydrogenfumarate, 5 mg 5 mg Magnesium salt
Etylhydrogenfumarate, 3 mg 3 mg Zinc salt
[0003] The two strengths are intended to be applied in an
individually based dose regimen starting with Fumaderm.RTM. initial
in an escalating dose, and then after e.g. three weeks of treatment
switching to Fumaderm.RTM.. Both Fumaderm.RTM. initial and
Fumaderm.RTM. are enteric coated tablets.
[0004] Another marketed composition is Fumaraat 120.RTM. containing
120 mg of dimethylfumarate and 95 mg of calcium monoethylfumarate
(TioFarma, Oud-Beijerland, Netherlands). In a recent publication
(Litjens et al. Br. J. Clin. Pharmacol. 2004, vol. 58:4, pp.
429-432), the pharmacokinetic profile of Fumaraat 120.RTM. is
described in healthy subjects. The results show that a single oral
dose of Fumaraat 120.RTM. is followed by a rise in serum
monomethylfumarate concentration and only negligible concentrations
of dimethylfumarate and fumaric acid is observed. The results
indicate that dimethylfumarate is rapidly hydrolyzed to
monomethylfumarate in an alkaline environment, but according to the
authors not in an acid environment. As the composition is enteric
coated, it is contemplated that the uptake of fumarate takes place
mainly in the small intestine, where dimethylfumarate before uptake
is hydrolysed to the monoester due to an alkaline environment, or
it may rapidly be converted due to esterases in the circulation.
Furthermore, the study shows that t.sub.max and C.sub.max are
subject to food effect, i.e. t.sub.max is prolonged (mean for
fasted conditions is 182 min, whereas for fed conditions mean is
361 min) [lag time is 90 min for fasted and 300 min for fed] and
C.sub.max is decreased (fasted: 0.84 mg/l, fed: 0.48 mg/l) by
concomitant food-intake. Another study (Reddingius W. G.
Bioanalysis and Pharmacokinetics of Fumarates in Humans.
Dissertation ETH Zurich No. 12199 (1997)) in healthy subjects with
two tablets of Fumaderm.RTM. P forte revealed C.sub.max values
(determined as monoethyl- or monomethylfumarate) in a range from
1.0 to 2.4 .mu.g/ml and a t.sub.max in a range of from 4.8 to 6.0
hours.
[0005] U.S. Pat. No. 6,277,882 and U.S. Pat. No. 6,355,676 disclose
respectively the use of alkyl hydrogen fumarates and the use of
certain fumaric acid mono alkyl ester salts for preparing micro
tablets for treating psoriasis, psoriatic arthritis,
neurodermatitis and enteritis regionalis Crohn. U.S. Pat. No.
6,509,376 discloses the use of certain dialkyl fumarates for the
preparation of pharmaceutical preparations for use in
transplantation medicine or the therapy of autoimmune diseases in
the form of micro tablets or pellets. U.S. Pat. No. 4,959,389
disclose compositions containing different salts of fumaric acid
monoalkyl ester alone or in combination with dialkyl fumarate. GB
1,153,927 relates to medical compositions comprising dimethylmaleic
anhydride and/or dimethylmaleic acid and/or a dimethylfumaric acid
compounds. The Case report "Treatment of disseminated granuloma
annulare with fumaric acid esters" from BMC Dermatology, vol. 2,
no. 5, 2002, relates to treatment with fumaric acid esters.
[0006] However, therapy with fumarates like e.g. Fumaderm.RTM.
frequently gives rise to gastro-intestinal side effects such as
e.g. fullness, diarrhea, upper abdominal cramps, flatulence and
nausea.
[0007] Accordingly, there is a need to develop compositions
comprising one or more therapeutically or prophylactically active
fumaric acid esters that provide an improved treatment with a
reduction in gastro-intestinal related side effects upon oral
administration.
[0008] Furthermore, the present commercially available products
contain a combination of two different esters of which one of the
esters (namely the ethylhydrogenfumarate which is the
monoethylester of fumaric acid) is present in three different salt
forms (i.e. the calcium, magnesium and zinc salt). Although each
individual form may have its own therapeutic profile it would be
advantageous to have a much simpler product, if possible, in order
to obtain a suitable therapeutic effect.
[0009] The present inventors contemplate that an improved treatment
regimen may be obtained by administration of a pharmaceutical
composition that is designed to deliver the active substance in a
controlled manner, i.e. in a manner that is prolonged, slow and/or
delayed compared with the commercially available product.
Furthermore, it is contemplated that instead of using a combination
of different fumaric acid esters, a suitable therapeutic response
may be achieved by use of a single fumaric acid ester alone such as
dimethylfumaric acid.
SHORT DESCRIPTION OF THE FIGURES
[0010] FIG. 1 shows an example of an in vitro dissolution profile
of a capsule prepared as described in example 5.
[0011] FIG. 2 shows an example of an in vitro dissolution profile
of a sample of a tablet (before the enteric coating is applied)
prepared as described in example 16.
[0012] FIG. 3 shows an example of an in vitro dissolution profile
of a sample of a tablet (before the enteric coating is applied)
prepared as described in example 17.
DISCLOSURE OF THE INVENTION
[0013] Accordingly, the present invention relates to a
pharmaceutical composition comprising as an active substance one or
more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, which--upon oral
administration and in comparison to that obtained after oral
administration of Fumaderm.RTM. tablets in an equivalent
dosage--gives a reduction in GI (gastro-intestinal) related
side-effects.
[0014] As mentioned above, the present inventors contemplate that a
suitable way of reducing the gastro-intestinal related side-effects
is by administration of the active substance in the form of a
controlled release composition.
[0015] Accordingly, the present invention relates in a further
aspect to a controlled release pharmaceutical composition for oral
use comprising as an active substance one or more fumaric acid
esters selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric
acid and mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing 0.1 N hydrochloric acid as dissolution medium during
the first 2 hours of the test and then 0.05 M phosphate buffer pH
6.5 as dissolution medium--is as follows:
[0016] within the first 3 hours after start of the test at the most
about 70% w/w of the total amount of the fumaric acid ester
contained in the composition is released, and/or
[0017] within the first 4 hours after start of the test at the most
about 92% w/w of the total amount of the fumaric acid ester is
released, and/or
[0018] within the first 5 hours after start of the test at the most
about 94% w/w of the total amount of the fumaric acid ester is
released, and/or
[0019] within the first 6 hours after start of the test at the most
about 95% w/w of the total amount of the fumaric acid ester
contained in the composition is released, and/or
[0020] within the first 7 hours after start of the test at the most
about 98% w/w of the total amount of the fumaric acid ester
contained in the composition is released, and/or
[0021] within the first 9 hours after start of the test at the most
about 99% w/w of the total amount of the fumaric acid ester
contained in the composition is released and/or
[0022] within the first 12 hours after start of the test at the
most about 99% w/w of the total amount of the fumaric acid ester
contained in the composition is released.
[0023] In the present context, a controlled release composition is
a composition that is designed to release the fumaric acid ester in
a prolonged, slow and/or delayed manner compared to the release of
the commercially available product Fumaderm.RTM., when tested under
comparable conditions (e.g. for in vivo studies: dose equivalents,
with or without standardized meal etc., or for in vitro studies:
dose equivalents, dissolution test apparatus and working conditions
including e.g. composition, volume and temperature of dissolution
medium employed, rotation speed etc.).
[0024] The release in vivo may be tested by measuring the plasma
concentration at predetermined time periods and thereby obtaining a
plasma concentration versus time profile for the fumaric acid ester
in question or, if relevant, a metabolite thereof. (E.g. in the
case of dimethylfumarate, the active substance is envisaged to be
methylhydrogenfumarate, i.e. the monomethyl ester of fumaric acid).
Furthermore, it is contemplated that metabolism already takes place
within the gastro-intestinal tract or during passage of the
gastro-intestinal mucosa, or upon first passage through the hepatic
circulation. Accordingly, when dimethylfumarate is administered,
the relevant component to search for in the plasma may be the
monomethyl ester and not the dimethylester of fumaric acid.
[0025] Other tests may also be used to determine or to give a
measure of the release of the active substance in vivo. Thus,
animals (e.g. mice, rats, dogs etc.) may be used as a model. The
animals receive the compositions under investigation and after
specified periods of time, the animals are sacrificed and the
content of the active ingredient (or metabolite thereof, if
relevant) is determined in plasma or specific organs or extracted
from the intestinal contents.
[0026] Another test involves the use of a specific segment of an
animal intestine. The segment is placed in a suitable dissolution
apparatus containing two compartments (a donor and a receiver)
separated by the segment, and the composition under investigation
is placed in a suitable medium in one compartment (the donor
compartment). The composition will release the active substance
that subsequently is transported across the intestinal segment.
Accordingly, at suitable time intervals, the concentration of the
active substance (or, if relevant, the metabolite) is measured in
the receiver compartment.
[0027] A person skilled in the art will be able to adapt the
above-mentioned method to the specific composition.
[0028] With respect to in vitro methods, well-established methods
are available, especially methods described by official monographs
like e.g. United States Pharmacopeia (USP) or the European
Pharmacopoeia. A person skilled in the art will know which method
to choose and how to select the specific conditions to carry out
the in vitro test. For instance, the USP prescribes in vitro tests
be carried out at 37+/-1.0 such as 37+/-0.5 degrees
Celsius/Centigrade. A suitable dissolution test is, for example as
described in example 29, for capsules, wherein the dissolution
profile is determined as described in the United States
Pharmacopoeia at 37.degree. C. using a rotating basket at 100 rpm
employing 0.1 N hydrochloric acid as dissolution medium during the
first 2 hours of the test and then followed by 0.05 M phosphate
buffer pH 6.5 as dissolution medium for the remaining test period,
and, for example as described in example 30, for tablets wherein
the dissolution profile is determined as described in the United
States Pharmacopoeia at 37.degree. C. using a paddle dissolution
apparatus at 100 rpm employing 0.1 N hydrochloric acid as
dissolution medium during the first 2 hours of the test and then
followed by 0.05 M phosphate buffer pH 6.5 as dissolution medium
for the remaining test period.
[0029] As mentioned above, the in vivo release of the active
substance is prolonged, slow and/or delayed compared with the
commercially available Fumaderm.RTM. composition. In the present
context, the term "prolonged" is intended to indicate that the
active substance is released during a longer time period than
Fumaderm.RTM. such as at least during a time period that is at
least 1.2 times, such as, e.g., at least 1.5 times, at least 2
times, at least 3 times, at least 4 times or at least 5 times
greater than that of Fumaderm.RTM.. Thus, if e.g. 100% of
dimethylfumarate is released from Fumaderm.RTM. tablets 3 hours
after the start of a suitable test, then 100% of dimethylfumarate
in a composition according to the invention is released at least
3.6 hours after the start of a suitable test.
[0030] In the present context the term "delayed" is intended to
indicate that the release of the active substance starts at a later
point in time compared with that of Fumaderm.RTM. (such as at 30
min or more later such as, e.g., 45 min or more later, 1 hour or
more later or 1.5 hours or more later, alternatively, that the
initial release during the first 2 hours is much less compared with
that of Fumaderm.RTM. (i.e. less than 80% w/w such as, e.g., less
than 70% w/w, less than 60% w/w or less than 50% of that of
Fumaderm.RTM.).
[0031] As used in the present invention, a gastrointestinal (GI)
side effect may include, but is not limited to diarrhea, stomach
ache, stomach pain, abdominal pain, abdominal cramps, nausea,
flatulence, tenesmus, meteorism, an increased frequency of stools,
a feeling of fullness and upper abdominal cramps.
[0032] In the present context, a reduction of GI related side
effects is intended to denote a decrease in severity and/or
incidence among a given treated patient population, compared to the
GI side effects observed after administration of the composition
according to the invention compared with that of Fumaderm.RTM.. A
reduction in GI related side effects according to this definition
could thus be construed as a substantial reduction in incidence of
any of the GI side effect listed above, such as at least a 10%
reduction in incidence or more preferably at least 20% reduction in
incidence or even more preferable a more than 30% reduction in
incidence. A reduction in GI related side effect can also be
expressed as a substantial reduction in severity in any of the GI
side effects listed above, such as a reduction in severity and/or
frequency of diarrhea, stomach ache, stomach pain, abdominal pain,
abdominal cramps, nausea, flatulence, tenesmus, meteorism,
increased frequency of stools, a feeling of fullness or upper
abdominal cramps. The reduction of GI related side effects, as
described above, can be monitored in a clinical trial setting,
either comparing the administration of the composition according to
the invention head on with Fumaderm.RTM. or with placebo. In case
of a placebo controlled trial, the incidence of GI related side
effects in the patients receiving the composition according to the
invention compared to the placebo group, can be compared to
historical trials comparing Fumaderm.RTM. to placebo (see e.g.
Altmeyer et al, J. Am. Acad. Dermatol. 1994; full reference:
Altmeyer P J et al, Antipsoriatic effect of fumaric acid
derivatives. Results of a multicenter double-blind study in 100
patients. J. Am. Acad. Dermatol. 1994; 30:977-81). Typically,
patients suffering from psoriasis are included in such a study, and
typically more than 10% of the body surface area will be affected
by psoriasis (severe psoriasis). However, patients in whom between
2 and 10 percent of the body surface area is affected can also be
included (moderate psoriasis). Patients can also be selected based
on the psoriasis area severity index (PASI). Typically, patients
within a certain range of PASI are included, such as between 10 and
40, or such as between 12 and 30, or such as between 15 and 25.
Patients with any type of psoriasis may be included (chronic plaque
type, exanthematic guttate type, pustular type, psoriatic
erythroderma or palmoplantar type), but in some cases only patients
with the chronic plaque type are included. About 15 to 20 patients
in each treatment group (composition according to the invention and
Fumaderm.RTM. or placebo) are sufficient in most cases, but more
preferably about 30 to 50 patients are included in each arm of the
study. Total study duration can be as short as one day to one week,
but more preferably the study will run for 8 weeks to 12 weeks or
up to 16 weeks. The side effects can e.g. be assessed as the total
number of times a certain side effect was reported in each group
(irrespective of how many patients have experienced the side
effect), or the side effects can be assessed as the number of
patients that have experienced a certain side effect a certain
number of times, such as at least once or at least twice or at
least three times during the duration of the study. Furthermore,
the severity of a side effect can be monitored, or a certain
severity of a side effect can be required for it to qualify as a
side effect in the study. A convenient way of assessing the
severity of a side effect is via a visual analogue (VAS) scale.
[0033] Active Substance
[0034] The active substance in a composition of the invention is
any fumaric acid ester. In one embodiment of the invention the
fumaric acid ester is preferably selected from the group consisting
of dimethylfumarate, diethylfumarate, dipropylfumarate,
dibutylfumarate, dipentylfumarate, methyl-ethylfumarate,
methyl-propylfumarate, methyl-butylfumarate, methyl-pentylfumarate,
monomethylfumarate, monoethylfumarate, monopropylfumarate,
monobutylfumarate and monopentylfumarate, including
pharmaceutically acceptable salts thereof.
[0035] In a specific embodiment of the invention, the fumaric acid
ester is a mono-(C.sub.1-C.sub.5)alkylester of fumaric acid that is
present in the form of a pharmaceutically acceptable salt. Suitable
salts are e.g. metal salts such as a salt selected from alkali
metal salts and alkaline earth metal salts including sodium,
potassium, calcium, magnesium or zinc salt.
[0036] The term (C.sub.1-C.sub.5)alkyl refers to a branched or
un-branched alkyl group having from one to five carbon atoms
inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,
2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl and pentyl.
[0037] In another embodiment, the composition according to the
invention comprises dimethylfumarate as the active substance.
[0038] In a further embodiment, the composition according to the
invention comprises monomethylfumarate as the active substance
optionally in the form of a pharmaceutically acceptable salt like
e.g. its sodium, potassium, calcium, magnesium and/or zinc
salt.
[0039] In another embodiment, the composition according to the
invention consists essentially of dimethylfumarate as the active
substance.
[0040] In another embodiment, the composition according to the
invention consists of dimethylfumarate as the active substance.
[0041] In a further embodiment, the composition according to the
invention consists essentially of monomethylfumarate as the active
substance optionally in the form of a pharmaceutically acceptable
salt like e.g. its sodium, potassium, calcium, magnesium and/or
zinc salt.
[0042] In a further embodiment, the composition according to the
invention consists of monomethylfumarate as the active substance
optionally in the form of a pharmaceutically acceptable salt like
e.g. its sodium, potassium, calcium, magnesium and/or zinc
salt.
[0043] In a further embodiment, the composition according to the
invention comprises dimethylfumarate and monomethylfumarate
(optionally in the form of a pharmaceutically acceptable salt like
e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as
the active substances, in a weight ratio between about 1:10 and
about 10:1.
[0044] In a further embodiment, the composition according to the
invention consists essentially of dimethylfumarate and
monomethylfumarate (optionally in the form of a pharmaceutically
acceptable salt like e.g. its sodium, potassium, calcium, magnesium
and/or zinc salt) as the active substances, in a weight ratio
between about 1:10 and about 10:1.
[0045] In a further embodiment, the composition according to the
invention consists of dimethylfumarate and monomethylfumarate
(optionally in the form of a pharmaceutically acceptable salt like
e.g. its sodium, potassium, calcium, magnesium and/or zinc salt) as
the active substances, in a weight ratio between about 1:10 and
about 10:1.
[0046] Cosmetic and/or Pharmaceutical Compositions
[0047] The problem the invention solves is related to the
appearance of gastro-intestinal side-effects upon oral
administration of fumaric acid esters. By prolonging and/or
delaying the release of the active substance from the composition
it is envisaged that the local concentration of the active
substance at specific sites of the gastro-intestinal tract is
reduced (compared with that of Fumaderm.RTM.) which in turn leads
to a reduction in gastro-intestinal side-effects. Accordingly,
compositions that enable a prolonged and/or a slow release of a
fumaric acid ester as defined above are within the scope of the
present invention.
[0048] Such compositions are well-known to the skilled artisan and
include e.g. diffusion-controlled drug delivery systems, osmotic
pressure controlled drug delivery systems, erodible drug delivery
systems etc. Moreover, there are pharmaceutical companies that
based on a specific technology (such as mentioned above) can
provide a specific composition with specific release
characteristics of the active substance. Accordingly, a person
skilled in the art will know how to obtain a suitable product once
he has realized a specific need in respect of a particular drug
substance. By way of example, Eurand is one of such companies that
offer technical solutions in order to obtain a controlled release
pharmaceutical composition containing a specific active substance
and having specific requirements with respect to the release of the
active substance from the composition (see e.g.
http://www.eurand.com). Another company is MacroMed, Inc. that has
developed a technology involving a so-called SQZgel.TM.
(http://macromed.com, SQZgel.TM.'s mechanism of action is a
pH-sensitive polymer mixture combined with an outer coating. In the
acidic environment of the stomach the polymer imbibes with water
and swells, entrapping the drug. Upon entering the higher pH of the
intestines, the polymer slowly shrinks, or "squeezes" at a
"dialed-in" rate releasing the active composition in a sustained
manner), or Egalet a/s that has a specific extrusion based
technology (http://www.egalet.com, Key elements of the Egalet.RTM.
technology are a biodegradable coat and a matrix, comprising the
active drug, which is surface erodible, hydrophobic and composed of
PEG-stearate. One of the Egalet.RTM. technologies is the 2K
Egalet.RTM. constant release system, which is a 2-component
production model consisting of coat and matrix. The drug is evenly
distributed throughout the Egalet.RTM. matrix for constant release
over time. Also of interest in the present context are technologies
like e.g. the Eurand technologies Diffucaps (Drug release profiles
are created by layering active drug onto a neutral core such as
sugar spheres, crystals or granules followed by a rate-controlling,
functional membrane. Diffucaps/Surecaps beads are small in size,
approximately 1 mm or less in diameter. By incorporating beads of
differing drug release profiles into hard gelatin capsules,
combination release profiles can be achieved), Diffutabs (The
Diffutab technology incorporates a blend of hydrophilic polymers
that control drug release through diffusion and erosion of a matrix
tablet), Minitabs (Eurand Minitabs are tiny (2 mm.times.2 mm)
tablets containing gel-forming excipients that control drug release
rate. Additional membranes may be added to further control release
rate), Orbexa (This technology produces beads that are of
controlled size and density with a defined-based granulation
extrusion and spheronization techniques. The resultant beads can be
coated with release rate controlling membranes for additional
release rate control and may be filled into capsules or provided in
sachet form) and SDS (Eurand's SDS technology uses functional
polymers or a combination of functional polymers and specific
additives, such as composite polymeric materials, to deliver a drug
to a site of optimal absorption along the intestinal tract. In
order to achieve this, Eurand first produces multiparticulate
dosage forms such as Diffucaps or Eurand Minitabs, which
incorporate the active drug. These dosage forms are then coated
with pH dependent/independent polymeric membranes that will deliver
the drug to the desired site. These are then filled into hard
gelatin capsules).
[0049] Another interesting technology for use in formulating
compositions according to the present invention is the so-called
MeltDose.RTM. technology as described in WO 03/004001 (see
http://www.lifecyclepharma.com. MeltDose.RTM. involves formulating
solubilized, individual molecules into tablets. By formulating
individual molecules, the primary limitation of oral absorption of
drugs with low water-solubility is removed, and a superior
bioavailability can be attained). By employing this technology it
is possible to obtain a particulate material that is suitable for
processing into various pharmaceutical dosage forms e.g. in the
form of pellets or tablets. Furthermore, the technology is suitable
for use as it is possible to obtain a suitable release profile of
the active substance, e.g. such as those release profiles described
herein. In one embodiment, pellets suitable for use may have a mean
particle size larger than 2000 .mu.m. In another embodiment,
pellets suitable for use may have a mean particle size of from
about 0.01 .mu.m to about 250 .mu.m.
[0050] Another specific suitable formulation principle for use in
the present context is formulation in a lipophilic environment such
as, e.g., soft gelatin capsules. A suitable example of this
formulation principle is Vegicaps Soft from Scherer (a soft capsule
technology based on carrageenan and starch, which despite being
100% plant-derived, still offers all the key attributes of
traditional soft gelatin capsules. These include a soft and
flexible dosage form that provides ease of swallowing.) (For
further information see
http://www.rpscherer.de/page.php?pageID=94).
[0051] A further specific example of a suitable formulation
comprises the formulation of the active substance together with
Vitamin E concentrate in soft or hard gelatin capsules. This
formulation, in a modified form, is the basis of the commercial
cyclosporine product, Neoral.RTM., containing, among other things,
corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil
NF, DL-.alpha.-tocopherol USP (part of the vitamin E family),
gelatin NF, glycerol, iron oxide black, propylene glycol USP,
titanium dioxide USP, carmine, and alcohol in addition to
cyclosporine.
[0052] Another specific example of a suitable formulation comprises
the formulation of active substance together with ethanol,
tocopherolethylene glycol 1000 succinate (TPGS), corn oil and wax
in soft or hard gelatin capsules. This product can be a semi-solid
or solid dosage form. The release rate of this formulation is
dependent on degradation due to lipases in the intestine.
[0053] A further example of a suitable formulation comprises the
formulation of the active substance together with ethanol,
tocopherolethylene glycol 1000 succinate (TPGS), corn oil and
polyglycolized glycerides (e.g. Gelucire) in soft or hard gelatin
capsules. This product can be a semi-solid or solid dosage form.
The release rate of this formulation is dependent on degradation
due to lipases in the intestine.
[0054] A further example of a suitable formulation is an oral
pulsed dose drug delivery system. This dosage form can be perceived
as a modified form of the Schering Repetab tablets. A portion of
the composition of the present invention is put in the core of a
tablet.
[0055] The core can for example be made by conventional wet
granulation or continuous granulation such as extrusion followed by
compaction of the granulate into tablets. The core is then coated
using an appropriate technology, preferably by airsuspension using
an enteric coating polymer such as Eudragits.
[0056] The first releasing dose is compression coated on the core
or air-suspension coated either with the enteric coat or on top of
the enteric coat. In a embodiment of the invention, the first
releasing dose is air-suspension coated with the enteric coat. In a
further embodiment of the invention, the first releasing dose is
compression coated on the core, in order to avoid release of the
composition according to the invention prior to the degradation of
the enteric coat, such degradation typically occurring at pH values
higher than those found in the gastric ventricle; i.e. the
degradation of the enteric coat typically occurs after passage of
the gastric ventricle.
[0057] A further example of a suitable formulation is an oral
sustained drug delivery system. A portion of the composition of the
present invention is put in the core of a tablet.
[0058] The core can for example be made by conventional wet
granulation or continuous granulation such as extrusion followed by
compaction of the granulate into tablets. The core is coated using
an appropriate technology, preferably by airsuspension using
ethylcellulose and a hydrophilic excipient such as hydroxyl propyl
cellulose (HPC).
[0059] The first releasing dose is compression coated on the core
or air-suspension coated either with the enteric coat or on top of
the enteric coat. In a preferred embodiment of the invention, the
first releasing dose is air-suspension coated with the enteric
coat. In a further embodiment of the invention, the first releasing
dose is compression coated on the core, in order to avoid release
of the composition according to the invention prior to the
degradation of the enteric coat, such degradation typically
occurring at pH values higher than those found in the gastric
ventricle; i.e. the degradation of the enteric coat typically
occurs after passage of the gastric ventricle.
[0060] A further example of a suitable formulation is obtained via
crystal engineering, such as e.g. described in WO 03/080034, which
is hereby incorporated by reference.
[0061] Accordingly, in another embodiment the composition of the
invention comprises the active substance in the form of
micro-crystals with hydrophilic surfaces. Furthermore, in another
embodiment of the invention, the micro-crystals are filmcoated
directly, in order to achieve a sustained release formulation.
[0062] Another specific example of a suitable formulation comprises
complexation of the composition according to the present invention
with genuine cyclodextrins and cyclodextrin-derivatives (e.g.
alkyl- and hydroxyalkyl-derivatives or sulfobutyl-derivatives). The
complexation is achieved in accordance with well known methods. It
is contemplated that such a complexation leads to a higher
solubility and a higher dissolution rate of the composition
according to the invention, compared to the composition prior to
complexation. Furthermore, it is contemplated that such a
complexation leads to a higher bioavailability of the composition
according to the invention, compared to the composition prior to
complexation.
[0063] In specific embodiments, the invention relates to a
controlled release pharmaceutical composition that may be
administered one, two or more times daily, such as once or twice or
three times daily. Furthermore, the composition may be designed so
that it releases the fumaric acid ester relatively independent on
pH, i.e. the release is not dependent on pH in the gastrointestinal
tract. Examples of such compositions are e.g. compositions in the
form of solid dosages forms (e.g. tablets, capsules, pellets, beads
etc.) that are coated with a controlled release coating. Suitable
materials for controlled release coatings are e.g. cellulose and
cellulose derivatives including methylcellulose, ethylcellulose and
cellulose acetate, or poly(ethylene-co-vinyl acetate), poly (vinyl
chloride).
[0064] The release of the fumaric acid ester typically takes place
in three steps from a composition coated with a diffusion
controlled membrane:
[0065] i) firstly, water (from the GI tract) diffuses into the
dosage form from the surroundings,
[0066] ii) secondly, at least some of the fumaric acid ester
present in the dosage form dissolves by the action of water,
[0067] iii) the dissolved fumaric acid ester diffuses out of the
dosage form and into the surroundings (i.e. the GI tract)
[0068] Other examples include e.g. matrix tablets or dosage form
containing a multiplicity of units each in the form of a matrix
system. The active substance is embedded in a matrix containing
e.g. cellulose and cellulose derivatives including microcrystalline
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose
and methylcellulose, povidone, poly(ethyleneoxide) (PEO),
polyethylene glycol (PEG), poly (vinyl alcohol) (PVA), xanthan gum,
carrageenan and other synthetic materials. Substances normally used
as pharmaceutically acceptable excipients or additives may be added
to a matrix composition.
[0069] Other examples of suitable compositions are e.g. hydrogels,
i.e. monolithic systems wherein the active substance is embedded in
a water-swellable network polymer. Materials suitable for use
include e.g. hydrophilic vinyl and acrylic polymers,
polysaccharides like alginates, and poly(ethylene oxide).
[0070] In specific embodiments, a composition according to the
invention has a pH controlled release (also known as a pH dependent
release) of the fumaric acid ester. Normally, the release is
designed so that only a small amount, if any, of the fumaric acid
ester is released in the stomach (pH up to about 3), whereas the
fumaric acid ester is released in the intestines (pH shifts to
about 6-7). Such a pH controlled release can be obtained by
providing a composition of the invention with an enteric coating
(the whole composition or, if the composition is a multiparticulate
composition, the individual units) or by providing a composition
that releases the fumaric acid by a pH-dependent osmotic mechanism,
or by employment of suitable enzymes.
[0071] Examples of suitable substances for use as enteric coating
materials include polyacrylamides, phthalate derivatives such as
acid phthalates of carbohydrates, amylose acetate phthalate,
cellulose acetate phthalate, other cellulose ester phthalates,
cellulose ether phthalates, hydroxypropylcellulose phthalate,
hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose
phthalate, methylcellulose phthalate, polyvinyl acetate phthalate,
poly acrylic methacrylic acid copolymers, shellac and vinyl acetate
and crotonic acid copolymers, etc.
[0072] The compositions mentioned above having a pH independent
release may also be formulated to release the fumaric acid ester
e.g. by providing the composition with an outer layer of an enteric
coating.
[0073] Furthermore, the compositions may be formulated in such a
manner that an initial delay in release of the fumaric acid ester
is obtained. Such a delay may be obtained e.g. by choosing an
outermost coating that in a time-controlled manner degrades (e.g.
erodes) and only when this outermost coating is eroded away, the
release of the fumaric acid ester starts.
[0074] In the following is given a description of various
compositions according to the invention that are designed to obtain
a suitable release of the fumaric acid ester. Based on the
description above and handbooks within the field of controlled
release of pharmaceutics, a person skilled in the art will know how
to choose different formulation principles in order to achieve the
required release profile.
[0075] Compositions Designed to be Administered Two or More Times
Daily
[0076] pH Independent Release
[0077] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released
independently of pH and wherein the release pattern is suitable for
compositions that are administered two or more times daily.
Examples of suitable formulation principles are e.g. compositions
provided with a diffusion coating such as a controlled release
diffusion coating, matrix particulates or matrix tablets,
hydrogels, pulsed dose drug delivery systems, co-formulation with
vitamin E concentrate or ethanol, TPGS, corn oil and wax etc.,
including any of the formulation principles mentioned above.
[0078] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing water as dissolution medium--is as follows:
[0079] within the first 6 hours after start of the test at the most
about 60% w/w such as, e.g., from about 30% to about 60% w/w, from
about 40% to about 55% w/w, or about 50% of the total amount of the
fumaric acid ester contained in the composition is released,
and/or
[0080] within the first 9 hours after start of the test at the most
about 85% w/w such as, e.g., from about 50% to about 85% w/w, from
about 60% to about 80% w/w, or about 75% of the total amount of the
fumaric acid ester contained in the composition is released,
and/or
[0081] within the first 12 hours after start of the test at least
about 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w
or more, about 90% w/w or more or about 95% w/w or more of the
total amount of the fumaric acid ester contained in the composition
is released, and/or
[0082] the total amount of the fumaric acid ester contained in the
composition is released within the first 12 hours after start of
the test.
[0083] pH Controlled Release
[0084] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released depending
on pH and wherein the release pattern is suitable for compositions
that are administered two or more times daily. Examples of suitable
formulation principles are e.g. compositions provided with an
enteric coating or hydrogels of a type described by Zentner et al
(U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No. 5,484,610), which
hereby are incorporated by reference. Further examples of suitable
formulation principles are e.g. compositions provided with a
diffusion coating such as a controlled release diffusion coating,
matrix particulates or matrix tablets, hydrogels, pulsed dose drug
delivery systems, co-formulation with vitamin E concentrate or
ethanol, TPGS, corn oil and wax etc., including any of the
formulation principles mentioned above, optionally with an enteric
coating.
[0085] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing 0.1 N hydrochloric acid as dissolution medium during
the first 2 hours of the test and then 0.05 M phosphate buffer pH
6.5 or 6.8 as dissolution medium--is as follows:
[0086] within the first 2 hours after start of the test at least
about 1% w/w such as, e.g. at least about 2% w/w, at least about 3%
w/w, or about 5% w/w of the total amount of the fumaric acid ester
is released, and/or
[0087] within the first 3 hours after start of the test at the most
about 35% w/w such as, e.g., from about 15% to about 35% w/w, from
about 20% to about 30% w/w, or about 25% w/w of the total amount of
the fumaric acid ester is released, and/or
[0088] within the first 3 hours after start of the test from about
10% to about 70% w/w, from about 10% to about 65% w/w, from about
10% to about 60% w/w, from about 15% to about 50% w/w, from about
15% to about 35% w/w, from about 20% to about 30% w/w, or about 20%
w/w, or about 25% w/w of the total amount of the fumaric acid ester
is released, and/or
[0089] within the first 4 hours after start of the test at the most
about 92% w/w such as, e.g., from about 10% to about 92% w/w, from
about 20% to about 85% w/w, from about 20% to about 80% w/w, from
about 20% to about 70% w/w, from about 25% to about 60% w/w, from
about 25% to about 55% w/w, from about 30% to about 50% w/w, or
about 35% w/w, or about 40% w/w, or about 45% w/w of the total
amount of the fumaric acid ester is released, and/or
[0090] within the first 5 hours after start of the test at the most
about 94% w/w such as, e.g., from about 15% to about 94% w/w, from
about 25% to about 90% w/w, from about 30% to about 85% w/w, from
about 35% to about 80% w/w, from about 35% to about 75% w/w, from
about 40% to about 70% w/w, from about 45% to about 70% w/w, from
about 55% to about 70% w/w, from about 60% to about 70% w/w, or
about 45% w/w, or about 50% w/w, or about 55% w/w, or about 60%
w/w, or about 65% w/w of the total amount of the fumaric acid ester
is released, and/or
[0091] within the first 6 hours after start of the test at the most
about 60% w/w such as, e.g., from about 30% to about 60% w/w, from
about 40% to about 55% w/w, or about 50% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0092] within the first 6 hours after start of the test at the most
about 95% w/w such as, e.g., from about 35% to about 95% w/w, from
about 40% to about 90% w/w, from about 45% to about 85% w/w, from
about 50% to about 85% w/w, from about 55% to about 85% w/w, from
about 60% to about 85% w/w, from about 65% to about 85% w/w, from
about 70% to about 85% w/w, from about 75% to about 85% w/w, or
about 65% w/w, or about 70% w/w, or about 75% w/w, or about 80% w/w
of the total amount of the fumaric acid ester contained in the
composition is released, and/or
[0093] within the first 7 hours after start of the test at the most
about 98% w/w such as, e.g., from about 45% to about 98% w/w, from
about 50% to about 98% w/w, from about 55% to about 98% w/w, from
about 60% to about 98% w/w, from about 65% to about 98% w/w, from
about 70% to about 98% w/w, from about 75% to about 95% w/w, from
about 80% to about 95% w/w, from about 85% to about 95% w/w, or
about 75% w/w, or about 80% w/w, or about 85% w/w, or about 90% w/w
of the total amount of the fumaric acid ester contained in the
composition is released, and/or
[0094] within the first 9 hours after start of the test at the most
about 85% w/w such as, e.g., from about 50% to about 85% w/w, from
about 60% to about 80% w/w, or about 75% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0095] within the first 9 hours after start of the test at the most
about 99% w/w such as, e.g., from about 60% to about 99% w/w, from
about 70% to about 99% w/w, from about 80% to about 99% w/w, from
about 90% to about 99% w/w, or about 95% w/w of the total amount of
the fumaric acid ester contained in the composition is
released.
[0096] In another aspect of the invention a controlled release
pharmaceutical composition for oral use comprising as an active
substance one or more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, characterized in that it
consists of a controlled-release dosage form adapted to release
di-(C.sub.1-C.sub.5)alkylester and/or a
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid or a
pharmaceutically acceptable salt thereof over a predetermined time
period, according to a in vitro profile of dissolution when
measured according to USP in 0.1 N hydrochloric acid during the
first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or
6.8,
[0097] wherein at the most 5% w/w of the total amount of the
fumaric acid ester contained in the composition is released within
the first 2 hours after start of the test, and/or
[0098] wherein from about 20% to about 75% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 3 hours after start of the test, and/or
[0099] wherein from about 50% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 4 hours after start of the test, and/or
[0100] wherein from about 60% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 5 hours after start of the test, and/or
[0101] wherein from about 70% to about 95% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 6 hours after start of the test, and/or
[0102] wherein from about 75% to about 97% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 7 hours after start of the test, is provided.
[0103] In a further aspect of the invention a controlled release
pharmaceutical composition for oral use comprising as an active
substance one or more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, characterized in that it
consists of a controlled-release dosage form adapted to release
di-(C.sub.1-C.sub.5)alkylester and/or a
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid or a
pharmaceutically acceptable salt thereof over a predetermined time
period, according to a in vitro profile of dissolution when
measured according to USP in 0.1 N hydrochloric acid during the
first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or 6.8,
wherein at the most 5 w/w of the total amount of the fumaric acid
ester contained in the composition is released within the first 2
hours after start of the test, wherein from about 20% to about 75%
w/w of the total amount of the fumaric acid ester contained in the
composition is released within the first 3 hours after start of the
test, wherein from about 50% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 4 hours after start of the test, wherein from
about 60% to about 90% w/w of the total amount of the fumaric acid
ester contained in the composition is released within the first 5
hours after start of the test, wherein from about 70% to about 95%
w/w of the total amount of the fumaric acid ester contained in the
composition is released within the first 6 hours after start of the
test, wherein from about 75% to about 97% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 7 hours after start of the test, and wherein at
least 85% w/w of the total amount of the fumaric acid ester
contained in the composition is released within the first 8 hours
after start of the test, is provided.
[0104] In another further aspect of the invention a controlled
release pharmaceutical composition comprising as an active
substance one or more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, characterized in that it
consists of a controlled-release dosage form adapted to release
di-(C.sub.1-C.sub.5)alkylester and/or a
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid or a
pharmaceutically acceptable salt thereof over a predetermined time
period, according to a in vitro profile of dissolution when
measured according to USP in 0.1 N hydrochloric acid during the
first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or
6.8,
[0105] wherein at the most 5% w/w of the total amount of the
fumaric acid ester contained in the composition is released within
the first 2 hours after start of the test and/or,
[0106] wherein from about 20% to about 50% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 3 hours after start of the test, and/or
[0107] wherein from about 45% to about 70% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 4 hours after start of the test, and/or
[0108] wherein from about 65% to about 85% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 5 hours after start of the test, and/or
[0109] wherein from about 75% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 6 hours after start of the test, is provided.
[0110] In yet another aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance one or
more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, characterized in that it
consists of a controlled-release dosage form adapted to release
di-(C.sub.1-C.sub.5)alkylester and/or a
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid or a
pharmaceutically acceptable salt thereof over a predetermined time
period, according to a in vitro profile of dissolution when
measured according to USP in 0.1 N hydrochloric acid during the
first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or 6.8,
wherein at the most 5% w/w of the total amount of the fumaric acid
ester contained in the composition is released within the first 2
hours after start of the test, wherein from about 20% to about 50%
w/w of the total amount of the fumaric acid ester contained in the
composition is released within the first 3 hours after start of the
test, wherein from about 45% to about 70% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 4 hours after start of the test, wherein from
about 65% to about 85% w/w of the total amount of the fumaric acid
ester contained in the composition is released within the first 5
hours after start of the test, wherein from about 75% to about 90%
w/w of the total amount of the fumaric acid ester contained in the
composition is released within the first 6 hours after start of the
test, and wherein at least 80% of the total amount of the fumaric
acid ester contained in the composition is released within the
first 7 hours after start of the test, is provided.
[0111] In yet another aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance one or
more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, characterized in that it
consists of a controlled-release dosage form adapted to release
di-(C.sub.1-C.sub.5)alkylester and/or a
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid or a
pharmaceutically acceptable salt thereof over a predetermined time
period, according to a in vitro profile of dissolution when
measured according to USP in 0.1 N hydrochloric acid during the
first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or
6.8,
[0112] wherein at the most 5% w/w of the total amount of the
fumaric acid ester contained in the composition is released within
the first 2 hours after start of the test, and/or
[0113] wherein from about 50% to about 75% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 3 hours after start of the test, and/or
[0114] wherein from about 70% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 4 hours after start of the test, and/or
[0115] wherein from about 80% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 5 hours after start of the test, is provided.
[0116] In yet another aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance one or
more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, characterized in that it
consists of a controlled-release dosage form adapted to release
di-(C.sub.1-C.sub.5)alkylester and/or a
mono-(C.sub.1-C.sub.5)alkylester of fumaric acid or a
pharmaceutically acceptable salt thereof over a predetermined time
period, according to a in vitro profile of dissolution when
measured according to USP in 0.1 N hydrochloric acid during the
first 2 hours and then 0.05 M phosphate buffer at a pH 6.5 or 6.8,
wherein at the most 5% w/w of the total amount of the fumaric acid
ester contained in the composition is released within the first 2
hours after start of the test, wherein from about 50% to about 75%
w/w of the total amount of the fumaric acid ester contained in the
composition is released within the first 3 hours after start of the
test, wherein from about 70% to about 90% w/w of the total amount
of the fumaric acid ester contained in the composition is released
within the first 4 hours after start of the test, wherein from
about 80% to about 90% w/w of the total amount of the fumaric acid
ester contained in the composition is released within the first 5
hours after start of the test and wherein from about at least 90%
w/w of the total amount of the fumaric acid ester contained in the
composition is released within the first 6 hours after start of the
test, is provided.
[0117] Release Over Gradually Shifting pH ("Half-Change"
Method)
[0118] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released depending
on pH and wherein the release pattern is suitable for compositions
that are administered two or more times daily. Examples of suitable
formulation principles are e.g. compositions provided with an
enteric coating or hydrogels of a type described by Zentner et al
(U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No. 5,484,610), which
hereby are incorporated by reference. Further examples of suitable
formulation principles are e.g. compositions provided with a
diffusion coating such as a controlled release diffusion coating,
matrix particulates or matrix tablets, hydrogels, pulsed dose drug
delivery systems, co-formulation with vitamin E concentrate or
ethanol, TPGS, corn oil and wax etc., including any of the
formulation principles mentioned above, optionally with an enteric
coating.
[0119] The "half-change" method has specifically been developed for
enteric-coated or sustained release preparations. This method
encompasses hourly replacing half of the dissolution medium by an
aliquot of neutral dissolution medium (to simulate the GI passage
with respect to the slightly shifting pH values from duodenum to
ileum). The approach is described in the following table:
TABLE-US-00002 Ratio of simulated Time from start gastric
fluid/simulated (hours) intestinal fluid (%) pH value 0-1 100/0 1.3
1-2 50/50 2.4 2-3 25/75 6.2 3-4 12.5/87.5 6.8 4-5 6.25/93.75 7.1
5-6 ~3/97 7.2 6-7 ~1/99 7.3 7-8 ~0/100 7.3
[0120] The composition of the simulated gastric fluid can e.g. be
found in the United States Pharmacopeia (USP) 2005:
[0121] 2.0 g of NaCl and 3.2 g of purified pepsin, derived from
porcine gastric mucosa, with an activity of 800 to 2500 units per
mg of protein, is dissolved in 7.0 mL of hydrochloric acid and
sufficient water to make 1000 mL. The resulting test solution has a
pH of about 1.2.
[0122] Another composition of the simulated gastric fluid is found
in the German E DIN 19738 (Deutsche Industrie Norm):
[0123] 100 mL of synthetic/simulated gastric fluid contains 290 mg
of NaCl, 70 mg of KCl, 27 mg of KH.sub.2PO.sub.4 and enough HCl to
adjust the pH to 2.0. In addition, it contains 100 mg pepsin and
300 mg of mucin.
[0124] The composition of the simulated intestinal fluid can e.g.
be found in the United States Pharmacopeia (USP) 2005:
[0125] 6.8 g of monobasic potassium phosphate is dissolved in 250
mL of water. Mix and add 77 mL of 0.2 N sodium hydroxide and 500 mL
of water. 10.0 g of pancreatin is added, the solution is mixed and
adjusted to a pH of 6.8.+-.0.1 by adding either 0.2 N sodium
hydroxide or 0.2 N hydrochloric acid. The resulting solution is
diluted with water to 1000 mL.
[0126] Another composition of the simulated intestinal fluid is
found in the German E DIN 19738 (Deutsche Industrie Norm):
[0127] 100 mL of synthetic/simulated intestinal fluid contains 30
mg of KCl, 50 mg of CaCl.sub.2, 20 mg of MgCl.sub.2 and sufficient
NaHCO.sub.3 to adjust the pH to 7.5. Furthermore, it contains 30 mg
of trypsin, 900 mg of pancreatin, 900 mg of lyophilized bile and 30
mg of urea.
[0128] In a preferred embodiment of the present invention, the
"half-change" method is carried out with the simulated gastric
fluid and the simulated intestinal fluid as defined by the USP
2005.
[0129] In another embodiment of the present invention, the
"half-change" method is carried out with the simulated gastric
fluid and the simulated intestinal fluid as defined by the USP
2005, but without the proteins (i.e. without the pepsin in the
simulated gastric fluid, and without the pancreatin in the
simulated intestinal fluid).
[0130] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test according to the "half-change" method--is as follows:
[0131] within the first 3 hours after start of the test from about
20% to about 40% w/w, from about 20% to about 35% w/w, or about 30%
w/w of the total amount of the fumaric acid ester is released,
and/or
[0132] within the first 3 hours after start of the test at least
about 12% w/w such as, e.g., from about 12% to about 50% w/w, from
about 15% to about 45% w/w, from about 20% to about 40% w/w, from
about 20% to about 35% w/w, from about 22% to about 35% w/w, or
about 25% w/w, or about 30% w/w of the total amount of the fumaric
acid ester is released, and/or
[0133] within the first 4 hours after start of the test from about
25% to about 40% w/w, from about 30% to about 40% w/w, or about 40%
w/w of the total amount of the fumaric acid ester is released,
and/or
[0134] within the first 4 hours after start of the test at least
about 76% w/w such as, e.g., from about 76% to about 95% w/w, from
about 80% to about 90% w/w, or about 80% w/w, or about 85% w/w of
the total amount of the fumaric acid ester is released, and/or
[0135] within the first 4 hours after start of the test at the most
about 40% w/w such as, e.g., from about 10% to about 40% w/w, from
about 15% to about 35% w/w, from about 20% to about 30% w/w, or
about 25% w/w, or about 30% w/w of the total amount of the fumaric
acid ester is released, and/or
[0136] within the first 6 hours after start of the test at least
about 81% w/w such as, e.g., from about 81% to about 96% w/w, from
about 85% to about 95% w/w, from about 85% to about 90% w/w, or
about 80% w/w, or about 85% w/w, or about 90% w/w of the total
amount of the fumaric acid ester contained in the composition is
released, and/or
[0137] within the first 6 hours after start of the test at the most
about 50% w/w such as, e.g., from about 20% to about 50% w/w, from
about 25% to about 45% w/w, from about 30% to about 45% w/w, or
about 40% w/w, or about 45% w/w of the total amount of the fumaric
acid ester contained in the composition is released, and/or
[0138] within the first 7 hours after start of the test at least
about 82% w/w such as, e.g., from about 82% to about 99% w/w, from
about 85% to about 99% w/w, from about 85% to about 95% w/w, or
about 90% w/w of the total amount of the fumaric acid ester
contained in the composition is released, and/or
[0139] within the first 7 hours after start of the test at the most
about 65% w/w such as, e.g., from about 25% to about 65% w/w, from
about 30% to about 65% w/w, from about 35% to about 60% w/w, from
about 40% to about 60% w/w, from about 50% to about 60% w/w, or
about 55% w/w, or about 60% w/w of the total amount of the fumaric
acid ester contained in the composition is released, and/or
[0140] within the first 8 hours after start of the test at the most
about 85% w/w such as, e.g., from about 50% to about 85% w/w, from
about 60% to about 80% w/w, or about 75% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0141] within the first 8 hours after start of the test at the most
about 92% w/w such as, e.g., from about 30% to about 92% w/w, from
about 35% to about 90% w/w, from about 40% to about 85% w/w, from
about 45% to about 80% w/w, from about 50% to about 75% w/w, from
about 55% to about 75% w/w, from about 60% to about 75% w/w, or
about 65% w/w, or about 70% w/w of the total amount of the fumaric
acid ester contained in the composition is released, and/or
[0142] within the first 12 hours after start of the test at least
about 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w
or more, about 90% w/w or more or about 95% w/w or more of the
total amount of the fumaric acid ester contained in the composition
is released.
[0143] Slow Release
[0144] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released in a slow
or delayed manner wherein the release pattern is suitable for
compositions that are administered two or more times daily.
Examples of suitable formulation principles are any of those
described above.
[0145] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing water as dissolution medium--is as follows:
[0146] within the first 6 hours after start of the test at the most
about 35% w/w such as, e.g., from about 15% to about 35% w/w such
as, e.g., from about 20% to about 30% w/w, or about 25% w/w of the
total amount of the fumaric acid ester contained in the composition
is released, and/or
[0147] within the first 8 hours after start of the test at the most
about 60% w/w such as, e.g., from about 30% to about 60% w/w such
as, e.g., from about 40% to about 55% w/w, or about 50% w/w of the
total amount of the fumaric acid ester contained in the composition
is released, and/or
[0148] within the first 10 hours after start of the test at the
most about 85% w/w such as, e.g., from about 50% to about 85% w/w
such as, e.g., from about 60% to about 80% w/w, or about 75% w/w of
the total amount of the fumaric acid ester contained in the
composition is released, and/or
[0149] within the first 12 hours after start of the test at least
about 80% w/w such as, e.g., about 80% w/w or more such as, e.g.,
about 85% w/w or more, about 90% w/w or more or about 95% w/w or
more of the total amount of the fumaric acid ester contained in the
composition is released.
[0150] Compositions Designed to be Administered Once Daily
[0151] pH Independent Release
[0152] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released independent
of pH and wherein the release pattern is suitable for compositions
that are administered once daily. Examples of suitable formulation
principles are e.g. compositions provided with a diffusion coating
such as a controlled release diffusion coating, matrix particulates
or matrix tablets, hydrogels, pulsed dose drug delivery systems,
co-formulation with vitamin E concentrate or ethanol, TPGS, corn
oil and wax etc., including any of the formulation principles
mentioned above.
[0153] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing water as dissolution medium--is as follows:
[0154] within the first 9 hours after start of the test at the most
about 60% w/w such as, e.g., from about 30% to about 60% w/w, from
about 40% to about 55% w/w, or about 50% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0155] within the first 13.5 hours after start of the test at the
most about 85% w/w such as, e.g., from about 50% to about 85% w/w,
from about 60% to about 80% w/w, or about 75% w/w of the total
amount of the fumaric acid ester contained in the composition is
released, and/or
[0156] within the first 18 hours after start of the test at least
about 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w
or more, about 90% w/w or more or about 95% w/w or more of the
total amount of the fumaric acid ester contained in the composition
is released, and/or
[0157] the total amount of the fumaric acid ester contained in the
composition is released within the first 18 hours after start of
the test.
[0158] pH Controlled Release
[0159] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released dependently
of pH and wherein the release pattern is suitable for compositions
that are administered once daily. Examples of suitable formulation
principles are e.g. compositions provided with an enteric coating
or hydrogels of a type described by Zentner et al (U.S. Pat. No.
6,537,584) and Bae (U.S. Pat. No. 5,484,610). Further examples of
suitable formulation principles are e.g. compositions provided with
a diffusion coating such as a controlled release diffusion coating,
matrix particulates or matrix tablets, hydrogels, pulsed dose drug
delivery systems, co-formulation with vitamin E concentrate or
ethanol, TPGS, corn oil and wax etc., including any of the
formulation principles mentioned above, optionally with an enteric
coating.
[0160] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing 0.1 N hydrochloric acid as dissolution medium during
the first 2 hours of the test and then 0.05 M phosphate buffer pH
6.5 or 6.8 as dissolution medium--is as follows:
[0161] within the first 2 hours after start of the test at least
about 1% w/w such as, e.g. at least about 2% w/w, at least about 3%
w/w, or about 5% w/w of the total amount of the fumaric acid ester
is released, and/or
[0162] within the first 4 hours after start of the test at the most
about 90% w/w such as, e.g., from about 5% to about 90% w/w, from
about 5% to about 85% w/w, from about 10% to about 80% w/w, from
about 10% to about 70% w/w, from about 10% to about 65% w/w, from
about 10% to about 60% w/w, from about 15% to about 50% w/w, from
about 15% to about 35% w/w, from about 20% to about 30% w/w, or
about 20% w/w, or about 25% w/w of the total amount of the fumaric
acid ester is released, and/or
[0163] within the first 4.5 hours after start of the test at the
most about 35% w/w such as, e.g., from about 15% to about 35% w/w,
from about 20% to about 30% w/w, or about 25% w/w of the total
amount of the fumaric acid ester is released, and/or
[0164] within the first 5 hours after start of the test at the most
about 92% w/w such as, e.g., from about 10% to about 92% w/w, from
about 20% to about 85% w/w, from about 20% to about 80% w/w, from
about 20% to about 70% w/w, from about 25% to about 60% w/w, from
about 25% to about 55% w/w, from about 30% to about 50% w/w, or
about 35% w/w, or about 40% w/w, or about 45% w/w of the total
amount of the fumaric acid ester is released, and/or
[0165] within the first 6 hours after start of the test at the most
about 94% w/w such as, e.g., from about 15% to about 94% w/w, from
about 25% to about 90% w/w, from about 30% to about 85% w/w, from
about 35% to about 80% w/w, from about 35% to about 75% w/w, from
about 40% to about 70% w/w, from about 45% to about 70% w/w, from
about 55% to about 70% w/w, from about 60% to about 70% w/w, or
about 45% w/w, or about 50% w/w, or about 55% w/w, or about 60%
w/w, or about 65% w/w of the total amount of the fumaric acid ester
is released, and/or
[0166] within the first 7 hours after start of the test at the most
about 95% w/w such as, e.g., from about 35% to about 95% w/w, from
about 40% to about 90% w/w, from about 45% to about 85% w/w, from
about 50% to about 85% w/w, from about 55% to about 85% w/w, from
about 60% to about 85% w/w, from about 65% to about 85% w/w, from
about 70% to about 85% w/w, from about 75% to about 85% w/w, or
about 65% w/w, or about 70% w/w, or about 75% w/w, or about 80% w/w
of the total amount of the fumaric acid ester contained in the
composition is released, and/or
[0167] within the first 9 hours after start of the test at the most
about 98% w/w such as, e.g., from about 45% to about 98% w/w, from
about 50% to about 98% w/w, from about 55% to about 98% w/w, from
about 60% to about 98% w/w, from about 65% to about 98% w/w, from
about 70% to about 98% w/w, from about 75% to about 95% w/w, from
about 80% to about 95% w/w, from about 85% to about 95% w/w, or
about 75% w/w, or about 80% w/w, or about 85% w/w, or about 90% w/w
of the total amount of the fumaric acid ester contained in the
composition is released, and/or
[0168] within the first 9 hours after start of the test at the most
about 60% w/w such as, e.g., from about 30% to about 60% w/w, from
about 40% to about 55% w/w, or about 50% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0169] within the first 12 hours after start of the test at the
most about 99% w/w such as, e.g., from about 60% to about 99% w/w,
from about 70% to about 99% w/w, from about 80% to about 99% w/w,
from about 90% to about 99% w/w, or about 95% w/w of the total
amount of the fumaric acid ester contained in the composition is
released, and/or
[0170] within the first 13.5 hours after start of the test at the
most about 85% w/w such as, e.g., from about 50% to about 85% w/w,
from about 60% to about 80% w/w, or about 75% w/w of the total
amount of the fumaric acid ester contained in the composition is
released.
[0171] Release Over Gradually Shifting pH ("Half-Change"
Method)
[0172] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released depending
on pH and wherein the release pattern is suitable for compositions
that are administered once daily. Examples of suitable formulation
principles are e.g. compositions provided with an enteric coating
or hydrogels of a type described by Zentner et al (U.S. Pat. No.
6,537,584) and Bae (U.S. Pat. No. 5,484,610), which hereby are
incorporated by reference. Further examples of suitable formulation
principles are e.g. compositions provided with a diffusion coating
such as a controlled release diffusion coating, matrix particulates
or matrix tablets, hydrogels, pulsed dose drug delivery systems,
co-formulation with vitamin E concentrate or ethanol, TPGS, corn
oil and wax etc., including any of the formulation principles
mentioned above, optionally with an enteric coating.
[0173] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test according to the "half-change" method--is as follows:
[0174] within the first 3 hours after start of the test at least
about 12% w/w such as, e.g., from about 12% to about 60% w/w, from
about 15% to about 50% w/w, from about 20% to about 40% w/w, from
about 20% to about 35% w/w, or about 25% w/w, or about 30% w/w of
the total amount of the fumaric acid ester is released, and/or
[0175] within the first 4 hours after start of the test at the most
about 35% w/w such as, e.g., from about 15% to about 35% w/w, from
about 20% to about 30% w/w, or about 25% w/w of the total amount of
the fumaric acid ester is released, and/or
[0176] within the first 5 hours after start of the test at the most
about 45% w/w such as, e.g., from about 10% to about 45% w/w, from
about 15% to about 40% w/w, from about 15% to about 35% w/w, from
about 20% to about 30% w/w, or about 25% w/w, or about 30% w/w of
the total amount of the fumaric acid ester is released, and/or
[0177] within the first 7 hours after start of the test at the most
about 65% w/w such as, e.g., from about 20% to about 65% w/w, from
about 20% to about 60% w/w, from about 20% to about 50% w/w, from
about 25% to about 45% w/w, from about 30% to about 45% w/w, or
about 40% w/w, or about 45% w/w of the total amount of the fumaric
acid ester is released, and/or
[0178] within the first 8 hours after start of the test at the most
about 92% w/w such as, e.g., from about 25% to about 92% w/w, from
about 25% to about 90% w/w, from about 30% to about 80% w/w, from
about 35% to about 70% w/w, from about 40% to about 65% w/w, from
about 45% to about 60% w/w, from about 50% to about 60% w/w, or
about 55% w/w, or about 60% w/w of the total amount of the fumaric
acid ester contained in the composition is released, and/or
[0179] within the first 8 hours after start of the test at the most
about 60% w/w such as, e.g., from about 30% to about 60% w/w, from
about 40% to about 55% w/w, or about 50% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0180] within the first 12 hours after start of the test at the
most about 99% w/w such as, e.g., from about 30% to about 99% w/w,
from about 30% to about 95% w/w, from about 35% to about 90% w/w,
from about 40% to about 85% w/w, from about 45% to about 80% w/w,
from about 50% to about 75% w/w, from about 55% to about 75% w/w,
from about 60% to about 75% w/w, or about 65% w/w, or about 70% w/w
of the total amount of the fumaric acid ester contained in the
composition is released, and/or
[0181] within the first 12.5 hours after start of the test at the
most about 85% w/w such as, e.g., from about 50% to about 85% w/w,
from about 60% to about 80% w/w, or about 75% w/w of the total
amount of the fumaric acid ester contained in the composition is
released, and/or
[0182] within the first 18 hours after start of the test at least
about 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w
or more, about 90% w/w or more or about 95% w/w or more of the
total amount of the fumaric acid ester contained in the composition
is released.
[0183] Slow Release
[0184] In the following is given a description of specific
embodiments, wherein the fumaric acid ester is released in a slow
or delayed manner wherein the release pattern is suitable for
compositions that are administered once daily. Examples of suitable
formulation principles are any of those described above.
[0185] Accordingly, in one aspect the invention relates to a
controlled release pharmaceutical composition for oral use
comprising as an active substance one or more fumaric acid esters
selected from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, wherein the release of
the fumaric acid ester--when subjected to an in vitro dissolution
test employing water as dissolution medium--is as follows:
[0186] within the first 7 hours after start of the test at the most
about 35% w/w such as, e.g., from about 15% to about 35% w/w, from
about 20% to about 30% w/w, or about 25% w/w of the total amount of
the fumaric acid ester contained in the composition is released,
and/or
[0187] within the first 11 hours after start of the test at the
most about 60% w/w such as, e.g., from about 30% to about 60% w/w,
from about 40% to about 55% w/w, or about 50% w/w of the total
amount of the fumaric acid ester contained in the composition is
released, and/or
[0188] within the first 14 hours after start of the test at the
most about 85% w/w such as, e.g., from about 50% to about 85% w/w,
from about 60% to about 80% w/w, or about 75% w/w of the total
amount of the fumaric acid ester contained in the composition is
released, and/or
[0189] within the first 18 hours after start of the test at least
about 80% w/w such as, e.g., about 80% w/w or more, about 85% w/w
or more, about 90% w/w or more or about 95% w/w or more of the
total amount of the fumaric acid ester contained in the composition
is released.
[0190] Typically, as described above, the compositions according to
the invention are designed to deliver the active substance (i.e.
the monoalkylester of fumaric acid, which in turn is metabolised to
fumaric acid and, which subsequently is subjected to a rapid
elimination process) in a prolonged manner. Apart from the
characteristic in vitro release patterns described herein, such a
prolonged release is reflected in the pharmacokinetic parameters
obtained after a clinical study as well. Accordingly, it is
contemplated that the C.sub.max of the monoalkylester of fumaric
acid (which appears in the plasma upon hydrolysis or metabolism of
the dialkylester administered) is of the same order of magnitude as
previously described in the literature provided that a similar or
equivalent dose is administered (i.e. C.sub.max of
monomethylfumarate in a range of from about 0.4 to about 2.0 mg/l
corresponding to an oral dose of 120 to 240 mg dimethylfumarate).
However, in order to avoid many frequent daily administrations (2-4
tablets 1-3 times daily) it is an aim to prolong the time period
where the concentration is within the therapeutic window.
Accordingly, it is contemplated that W.sub.50 (i.e. the time period
in which the plasma concentration is 50% of C.sub.max or more) is
prolonged compared to the marketed treatment with at least 10% such
as, e.g. at least 20%, at least 30%, at least 40% or at least 50%.
A suitable W.sub.50 is believed to be at least 2 hours such as in a
range of from about 2 to about 15 hours or from about 2.5 to about
10 hours or from about 3 to about 8 hours.
[0191] Furthermore, it is contemplated that a controlled release
composition according to the invention may lead to a reduced
interindividual and/or intraindividual variation in the plasma
profile and to a reduced dependency on whether the composition is
taken together with or without food (a reduced variation of the
plasma concentration profile of monomethylfumarate when the
pharmaceutical composition is administered with or without
concomitant food intake). Therefore, the controlled release
composition according to the invention may lead to a reduced
frequency of dosing and/or a reduced average total daily dose,
and/or an increased efficacy at the same total daily dose of the
active substance compared to Fumaderm.RTM..
[0192] Different kinetic models, such as zero-order (1),
first-order (2), square-root (Higuchi's equation) (3) can be
applied to the interpretation of the drug release kinetic.
M.sub.t=M.sub.0+k.sub.0*t 1:
ln M.sub.t=ln M+k.sub.1*t 2:
M.sub.t=M.sub.0+k.sub.H*t.sup.1/2 3:
[0193] In these equations, M.sub.t is the cumulative amount of drug
released at any specified time point and M.sub.0 is the dose of
active substance incorporated in the pharmaceutical compostion.
k.sub.0, k.sub.1 and k.sub.H are rate constants for zero-order,
first-order and Higuchi's equation, respectively.
[0194] One aspect of the invention relates to a zero-order
dissolution release profile. Another aspect relates to a
first-order dissolution release profile. A further aspect relates
to a square-root (Higuchi's equation) dissolution release
profile.
[0195] In one aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance from
10% to 90% by weight of one or more fumaric acid esters selected
from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, from 2% to 40% by weight
pharmaceutically acceptable polymer(s), and from 1% to 40% by
weight hydrophilic excipient(s), and optionally pharmaceutically
acceptable excipients or additives, is provided.
[0196] In another aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance from
40% to 60% by weight of one or more fumaric acid esters selected
from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, from 15% to 25% by weight
pharmaceutically acceptable polymer(s), and from 2% to 15% by
weight hydrophilic excipient(s), and optionally pharmaceutically
acceptable excipients or additives, is provided.
[0197] In a further aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance from
65% to 80% by weight of one or more fumaric acid esters selected
from di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, from 10% to 25% by weight
pharmaceutically acceptable polymer(s), and from 2% to 15% by
weight hydrophilic excipient(s), and optionally pharmaceutically
acceptable excipients or additives, is provided.
[0198] Examples of "pharmaceutically acceptable polymer(s)"
comprises but are not limited to ethylcellulose, or
methacrylic/acrylic acid copolymers, such as ammonio methacrylate
copolymer type A and B or methacrylic acid copolymer A and B.
[0199] Examples of "hydrophilic excipient(s)" comprises but are not
limited to polyethylene glycol (PEG), povidone, hydroxyl propyl
cellulose (HPC), hydroxyethyl starch (HES) or hydroxypropyl methyl
cellulose (HPMC) or a material with similar properties, or a
combination thereof.
[0200] In a further aspect of the invention a controlled release
pharmaceutical composition, wherein the pharmaceutically acceptable
polymer is ethyl cellulose, is provided.
[0201] In another aspect of the invention a controlled release
pharmaceutical composition, wherein the hydrophilic excipient is
hydroxyl propyl cellulose, is provided.
[0202] In another aspect of the invention a controlled release
pharmaceutical composition, wherein the hydrophilic excipient is
polyethylene glycol, is provided.
[0203] In yet another aspect of the invention a controlled release
pharmaceutical composition comprising as an active substance as an
active substance from 10% to 90% by weight of one or more fumaric
acid esters selected from di-(C.sub.1-C.sub.5)alkylesters of
fumaric acid and mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid,
or a pharmaceutically acceptable salt thereof, and 2% to 40% by
weight methacrylic acid copolymer A and B in a weight ratio between
1:9 and 9:1, and optionally pharmaceutically acceptable excipients
or additives, is provided.
[0204] In a further aspect of the invention a controlled release
pharmaceutical composition comprising from 50% to 90% of one or
more fumaric acid esters selected from
di-(C.sub.1-C.sub.5)alkylesters of fumaric acid and
mono-(C.sub.1-C.sub.5)alkylesters of fumaric acid, or a
pharmaceutically acceptable salt thereof, is provided.
[0205] Various controlled release formulations, not limiting the
scope of the present invention, illustrating the invention are
described hereafter (all concentrations based on the final
tablet):
[0206] 1) Granules
[0207] Granules may be prepared by mixing and/or granulating the
active substance at a concentration of about 10 to about 90%,
especially from about 50 to about 70%, with granulating excipients,
such as pharmaceutical acceptable polymers, e.g. ethylcellulose
such as Ethocel.RTM. NF premium, or methacrylic/acrylic acid
copolymers, such as ammonio methacrylate copolymer type A and B (in
a weight ratio of 1:9 to 9:1) or methacrylic acid copolymer A and B
(in a weight ratio of 1:9 to 9:1), incorporated at a concentration
between about 2 to about 40%. Hydrophilic excipients such as
polyethylene glycol (PEG), povidone, hydroxyl propyl cellulose
(HPC), hydroxyethyl starch (HES) or hydroxypropyl methyl cellulose
(HPMC) at a concentration of about 1 to about 40% and/or
pharmaceutical acceptable surfactants with HLB values above 8 at a
concentration of about 0.01 to about 3% may be incorporated.
[0208] 2) Micro-Crystal Formulation
[0209] Crystallization is performed in any suitable organic solvent
for re-crystallisation, such as isopropanol, at an appropriate
temperature such as e.g. between +70.degree. C. and -20.degree. C.
A hydrocolloid (e.g. HPMC) or a surfactant (e.g. polysorbate) can
be used at an appropriate concentration to manipulate the growth of
the crystals during recrystallization. Any granulating/coating
excipient, such as pharmaceutically acceptable polymers, may be
used e.g. ethylcellulose at a concentration of about 10 to about
50%, especially about 20 to about 35%, polymethacryllates such as
ammonio methacrylate copolymer type A and B or methacrylic acid
copolymer A and B. As a hydrophilic excipient mention can be made
of e.g PEG 400.
[0210] 3) Capsules and Sachets
[0211] A capsule (e.g. a capsule of gelatine, HPMC or a starch
derivative) or a sachet may be filled with coated micro-crystals or
coated granules and if necessary appropriate amounts of filling
excipients such as sugaralcoholes e.g. mannitol, and/or
glidants.
[0212] 4) Tablets
[0213] Tablets may be based on either micro-crystals or granules.
When it comes to producing tablets in large scale, especially on a
rotary machine, further excipients to increase flow ability or to
improve tabletting-behaviour may be needed. As filling and binding
excipients, if required, mention can be made of e.g.
microcrystalline cellulose, such as Avicel.RTM. 102, and cellulose
at a concentration of about 1 to about 60%, crystalline, spray
dried or granulated lactose monohydrate e.g. Tablettose.RTM., as
well as anhydrous lactose monohydrate, at a concentration of about
5 to about 60%, sugar alcohols, such as sorbitol and mannitol, at a
concentration of about 0 to about 40% and modified starch at a
concentration of about 0 to about 40%. Furthermore disintegration
agents such as starch and starch-derivates such as sodium starch
glycolate (at a concentration of about 0.2 to about 10.degree. A)),
crospovidone (at a concentration of about 0.2 to about 10%), sodium
carboxymethylcellulose (at a concentration of about 0.1 to about
10%), glidants such as colloidal anhydrous and hydrous silica (at a
concentration of about 0.2 to about 4%), and lubricants, e.g.
magnesium stearate, calcium behenate, and calciumarachinate (at a
concentration of about 0.2 to about 3%) or sodium stearyl fumarate
(at a concentration of about 1 to about 8%) can be added.
[0214] Dosage
[0215] Apart from providing compositions having different content
of fumaric acid present, the invention also provides e.g. kits
containing two or more containers e.g. with compositions having
various amounts of the fumaric acid included. Such kits are
suitable for use in those situations where an increasing dosage is
required over time. A normal up-scale of the dosage is given
below:
TABLE-US-00003 Week Morning Noon Evening Strength 1 1 -- -- A 2 1
-- 1 A 3 1 -- 1 B 4 1 -- -- B 5 1 -- 1 B 6 1 1 1 B 7 2 1 1 B 8 2 1
2 B 9 2 2 2 B
[0216] A corresponds to a low strength such as about 30 mg
dimethylfumarate (or a corresponding effective dose of another
fumaric acid ester)
[0217] B corresponds to a higher strength such as about 120 mg
dimethylfumarate (or a corresponding effective dose of another
fumaric acid ester)
[0218] In one aspect of the invention a controlled release
pharmaceutical composition, wherein the amount of one or more
fumaric acid esters selected from di-(C.sub.1-C.sub.5)alkylesters
of fumaric acid and mono-(C.sub.1-C.sub.5)alkylesters of fumaric
acid, or a pharmaceutically acceptable salt thereof, in a dosage
form is from 90 mg to 360 mg active substance, such as 90, 120,
180, 240 or 360 mg active substance, is provided. In a further
aspect of the invention the amount of active substance is 120, 180
or 240 mg active substance. In yet a further aspect of the
invention, the amount of active substance is 180 or 360 mg.
[0219] The daily dosage of the controlled release pharmaceutical
composition according to the invention that is administered to
treat a patient depends on a number of factors among which are
included, without limitation, weight and age and the underlying
causes of the condition or disease to be treated, and is within the
skill of a physician to determine. In one aspect of the invention
the daily dosage can be e.g. from 240 to 360 mg active substance
given in one to three doses, in another aspect from 360 to 480 mg
active substance given in one to three doses, in another aspect 480
to 600 mg active substance given in one to three doses, in another
aspect 600 to 720 mg active substance given in one to three doses,
in another aspect 720 to 840 mg active substance given in one to
three doses, in another aspect 840 to 960 mg active substance given
in one to three doses and in yet another aspect 960 to 1080 mg
active substance given in one to three doses.
[0220] In one aspect of the invention the controlled release
pharmaceutical composition is in the form of a capsule.
[0221] In another aspect of the invention the controlled release
pharmaceutical composition in the form of a tablet is provided,
such as a tablet which has a shape that makes it easy and
convenient for a patient to swallow e.g. a tablet which has a
rounded or a rod-like shape without any sharp edges.
[0222] In another aspect of the invention a pharmaceutical
composition in the form of a tablet designed to be divided into two
or more parts, is provided.
[0223] The compositions according to the invention may be
administered together with a meal or in relation to a meal such as
e.g. in a time period corresponding to a range from at least about
30 minutes before a meal to about 2 hours after the meal, or the
composition may be administered at any specific point(s) in time
during the day.
[0224] In one embodiment, the total daily dose is given at bedtime,
such as up to or about 30 minutes before bedtime, up to or about 60
minutes before bedtime, up to or about 90 minutes before bedtime,
up to or about 120 minutes before bedtime or up to or about 180
minutes before bedtime.
[0225] The compositions and kits according to the invention are
contemplated to be suitable to use in the treatment of one or more
of the following conditions: [0226] a. Psoriasis [0227] b.
Psoriatic arthritis [0228] c. Neurodermatitis [0229] d.
Inflammatory bowel disease, such as [0230] i. Crohn's disease
[0231] ii. Ulcerative colitis [0232] e. autoimmune diseases: [0233]
i. Polyarthritis [0234] ii. Multiple sclerosis (MS) [0235] iii.
Juvenile-onset diabetes mellitus [0236] iv. Hashimoto's thyroiditis
[0237] v. Grave's disease [0238] vi. SLE (systemic lupus
erythematosus) [0239] vii. Sjogren's syndrome [0240] viii.
Pernicious anemia [0241] ix. Chronic active (lupoid) hepatitis
[0242] x. Rheumatoid arthritis (RA) [0243] xi. Optic neuritis
[0244] Moreover, the novel composition or kit according to the
invention may be used in the treatment of [0245] 1. Pain such as
radicular pain, pain associated with radiculopathy, neuropathic
pain or sciatica/sciatic pain [0246] 2. Organ transplantation
(prevention of rejection) [0247] 3. Sarcoidosis [0248] 4.
Necrobiosis lipoidica [0249] 5. Granuloma annulare
[0250] Psoriasis has been proposed to potentially be associated
with Crohn's disease (Najarian D J, Gottlieb A B, Connections
between psoriasis and Crohn's disease. J Am Acad Dermatol. 2003
June; 48(6):805-21), celiac disease (Ojetti V et al, High
prevalence of celiac disease in psoriasis. Am J Gastroenterol. 2003
November; 98(11):2574-5.), psychiatric or psychological disease,
such as depression or a life crisis (Gupta M A, Gupta A K,
Psychiatric and psychological co-morbidity in patients with
dermatologic disorders: epidemiology and management. Am J Clin
Dermatol. 2003; 4(12):833-42. and Mallbris L et al, Psoriasis
phenotype at disease onset: clinical characterization of 400 adult
cases. J Invest Dermatol. 2005 March; 124(3):499-504.), overweight,
diabetes mellitus, excess consumption of alcohol/alcoholism, as
well as psoriatic arthritis.
[0251] The present invention thus relates in one aspect to a method
of treating psoriasis, psoriatic arthritis, neurodermatitis,
inflammatory bowel disease, such as Crohn's disease and ulcerative
colitis, autoimmune diseases, such as polyarthritis, multiple
sclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto's
thyroiditis, Grave's disease, SLE (systemic lupus erythematosus),
Sjogren's syndrome, Pernicious anemia, Chronic active (lupoid)
hepatitis, Rheumatoid arthritis (RA) and optic neuritis, pain such
as radicular pain, pain associated with radiculopathy, neuropathic
pain or sciatica/sciatic pain, organ transplantation (prevention of
rejection), sarcoidosis, necrobiosis lipoidica or granuloma
annulare, which method comprises administering orally to a patient
in need thereof, an effective dosage of a controlled release
pharmaceutical composition according the invention.
[0252] The present invention relates in another aspect to the use
of a controlled release pharmaceutical composition according to the
invention for the preparation of a medicament for the treatment of
psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel
disease, such as Crohn's disease and ulcerative colitis, autoimmune
diseases, such as polyarthritis, multiple sclerosis (MS),
juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's
disease, SLE (systemic lupus erythematosus), Sjogren's syndrome,
Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoid
arthritis (RA) and optic neuritis, pain such as radicular pain,
pain associated with radiculopathy, neuropathic pain or
sciatica/sciatic pain, organ transplantation (prevention of
rejection), sarcoidosis, necrobiosis lipoidica or granuloma
annulare.
[0253] Furthermore, the invention also relates to treating an
individual suffering from one of the conditions in the
abovementioned lists, more specifically psoriasis or psoriatic
arthritis, with a composition or kit according to the invention,
said individual further being in treatment with
[0254] a) a topical anti-psoriatic drug such as 1) vitamin D or
derivatives thereof (calcipotriol, calcipotriene), 2) a
corticosteroid (such as e.g. betamethasone, desoximethasone,
fluocinolone, momethasone, hydrocortisone aceponate, fluticasone,
clobethasol, clobethasone, hydrocortisone butyrate, desonide,
triamcinolone or hydrocortisone), 3) tazaroten, 4) ditranol, 5)
tacrolimus (FK-506), and other calcineurin inhibitors, such as
pimecrolimus or 6) any combination of 1-5 and/or
[0255] b) an oral anti-psoriatic drug such as 1) an oral retinoid
(such as acitretin or etretinate) combined or not combined with
PUVA, 2) cyclosporine and other calcineurin inhibitors, such as
ISA247, tacrolimus and pimecrolimus, 3) methotrexate, 4)
hydroxyurea, 5) azathioprine, 6) sulphasalazine, 7) a fumarate
derivative (such as e.g. Fumaderm.RTM. or BG-12), 8) rosiglitazone
(Avandia) and other peroxisome proliferator-activated-.gamma.
(PPAR.gamma.) agonists or modulators, such as pioglitazone,
farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10, MBX-1828,
MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar
(LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone,
ciglitazone, tesaglitazar, isaglitazone, balaglitazone,
muraglitazar, TAK-654, LBM642, DRF 4158, EML 4156, T-174, TY-51501,
TY-12780, VDO-52 or AMG-131(T131) or any combination of 1-8
and/or
[0256] c) a parenterally administered anti-psoriatic drug such as
1) alefacept (Amevive), 2) etanercept (Enbrel), 3) efalizumab
(Raptiva), 4) onercept, 5) adalimumab (Humira) or any combination
of 1-5 and/or
[0257] d) an inhibitor of TNF-.alpha. not mentioned in the list
under section c) above (e.g. CDP 870 or infliximab (Remicade)),
administered via an enteral or parenteral route and/or
[0258] e) tisocalicitrate and/or NCX 1022 and/or IDEC-131 and/or
MEDI-507, and/or
[0259] f) An NSAID or a COX or a LOX inhibitor such as e.g. a COX-2
inhibitor or a COX/5-LOX inhibitor, and/or
[0260] g) an anti-diabetic or anti-obesity drug, such as biguanides
such as metformin; metformin XR; a sulphonylurea such as
chlorpropamide, glipizide, gliclazide, glyburide/glibenclamide or
glimepiride; Glucovance (metformin+glyburide); Metaglip
(glipizide+metformin); a peroxisome proliferator-activated-.gamma.
(PPAR.gamma.) agonist or modulator, such as rosiglitazone
(Avandia), pioglitazone, farglitazar, GW1929, GW7845, MC-555,
MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar,
naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017,
troglitazone, ciglitazone, tesaglitazar, isaglitazone,
balaglitazone, muraglitazar, TAK-654, LBM642, DRF 4158, EML 4156,
T-174, TY-51501, TY-12780, VDO-52 or AMG-131(T131); Avandamet
(rosiglitazone+metformin); Actos (pioglitazone+metformin);
Avandaryl (rosiglitazone maleate+glimepiride); a benzoimidazole
such as FK-614; CS-917; TA-1095; ONO-5129; TAK-559;
TAK-677/AJ-9667; a d-phenylalanine inducer such as senaglinide;
c-3347; NBI-6024; ingliforib; BVT 3498; LY 929; SGLT2 inhibitors;
CS 011; BIM 51077; R1438; R1439; R1440; R1498; R1499; AVE 0847; AVE
2268; AVE 5688; AVE 8134; TA-6666; AZD 6370; SSR 162369; TLK-17411;
NN 2501; MK 431; KGA-2727; MK-767; CS-872; a beta-3 receptor
antagonist such as N-5984; an alpha-glucosidase inhibitor such as
acarbose, voglibose or miglitol; a glinitide/meglitinide analogue
or carbamoylmethylbensoeic acid derivative such as mitiglinide,
repaglinide or nateglinide; a DPP-IV inhibitor such as LAF 237
(vildagliptin), DPP728, P93/01, P32/98, PT-630 or saxagliptin;
GLP-1 or GLP-1 analogues, such as exenatide, Exenatide-LAR,
liraglutide (NN 2211), ZP 10/AVE 0010, LY 307161, betatropin,
CJC-1131, GTP-010, SUN E7001 or AZM 134; pramlinitide acetate;
insulin or insulin analogues, such as Humalog (insulin lispro),
Humulin, Novolin, Novolog/NovoRapid (insulin aspart), Apidra
(insulin glulisine), Lantus (insulin glargine), Exubera, Levemir/NN
304 (insulin detemir), AERx/NN 1998, Insuman, Pulmonary insulin or
NN 344; sibutramine or other blockers of the presynaptic reuptake
of serotonin and noradrenalin; orlistat and other inhibitors of GI
lipases; .beta.3-adrenergic receptor agonists; uncoupling proteins;
(specific) antagonists of PPAR.gamma. (Peroxisome
Proliferator-Activated Receptor .gamma.); insulin secretagogues;
rimonabant and other CB1 endocannabinoid receptor antagonists;
bupropion; topiramate; leptin agonists; ciliary neurotrophic
factor; peptide analogues of the human growth hormone fragment
177-191; cholecystokinin-A receptor agonists; melanocortin-3
agonists; noradrenergic drugs such as phentermine, diethylpropion,
phendimetrazine or benzphetamine; or any combination of the
anti-diabetic or anti-obesity drugs mentioned above, and/or
[0261] h) a drug potentially useful in the treatment of substance
abuse e.g. alcohol abuse such as naltrexone, acamprosate,
disulphiram or Vivitrex (naltrexone long acting injection),
and/or,
[0262] i) a drug potentially useful in the treatment of Crohn's
disease such as [0263] 1. 5-ASA compounds such as sulfasalazine,
oral 5-ASA formulations or rectal 5-ASA formulations, [0264] 2.
glucocorticosteroids such as systemic steroids (e.g. budesonide or
prednisolone) or topically acting steroids (e.g. budesonide),
[0265] 3. antibiotics such as metronidazole or quinolones (e.g.
ciprofloxacine, ofloxacine, norfloxacine, levofloxacine or
moxifloxacine), [0266] 4. immunosuppressives such as azathioprine,
6-mercaptopurine or methotrexate, [0267] 5. nutritional therapies
such as elemental or polymeric formulas or pre- and probiotics,
[0268] 6. biological therapies e.g. TNF-.alpha. inhibitors such as
infliximab, adalimumab, CDP870, CDP571, etanercept or onercept,
[0269] 7. symptomatic agents such as anti-diarrheals or
anti-spasmodics.
[0270] Examples of suitable NSAIDs are piroxicam, diclofenac,
nabumetone, propionic acids including naproxen, flurbiprofen,
fenoprofen, ketoprofen and ibuprofen, fenamates including mefenamic
acid, paracetamol, indomethacin, sulindac, meloxicam, apazone,
pyrazolones including phenylbutazone, salicylates including
aspirin.
[0271] Examples of suitable COX-2 inhibitors are rofecoxib (Vioxx),
valdecoxib (Bextra), celecoxib (Celebrex), etoricoxib (Arcoxia),
lumiracoxib (Prexige), parecoxib (Dynastat), deracoxib (Deram),
tiracoxib, meloxicam, nimesolide,
(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dib-
enzo[b,d]pyran carboxylic acid (CT-3), 2(5H)-Furanone, 5,5-dimethyl
(1-methylethoxy) [4(methylsulfonyl)phenyl]-(DFP); Carprofen
(RIMADYL), (Acetyloxy)-benzoic acid, 3-[(nitrooxy)methyl]phenyl
ester (NCX4016), P54 (CAS Reg. No. 130996 0)
2,6-Bis(1,1-dimethylethyl) [(E)-(2-ethyl-1,1-dioxo
isothiazolidinylidene)methyl]phenoI (S-2474), 5(R)-Thio
sulfonamide-3(2H)-benzofuranone (SVT-2016) and N-[3-(Formyl-amino)
oxo phenoxy-4H benzopyran yl]methanesulfonamide ("T-614"); or a
pharmaceutically acceptable salt thereof.
[0272] Examples of suitable COX/5-LOX inhibitors are licofelone
(ML-3000 or
[2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-
-yl]-acetic acid), di-tert-butylphenols, such as
(E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidence)-2-ethyl-1,2-isothiazoli-
dine-1,1-dioxide (S-2474), darbufelone or tebufelone and
pharmacologically active metabolites as well as derivatives such as
dihydro-dimethyl-benzofuran and PGV-20229,
dihydro-dimethyl-benzofuran, thiophene derived compounds such as
RWJ-63556,
N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)-butanamide
(S19812), methoxytetrahydropyran derivatives, oxygenated xanthones
such as 1,3,6,7-Tetrahydroxyxanthone (norathyriol)-pyrazole
thiocarbamates, pyrazoles such as modified forms of phenidone
containing compounds or the tri-fluoro-benzole substituted
pyrazoline derivative BW-755C, tepoxaline and derivatives and
di-tert-butylpyrimidines.
[0273] It is contemplated that such combination therapy leads to an
improved therapeutic response and/or an increased convenience for
the individual, compared to said individual being treated without
the composition or kit according to the invention.
[0274] In a further aspect, the invention relates to a method of
reducing side effects associated with oral treatment of any of the
conditions a-e and 1-5 listed above, in which method the active
pharmaceutical ingredient for treating said condition is used in
combination with one or more of the following agents:
[0275] a) an antacid such as 1) magnesium hydroxide, 2) magnesium
trisilicate, 3) aluminium hydroxyde gel, 3) sodium
hydrogencarbonate, 4) magaldrat or any combination of 1-5
and/or
[0276] b) a histamine H-2 antagonist such as 1) cimetidine, 2)
ranitidine, 3) nizatidine, 4) famotidine, 5) roxatidine, 6)
lafutadine or any combination of 1-6 and/or
[0277] c) a cytoprotective agent such as 1) sucralfate, 2)
tripotassium dictitratobismuthate, 3) carbenoxolone, 4)
prostaglandin E-2 analogues such as misoprostol, 5) ecabet, 6)
cetraxate HCl, 7) teprenone, 8) troxipide, 9) dicyclomine
hydrochloride, 10) sofalcon or any combination of 1-10 and/or
[0278] d) a proton pump inhibitor (PPI) such as 1) omeprazole, 2)
esomeprazole, 3) lansoproazole, 4) pantoprazole, 5) rabeprazole, 6)
CS-526/R-105266, 7) AZD 0865, 8) soraprazan or any combination of
1-8, and/or
[0279] e) an NSAID or a COX or a LOX inhibitor such as e.g. a COX-2
inhibitor or a COX/5-LOX inhibitor, and/or
[0280] f) pentoxifylline, e.g. at a dose range of from 400 to 800
mg/day.
[0281] In a specific embodiment, the active substance is a fumaric
acid ester containing compound. In particular, the fumaric ester
containing compound is any and all of the salts contained in
Fumaderm.RTM. or Fumaraat.RTM. or Panaclar.RTM. (BG-12) or
described in U.S. Pat. No. 6,277,882, U.S. Pat. No. 6,355,676 or
U.S. Pat. No. 6,509,376 or a formulation according to the present
invention. The active pharmaceutical ingredient may be provided in
a formulation according to the present invention, or any
Fumaderm.RTM. or Fumaraat.RTM. or Panaclar.RTM. formulation or as
e.g. described in U.S. Pat. No. 6,277,882, U.S. Pat. No. 6,355,676
or U.S. Pat. No. 6,509,376.
[0282] It is to be understood that this invention is not limited to
particular embodiments described, as such may, of course, vary. It
is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only, and is not
intended to be limiting, since the scope of the present invention
will be limited only by the appended claims. Where a range of
values is provided, it is understood that each intervening value,
to the tenth of the unit of the lower limit unless the context
clearly dictates otherwise, between the upper and lower limit of
that range and any other stated or intervening value in that stated
range is encompassed within the invention. The upper and lower
limits of these smaller ranges may independently be included in the
smaller ranges and are encompassed within the invention, subject to
any specifically excluded limit in the stated range. Where the
stated range includes one or both of the limits, ranges excluding
either or both of those included limits are also included in the
invention. Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which this invention belongs.
Although any methods and materials similar or equivalent to those
described herein can also be used in the practice or testing of the
present invention, the preferred methods and materials are
described. All publications mentioned herein are incorporated
herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited. It
must be noted that as used herein and in the appended claims, the
singular forms "a", "an", and "the" include plural referents unless
the context clearly dictates otherwise. The patents and
publications discussed herein are provided solely for their
disclosure prior to the filing date of the present application.
Nothing herein is to be construed as an admission that the present
invention is not entitled to antedate such patent or publication by
virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed. As will be apparent to
those of skill in the art upon reading this disclosure, each of the
individual embodiments described and illustrated herein has
discrete components and features which may be readily separated
from or combined with the features of any of the other several
embodiments without departing from the scope or spirit of the
present invention. The figures shown herein are not necessarily
drawn to scale, with some components and features being exaggerated
for clarity.
[0283] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is readily apparent to those of ordinary skill
in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing
from the spirit or scope of the appended claims.
EXAMPLES
Example 1
Preparation of Tablets
[0284] 200 g granules are mixed with 150 g microcrystalline
cellulose (e.g. Avicel.RTM. 102), 97.5 g lactose (e.g.
Tablettose.RTM.), 10 g sodium carboxymethylcellulose (e.g.
Ac-Di-Sol.RTM.) and 25 g starch for 30 min. Then 10 g magnesium
stearate and 7.5 g amorphous silicium dioxide (e.g. Aerosil.RTM.
200) is added and the powder mixture is mixed for 5 min.
[0285] This powder mixture is compressed to tablets in tabletting
equipment (tablet diameter 10 mm, surface about 280-300 mm.sup.2).
The tablets are enteric coated in a pan-coating or in a fluid-bed
coating process as described in Example 4.
Example 2
Preparation of Tablets
[0286] 200 g micro-crystals are mixed with 150 g microcrystalline
cellulose (e.g. Avicel.RTM. 102), 130 g lactose (e.g.
Tablettose.RTM.), 10 g of sodium carboxymethylcellulose (e.g.
Ac-Di-Sol.RTM.) and 25 mg starch for 30 min. Then 10 g magnesium
stearate and 7.5 g of amorphous silicium dioxide is added and the
powder mixture is mixed for 5 min. This powder mixture is
compressed to tablets in tabletting equipment (tablet diameter 10
mm, surface about 280-300 mm.sup.2). The tablets are enteric coated
in a pan-coating or in a fluid-bed coating process as described in
Example 4.
Example 3
Preparation of Capsules
[0287] Granules or micro-crystals are filled in HPMC capsules and
these capsules are enteric coated as described in the following. In
a pan coater Eudragit.RTM. L30D-55 is sprayed at drying
temperatures of 60.degree. C. to 80.degree. C. onto the capsules in
an amount of 20 mg polymeric material per mm.sup.2. Pigments and
talc are added in an appropriate amount.
Example 4
Enteric Coating of Tablets
[0288] In a pan coater Eudragit.RTM. L30D-55 is sprayed at drying
temperatures of 60.degree. C. to 80.degree. C. onto the tablets in
an amount of 6 mg polymeric material per mm.sup.2. Pigments and
talc are added in an appropriate amount.
Example 5
Preparation of Capsules
[0289] 156 mg of micro-crystals, prepared as described in Example
15, is filled in a hard-gelatine-capsule size 0. The capsules are
enteric coated by dipping them into a solution of 5% HPMCP
(Pharmacoat HP 50.RTM.) in acetone four times each
capsule-side.
Example 6
Preparation of Granules
[0290] In a granulation process 50 g dimethylfumarate (in the
following DMF) is mixed with 1 g ethyl cellulose (e.g. Ethocel.RTM.
NF premium) which is dissolved in 10 ml ethanol 96%, passed through
a sieve 1.0 mm and dried at 50.degree. C. to 60.degree. C. for 30
min. These granules are manufactured to tablets and capsules using
the same process as described in Examples 1 and 3.
Example 7
Preparation of Granules
[0291] In a granulation process 50 g DMF is mixed with 1 g
polyvinylacetate (PVA) (e.g. Kollicoat.RTM. SR30) which is
dissolved in 10 ml ethanol 96%, passed through a sieve 1.00 mm and
dried at 50.degree. C. to 60.degree. C. for 30 min.
Example 8
Preparation of Granules
[0292] In a granulation process 50 g DMF is mixed with 15 g of
powdered Eudragit.RTM. RL 100. After adding an appropriate amount
of 2-propanol and passing through a 1.00 mm sieve, the granules are
dried at 60.degree. C. These granules are manufactured to tablets
and capsules using the same process as described in Examples 1 and
3.
Example 9
Preparation of Coated Granules
[0293] In a granulation process 50 g DMF is directly mixed with 5 g
Eudragit.RTM. RL30D, passed through a sieve (1.00 mm) and dried at
80.degree. C. After sieving the granules are coated in a fluid-bed
coater (Mini-Glatt) with 15 g of a 1:1 mixture Eudragit.RTM.
RL30D/RS30D. The coated granules can be manufactured to tablets and
capsules using the same process as described in Examples 1 and
3.
Example 10
Preparation of Coated Granules
[0294] In a granulation process 50 g DMF is mixed with 20% ethyl
cellulose (e.g. Ethocel.RTM. NF premium) which is dissolved in an
appropriate amount of ethanol 96%. 15% polyethylene glycole 6000
are added to the granulation liquid. The mixture is passed through
a sieve 1.00 mm and dried at 50.degree. to 60.degree. C. for 30
min. After sieving the granules are coated in a fluid-bed coated
(Mini-Glatt) with a 2:1 mixture of ethyl cellulose and polyethylene
glycole 6000 in an amount of 20 mg per mm.sup.2 granules surface
area. These granules can be manufactured to tablets or capsules
using the processes described in Examples 1 and 3.
Example 11
Preparation of Coated Granules
[0295] In a granulation process 50 g DMF is mixed with 10% ethyl
cellulose (e.g. Ethocel.RTM. NF premium) which is dissolved in an
appropriate amount of ethanol 96%. 6% povidone (e.g. Kollidon.RTM.
25) is added to the granulation liquid. The mixture is passed
through a sieve 1.00 mm and dried at 50.degree. to 60.degree. C.
for 30 min. After sieving the granules are coated in a fluid-bed
coated (Mini-Glatt) with a 3:2 mixture of ethyl cellulose and
povidone in an amount of 20 mg per mm.sup.2 granule surface
area.
[0296] These granules can be manufactured to tablets or capsules
using the processes described in Examples 1 and 3.
Example 12
Preparation of Coated Granules
[0297] In a granulation process 50 g DMF is mixed with 10% ethyl
cellulose (e.g. Ethocel.RTM. NF premium) which is dissolved in an
appropriate amount of ethanol 96%. 5% hydroxypropyl cellulose (HPC)
(e.g. Klucel.RTM.) are added to the granulation liquid. The mixture
is passed through a sieve 1.00 mm and dried at 50.degree. to
60.degree. C. for 30 min. After sieving, the granules are coated in
a fluid-bed coater (mini-Glatt) with a 2:1 mixture of ethyl
cellulose and HPC in an amount of 20 mg per mm.sup.2 granule
surface area.
[0298] These granules can be manufactured to tablets or capsules
using the processes described in Examples 1 and 3.
Example 13
Preparation of Coated Granules
[0299] In a granulation process 50 g DMF is directly mixed with an
appropriate amount of an aqueous dispersion of Eudragit.RTM. NE30D,
passed through a sieve (1.00 mm) and dried at 80.degree. C. After
sieving the granules are coated in a fluid-bed coater (Mini-Glatt)
with 15 g of a 1:1 mixture Eudragit.RTM. RL30D/RS30D. The coated
granules can be manufactured to tablets and capsules using the
processes described in Examples 1 and 3.
Example 14
Preparation of Coated Granules
[0300] In a granulation process 50 g DMF is directly mixed with an
appropriate amount of an aqueous dispersion of Eudragit.RTM. RL30D,
passed through a sieve (1.00 mm) and dried at 80.degree. C. After
sieving, the granules are coated in a fluid-bed coater (Mini-Glatt)
with Eudragit.RTM. NE30D. The coated granules can be manufactured
to tablets and capsules using the processes described in Examples 1
and 3.
Example 15
Preparation of Coated Micro-Crystals
[0301] A saturated solution of 50 g DMF in 300 ml 2-propanol is
prepared at 60.degree. C. and slowly cooled under permanent
stirring. The precipitated crystals are filtered off and dried at
50.degree. C. The crystals are sieved and the 315-710 .mu.m
fraction is used for a coating process in either a pan coater or a
fluid-bed coater (Mini-Glatt). A coating solution of 12 g ethyl
cellulose (e.g. Ethocel.RTM. NF premium) and 3 g polyethylene
glycole 400 in 500 g ethanol is sprayed at 60.degree. C. onto the
powder surface. After drying, the coated crystals are sieved
through a 1.00 mm sieve. These coated DMF crystals can be
manufactured to tablets and capsules using the processes described
in Examples 2 and 3.
Example 16
Preparation of Tablets
[0302] In a granulation process 50 g DMF is mixed with 12 g
Ethylcellulose (e.g. Ethocel.RTM. NF premium) and 3 g
Polyethylenglycole 400 which is dissolved in 150 ml Ethanol 96%,
passed through a 1.0 mm sieve, dried at 50.degree. to 60.degree. C.
over 30 min and again passed through a sieve 1.0 mm. A placebo
granulate is prepared as follows: Tablettose.RTM. and Avicel.RTM.
102 are mixed in equal shares and granulated with 2% povidone (e.g.
Kollidon.RTM. 25) dissolved in water (q.s.), passed through a 1.0
mm sieve, dried at 50.degree. to 60.degree. C. over 30 min and
again passed through a 1.0 mm sieve. 60 parts of the DMF-granulate
and 38 parts of the placebo-granulate are mixed for 30 minutes in a
Turbula Shaker Mixer. One part Aerosil.RTM. 200 and one part
magnesium stearate are added and the blend is mixed again for 5
minutes. The blend is compressed to tablets with a diameter of 10
mm, a weight of about 260 mg and a hardness of about 50 N. The
tablets are enteric coated using the processes described in Example
4.
Example 17
Preparation of Tablets
[0303] In a granulation process 50 g DMF is mixed with 12 g
Ethylcellulose (e.g. Ethocel.RTM. NF premium) and 3 g
Polyethylenglycole 400 which is dissolved in 150 ml Ethanol 96%,
passed through a 1.0 mm sieve, dried at 50.degree. to 60.degree. C.
over 30 min and again passed through a sieve 1.0 mm. A placebo
granulate is prepared as follows: Tablettose.RTM. and Avicel.RTM.
102 are mixed in equal shares and granulated with 2% povidone (e.g.
Kollidon.RTM. 25) dissolved in water (q.s.), passed through a 1.0
mm sieve, dried at 50.degree. to 60.degree. C. over 30 min and
again passed through a 1.0 mm sieve. 60 parts of the DMF-granulate
and 37 parts of the placebo-granulate are mixed for 30 minutes in a
Turbula Shaker Mixer. One part carboxymethylcellulose (e.g.
Ac-Di-Sol.RTM.), one part Aerosil.RTM. 200 and one part magnesium
stearate are added and the blend is mixed again for 5 minutes.
[0304] The blend is compressed to tablets with a diameter of 10 mm,
a weight of about 260 mg and a hardness of about 50 N. The tablets
are enteric coated using the processes described in Example 4.
Example 18
Preparation of Coated Micro-Crystals
[0305] A saturated solution of 50 g DMF in 300 ml 2-propanol is
prepared at 60.degree. C. and slowly cooled under permanent
stirring. The precipitated crystals are filtered off and dried at
50.degree. C. The crystals are sieved and the 315-710 .mu.m
fraction is used for a coating process in either a pan coater or a
fluid-bed coater (Mini-Glatt). A coating solution of 12 g ethyl
cellulose (e.g. Ethocel.RTM. NF premium) and 3 g povidone (PVP) in
500 g ethanol is sprayed at 60.degree. C. onto the surface of the
crystals. After drying the coated crystals are sieved through a
1.00 mm sieve. The coated DMF crystals can be manufactured to
tablets and capsules using the processes described in Example 2 and
3.
Example 19
Preparation of Coated Micro-Crystals
[0306] A saturated solution of 50 g DMF in 300 ml 2-propanol is
prepared at 60.degree. C. and slowly cooled under permanent
stirring. The precipitated crystals are filtered off and dried at
50.degree. C. The crystals are sieved and the 315-710 .mu.m
fraction is used for a coating process in either a pan coater or a
fluid-bed coater (Mini-Glatt). A coating solution of 12 g ethyl
cellulose (e.g. Ethocel.RTM. NF premium) and 3 g
hydroxylpropylcellulose (HPC) in 500 g ethanol is sprayed at
60.degree. C. onto the powder surface. After drying the coated
crystals are sieved through a 1.00 mm sieve. These coated DMF
crystals can be manufactured to tablets and capsules using the
processes described in Examples 2 and 3.
Example 20
Preparation of Micro-Crystals
[0307] DMF-crystals are prepared as described in Example 15, but 2%
of ethyl cellulose, related to the mass of the crystals, is added
directly to the 2-propanol before precipitation of the
crystals.
Example 21
Preparation of Coated Micro-Crystals
[0308] 50 g DMF crystals prepared as described in Example 15 are
coated in a fluid-bed coater (Mini-Glatt) at a temperature of
80.degree. C. with 20 g of an aqueous dispersion of a 1:1 mixture
of Eudragit.RTM. RL30D/RS30D. These coated DMF crystals are
manufactured to tablets and capsules using the processes described
in Examples 2 and 3.
Example 22
Preparation of Tablets
[0309] DMF crystals prepared as described in Example 15 are
directly mixed with 25% solid Eudragit.RTM. RS PO/RL PO in a ratio
of 1:2 and manufactured to tablets as described in Example 2.
Example 23
Preparation of Coated Micro-Crystals
[0310] DMF crystals prepared as described in Example 15 are coated
in a fluid-bed coater (Mini-Glatt) with an amount of 5% (related to
the mass of the crystals) aqueous dispersion of polyvinyl acetate
(e.g. Kollicoat.RTM. SR 30D). These coated DMF crystals can be
manufactured to tablets and capsules using the processes described
in Examples 2 and 3.
Example 24
Preparation of Granules
[0311] In a granulation process, 50 g DMF is mixed with 15% ethyl
cellulose (e.g. Ethocel.RTM. NF premium) which is dissolved in an
appropriate amount of ethanol 96%. 10% polyethylene glycole 6000 is
added to the granulation liquid. The mixture is passed through a
sieve 1.00 mm and dried at 50.degree. to 60.degree. C. for 30 min.
These granules can be manufactured to tablets or capsules using the
processes described in Examples 1 and 3.
Example 25
Preparation of Granules
[0312] In a granulation process, 50 g diethylfumarate (DEF) is
mixed with 15% ethyl cellulose (e.g. Ethocel.RTM. NF premium) which
is dissolved in an appropriate amount of ethanol 96%. 10%
polyethylene glycole 6000 is added to the granulation liquid. The
mixture is passed through a sieve 1.00 mm and dried at 50.degree.
to 60.degree. C. for 30 min. These granules can be manufactured to
tablets or capsules using the processes described in Examples 1 and
3.
Example 26
Preparation of Tablets
[0313] A granulate is prepared as described in Example 24 but
instead of PEG 6000, 10% of povidone (e.g. Kollidon.RTM. 25) is
added. This mixture can be manufactured to tablets or capsules
using the processes described in Examples 1 and 3.
Example 27
Preparation of Tablets
[0314] A granulate is prepared as described in Example 24 but
instead of PEG 6000, 10% hydroxyl propyl methylcellulose is added.
This mixture can be manufactured to tablets or capsules using the
processes described in Examples 1 and 3.
Example 28
[0315] 50 g DMF crystals prepared as described in Example 15 are
coated in a fluid-bed coater (Mini-Glatt) at a temperature of
80.degree. C. with 20 g of an aqueous dispersion of a 1:1 mixture
of Eudragit.RTM. RL30D/RS30D. The coated crystals are enteric
coated in a pan coater as described in the following. Eudragit.RTM.
L30D-55 are sprayed at drying temperatures of 60.degree. C. to
80.degree. C. onto the coated crystals in an amount of 6 mg
polymeric material per mm.sup.2
[0316] These double coated DMF crystals are either filled into hard
gelatine or soft gelatine capsules or manufactured to tablets using
the process described in Example 2.
Example 29
Preparation of Tablets
[0317] In a granulation process 50 g DMF is mixed with 12 g
Ethylcellulose (e.g. Ethocel.RTM. NF premium) and 3 g hydroxypropyl
cellulose (e.g. Klucel.RTM.) which is dissoloved in 150 ml Ethanol
96%, passed through a sieve 1.0 mm, dried at 50.degree. to
60.degree. C. over 30 min and again passed through a sieve 1.0
mm.
[0318] Tablettose.RTM. and Avicel.RTM. 102 are mixed in equal
shares and granulated with 2% povidone (Kollidon.RTM. 25) dissolved
in water (q.s.). 60 parts of the DMF-granulate and 38 parts of the
placebo-granulate are mixed for 30 minutes in a Turbula Shaker
Mixer. One part Aerosil.RTM. 200 and one part magnesium stearate
are added and the blend is mixed again for 5 minutes. The blend is
compressed to tablets with a diameter of 10 mm, a weight of about
260 mg and a hardness of about 50 N. The tablets are enteric coated
using the process described in Example 4.
Example 30
Determination of pH Controlled Release Dissolution Profile of
Capsules
[0319] The dissolution profile is determined as described in the
United States Pharmacopoeia using a rotating basket with 6 so
called Levy-glasses with a capacity of 1 liter and 6 basket
stirring elements powered by an electric motor (at 100 rpm). The
Levy-glasses are filled with 0.1N HCl (the water bath has a
temperature of 37.degree. C.+/-0.5.degree. C.) and the capsules are
applied to the baskets. After 2 hours, the acid is removed from the
vessels and replaced with dissolution medium (USP phosphate buffer,
pH 6.5) and tested for another 6 hours. Samples (5 ml) are taken
after 0, 60 and 120 minutes from the acid medium, and after 30, 60,
90, 120, 180, 240, 300 and 360 minutes from the buffer medium after
replacing the dissolution medium with USP buffer. Instead of
replacing the amount of drawn buffer solution after each sample,
the loss of buffer is taken into account when calculating the
amount of released DMF. The amount of DMF is determined by HPLC
(Kontron XXX) using a Merck LiChroCART RP8 5 .mu.M, 20 cm column,
tempered at 25.degree. C. The mobile phase consists of a mixture
(35:65) of acetonitrile and 0.0725 mol/l
NaH.sub.2PO.sub.4*H.sub.2O-buffer adjusted to pH 3.2 with
phosphoric acid. The UV detector is set at a wavelength of 230 nm
and a flow rate of 1.0 ml per minute. The DMF peak is detectable
after a retention time of about 5 min.
Example 31
Determination of pH Controlled Release Dissolution Profile of
Non-Enteric Coated Tablets
[0320] The dissolution profile is determined using 6 so called
Levy-glasses with a capacity of 1 liter and 6 paddles as stirring
elements powered by an electric motor. The rotating speed of the
paddles is 100 rpm. The Levy-glasses are filled with USP phosphate
buffer, pH 6.5 (the water bath has a temperature of 37.degree.
C.+/-0.5.degree. C.) and the tables are into the Levy-glasses.
Samples (5 ml) are taken after 0, 30, 60, 90, 120, 180, 240, 300
and 360 minutes from the buffer medium after replacing the
dissolution medium with USP buffer. Instead of replacing the amount
of drawn buffer solution after each sample, the loss of buffer is
taken into account when calculating the amount of released DMF. The
amount of DMF is determined by HPLC (Kontron XXX) using a Merck
LiChroCART RP8 5 .mu.M, 20 cm column, tempered at 25.degree. C. The
mobile phase consists of a mixture (35:65) of acetonitrile and
0.0725 mol/l NaH.sub.2PO.sub.4*H.sub.2O-buffer adjusted to pH 3.2
with phosphoric acid. The UV detector is set at a wavelength of 230
nm and a flow rate of 1.0 ml per minute. The DMF peak is detectable
after a retention time of about 5 min.
Example 32
[0321] The dissolution profile of capsules prepared as described in
Example 5 is determined as described in Example 30. The dissolution
profile is shown in FIG. 1.
Example 33
[0322] The dissolution profile of the tablets (before the enteric
coating is applied) prepared as described in example 16 is
determined as described in Example 31. The dissolution profile is
shown in FIG. 2.
Example 34
[0323] The dissolution profile of the tablets (before the enteric
coating is applied) prepared as described in example 17 is
determined as described in Example 31. The dissolution profile is
shown in FIG. 3.
* * * * *
References