U.S. patent application number 17/319694 was filed with the patent office on 2021-12-02 for pharmaceutical bead formulations comprising dimethyl fumarate.
The applicant listed for this patent is BIOGEN MA INC.. Invention is credited to Shyam B. Karki, Cheuk-Yui Leung, Yiqing Lin, Ivan Nestorov, Andrea Trementozzi, Kalyan Vasudevan, Jin Xu, Peter Zawaneh.
Application Number | 20210369629 17/319694 |
Document ID | / |
Family ID | 1000005767602 |
Filed Date | 2021-12-02 |
United States Patent
Application |
20210369629 |
Kind Code |
A1 |
Karki; Shyam B. ; et
al. |
December 2, 2021 |
PHARMACEUTICAL BEAD FORMULATIONS COMPRISING DIMETHYL FUMARATE
Abstract
The present invention provides novel pharmaceutical compositions
of dimethyl fumarate. The pharmaceutical compositions of the
present invention comprises a first pharmaceutical bead composition
and a second pharmaceutical bead composition, wherein the first
pharmaceutical bead composition is an enterically coated
immediate-release composition and the second pharmaceutical bead
composition is an enterically coated controlled-release
composition, wherein the first pharmaceutical bead composition and
the second pharmaceutical bead composition both comprise dimethyl
fumarate Methods of using the pharmaceutical compositions of the
present invention for treating multiple sclerosis are also
included.
Inventors: |
Karki; Shyam B.;
(Hillsborough, NJ) ; Zawaneh; Peter; (Brookline,
MA) ; Leung; Cheuk-Yui; (Acton, MA) ;
Vasudevan; Kalyan; (Cambridge, MA) ; Lin; Yiqing;
(Lexington, MA) ; Xu; Jin; (Waltham, MA) ;
Trementozzi; Andrea; (Sherborn, MA) ; Nestorov;
Ivan; (Acton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIOGEN MA INC. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005767602 |
Appl. No.: |
17/319694 |
Filed: |
May 13, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16076849 |
Aug 9, 2018 |
11033509 |
|
|
PCT/US2017/016934 |
Feb 8, 2017 |
|
|
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17319694 |
|
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62294054 |
Feb 11, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/225 20130101;
A61K 9/5084 20130101; A61K 9/5047 20130101; A61K 9/5078 20130101;
A61K 9/4825 20130101; A61K 9/5026 20130101 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/225 20060101 A61K031/225; A61K 9/48 20060101
A61K009/48 |
Claims
1. A pharmaceutical composition comprising a first pharmaceutical
bead composition and a second pharmaceutical bead composition,
wherein the first pharmaceutical bead composition is an enterically
coated immediate-release composition and the second pharmaceutical
bead composition is an enterically coated controlled-release
composition, wherein the first pharmaceutical bead composition and
the second pharmaceutical bead composition both comprise dimethyl
fumarate.
2. The pharmaceutical composition of claim 1, wherein: (1) the
first pharmaceutical bead composition comprises: an inert core; a
first layer surrounding the inert core, wherein the first layer
comprises dimethyl fumarate and a binder; and an enteric coating
surrounding the first layer; and (2) the second pharmaceutical bead
composition comprises: an inert core; a first layer surrounding the
inert core, wherein the first layer comprises dimethyl fumarate and
a binder; an enteric coating surrounding the first layer; and a
functional coating surrounding the enteric coating.
3-4. (canceled)
5. The pharmaceutical composition of claim 2, wherein the inert
core in the first pharmaceutical bead composition comprises one or
more inert substance selected from the group consisting of starch,
dextrose, sucrose, lactose, maltose, and microcrystalline
cellulose; and wherein the inert core in the second pharmaceutical
bead composition comprises one or more inert substance selected
from the group consisting of starch, dextrose, sucrose, lactose,
maltose, and microcrystalline cellulose.
6. (canceled)
7. The pharmaceutical composition of claim 2, wherein the weight
percentage of the inert core in the first pharmaceutical bead
composition is 15%-30%, 16%-26%, 16%-22% or 20%-24% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition; and wherein the weight percentage
of the inert core in the second pharmaceutical bead composition is
15%-30%, 16%-26%, 16%-22% or 20%-24% of the total weight of the
inert core and the first layer in the second pharmaceutical bead
composition.
8-10. (canceled)
11. The pharmaceutical composition of claim 2, wherein the inert
core in the first pharmaceutical bead composition is a sphere
having a diameter of 200-850 .mu.m, 250-350 .mu.m, 500-600 .mu.m or
700-850 .mu.m; and wherein the inert core in the second
pharmaceutical bead composition is a sphere having a diameter of
200-850 .mu.m, 250-350 .mu.m, 500-600 .mu.m or 700-850 .mu.m.
12. (canceled)
13. The pharmaceutical composition of claim 2, wherein the weight
percentage of dimethyl fumarate in the first pharmaceutical bead
composition is 60%-80%, 72%-76%, 74%, 68%-72% or 70% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition; and wherein the weight percentage
of dimethyl fumarate in the second pharmaceutical bead composition
is 60%-80%, 72%-76%, 74%, 68%-72% or 70% of the total weight of the
inert core and the first layer in the second pharmaceutical bead
composition.
14-17. (canceled)
18. The pharmaceutical composition of claim 2, wherein the binder
in the first pharmaceutical bead composition and the binder in the
second pharmaceutical bead composition is independently selected
from the group consisting of acacia, agar, alginic acid, amino
methacrylate copolymer, ammonio methacrylate copolymer, ammonio
methacrylate copolymer dispersion, calcium carbonate, calcium
lactate, carbomer copolymer, carbomer homopolymer, carbomer
interpolymer, carboxymethylcellulose sodium, microcrystalline
cellulose, silicified microcrystalline cellulose, hydrogenated
coconut oil, copovidone, corn syrup, corn syrup solids, dextrates,
dextrin, ethyl acrylate and methyl methacrylate copolymer
dispersion, ethylcellulose, ethylene glycol and vinyl alcohol graft
copolymer, gelatin, liquid glucose, glyceryl behenate, guar gum,
hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted
hydroxypropyl cellulose, hypromellose, hypromellose acetate
succinate, inulin, alpha-lactalbumin, monohydrate lactose,
maltodextrin, maltose, methacrylic acid copolymer, methacrylic acid
copolymer dispersion, methacrylic acid and ethyl acrylate copolymer
dispersion, methylcellulose, hydrogenated palm oil, polycarbophil,
hydrogenated polydextrose, polyethylene oxide, polyvinyl acetate,
povidone, pullulan, sodium alginate, pregelatinized starch,
pregelatinized modified starch, corn starch, hydroxypropyl corn
starch, pregelatinized hydroxypropyl corn starch, pea starch,
hydroxypropyl pea starch, pregelatinized hydroxypropyl pea starch,
potato starch, hydroxypropyl potato starch, pregelatinized
hydroxypropyl potato starch, tapioca starch, wheat starch,
hydrogenated starch hydrolysate, sucrose, sunflower oil, syrup,
trehalose, hydrogenated vegetable oil, vitamin E polyethylene
glycol succinate, zein, hydroxypropyl methylcellulose (HPMC),
polyvinylpyrrolidone (PVP), methyl cellulose, ethyl cellulose,
sodium carboxy methyl cellulose, polyethylene glycol (PEG),
polyvinyl alcohols, polymethacrylate, starch paste, sodium starch,
tragacanth, gelatin, alginate, sodium alginate, alginic acid,
cellulose, candelilla wax, carnuba wax, copolyvidone, and lactose
hydrous.
19. (canceled)
20. The pharmaceutical composition of claim 2, wherein the weight
percentage of the binder in the first pharmaceutical bead
composition is 1%-20%, 5%-10% or 7% of the total weight of the
inert core and the first layer in the first pharmaceutical bead
composition; and wherein the weight percentage of the binder in the
second pharmaceutical bead composition is 1%-20%, 5%-10% or 7% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
21-22. (canceled)
23. The pharmaceutical composition of claim 2, wherein the enteric
coating in the first pharmaceutical bead composition comprises an
excipient selected from the group consisting of a copolymer of
methacrylic acid and methyl methacrylate, a copolymer of
methacrylic acid and ethyl acrylate, hypromellose phthalate
(HPMCP), cellulose acetate phthalate; and wherein the enteric
coating in the second pharmaceutical bead composition comprises an
excipient selected from the group consisting of a copolymer of
methacrylic acid and methyl methacrylate, a copolymer of
methacrylic acid and ethyl acrylate, hypromellose phthalate
(HPMCP), cellulose acetate phthalate.
24-26. (canceled)
27. The pharmaceutical composition of claim 2, wherein the enteric
coating in the first pharmaceutical bead composition comprises a
plasticizer wherein the plasticizer is selected from the group
consisting of acetyltributyl citrate, acetyltriethyl citrate,
benzyl benzoate, castor oil, chlorobutanol, diacetylated
monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,
mannitol, polyethylene glycol, polyethylene glycol monomethyl
ether, propylene glycol, pullulan, sorbitol, sorbitol sorbitan
solution, triacetin, tributyl citrate, triethyl citrate and vitamin
E; and wherein the enteric coating in the second pharmaceutical
bead composition comprises a plasticizer, wherein the plasticizer
in the second pharmaceutical bead composition is selected from the
group consisting of acetyltributyl citrate, acetyltriethyl citrate,
benzyl benzoate, castor oil, chlorobutanol, diacetylated
monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,
mannitol, polyethylene glycol, polyethylene glycol monomethyl
ether, propylene glycol, pullulan, sorbitol, sorbitol sorbitan
solution, triacetin, tributyl citrate, triethyl citrate and vitamin
E.
28-31. (canceled)
32. The pharmaceutical composition of claim 2, wherein the weight
percentage of the enteric coating in the first pharmaceutical bead
composition is 5-15%, 10-15% or 12% of the total weight of the
inert core and the first layer in the first pharmaceutical bead
composition; and wherein the weight percentage of the enteric
coating in the second pharmaceutical bead composition is 5-15%,
10-15% or 12% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition.
33-64. (canceled)
65. The pharmaceutical composition of claim 2, wherein the
functional coating in the second pharmaceutical bead composition
comprises one or more excipients selected from the group consisting
of polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), glyceryl
monostearate, hydroxyl propyl methyl cellulose (HPMC), SoluPlus,
polyvinyl alcohol (PVA), polyvinyl alcohol (PVA),
hydroxypropylmethylcellulose, acetate succinate (HPMCAS), ethylene
vinyl acetate (EVA), methacrylates (Eudragit.TM.), cellulose
acetate butyrate (CAB), cellulose acetate phthalate (CAP),
poly(ethylene glycol), poly(vinyl acetate) (PVAc), polylactide
(PLA), polyglycolide (PGA), copolymers of PLA/PGA and
polycaprolactone (PCL), polyvinylpyrrolidone-co-vinyl acetate
(Kollidon VA-64), polyrethanes, poly(lactic acid), poly(glycolic
acid), poly(anhydride-imides), poly(anhydride-esters),
poly(iminocarbonates), poly(phosphazenes), poly(phosphoesters),
ethylcellulose (EC), hydroxypropyl cellulose (HPC), alginic acid,
carbomer copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, carrageenan, cellaburate,
ethylcellulose aqueous dispersion, ethylcellulose dispersion Type
B, glyceryl monooleate, guar gum, hydroxypropyl betadex, polyvinyl
acetate dispersion, shellac, sodium alginate, pregelatinized
starch, pregelatinized modified starch and xanthan gum.
66. The pharmaceutical composition of claim 65, wherein the
functional coating comprises a mixture of ethylcellulose (EC) and
hydroxypropyl cellulose (HPC).
67. (canceled)
68. The pharmaceutical composition of claim 66, wherein the weight
ratio of ethylcellulose to hydroxypropyl cellulose is between 70:30
and 50:50, between 65:35 and 55:45, or the weight ratio of
ethylcellulose to hydroxypropyl cellulose is 60:40 or 65:35.
69-71. (canceled)
72. The pharmaceutical composition of claim 68, wherein the weight
percentage of the functional coating in the second pharmaceutical
bead composition is 4-12%, 4.0-5.0%, 4.5%, 4.5-5.5%, 5.0-6.0% or
11.5-12.5% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition.
73-77. (canceled)
78. The pharmaceutical composition of claim 1, wherein: (1) the
first pharmaceutical bead composition comprises: an inert core; a
first layer surrounding the inert core, wherein the first layer
comprises dimethyl fumarate and a binder and wherein the weight
percentage of dimethyl fumarate is 72%-76% of the total weight of
the inert core and the first layer and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer; an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; wherein the weight
percentage of the inert core is 16-22% of the total weight of the
inert core and the first layer; and (2) the second pharmaceutical
bead composition comprises: an inert core; a first layer
surrounding the inert core, wherein the first layer comprises
dimethyl fumarate and a binder and wherein the weight percentage of
dimethyl fumarate is 72%-76% of the total weight of the inert core
and the first layer and the weight percentage of the binder is
5-10% of the total weight of the inert core and the first layer; an
enteric coating surrounding the first layer, wherein the weight
percentage of the enteric coating is 11-13% of the total weight of
the inert core and the first layer; and a functional coating
surrounding the enteric coating, wherein the weight percentage of
the functional coating is 4%-12% of the total weight of the inert
core and the first layer, wherein the weight percentage of the
inert core is 16-22% of the total weight of the inert core and the
first layer.
79. The pharmaceutical composition of claim 1, wherein: (1) the
first pharmaceutical bead composition comprises: an inert core; a
first layer surrounding the inert core, wherein the first layer
comprises dimethyl fumarate and a binder and wherein the weight
percentage of dimethyl fumarate is 68%-72% of the total weight of
the inert core and the first layer and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer; an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; wherein the weight
percentage of the inert core is 20-24% of the total weight of the
inert core and the first layer; and (2) the second pharmaceutical
bead composition comprises: an inert core; a first layer
surrounding the inert core, wherein the first layer comprises
dimethyl fumarate and a binder and wherein the weight percentage of
dimethyl fumarate is 68%-72% of the total weight of the inert core
and the first layer and the weight percentage of the binder is
5-10% of the total weight of the inert core and the first layer; an
enteric coating surrounding the first layer, wherein the weight
percentage of the enteric coating is 11-13% of the total weight of
the inert core and the first layer; and a functional coating
surrounding the enteric coating, wherein the weight percentage of
the functional coating is 4%-12% of the total weight of the inert
core and the first layer, wherein the weight percentage of the
inert core is 20-24% of the total weight of the inert core and the
first layer.
80-83. (canceled)
84. The pharmaceutical composition of claim 1, wherein: (1) the
first pharmaceutical bead composition comprises: an inert core; a
first layer surrounding the inert core, wherein the first layer
comprises dimethyl fumarate and a binder and wherein the weight
percentage of dimethyl fumarate is 72%-76% of the total weight of
the inert core and the first layer and the weight percentage of the
binder is 6-8% of the total weight of the inert core and the first
layer; an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; and (2) the second
pharmaceutical bead composition comprises: an inert core; a first
layer surrounding the inert core, wherein the first layer comprises
dimethyl fumarate and a binder and wherein the weight percentage of
dimethyl fumarate is 72%-76% of the total weight of the inert core
and the first layer and the weight percentage of the binder is 6-8%
of the total weight of the inert core and the first layer; an
enteric coating surrounding the first layer, wherein the weight
percentage of the enteric coating is 11-13% of the total weight of
the inert core and the first layer; and a functional coating
surrounding the enteric coating, wherein the weight percentage of
the functional coating is 4.0%-5.0% of the total weight of the
inert core and the first layer.
85. The pharmaceutical composition of claim 84, wherein the inert
core in the first and the second pharmaceutical bead compositions
comprises sucrose or starch; the binder in the first and the second
pharmaceutical bead compositions is HPMC; the enteric coating the
first and the second pharmaceutical bead compositions comprises a
copolymer of methacrylic acid and methyl methacrylate and the ratio
of methacrylic acid to methyl methacrylate in the copolymer is 1:1;
and the functional coating in the second pharmaceutical bead
composition comprises of a mixture of ethylcellulose (EC) and
hydroxypropyl cellulose (HPC) and the weight ratio of
ethylcellulose (EC) to hydroxypropyl cellulose (HPC) is between
70:30 and 50:50, or between 65:35 and 55:45, or the weight ratio of
ethylcellulose (EC) to hydroxypropyl cellulose (HPC) is 65:35, or
60:40.
86-91. (canceled)
92. The pharmaceutical composition of claim 84, wherein the weight
ratio of the first pharmaceutical bead composition to the second
pharmaceutical bead composition is between 10:1 to 1:1, 5:1 to
1.5:1, 4:1 to 2:1 or 3:1.
93-100. (canceled)
101. The pharmaceutical composition of claim 1, wherein the first
pharmaceutical bead composition and the second pharmaceutical bead
composition are in a capsule.
102. A method of treating a subject having multiple sclerosis
comprising administering to the subject an effective amount of a
pharmaceutical composition of claim 1.
103-109. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/076,849, filed on Aug. 9, 2018, which is a
35 U.S.C. .sctn. 371 national stage filing of International
Application No. PCT/US2017/016934, filed Feb. 8, 2017, which claims
the benefit of U.S. Provisional Application No. 62/294,054, filed
on Feb. 11, 2016. The entire contents of each of the foregoing
applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Tecfidera.RTM. (dimethyl fumarate) was approved by FDA in
March, 2013 to be used for treating adults with relapsing forms of
multiple sclerosis (MS). The starting dose for the currently
approved formulation of Tecfidera.RTM. is 120 mg twice a day
orally. After 7 days, the dose is increased to the maintenance dose
of 240 mg twice a day orally.
[0003] Dimethyl fumarate (DMF) quickly gets absorbed in vivo and
converted to monomethyl fumarate (MMF). The half-life of MMF was
shown to be approximately 1 hour (0.9 h in rat at 100 mg/Kg oral
dose). Both DMF and MMF are metabolized by esterases which are
ubiquitous in the GI tract, blood and tissues.
[0004] DMF has demonstrated an acceptable safety profile in phase 3
clinical trials. However, tolerability issues such as flushing and
gastrointestinal events were observed. While these events are
generally mild to moderate in severity, it is desirable to reduce
these side effects. It is also desirable to develop a once a day
dosing formulation as opposed to the current twice a day
formulation to improve patient compliance and convenience.
[0005] As such, there is a need for new pharmaceutical formulations
of dimethyl fumarate with improved pharmacokinetic profiles and/or
dosing regimen and reduced side effects.
SUMMARY OF THE INVENTION
[0006] The present invention provides novel pharmaceutical
compositions of dimethyl fumarate that have pharmacokinetic
profiles suitable for a once daily dosing regimen. In addition, the
pharmaceutical compositions of the present invention have a
desirable extended release profile that may reduce the GI side
effects observed for the current formulation. Moreover, the
pharmaceutical compositions of the present invention are believed
to have maximized absorption of dimethyl fumarate in vivo.
[0007] One aspect of the present invention is directed to a
pharmaceutical composition comprising a first pharmaceutical bead
composition and a second pharmaceutical bead composition. The first
pharmaceutical bead composition is an enterically coated
immediate-release composition and the second pharmaceutical bead
composition is an enterically coated controlled-release
composition, wherein the first pharmaceutical bead composition and
the second pharmaceutical bead composition both comprise dimethyl
fumarate as the active ingredient.
[0008] In yet another aspect, the present invention provides a
method of treating a subject having multiple sclerosis. The method
comprises administering to the subject an effective amount of a
pharmaceutical composition of the present invention described
herein.
[0009] The present invention also provides a pharmaceutical
composition described herein for use in treating a subject having
multiple sclerosis.
[0010] Use of a pharmaceutical composition described herein for the
manufacture of a medicament in treating multiple sclerosis is also
included in the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1. shows in vitro dissolution profiles for the
pharmaceutical compositions comprising mixed beads of the present
invention (Formulations 1 and 2) as compared to pharmaceutical
composition comprising a single type of beads (Formulation 3) using
dissolution test 1.
[0012] FIG. 2. shows in vitro dissolution profiles for the
pharmaceutical compositions comprising mixed beads of the present
invention (Formulations 1 and 2) as compared to pharmaceutical
composition comprising a single type of beads (Formulation 3) using
dissolution test 2.
DETAILED DESCRIPTION OF THE INVENTION
[0013] As used herein, the term "immediate-release" refers to a
pharmaceutical composition that releases substantially all (e.g.,
greater than 90%, 95%, 99% or 99.9%) of the active ingredient
(e.g., dimethyl fumarate) in a body within a short period of time,
such as less than 30 minutes.
[0014] As used herein, the term "controlled-release" and
"extended-release" are used interchangeably herein. They refer to a
pharmaceutical composition that releases the active ingredient
(e.g., dimethyl fumarate) in a body over an extended period of
time, such as within 2 hours, 3 hours, 4 hours, 6 hours, 8 hours,
12 hours, 16 hours or 24 hours. In one embodiment, the active
substance dimethyl fumarate is released from the controlled-release
pharmaceutical bead compositions of the present invention in a
prolonged manner compared to the immediate-release formulations.
The term "prolonged" means that the active substance is released
during a longer period of time than the current commercially
available formulation of Tecfidera.RTM. (dimethyl fumarate), such
as at least during a time period that is at least 1.2 times, 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 current commercial
available formulation of Tecfidera.RTM..
[0015] As used herein, the term "enterically coated" refers to a
pharmaceutical composition having an enteric coating around the
core or the layer that containing the active ingredient (e.g.,
dimethyl fumarate).
[0016] In a first embodiment, the present invention is directed to
a pharmaceutical composition comprising a first pharmaceutical bead
composition and a second pharmaceutical bead composition, wherein
the first pharmaceutical bead composition is an enterically coated
immediate-release bead composition and the second pharmaceutical
bead composition is an enterically coated controlled-release bead
composition, wherein the first pharmaceutical bead composition and
the second pharmaceutical bead composition both comprise dimethyl
fumarate.
[0017] In a second embodiment, for the pharmaceutical composition
described in the first embodiment, the first pharmaceutical bead
composition comprises:
[0018] an inert core;
[0019] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder; and
[0020] an enteric coating surrounding the first layer; and
[0021] the second pharmaceutical bead composition comprises:
[0022] an inert core;
[0023] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder;
[0024] an enteric coating surrounding the first layer; and
[0025] a functional coating surrounding the enteric coating.
[0026] In certain embodiments, the inert core, the first layer
and/or the enteric coating for the first pharmaceutical bead
composition are different from the inert core, the first layer
and/or the enteric coating for the second pharmaceutical bead
composition.
[0027] In certain embodiments, the inert core, the first layer
and/or the enteric coating for the first pharmaceutical bead
composition are the same as the inert core, the first layer and/or
the enteric coating for the second pharmaceutical bead
composition.
[0028] As used herein, the term "inert core" refers to a core
comprising material(s) that are unreactive towards the active
substance and any components of the bead and/or have no effect on
the biological activity of the active substance, i.e., dimethyl
fumarate. In addition, the inert core does not contain any active
substance. In certain embodiments, the inert core in the first
pharmaceutical bead composition or the second pharmaceutical bead
composition or both the first and the second pharmaceutical bead
compositions of the present invention comprises a pharmaceutically
acceptable inert material(s). Exemplary inert core materials
include, but are not limited to, starch, dextrose, sucrose,
lactose, maltose, and microcrystalline cellulose. In one
embodiment, the inert core comprises lactose. In an alternative
embodiment, the inert core comprises starch. In yet another
alternative, the inert core comprises sucrose.
[0029] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the weight percentage for the inert core is
10%-60% or 20-40% of the total weight of the inert core and the
first layer. More specifically, the weight percentage for the inert
core is 30%-40% or 20-30% of the total weight of the inert core and
the first layer. Even more specifically, the weight percentage for
the inert core is 20-24% of the total weight of the inert core and
the first layer. Alternatively, the weight percentage for the inert
core is 16-20% of the total weight of the inert core and the first
layer. In another alternative, the weight percentage for the inert
core is 16-22% of the total weight of the inert core and the first
layer. In another embodiment, the weight percentage for the inert
core is 15-30% of the total weight of the inert core and the first
layer. In yet another embodiment, the weight percentage for the
inert core is 16-26% of the total weight of the inert core and the
first layer.
[0030] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the inert core is a sphere having a diameter of
200-850 .mu.m. More specifically, the sphere has a diameter of
250-350 .mu.m, 300-400 .mu.m, 500-600 .mu.m or 700-850 .mu.m. Even
more specifically, the sphere has a diameter of 350 .mu.m, 550
.mu.m or 750 .mu.m.
[0031] In certain embodiment, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the beads have a diameter of 0.5-2 mm, 0.5-1.5
mm, 0.8-2 mm, 0.8-1.5 mm, 1-2 mm or 1-1.5 mm. More specifically,
the beads have a diameter of 0.9-1.5 mm, 0.9-1.4 mm, 0.9-1.3 mm,
0.9-1.2 mm, 1-1.4 mm, 1-1.3 mm or 1-1.2 mm.
[0032] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the active substance dimethyl fumarate is
layered on the inert core. More specifically, dimethyl fumarate is
layered on the inert core by spraying a solution containing
dimethyl fumarate onto the inert core in a fluidized bed system,
such as a fluidized bed spray coating apparatus. A fluidized bed
system can also be referred to as a fluid bed.
[0033] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the weight percentage of dimethyl fumarate is
40%-80%, 50%-75%, 60-80%, 60%-70%, 65%-75%, or 70%-80% of the total
weight of the inert core and the first layer. More specifically,
the weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer. In a specific
embodiment, the weight percentage of dimethyl fumarate is 70% of
the total weight of the inert core and the first layer.
Alternatively, the weight percentage of dimethyl fumarate is
60%-63% of the total weight of the inert core and the first layer.
In another embodiment, the weight percentage of dimethyl fumarate
is 72%-76% of the total weight of the inert core and the first
layer. In yet another embodiment, the weight percentage of dimethyl
fumarate is 74% of the total weight of the inert core and the first
layer.
[0034] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the first layer further comprises a binder.
Exemplary binders include, but are not limited to, acacia, agar,
alginic acid, amino methacrylate copolymer, ammonio methacrylate
copolymer, ammonio methacrylate copolymer dispersion, calcium
carbonate, calcium lactate, carbomer copolymer, carbomer
homopolymer, carbomer interpolymer, carboxymethylcellulose sodium,
microcrystalline cellulose, silicified microcrystalline cellulose,
hydrogenated coconut oil, copovidone, corn syrup, corn syrup
solids, dextrates, dextrin, ethyl acrylate and methyl methacrylate
copolymer dispersion, ethylcellulose, ethylene glycol and vinyl
alcohol graft copolymer, gelatin, liquid glucose, glyceryl
behenate, guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose, low-substituted hydroxypropyl cellulose, hypromellose,
hypromellose acetate succinate, inulin, alpha-lactalbumin,
monohydrate lactose, maltodextrin, maltose, methacrylic acid
copolymer, methacrylic acid copolymer dispersion, methacrylic acid
and ethyl acrylate copolymer dispersion, methylcellulose,
hydrogenated palm oil, polycarbophil, hydrogenated polydextrose,
polyethylene oxide, polyvinyl acetate, povidone, pullulan, sodium
alginate, pregelatinized starch, pregelatinized modified starch,
corn starch, hydroxypropyl corn starch, pregelatinized
hydroxypropyl corn starch, pea starch, hydroxypropyl pea starch,
pregelatinized hydroxypropyl pea starch, potato starch,
hydroxypropyl potato starch, pregelatinized hydroxypropyl potato
starch, tapioca starch, wheat starch, hydrogenated starch
hydrolysate, sucrose, sunflower oil, syrup, trehalose, hydrogenated
vegetable oil, vitamin E polyethylene glycol succinate, zein,
hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP),
methyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose,
polyethylene glycol (PEG), polyvinyl alcohols, polymethacrylate,
starch paste, sodium starch, tragacanth, gelatin, alginate, sodium
alginate, alginic acid, cellulose, candelilla wax, carnuba wax,
copolyvidone, and lactose hydrous. More specifically, the binder is
HPMC.
[0035] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the weight percentage for the binder is 1-25%,
1-20%, or 5-15% of the total weight of the inert core and the first
layer. More specifically, the weight percentage for the binder is
5-10% (e.g., 5%, 6%, 7%, 8%, 9% or 10%) of the total weight of the
inert core and the first layer. In another specific embodiment, the
weight percentage for the binder is 1-5% (e.g., 1%, 2%, 3%, 4% or
5%) total weight of the inert core and the first layer. In a even
more specific embodiment, the weight percentage for the binder is
7%.
[0036] In certain embodiment, the pharmaceutical bead compositions
of the present invention have an enteric coating surrounding the
first layer comprising dimethyl fumarate. As used herein, "enteric
coating" refers to a coating that is stable at the highly acidic pH
(e.g., pH .about.3) found in the stomach, but breaks down rapidly
at a less acidic pH (e.g., pH 7-9). Enteric coating materials known
in the art can generally be used in the present invention. In one
embodiment, for the pharmaceutical compositions described herein,
the enteric coating is layered on the first layer comprising
dimethyl fumarate. More specifically, the enteric coating is
layered on the first layer by spraying a solution containing
enteric coating materials onto the first layer in a fluid bed.
[0037] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the enteric coating is layered on the functional
coating. More specifically, the enteric coating is layered on the
functional coating by spraying a solution containing the enteric
coating materials onto the functional coating in a fluid bed.
[0038] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the enteric coating comprises an excipient
selected from the group consisting of a copolymer of methacrylic
acid and methyl methacrylate, a copolymer of methacrylic acid and
ethyl acrylate, hypromellose phthalate (HPMCP), cellulose acetate
phthalate. More specifically, the enteric coating comprises a
copolymer of methacrylic acid and methyl methacrylate. Even more
specifically, the ratio of methacrylic acid to methyl methacrylate
in the copolymer is 0.8:1 to 1.2:1, (e.g., 1:1). In an even more
specific embodiment, the enteric coating comprises EUDRAGIT.RTM. L
100 (poly(methacylic acid-co-methyl methacrylate) 1:1).
[0039] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the enteric coating of the present invention
further comprises one or more plasticizers. Exemplary plasticizers
include, but are not limited to, acetyltriethyl citrate, benzyl
benzoate, castor oil, chlorobutanol, diacetylated monoglycerides,
dibutyl sebacate, diethyl phthalate, glycerin, mannitol,
polyethylene glycol, polyethylene glycol monomethyl ether,
propylene glycol, pullulan, sorbitol, sorbitol sorbitan solution,
triacetin, tributyl citrate, triethyl citrate and Vitamin E. In a
more specific embodiment, the plasticizer is triethyl citrate.
[0040] In one embodiment, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the enteric coating of the present invention
comprises EUDRAGIT.RTM. L 100 and triethyl citrate. More
specifically, the weight ratio of the triethyl citrate to
EUDRAGIT.RTM. L 100 is from 1:1 to 1:20. Even more specifically,
the weight ratio of the triethyl citrate to EUDRAGIT.RTM. L 100 is
1:5.
[0041] In certain embodiments, for the first pharmaceutical bead
composition or the second pharmaceutical bead composition or both
the first and the second pharmaceutical bead compositions of the
present invention, the weight percentage for the enteric coating is
1-20% or 5-15% of the total weight of the inert core and the first
layer. More specifically, the weight percentage for the enteric
coating is 10-15% (e.g., 10%, 11%, 12%, 13% or 15%) of the total
weight of the inert core and the first layer. In another more
specific embodiment, the weight percentage for the enteric coating
is 11-13% of the total weight of the inert core and the first
layer. Even more specifically, the weight percentage of the enteric
coating is 12% of the total weight of the inert core and the first
layer.
[0042] In certain embodiments, for the pharmaceutical bead
compositions described herein, the functional coating is layered
onto the enteric coating of the beads. More specifically, the
functional coating is layered onto the enteric coating by spraying
a solution containing functional coating materials onto the enteric
coating in a fluid bed.
[0043] In certain embodiments, for the pharmaceutical bead
compositions described herein, the functional coating is layered
onto the first layer of the beads. More specifically, the
functional coating is layered onto the first layer by spraying a
solution containing functional coating materials onto the
functional coating in a fluid bed.
[0044] As used herein, the "functional coating" refers to a coating
that provides an extended release of the active substance (i.e.,
dimethyl fumarate).
[0045] In certain embodiments, for the second pharmaceutical bead
compositions of the present invention, the functional coating
comprises a mixture of one or more water soluble polymers and one
or more water insoluble polymers. In certain embodiments, the
functional coating comprises one or more excipients selected from
the group consisting of polyvinylpyrrolidone (PVP), polyethylene
oxide (PEO), glyceryl monostearate, hydroxyl propyl methyl
cellulose (HPMC), SoluPlus, polyvinyl alcohol (PVA), polyvinyl
alcohol (PVA), hydroxypropylmethylcellulose, acetate succinate
(HPMCAS), ethylene vinyl acetate (EVA), methacrylates
(Eudragit.TM.), cellulose acetate butyrate (CAB), cellulose acetate
phthalate (CAP), poly(ethylene glycol), poly(vinyl acetate) (PVAc),
polylactide (PLA), polyglycolide (PGA), copolymers of PLA/PGA and
polycaprolactone (PCL), polyvinylpyrrolidone-co-vinyl acetate
(Kollidon VA-64), polyrethanes, poly(lactic acid), poly(glycolic
acid), poly(anhydride-imides), poly(anhydride-esters),
poly(iminocarbonates), poly(phosphazenes), poly(phosphoesters),
ethylcellulose (EC), hydroxypropyl cellulose (HPC), alginic acid,
carbomer copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, carrageenan, cellaburate,
ethylcellulose aqueous dispersion, ethylcellulose dispersion Type
B, glyceryl monooleate, guar gum, hydroxypropyl betadex, polyvinyl
acetate dispersion, shellac, sodium alginate, pregelatinized
starch, pregelatinized modified starch and xanthan gum.
[0046] In one embodiment, for the second pharmaceutical bead
compositions described herein, the functional coating comprises a
mixture of ethylcellulose (EC) and hydroxypropyl cellulose (HPC).
More specifically, the functional coating comprises a mixture of
ETHOCEL.TM. 10 (ethylcellulose polymer with viscosity in the range
of 9-11 cP for 5% weight solution in 80% toluene and 20% ethanol)
and JF Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity
in the range of 150-400 cP for 5% by weight solution in water). In
one embodiment, the weight ratio of ethylcellulose (EC) to
hydroxypropyl cellulose (HPC) (e.g., ETHOCEL.TM. 10 to JF
Klucel.RTM.) is between 90:10 and 10:90, between 80:20 and 20:80,
between 80:20 and 50:50, between 75:25 and 60:40, between 70:30 and
55:45, between 70:30 and 50:50, or between 65:35 and 55:45. More
specifically, the weight ratio of ethylcellulose (EC) to
hydroxypropyl cellulose (HPC) (e.g., ETHOCEL.TM. 10 to JF
Klucel.RTM.) is 70:30. Alternatively, the weight ratio of
ethylcellulose (EC) to hydroxypropyl cellulose (HPC) (e.g.,
ETHOCEL.TM. 10 to JF Klucel.RTM.) is 65:35. In another specific
embodiment, the weight ratio of ethylcellulose (EC) to
hydroxypropyl cellulose (HPC) (e.g., ETHOCEL.TM. 10 to JF
Klucel.RTM.) is 60:40.
[0047] In another embodiment, for the second pharmaceutical bead
compositions described herein, the functional coating of the
present invention comprises a mixture of Eudragit.RTM. RS
(poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1) and Eudragit.RTM. RL (poly(ethyl acrylate-co-methyl
methacrylate-co-trimetylammonioethyl methacrylate chloride)
1:2:0.2). The weight ratio of Eudragit.RTM. RS to Eudragit.RTM. RL
is between 95:5 and 5:95, between 90:10 and 50:50, between 90:10
and 60:40, or between 85:15 and 70:30. More specifically, the
weight ratio of Eudragit.RTM. RS to Eudragit.RTM. RL is 75:25.
Alternatively, the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is 80:20.
[0048] In certain embodiments, for the second pharmaceutical bead
compositions described herein, the weight percentage for the
functional coating is 1-30%, 1-20%, 4-12%, 1-10%, 1-7% or 10-15% of
the total weight of the inert core and the first layer. More
specifically, the weight percentage for the functional coating is
2.0-3.0% of the total weight of the inert core and the first layer.
In another more specific embodiment, the weight percentage for the
functional coating is 4.0-5.0% of the total weight of the inert
core and the first layer. In another more specific embodiment, the
weight percentage for the functional coating is 4.5-5.5% of the
total weight of the inert core and the first layer. In another more
specific embodiment, the weight percentage or the functional
coating is 5.0-6.0% of the total weight of the inert core and the
first layer. In yet another more specific embodiment, the weight
percentage or the functional coating is 11.5-12.5% of the total
weight of the inert core and the first layer. Even more
specifically, the weight percentage for the functional coating is
2.5% of the total weight of the inert core and the first layer.
Alternatively, the weight percentage or the functional coating is
4.5% of the total weight of the inert core and the first layer. In
another alternative, the weight percentage or the functional
coating is 5.0% of the total weight of the inert core and the first
layer. In yet another alternative, the weight percentage or the
functional coating is 5.5% of the total weight of the inert core
and the first layer. In yet another alternative, the weight
percentage or the functional coating is 12% of the total weight of
the inert core and the first layer.
[0049] In a 1.sup.st specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0050] (1) the first pharmaceutical bead composition comprises:
[0051] an inert core;
[0052] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 40%-80% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 1-25% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition; and
[0053] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 1-20% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0054] wherein the weight percentage of the inert core is 10-60% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0055] (2) the second pharmaceutical bead composition
comprises:
[0056] an inert core;
[0057] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 40%-80% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 1-25% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition; and
[0058] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 1-20% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition; and
[0059] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is 1-30% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition,
[0060] wherein the weight percentage of the inert core is 10-60% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0061] In a 2.sup.nd specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0062] (1) the first pharmaceutical bead composition comprises:
[0063] an inert core;
[0064] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 50%-75% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 1-20% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition; and
[0065] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 5-15% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0066] wherein the weight percentage of the inert core is 20-40% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0067] (2) the second pharmaceutical composition comprises:
[0068] an inert core;
[0069] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 50%-75% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 1-20% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0070] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 5-15% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition; and
[0071] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is 1-20% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition,
[0072] wherein the weight percentage of the inert core is 20-40% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0073] In a 3.sup.rd specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0074] (1) the first pharmaceutical bead composition comprises:
[0075] an inert core;
[0076] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 65%-75% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-15% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0077] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 10-15% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0078] wherein the weight percentage of the inert core is 20-30% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0079] (2) the second pharmaceutical bead composition
comprises:
[0080] an inert core;
[0081] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 65%-75% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-15% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0082] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 10-15% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition; and
[0083] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is 1-10% or
10-15% of the total weight of the inert core and the first layer in
the second pharmaceutical bead composition,
[0084] wherein the weight percentage of the inert core is 20-30% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0085] In a 4.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0086] (1) the first pharmaceutical bead composition comprises:
[0087] an inert core;
[0088] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0089] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0090] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0091] (2) a second pharmaceutical bead composition comprises:
[0092] an inert core;
[0093] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the second layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0094] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0095] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
2.0%-3.0% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0096] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0097] In a 5.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0098] (1) the first pharmaceutical bead composition comprises:
[0099] an inert core;
[0100] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0101] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0102] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0103] (2) the second pharmaceutical bead composition
comprises:
[0104] an inert core;
[0105] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0106] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0107] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.5%-5.5% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0108] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0109] In a 6.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0110] (1) the first pharmaceutical bead composition comprises:
[0111] an inert core;
[0112] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0113] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0114] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0115] (2) the second pharmaceutical bead composition
comprises:
[0116] an inert core;
[0117] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0118] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition; and
[0119] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
5.0%-6.0% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0120] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0121] In a 7.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0122] (1) the first pharmaceutical bead composition comprises:
[0123] an inert core;
[0124] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0125] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0126] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0127] (2) the second pharmaceutical bead composition
comprises:
[0128] an inert core;
[0129] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0130] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0131] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
11.5%-12.5% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition,
[0132] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0133] In a 8.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0134] (1) the first pharmaceutical bead composition comprises:
[0135] an inert core;
[0136] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0137] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0138] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0139] (2) the second pharmaceutical bead composition
comprises:
[0140] an inert core;
[0141] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0142] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0143] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
2.0%-3.0% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0144] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0145] In a 9.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0146] (1) the first pharmaceutical bead composition comprises:
[0147] an inert core;
[0148] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0149] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0150] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0151] (2) the second pharmaceutical bead composition
comprises:
[0152] an inert core;
[0153] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0154] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0155] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.5%-5.5% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0156] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0157] In a 10.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0158] (1) the first pharmaceutical bead composition comprises:
[0159] an inert core;
[0160] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0161] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0162] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0163] (2) the second pharmaceutical composition comprises:
[0164] an inert core;
[0165] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0166] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0167] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
5.0%-6.0% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0168] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0169] In a 11.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0170] (1) the first pharmaceutical bead composition comprises:
[0171] an inert core;
[0172] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0173] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0174] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0175] (2) the second pharmaceutical bead composition
comprises:
[0176] an inert core;
[0177] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0178] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition; and
[0179] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
11.5%-12.5% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition,
[0180] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0181] In a 12.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0182] (1) the first pharmaceutical bead composition comprises:
[0183] an inert core;
[0184] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0185] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0186] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition; and
[0187] (2) the second pharmaceutical bead composition
comprises:
[0188] an inert core;
[0189] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 5-10% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0190] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition;
[0191] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.0%-5.0% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition,
[0192] wherein the weight percentage of the inert core is 16-22% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0193] In a 13.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0194] (1) the first pharmaceutical bead composition comprises:
[0195] an inert core;
[0196] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition and the weight percentage of the
binder is 6-8% of the total weight of the inert core and the first
layer in the first pharmaceutical bead composition;
[0197] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0198] (2) the second pharmaceutical bead composition
comprises:
[0199] an inert core;
[0200] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition and the weight percentage of the
binder is 6-8% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition;
[0201] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition; and
[0202] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.0%-5.0% of the total weight of the inert core and the first layer
in the second pharmaceutical bead composition.
[0203] In a 14.sup.th specific embodiment, the pharmaceutical
composition of the present invention comprises a first
pharmaceutical bead composition and a second pharmaceutical bead
composition, wherein:
[0204] (1) the first pharmaceutical bead composition comprises:
[0205] an inert core;
[0206] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 74% of the total weight
of the inert core and the first layer in the first pharmaceutical
bead composition and the weight percentage of the binder is 7% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition;
[0207] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 12% of the total weight
of the inert core and the first layer in the first pharmaceutical
bead composition;
[0208] (2) the second pharmaceutical bead composition
comprises:
[0209] an inert core;
[0210] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 74% of the total weight
of the inert core and the first layer in the second pharmaceutical
bead composition and the weight percentage of the binder is 7% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition;
[0211] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 12% of the total weight
of the inert core and the first layer in the second pharmaceutical
bead composition; and
[0212] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is 4.5% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0213] More specifically, for the pharmaceutical bead composition
in the 1.sup.st, 2.sup.nd, 3.sup.rd, 4.sup.th, 5.sup.th, 6.sup.th,
7.sup.th, 8.sup.th, 9.sup.th, 10.sup.th, 11.sup.th, 12.sup.th,
13.sup.th or 14.sup.th specific embodiment, the inert core
comprises sucrose or starch; the binder is HPMC; the enteric
coating comprises a copolymer of methacrylic acid and methyl
methacrylate and the ratio of methacrylic acid to methyl
methacrylate is 1:1; and the functional coating comprises of a
mixture of ethylcellulose (EC) and hydroxypropyl cellulose (HPC)
and weight ratio of ethylcellulose (EC) to hydroxypropyl cellulose
(HPC) is 65:35. More specifically, the enteric coating further
comprises triethyl citrate and the weight ratio of the copolymer of
methacrylic acid and methyl methacrylate to triethyl citrate is
5:1; and the functional coating comprises a mixture of ETHOCEL.TM.
10 (ethylcellulose polymer with viscosity in the range of 9-11 cP
for 5% weight solution in 80% toluene and 20% ethanol) and JF
Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity in the
range of 150-400 cP for 5% by weight solution in water), wherein
the weight ratio of ETHOCEL.TM. 10 to JF Klucel.RTM. is 65:35.
[0214] In another more specific embodiment, for the pharmaceutical
bead composition in the 1.sup.st, 2.sup.nd, 3.sup.rd, 4.sup.th,
5.sup.th, 6.sup.th, 7.sup.th, 8.sup.th, 9.sup.th, 10.sup.th,
11.sup.th, 12.sup.th, 13.sup.th or 14.sup.th specific embodiment,
the inert core comprises sucrose or starch; the binder is HPMC; the
enteric coating comprises a copolymer of methacrylic acid and
methyl methacrylate and the ratio of methacrylic acid to methyl
methacrylate is 1:1; and the functional coating comprises of a
mixture of ethylcellulose (EC) and hydroxypropyl cellulose (HPC)
and weight ratio of ethylcellulose (EC) to hydroxypropyl cellulose
(HPC) is 60:40. More specifically, the enteric coating further
comprises triethyl citrate and the weight ratio of the copolymer of
methacrylic acid and methyl methacrylate to triethyl citrate is
5:1; and the functional coating comprises a mixture of ETHOCEL.TM.
10 (ethylcellulose polymer with viscosity in the range of 9-11 cP
for 5% weight solution in 80% toluene and 20% ethanol) and JF
Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity in the
range of 150-400 cP for 5% by weight solution in water), wherein
the weight ratio of ETHOCEL.TM. 10 to JF Klucel.RTM. is 60:40.
[0215] In certain embodiments, the amount of dimethyl fumarate in
the pharmaceutical compositions described herein is from is from 90
mg to 960 mg, more specifically from 120 mg to 480 mg. In one
embodiment, the amount of dimethyl fumarate in a single capsule
described herein is 240 mg. Alternatively, the amount of dimethyl
fumarate in a single capsule described herein is 480 mg.
[0216] In one aspect, the present invention is described in the
following embodiments: In embodiment (1), for the pharmaceutical
composition described in the first embodiment, the first
pharmaceutical bead composition comprises an inert core; a first
layer surrounding the inert core, wherein the first layer comprises
dimethyl fumarate; and an enteric coating surrounding the first
layer.
[0217] In embodiment (2), for the pharmaceutical composition of
embodiment (1), the inert core in the first pharmaceutical bead
composition comprises one or more inert substance selected from the
group consisting of starch, dextrose, sucrose, lactose, maltose,
and microcrystalline cellulose.
[0218] In embodiment (3), for the pharmaceutical composition of
embodiment (1), the inert core in the first pharmaceutical bead
composition comprises lactose.
[0219] In embodiment (4), for the pharmaceutical composition of
embodiment (1), the inert core in the first pharmaceutical bead
composition comprises sucrose.
[0220] In embodiment (5), for the pharmaceutical composition of
embodiment (1), the inert core in the first pharmaceutical bead
composition comprises starch.
[0221] In embodiment (6), for the pharmaceutical composition of any
one of embodiments (1)-(5), the weight percentage of the inert core
in the first pharmaceutical bead composition is 10%-60% of the
total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0222] In embodiment (7), for the pharmaceutical composition of
embodiment (6), the weight percentage of the inert core in the
first pharmaceutical bead composition is 20%-40% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0223] In embodiment (8), for the pharmaceutical composition of
embodiment (6), the weight percentage of the inert core in the
first pharmaceutical bead composition is 20%-30% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0224] In embodiment (9), for the pharmaceutical composition of
embodiment (6), the weight percentage of the inert core in the
first pharmaceutical bead composition is 20%-24% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0225] In embodiment (10), for the pharmaceutical composition of
embodiment (6), the weight percentage of the inert core in the
first pharmaceutical bead composition is 16%-20% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0226] In embodiment (11), for the pharmaceutical composition of
any one of embodiments (1)-(10), the inert core in the first
pharmaceutical bead composition is a sphere having a diameter of
200-850 .mu.m.
[0227] In embodiment (12), for the pharmaceutical composition of
embodiment (11), the sphere of the inert core in the first
pharmaceutical bead composition has a diameter of 250-350 .mu.m,
500-600 .mu.m or 700-850 .mu.m.
[0228] In embodiment (13), for the pharmaceutical composition of
embodiment (11), the sphere of the inert core in the first
pharmaceutical bead composition has a diameter of 350 .mu.m, 550
.mu.m, or 750 .mu.m.
[0229] In embodiment (14), for the pharmaceutical composition of
any one of embodiments (1)-(13), the weight percentage of dimethyl
fumarate in the first pharmaceutical bead composition is 40%-80% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0230] In embodiment (15), for the pharmaceutical composition of
embodiment (14), wherein the weight percentage of dimethyl fumarate
in the first pharmaceutical bead composition is 50%-75% of the
total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0231] In embodiment (16), for the pharmaceutical composition of
embodiment (14), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 65%-75% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0232] In embodiment (17), for the pharmaceutical composition of
embodiment (14), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 68%-72% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0233] In embodiment (18), for the pharmaceutical composition of
embodiment (14), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 72-76% of the total weight
of the inert core and the first layer in the first pharmaceutical
bead composition.
[0234] In embodiment (19), for the pharmaceutical composition of
any one of embodiments (1)-(18), the first layer in the first
pharmaceutical bead composition further comprises a binder.
[0235] In embodiment (20), for the pharmaceutical composition of
embodiment (19), the binder in the first layer of the first
pharmaceutical bead composition is selected from the group
consisting of acacia, agar, alginic acid, amino methacrylate
copolymer, ammonio methacrylate copolymer, ammonio methacrylate
copolymer dispersion, calcium carbonate, calcium lactate, carbomer
copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, microcrystalline cellulose,
silicified microcrystalline cellulose, hydrogenated coconut oil,
copovidone, corn syrup, corn syrup solids, dextrates, dextrin,
ethyl acrylate and methyl methacrylate copolymer dispersion,
ethylcellulose, ethylene glycol and vinyl alcohol graft copolymer,
gelatin, liquid glucose, glyceryl behenate, guar gum, hydroxyethyl
cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl
cellulose, hypromellose, hypromellose acetate succinate, inulin,
alpha-lactalbumin, monohydrate lactose, maltodextrin, maltose,
methacrylic acid copolymer, methacrylic acid copolymer dispersion,
methacrylic acid and ethyl acrylate copolymer dispersion,
methylcellulose, hydrogenated palm oil, polycarbophil, hydrogenated
polydextrose, polyethylene oxide, polyvinyl acetate, povidone,
pullulan, sodium alginate, pregelatinized starch, pregelatinized
modified starch, corn starch, hydroxypropyl corn starch,
pregelatinized hydroxypropyl corn starch, pea starch, hydroxypropyl
pea starch, pregelatinized hydroxypropyl pea starch, potato starch,
hydroxypropyl potato starch, pregelatinized hydroxypropyl potato
starch, tapioca starch, wheat starch, hydrogenated starch
hydrolysate, sucrose, sunflower oil, syrup, trehalose, hydrogenated
vegetable oil, vitamin E polyethylene glycol succinate, zein,
hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP),
methyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose,
polyethylene glycol (PEG), polyvinyl alcohols, polymethacrylate,
starch paste, sodium starch, tragacanth, gelatin, alginate, sodium
alginate, alginic acid, cellulose, candelilla wax, carnuba wax,
copolyvidone, and lactose hydrous.
[0236] In embodiment (21), for the pharmaceutical composition of
embodiment (20), the binder in the first layer of the first
pharmaceutical bead composition is hydroxypropyl methylcellulose
(HPMC).
[0237] In embodiment (22), for the pharmaceutical composition of
any one of embodiments (19)-(21), the weight percentage of the
binder in the first layer of the first pharmaceutical bead
composition is 1%-25% of the total weight of the inert core and the
first layer in the first pharmaceutical bead composition.
[0238] In embodiment (23), for the pharmaceutical composition of
embodiment (22), the weight percentage of the binder in the first
layer of the first pharmaceutical bead composition is 1%-20% of the
total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0239] In embodiment (24), for the pharmaceutical composition of
embodiment (22), the weight percentage of the binder in the first
layer of the first pharmaceutical bead composition is 5%-15% of the
total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0240] In embodiment (25), for the pharmaceutical composition of
embodiment (22), the weight percentage of the binder in the first
layer of the first pharmaceutical bead composition is 5%-10% of the
total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0241] In embodiment (26), for the pharmaceutical composition of
embodiment (22), the weight percentage of the binder in the first
layer of the first pharmaceutical bead composition is 7% of the
total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0242] In embodiment (27), for the pharmaceutical composition of
any one of embodiments (1)-(26), the weight percentage of the
enteric coating in the first pharmaceutical bead composition is
1-20% of the total weight of the inert core and the first layer in
the first pharmaceutical bead composition.
[0243] In embodiment (28), for the pharmaceutical composition of
embodiment (27), the weight percentage of the enteric coating in
the first pharmaceutical bead composition is 5-15% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0244] In embodiment (29), for the pharmaceutical composition of
embodiment (27), the weight percentage of the enteric coating in
the first pharmaceutical bead composition is 10-15% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0245] In embodiment (30), for the pharmaceutical composition of
embodiment (27), the weight percentage of the enteric coating in
the first pharmaceutical bead composition is 11-13% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0246] In embodiment (31), for the pharmaceutical composition of
embodiment (27), the weight percentage of the enteric coating in
the first pharmaceutical bead composition is 12% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0247] In embodiment (32), for the pharmaceutical composition of
the first embodiment, the first pharmaceutical bead composition
comprises a core comprising dimethyl fumarate; and an enteric
coating surrounding the core.
[0248] In embodiment (33), for the pharmaceutical composition of
embodiment (32), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 40%-80% of the total
weight of the core in the first pharmaceutical bead
composition.
[0249] In embodiment (34), for the pharmaceutical composition of
embodiment (33), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 60%-80%, 60-70% or 70-80%
of the total weight of the core in the first pharmaceutical bead
composition.
[0250] In embodiment (35), for the pharmaceutical composition of
embodiment (34), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 65% of the total weight of
the core in the first pharmaceutical bead composition.
[0251] In embodiment (36), for the pharmaceutical composition of
embodiment (34), the weight percentage of dimethyl fumarate in the
first pharmaceutical bead composition is 75% of the total weight of
the core in the first pharmaceutical bead composition.
[0252] In embodiment (37), for the pharmaceutical composition of
any one of embodiments (32)-(36), the core in the first
pharmaceutical bead composition further comprises a binder.
[0253] In embodiment (38), for the pharmaceutical composition of
embodiment (37), the binder in the core of the first pharmaceutical
bead composition is selected from the group consisting of acacia,
agar, alginic acid, amino methacrylate copolymer, ammonio
methacrylate copolymer, ammonio methacrylate copolymer dispersion,
calcium carbonate, calcium lactate, carbomer copolymer, carbomer
homopolymer, carbomer interpolymer, carboxymethylcellulose sodium,
microcrystalline cellulose, silicified microcrystalline cellulose,
hydrogenated coconut oil, copovidone, corn syrup, corn syrup
solids, dextrates, dextrin, ethyl acrylate and methyl methacrylate
copolymer dispersion, ethylcellulose, ethylene glycol and vinyl
alcohol graft copolymer, gelatin, liquid glucose, glyceryl
behenate, guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose, low-substituted hydroxypropyl cellulose, hypromellose,
hypromellose acetate succinate, inulin, alpha-lactalbumin,
monohydrate lactose, maltodextrin, maltose, methacrylic acid
copolymer, methacrylic acid copolymer dispersion, methacrylic acid
and ethyl acrylate copolymer dispersion, methylcellulose,
hydrogenated palm oil, polycarbophil, hydrogenated polydextrose,
polyethylene oxide, polyvinyl acetate, povidone, pullulan, sodium
alginate, pregelatinized starch, pregelatinized modified starch,
corn starch, hydroxypropyl corn starch, pregelatinized
hydroxypropyl corn starch, pea starch, hydroxypropyl pea starch,
pregelatinized hydroxypropyl pea starch, potato starch,
hydroxypropyl potato starch, pregelatinized hydroxypropyl potato
starch, tapioca starch, wheat starch, hydrogenated starch
hydrolysate, sucrose, sunflower oil, syrup, trehalose, hydrogenated
vegetable oil, vitamin E polyethylene glycol succinate, zein,
hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP),
methyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose,
polyethylene glycol (PEG), polyvinyl alcohols, polymethacrylate,
starch paste, sodium starch, tragacanth, gelatin, alginate, sodium
alginate, alginic acid, cellulose, candelilla wax, carnuba wax,
copolyvidone, and lactose hydrous.
[0254] In embodiment (39), for the pharmaceutical composition of
embodiment (38), the binder in the core of the first pharmaceutical
bead composition is microcrystalline cellulose or starch.
[0255] In embodiment (40), for the pharmaceutical composition of
embodiment (38) or (39), the weight percentage of the binder in the
core of the first pharmaceutical bead composition is 1-50% of the
weight of the core in the first pharmaceutical bead
composition.
[0256] In embodiment (41), for the pharmaceutical composition of
embodiment (38) or (39), the weight percentage of the binder in the
core of the first pharmaceutical bead composition is 15-35% of the
weight of the core in the first pharmaceutical bead
composition.
[0257] In embodiment (42), for the pharmaceutical composition of
any one of embodiments (32)-(41), the weight percentage of the
enteric coating in the first pharmaceutical bead composition is
1-20% of the total weight of the core in the first pharmaceutical
bead composition.
[0258] In embodiment (43), for the pharmaceutical composition of
embodiment (42), wherein the weight percentage of the enteric in
the first pharmaceutical bead composition coating is 5-15% of the
total weight of the core in the first pharmaceutical bead
composition.
[0259] In embodiment (44), for the pharmaceutical composition of
embodiment (42), wherein the weight percentage of the enteric
coating in the first pharmaceutical bead composition is 10-15% of
the total weight of the core in the first pharmaceutical bead
composition.
[0260] In embodiment (45), for the pharmaceutical composition of
embodiment (42), the weight percentage of the enteric coating in
the first pharmaceutical bead composition is 11-13% of the total
weight of the core in the first pharmaceutical bead
composition.
[0261] In embodiment (46), for the pharmaceutical composition of
embodiment (42), the weight percentage of the enteric coating in
the first pharmaceutical bead composition is 12% of the total
weight of the core in the first pharmaceutical bead
composition.
[0262] In embodiment (47), for the pharmaceutical composition of
any one of embodiments (1)-(46), the enteric coating in the first
pharmaceutical bead composition comprises an excipient selected
from the group consisting of a copolymer of methacrylic acid and
methyl methacrylate, a copolymer of methacrylic acid and ethyl
acrylate, hypromellose phthalate (HPMCP), cellulose acetate
phthalate.
[0263] In embodiment (48), for the pharmaceutical composition of
embodiment (47), the enteric coating in the first pharmaceutical
bead composition comprises a copolymer of methacrylic acid and
methyl methacrylate.
[0264] In embodiment (49), for the pharmaceutical composition of
embodiment (48), the ratio of the methacrylic acid to the methyl
methacrylate in the copolymer is 0.8:1 to 1.2:1.
[0265] In embodiment (50), for the pharmaceutical composition of
embodiment (49), the ratio of the methacrylic acid to the methyl
methacrylate in the copolymer is 1:1 (Eudragit L100).
[0266] In embodiment (51), for the pharmaceutical composition of
any one of embodiments (1)-(50), the enteric coating in the first
pharmaceutical bead composition comprises a plasticizer.
[0267] In embodiment (52), for the pharmaceutical composition of
embodiment (51), the plasticizer in the enteric coating of the
first pharmaceutical bead composition is selected from the group
consisting of acetyltributyl citrate, acetyltriethyl citrate,
benzyl benzoate, castor oil, chlorobutanol, diacetylated
monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,
mannitol, polyethylene glycol, polyethylene glycol monomethyl
ether, propylene glycol, pullulan, sorbitol, sorbitol sorbitan
solution, triacetin, tributyl citrate, triethyl citrate and vitamin
E.
[0268] In embodiment (53), for the pharmaceutical composition of
embodiment (52), the plasticizer is triethyl citrate.
[0269] In embodiment (54), for the pharmaceutical composition of
embodiment (53), the weight ratio of the triethyl citrate to the
copolymer of methacrylic acid and methyl methacrylate is from 1:1
to 1:20.
[0270] In embodiment (55), for the pharmaceutical composition of
embodiment (54), the weight ratio of the triethyl citrate to the
copolymer of methacrylic acid and methyl methacrylate is 1:5.
[0271] In embodiment (56), for the pharmaceutical composition of
any one of embodiments (1)-(31) and (47)-(55), the first
pharmaceutical bead formulation further comprises a functional
coating surround the enteric coating, wherein the weight percentage
of the functional coating is 0.1-3.9% of the total weight of the
inert core and the first layer of the first pharmaceutical bead
formulation.
[0272] In embodiment (57), for the pharmaceutical composition of
any one of embodiments (1)-(31) and (47)-(55), the first
pharmaceutical bead formulation further comprises a functional
coating, wherein the functional coating is in between the first
layer and the enteric coating (i.e., the functional coating
surrounds the first layer and the enteric coating surrounds the
functional coating) and the weight percentage of the functional
coating is 0.1-3.9% of the total weight of the inert core and the
first layer of the first pharmaceutical bead formulation.
[0273] In embodiment (58), for the pharmaceutical composition of
embodiment (56) or (57), the weight percentage of the functional
coating in the first pharmaceutical bead composition is 2.0-3.0% of
the total weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0274] In embodiment (59), for the pharmaceutical composition of
embodiment (58), the weight percentage of the functional coating in
the first pharmaceutical bead composition is 2.5% of the total
weight of the inert core and the first layer in the first
pharmaceutical bead composition.
[0275] In embodiment (60), for the pharmaceutical composition of
any one of embodiments (32)-(55), the first pharmaceutical bead
formulation further comprises a functional coating surrounding the
enteric coating, wherein the weight percentage of the functional
coating is 0.1-3.9% of the total weight of the core of the first
pharmaceutical bead formulation.
[0276] In embodiment (61), for the pharmaceutical composition of
any one of embodiments (32)-(55), the first pharmaceutical bead
formulation further comprises a functional coating, wherein the
functional coating is in between the core and the enteric coating
(i.e., the functional coating surrounds the core and the enteric
coating surrounds the functional coating) and the weight percentage
of the functional coating is 0.1-3.9% of the total weight of the
core of the first pharmaceutical bead formulation.
[0277] In embodiment (62), for the pharmaceutical composition of
embodiment (60) or (61), the weight percentage of the functional
coating in the first pharmaceutical bead composition is 2.0-3.0% of
the total weight of the core in the first pharmaceutical bead
composition.
[0278] In embodiment (63), for the pharmaceutical composition of
embodiment (60) or (61), the weight percentage of the functional
coating in the first pharmaceutical bead composition is 2.5% of the
total weight of the core in the first pharmaceutical bead
composition.
[0279] In embodiment (64), for pharmaceutical composition of any
one of embodiments (56)-(63), the functional coating in the first
pharmaceutical bead composition comprises a mixture of one or more
water-insoluble polymer and one or more water-soluble polymer.
[0280] In embodiment (65), for the pharmaceutical composition of
any one of embodiments (56)-(63), wherein the functional coating in
the first pharmaceutical bead composition comprises one or more
excipients selected from the group consisting of
polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), glyceryl
monostearate, hydroxyl propyl methyl cellulose (HPMC), SoluPlus,
polyvinyl alcohol (PVA), polyvinyl alcohol (PVA),
hydroxypropylmethylcellulose, acetate succinate (HPMCAS), ethylene
vinyl acetate (EVA), methacrylates (Eudragit.TM.), cellulose
acetate butyrate (CAB), cellulose acetate phthalate (CAP),
poly(ethylene glycol), poly(vinyl acetate) (PVAc), polylactide
(PLA), polyglycolide (PGA), copolymers of PLA/PGA and
polycaprolactone (PCL), polyvinylpyrrolidone-co-vinyl acetate
(Kollidon VA-64), polyrethanes, poly(lactic acid), poly(glycolic
acid), poly(anhydride-imides), poly(anhydride-esters),
poly(iminocarbonates), poly(phosphazenes), poly(phosphoesters),
ethylcellulose (EC), hydroxypropyl cellulose (HPC), alginic acid,
carbomer copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, carrageenan, cellaburate,
ethylcellulose aqueous dispersion, ethylcellulose dispersion Type
B, glyceryl monooleate, guar gum, hydroxypropyl betadex, polyvinyl
acetate dispersion, shellac, sodium alginate, pregelatinized
starch, pregelatinized modified starch and xanthan gum.
[0281] In embodiment (66), for the pharmaceutical composition of
embodiment (65), wherein the functional coating in the first
pharmaceutical bead composition comprises a mixture of
ethylcellulose (EC) and hydroxypropyl cellulose (HPC).
[0282] In embodiment (67), for the pharmaceutical composition of
embodiment (65), the functional coating in the first pharmaceutical
bead composition comprises a mixture of ETHOCEL.TM. 10
(ethylcellulose polymer with viscosity in the range of 9-11 cP for
5% weight solution in 80% toluene and 20% ethanol) and JF
Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity in the
range of 150-400 cP for 5% by weight solution in water).
[0283] In embodiment (68), for the pharmaceutical composition of
embodiment (66) or (67), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 90:10 and 10:90.
[0284] In embodiment (69), for the pharmaceutical composition of
embodiment (68), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 80:20 and 20:80.
[0285] In embodiment (70), for the pharmaceutical composition of
embodiment (68), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 80:20 and 50:50.
[0286] In embodiment (71), for the pharmaceutical composition of
embodiment (68), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 75:25 and 60:40.
[0287] In embodiment (72), for the pharmaceutical composition of
embodiment (68), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is 70:30.
[0288] In embodiment (73), for the pharmaceutical composition of
embodiment (68), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is 65:35.
[0289] In embodiment (74), for the pharmaceutical composition of
embodiment (68), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is 60:40.
[0290] In embodiment (75), for the pharmaceutical composition of
embodiment (65), the functional coating in the first pharmaceutical
bead composition comprises a mixture of Eudragit.RTM. RS
(poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1) and Eudragit.RTM. RL (poly(ethyl acrylate-co-methyl
methacrylate-co-trimetylammonioethyl methacrylate chloride)
1:2:0.2).
[0291] In embodiment (76), for the pharmaceutical composition of
embodiment (75), the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 95:5 to 5:95.
[0292] In embodiment (77), for the pharmaceutical composition of
embodiment (75), the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 90:10 to 50:50.
[0293] In embodiment (78), for the pharmaceutical composition of
embodiment (75), wherein the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 90:10 to 60:40.
[0294] In embodiment (79), for the pharmaceutical composition of
embodiment (75), wherein the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 85:15 to 70:30.
[0295] In embodiment (80), for the pharmaceutical composition of
embodiment (75), wherein the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is 75:25.
[0296] In embodiment (81), for the pharmaceutical composition of
embodiment (75), wherein the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is 80:20.
[0297] In embodiment (82), for the pharmaceutical composition of
any one of embodiments (1)-(81), the second pharmaceutical bead
composition comprises:
[0298] an inert core;
[0299] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate;
[0300] an enteric coating surrounding the first layer; and
[0301] a functional coating surrounding the enteric coating.
[0302] In embodiment (83), for the pharmaceutical composition of
any one of embodiments (1)-(81), the second pharmaceutical bead
composition comprises:
[0303] an inert core;
[0304] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate;
[0305] a functional coating surrounding the first layer; and
[0306] an enteric coating surrounding the functional coating.
[0307] In embodiment (84), for the pharmaceutical composition of
embodiment (82) or (83), the inert core in the second
pharmaceutical bead composition comprises one or more inert
substance selected from the group consisting of starch, dextrose,
sucrose, lactose, maltose, and microcrystalline cellulose.
[0308] In embodiment (85), for the pharmaceutical composition of
embodiment (82) or (83), the inert core in the second
pharmaceutical bead composition comprises lactose.
[0309] In embodiment (86), for the pharmaceutical composition of
embodiment (82) or (83), the inert core in the second
pharmaceutical bead composition comprises sucrose.
[0310] In embodiment (87), for the pharmaceutical composition of
embodiment (82) or (83), the inert core in the second
pharmaceutical bead composition comprises starch.
[0311] In embodiment (88), for the pharmaceutical composition of
any one of embodiments (82)-(87), the weight percentage of the
inert core in the second pharmaceutical bead composition is 10%-60%
of the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0312] In embodiment (89), for the pharmaceutical composition of
embodiment (88), the weight percentage of the inert core in the
second pharmaceutical bead composition is 20%-40% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0313] In embodiment (90), for the pharmaceutical composition of
embodiment (88), the weight percentage of the inert core in the
second pharmaceutical bead composition is 20%-30% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0314] In embodiment (91), for the pharmaceutical composition of
embodiment (88), the weight percentage of the inert core in the
second pharmaceutical bead composition is 20%-24% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0315] In embodiment (92), for the pharmaceutical composition of
embodiment (88), the weight percentage of the inert core in the
second pharmaceutical bead composition is 16%-20% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0316] In embodiment (93), for the pharmaceutical composition of
any one of embodiments (82)-(92), the inert core in the second
pharmaceutical bead composition is a sphere having a diameter of
200-850 .mu.m.
[0317] In embodiment (94), for the pharmaceutical composition of
embodiment (93), the sphere of the inert core in the second
pharmaceutical bead composition has a diameter of 250-350 .mu.m,
500-600 .mu.m or 700-850 .mu.m.
[0318] In embodiment (95), for the pharmaceutical composition of
embodiment (93), the sphere of the inert core in the second
pharmaceutical bead composition has a diameter of 350 .mu.m, 550
.mu.m, or 750 .mu.m.
[0319] In embodiment (96), for the pharmaceutical composition of
any one of embodiments (82)-(95), the weight percentage of dimethyl
fumarate in the second pharmaceutical bead composition is 40%-80%
of the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0320] In embodiment (97), for the pharmaceutical composition of
embodiment (96), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 50%-75% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0321] In embodiment (98), for the pharmaceutical composition of
embodiment (96), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 65%-75% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0322] In embodiment (99), for the pharmaceutical composition of
embodiment (96), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 68%-72% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0323] In embodiment (100), for the pharmaceutical composition of
embodiment (96), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 72-76% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0324] In embodiment (101), for the pharmaceutical composition of
any one of embodiments (82)-(100), the first layer in the second
pharmaceutical bead composition further comprises a binder.
[0325] In embodiment (102), for the pharmaceutical composition of
embodiment (101), the binder in the first layer of the second
pharmaceutical bead composition is selected from the group
consisting of acacia, agar, alginic acid, amino methacrylate
copolymer, ammonio methacrylate copolymer, ammonio methacrylate
copolymer dispersion, calcium carbonate, calcium lactate, carbomer
copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, microcrystalline cellulose,
silicified microcrystalline cellulose, hydrogenated coconut oil,
copovidone, corn syrup, corn syrup solids, dextrates, dextrin,
ethyl acrylate and methyl methacrylate copolymer dispersion,
ethylcellulose, ethylene glycol and vinyl alcohol graft copolymer,
gelatin, liquid glucose, glyceryl behenate, guar gum, hydroxyethyl
cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl
cellulose, hypromellose, hypromellose acetate succinate, inulin,
alpha-lactalbumin, monohydrate lactose, maltodextrin, maltose,
methacrylic acid copolymer, methacrylic acid copolymer dispersion,
methacrylic acid and ethyl acrylate copolymer dispersion,
methylcellulose, hydrogenated palm oil, polycarbophil, hydrogenated
polydextrose, polyethylene oxide, polyvinyl acetate, povidone,
pullulan, sodium alginate, pregelatinized starch, pregelatinized
modified starch, corn starch, hydroxypropyl corn starch,
pregelatinized hydroxypropyl corn starch, pea starch, hydroxypropyl
pea starch, pregelatinized hydroxypropyl pea starch, potato starch,
hydroxypropyl potato starch, pregelatinized hydroxypropyl potato
starch, tapioca starch, wheat starch, hydrogenated starch
hydrolysate, sucrose, sunflower oil, syrup, trehalose, hydrogenated
vegetable oil, vitamin E polyethylene glycol succinate, zein,
hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP),
methyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose,
polyethylene glycol (PEG), polyvinyl alcohols, polymethacrylate,
starch paste, sodium starch, tragacanth, gelatin, alginate, sodium
alginate, alginic acid, cellulose, candelilla wax, carnuba wax,
copolyvidone, and lactose hydrous.
[0326] In embodiment (103), for the pharmaceutical composition of
embodiment (102), the binder in the first layer of the second
pharmaceutical bead composition is hydroxypropyl methylcellulose
(HPMC).
[0327] In embodiment (104), for the pharmaceutical composition of
any one of embodiments (101)-(103), the weight percentage of the
binder in the first layer of the second pharmaceutical bead
composition is 1%-25% of the total weight of the inert core and the
first layer in the second pharmaceutical bead composition.
[0328] In embodiment (105), for the pharmaceutical composition of
embodiment (104), the weight percentage of the binder in the first
layer of the second pharmaceutical bead composition is 1%-20% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0329] In embodiment (106), for the pharmaceutical composition of
embodiment (104), the weight percentage of the binder in the first
layer of the second pharmaceutical bead composition is 5%-15% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0330] In embodiment (107), for the pharmaceutical composition of
embodiment (104), the weight percentage of the binder in the first
layer of the second pharmaceutical bead composition is 5%-10% of
the total weight of the inert core and the first layer in the
second pharmaceutical bead composition.
[0331] In embodiment (108), for the pharmaceutical composition of
embodiment (104), the weight percentage of the binder in the first
layer of the second pharmaceutical bead composition is 7% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0332] In embodiment (109), for the pharmaceutical composition of
any one of embodiments (82)-(108), the weight percentage of the
enteric coating in the second pharmaceutical bead composition is
1-20% of the total weight of the inert core and the first layer in
the second pharmaceutical bead composition.
[0333] In embodiment (110), for the pharmaceutical composition of
embodiment (109), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 5-15% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0334] In embodiment (111), for the pharmaceutical composition of
embodiment (109), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 10-15% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0335] In embodiment (112), for the pharmaceutical composition of
embodiment (109), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 11-13% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0336] In embodiment (113), for the pharmaceutical composition of
embodiment (109), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 12% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0337] In embodiment (114), for the pharmaceutical composition of
any one of embodiments (82)-(113), wherein the weight percentage of
the functional coating in the second pharmaceutical bead
composition is 1-30% of the total weight of the inert core and the
first layer in the second pharmaceutical bead composition.
[0338] In embodiment (115), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 1-20% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0339] In embodiment (116), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4-12% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0340] In embodiment (117), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 1-10% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0341] In embodiment (118), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 10-15% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0342] In embodiment (119), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4.5-5.5% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0343] In embodiment (120), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 5.0% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0344] In embodiment (121), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4.0-5.0% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0345] In embodiment (122), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4.5% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0346] In embodiment (123), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 5.0-6.0% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0347] In embodiment (124), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 5.5% of the total
weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0348] In embodiment (125), for the pharmaceutical composition of
embodiment (114), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 11.5-12.5% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0349] In embodiment (126), for the pharmaceutical composition of
embodiment (114), wherein the weight percentage of the functional
coating in the second pharmaceutical bead composition is 12% of the
total weight of the inert core and the first layer in the second
pharmaceutical bead composition.
[0350] In embodiment (127), for the pharmaceutical composition of
any one of embodiments (1)-(81), the second pharmaceutical bead
composition comprises:
[0351] an core comprising dimethyl fumarate;
[0352] an enteric coating surrounding the core; and
[0353] a functional coating surrounding the enteric coating.
[0354] In embodiment (128), for the pharmaceutical composition of
any one of embodiments (1)-(81), the second pharmaceutical bead
composition comprises:
[0355] a core comprising dimethyl fumarate;
[0356] a functional coating surrounding the core; and
[0357] an enteric coating surrounding the functional coating.
[0358] In embodiment (129), for the pharmaceutical composition of
embodiment (127) or (128), the weight percentage of dimethyl
fumarate in the second pharmaceutical bead composition is 40%-80%
of the total weight of the core in the second pharmaceutical bead
composition.
[0359] In embodiment (130), for the pharmaceutical composition of
embodiment (129), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 60%-80%, 60-70% or 70-80%
of the total weight of the core in the second pharmaceutical bead
composition.
[0360] In embodiment (131), for the pharmaceutical composition of
embodiment (130), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 65% of the total weight
of the core in the second pharmaceutical bead composition.
[0361] In embodiment (132), for the pharmaceutical composition of
embodiment (130), the weight percentage of dimethyl fumarate in the
second pharmaceutical bead composition is 75% of the total weight
of the core in the second pharmaceutical bead composition.
[0362] In embodiment (133), for the pharmaceutical composition of
any one of embodiments (127)-(132), the core in the second
pharmaceutical bead composition further comprises a binder.
[0363] In embodiment (134), for the pharmaceutical composition of
embodiment (133), the binder in the core of the second
pharmaceutical bead composition is selected from the group
consisting of acacia, agar, alginic acid, amino methacrylate
copolymer, ammonio methacrylate copolymer, ammonio methacrylate
copolymer dispersion, calcium carbonate, calcium lactate, carbomer
copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, microcrystalline cellulose,
silicified microcrystalline cellulose, hydrogenated coconut oil,
copovidone, corn syrup, corn syrup solids, dextrates, dextrin,
ethyl acrylate and methyl methacrylate copolymer dispersion,
ethylcellulose, ethylene glycol and vinyl alcohol graft copolymer,
gelatin, liquid glucose, glyceryl behenate, guar gum, hydroxyethyl
cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl
cellulose, hypromellose, hypromellose acetate succinate, inulin,
alpha-lactalbumin, monohydrate lactose, maltodextrin, maltose,
methacrylic acid copolymer, methacrylic acid copolymer dispersion,
methacrylic acid and ethyl acrylate copolymer dispersion,
methylcellulose, hydrogenated palm oil, polycarbophil, hydrogenated
polydextrose, polyethylene oxide, polyvinyl acetate, povidone,
pullulan, sodium alginate, pregelatinized starch, pregelatinized
modified starch, corn starch, hydroxypropyl corn starch,
pregelatinized hydroxypropyl corn starch, pea starch, hydroxypropyl
pea starch, pregelatinized hydroxypropyl pea starch, potato starch,
hydroxypropyl potato starch, pregelatinized hydroxypropyl potato
starch, tapioca starch, wheat starch, hydrogenated starch
hydrolysate, sucrose, sunflower oil, syrup, trehalose, hydrogenated
vegetable oil, vitamin E polyethylene glycol succinate, zein,
hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP),
methyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose,
polyethylene glycol (PEG), polyvinyl alcohols, polymethacrylate,
starch paste, sodium starch, tragacanth, gelatin, alginate, sodium
alginate, alginic acid, cellulose, candelilla wax, carnuba wax,
copolyvidone, and lactose hydrous.
[0364] In embodiment (135), for the pharmaceutical composition of
embodiment (133), the binder in the core of the second
pharmaceutical bead composition is microcrystalline cellulose or
starch.
[0365] In embodiment (136), for the pharmaceutical composition of
any one of embodiments (133)-(135), the weight percentage of the
binder in the core of the second pharmaceutical bead composition is
1-50% of the weight of the core in the second pharmaceutical bead
composition.
[0366] In embodiment (137), for the pharmaceutical composition of
embodiment (136), the weight percentage of the binder in the core
of the second pharmaceutical bead composition is 15-35% of the
weight of the core in the second pharmaceutical bead
composition.
[0367] In embodiment (138), for the pharmaceutical composition of
any one of embodiments (127)-(137), the weight percentage of the
enteric coating in the second pharmaceutical bead composition is
1-20% of the total weight of the core in the second pharmaceutical
bead composition.
[0368] In embodiment (139), for the pharmaceutical composition of
embodiment (138), the weight percentage of the enteric coating in
the second pharmaceutical bead composition coating is 5-15% of the
total weight of the core in the second pharmaceutical bead
composition.
[0369] In embodiment (140), for the pharmaceutical composition of
embodiment (138), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 10-15% of the total
weight of the core in the second pharmaceutical bead
composition.
[0370] In embodiment (141), for the pharmaceutical composition of
embodiment (138), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 11-13% of the total
weight of the core in the second pharmaceutical bead
composition.
[0371] In embodiment (142), for the pharmaceutical composition of
embodiment (138), the weight percentage of the enteric coating in
the second pharmaceutical bead composition is 12% of the total
weight of the core in the second pharmaceutical bead
composition.
[0372] In embodiment (143), for the pharmaceutical composition of
any one of embodiments (127)-(142), the weight percentage of the
functional coating in the second pharmaceutical bead composition is
1-30% of the total weight of the core in the second pharmaceutical
bead composition.
[0373] In embodiment (144), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 1-20% of the total
weight of the core in the second pharmaceutical bead
composition.
[0374] In embodiment (145), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4-12% of the total
weight of the core in the second pharmaceutical bead
composition.
[0375] In embodiment (146), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 1-10% of the total
weight of the core in the second pharmaceutical bead
composition.
[0376] In embodiment (147), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 10-15% of the
total weight of the core in the second pharmaceutical bead
composition.
[0377] In embodiment (148), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4.5-5.5% of the
total weight of the core in the second pharmaceutical bead
composition.
[0378] In embodiment (149), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 5.0% of the total
weight of the core in the second pharmaceutical bead
composition.
[0379] In embodiment (150), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 5.0-6.0% of the
total weight of the core in the second pharmaceutical bead
composition.
[0380] In embodiment (151), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 5.5% of the total
weight of the core in the second pharmaceutical bead
composition.
[0381] In embodiment (152), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 11.5-12.5% of the
total weight of the core in the second pharmaceutical bead
composition.
[0382] In embodiment (153), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 12% of the total
weight of the core in the second pharmaceutical bead
composition.
[0383] In embodiment (154), for the pharmaceutical composition of
embodiment (143), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4.0-5.0% of the
total weight of the core in the second pharmaceutical bead
composition.
[0384] In embodiment (155), for the pharmaceutical composition of
embodiment (154), the weight percentage of the functional coating
in the second pharmaceutical bead composition is 4.5% of the total
weight of the core in the second pharmaceutical bead
composition.
[0385] In embodiment (156), for the pharmaceutical composition of
any one of embodiments (82)-(155), the enteric coating in the
second pharmaceutical bead composition comprises an excipient
selected from the group consisting of a copolymer of methacrylic
acid and methyl methacrylate, a copolymer of methacrylic acid and
ethyl acrylate, hypromellose phthalate (HPMCP), cellulose acetate
phthalate.
[0386] In embodiment (157), for the pharmaceutical composition of
embodiment (156), the enteric coating in the second pharmaceutical
bead composition comprises a copolymer of methacrylic acid and
methyl methacrylate.
[0387] In embodiment (158), for the pharmaceutical composition of
embodiment (157), wherein the ratio of the methacrylic acid to the
methyl methacrylate in the copolymer is 0.8:1 to 1.2:1.
[0388] In embodiment (159), for the pharmaceutical composition of
embodiment (158), wherein the ratio of the methacrylic acid to the
methyl methacrylate in the copolymer is 1:1 (Eudragit L100).
[0389] In embodiment (160), for the pharmaceutical composition of
any one of embodiments (82)-(159), wherein the enteric coating in
the second pharmaceutical bead composition comprises a
plasticizer.
[0390] In embodiment (161), for the pharmaceutical composition of
embodiment (160), the plasticizer in the enteric coating of the
second pharmaceutical bead composition is selected from the group
consisting of acetyltributyl citrate, acetyltriethyl citrate,
benzyl benzoate, castor oil, chlorobutanol, diacetylated
monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,
mannitol, polyethylene glycol, polyethylene glycol monomethyl
ether, propylene glycol, pullulan, sorbitol, sorbitol sorbitan
solution, triacetin, tributyl citrate, triethyl citrate and vitamin
E.
[0391] In embodiment (162), for the pharmaceutical composition of
embodiment (161), the plasticizer in the enteric coating of the
second pharmaceutical bead composition is triethyl citrate.
[0392] In embodiment (163), for the pharmaceutical composition of
embodiment (162), weight ratio of the triethyl citrate to the
copolymer of methacrylic acid and methyl methacrylate is from 1:1
to 1:20.
[0393] In embodiment (164), for the pharmaceutical composition of
embodiment (163), wherein weight ratio of the triethyl citrate to
the copolymer of methacrylic acid and methyl methacrylate is
1:5.
[0394] In embodiment (165), for the pharmaceutical composition of
any one of embodiments (82)-(164), the functional coating in the
second pharmaceutical bead composition comprises a mixture of one
or more water-insoluble polymer and one or more water-soluble
polymer.
[0395] In embodiment (166), for the pharmaceutical composition of
any one of embodiments (82)-(164), the functional coating in the
second pharmaceutical bead composition comprises one or more
excipients selected from the group consisting of
polyvinylpyrrolidone (PVP), polyethylene oxide (PEO), glyceryl
monostearate, hydroxyl propyl methyl cellulose (HPMC), SoluPlus,
polyvinyl alcohol (PVA), polyvinyl alcohol (PVA),
hydroxypropylmethylcellulose, acetate succinate (HPMCAS), ethylene
vinyl acetate (EVA), methacrylates (Eudragit.TM.) cellulose acetate
butyrate (CAB), cellulose acetate phthalate (CAP), poly(ethylene
glycol), poly(vinyl acetate) (PVAc), polylactide (PLA),
polyglycolide (PGA), copolymers of PLA/PGA and polycaprolactone
(PCL), polyvinylpyrrolidone-co-vinyl acetate (Kollidon VA-64),
polyrethanes, poly(lactic acid), poly(glycolic acid),
poly(anhydride-imides), poly(anhydride-esters),
poly(iminocarbonates), poly(phosphazenes), poly(phosphoesters),
ethylcellulose (EC), hydroxypropyl cellulose (HPC), alginic acid,
carbomer copolymer, carbomer homopolymer, carbomer interpolymer,
carboxymethylcellulose sodium, carrageenan, cellaburate,
ethylcellulose aqueous dispersion, ethylcellulose dispersion Type
B, glyceryl monooleate, guar gum, hydroxypropyl betadex, polyvinyl
acetate dispersion, shellac, sodium alginate, pregelatinized
starch, pregelatinized modified starch and xanthan gum.
[0396] In embodiment (167), for the pharmaceutical composition of
any one of embodiments (82)-(164), the functional coating in the
second pharmaceutical bead composition comprises a mixture of
ethylcellulose (EC) and hydroxypropyl cellulose (HPC).
[0397] In embodiment (168), for the pharmaceutical composition of
embodiment (167), the functional coating in the second
pharmaceutical bead composition comprises a mixture of ETHOCEL.TM.
10 (ethylcellulose polymer with viscosity in the range of 9-11 cP
for 5% weight solution in 80% toluene and 20% ethanol) and JF
Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity in the
range of 150-400 cP for 5% by weight solution in water).
[0398] In embodiment (169), for the pharmaceutical composition of
embodiment (167) or (168), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 90:10 and 10:90.
[0399] In embodiment (170), for the pharmaceutical composition of
embodiment (169), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 80:20 and 20:80.
[0400] In embodiment (171), for the pharmaceutical composition of
embodiment (169), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 80:20 and 50:50.
[0401] In embodiment (172), for the pharmaceutical composition of
embodiment (169), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is between 75:25 and 60:40.
[0402] In embodiment (173), for the pharmaceutical composition of
embodiment (169), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is 70:30.
[0403] In embodiment (174), for the pharmaceutical composition of
embodiment (169), the weight ratio of ethylcellulose to
hydroxypropyl cellulose is 65:35.
[0404] In embodiment (175), for the pharmaceutical composition of
embodiment (166), wherein the weight ratio of ethylcellulose to
hydroxypropyl cellulose is 60:40.
[0405] In embodiment (176), for the pharmaceutical composition of
any one of embodiments (82)-(164), the functional coating in the
second pharmaceutical bead composition comprises a mixture of
Eudragit.RTM. RS (poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1) and Eudragit.RTM. RL (poly(ethyl acrylate-co-methyl
methacrylate-co-trimetylammonioethyl methacrylate chloride)
1:2:0.2).
[0406] In embodiment (177), for the pharmaceutical composition of
embodiment (176), the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 95:5 to 5:95.
[0407] In embodiment (178), for the pharmaceutical composition of
embodiment (176), the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 90:10 to 50:50.
[0408] In embodiment (179), for the pharmaceutical composition of
embodiment (176), the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 90:10 to 60:40.
[0409] In embodiment (180), for the pharmaceutical composition of
embodiment (176), the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is between 85:15 to 70:30.
[0410] In embodiment (181), for the pharmaceutical composition of
embodiment (176), wherein the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is 75:25.
[0411] In embodiment (182), for the pharmaceutical composition of
embodiment (176), wherein the weight ratio of Eudragit.RTM. RS to
Eudragit.RTM. RL is 80:20.
[0412] In embodiment (183), for the pharmaceutical composition of
any one of the embodiments (82), (84)-(127) and (129)-(182), the
second pharmaceutical bead composition further comprises a second
enteric coating surround the functional coating.
[0413] In embodiment (184), for the the pharmaceutical composition
of embodiment (183), the second enteric coating comprises an
excipient selected from the group consisting of a copolymer of
methacrylic acid and methyl methacrylate, a copolymer of
methacrylic acid and ethyl acrylate, hypromellose phthalate
(HPMCP), cellulose acetate phthalate.
[0414] In embodiment (185), for the pharmaceutical composition of
embodiment (183), the second enteric coating comprises a copolymer
of methacrylic acid and methyl methacrylate.
[0415] In embodiment (186), for the pharmaceutical composition of
embodiment (185), the ratio of the methacrylic acid to the methyl
methacrylate in the copolymer is 0.8:1 to 1.2:1.
[0416] In embodiment (187), for the pharmaceutical composition of
embodiment (186), wherein the ratio of the methacrylic acid to the
methyl methacrylate in the copolymer is 1:1 (Eudragit L100).
[0417] In embodiment (188), for the pharmaceutical composition of
any one of embodiments (183)-(187), the second enteric coating
comprises a plasticizer.
[0418] In embodiment (189), for the pharmaceutical composition of
embodiment (188), the plasticizer in the second enteric coating is
selected from the group consisting of acetyltributyl citrate,
acetyltriethyl citrate, benzyl benzoate, castor oil, chlorobutanol,
diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate,
glycerin, mannitol, polyethylene glycol, polyethylene glycol
monomethyl ether, propylene glycol, pullulan, sorbitol, sorbitol
sorbitan solution, triacetin, tributyl citrate, triethyl citrate
and vitamin E.
[0419] In embodiment (190), for the pharmaceutical composition of
embodiment (189), the plasticizer in the second enteric coating is
triethyl citrate.
[0420] In embodiment (191), for the pharmaceutical composition of
embodiment (190), the weight ratio of the triethyl citrate to the
copolymer of methacrylic acid and methyl methacrylate is from 1:1
to 1:20.
[0421] In embodiment (192), for the pharmaceutical composition of
embodiment (191), the weight ratio of the triethyl citrate to the
copolymer of methacrylic acid and methyl methacrylate is 1:5.
[0422] In embodiment (193), for the pharmaceutical composition of
any one of embodiments (183)-(192), the weight percentage of the
second enteric coating is 1-20% of the total weight of the inert
core and the first layer in the second pharmaceutical bead
composition.
[0423] In embodiment (194), for the pharmaceutical composition of
embodiment (193), the weight percentage of the second enteric
coating is 5-15% of the total weight of the inert core and the
first layer in the second pharmaceutical bead composition.
[0424] In embodiment (195), for the pharmaceutical composition of
embodiment (193), the weight percentage of the second enteric
coating is 10-15% of the total weight of the inert core and the
first layer in the second pharmaceutical bead composition.
[0425] In embodiment (196), for the pharmaceutical composition of
embodiment (193), the weight percentage of the second enteric
coating is 11-13% of the total weight of the inert core and the
first layer in the second pharmaceutical bead composition.
[0426] In embodiment (197), for the pharmaceutical composition of
embodiment (193), the weight percentage of the second enteric
coating is 12% of the total weight of the inert core and the first
layer in the second pharmaceutical bead composition.
[0427] In embodiment (198), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0428] an inert core;
[0429] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0430] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; and
[0431] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.5%-5.5% of the total weight of the inert core and the first
layer,
[0432] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0433] In embodiment (199), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0434] an inert core;
[0435] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0436] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; and
[0437] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
5.0%-6.0% of the total weight of the inert core and the first
layer,
[0438] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0439] In embodiment (200), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0440] an inert core;
[0441] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0442] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; and
[0443] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
11.5%-12.5% of the total weight of the inert core and the first
layer,
[0444] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0445] In embodiment (201), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0446] an inert core;
[0447] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0448] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; and
[0449] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.0%-5.0% of the total weight of the inert core and the first
layer, wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0450] In embodiment (202), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0451] an inert core;
[0452] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0453] an enteric coating surrounding the first layer, wherein the
weight percentage of the enteric coating is 11-13% of the total
weight of the inert core and the first layer; and
[0454] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.0%-5.0% of the total weight of the inert core and the first
layer,
[0455] wherein the weight percentage of the inert core is 16-20% of
the total weight of the inert core and the first layer.
[0456] In embodiment (203), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0457] an inert core;
[0458] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0459] a functional coating surrounding the first layer, wherein
the weight percentage of the functional coating is 4.5%-5.5% of the
total weight of the inert core and the first layer; and
[0460] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11-13% of
the total weight of the inert core and the first layer;
[0461] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0462] In embodiment (204), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0463] an inert core;
[0464] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0465] a functional coating surrounding the first layer, wherein
the weight percentage of the functional coating is 5.0%-6.0% of the
total weight of the inert core and the first layer; and
[0466] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11-13% of
the total weight of the inert core and the first layer; and
[0467] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0468] In embodiment (205), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0469] an inert core;
[0470] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 68%-72% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0471] a functional coating surrounding the first layer, wherein
the weight percentage of the functional coating is 11.5%-12.5% of
the total weight of the inert core and the first layer; and
[0472] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11-13% of
the total weight of the inert core and the first layer;
[0473] wherein the weight percentage of the inert core is 20-24% of
the total weight of the inert core and the first layer.
[0474] In embodiment (206), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0475] an inert core;
[0476] a first layer surrounding the inert core, wherein the first
layer comprises dimethyl fumarate and a binder and wherein the
weight percentage of dimethyl fumarate is 72%-76% of the total
weight of the inert core and the first layer and the weight
percentage of the binder is 5-10% of the total weight of the inert
core and the first layer;
[0477] a functional coating surrounding the first layer, wherein
the weight percentage of the functional coating is 4.0%-5.0% of the
total weight of the inert core and the first layer; and
[0478] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11-13% of
the total weight of the inert core and the first layer;
[0479] wherein the weight percentage of the inert core is 16-20% of
the total weight of the inert core and the first layer.
[0480] In embodiment (207), for the pharmaceutical composition of
any one of embodiments (198)-(206), wherein the inert core in the
second pharmaceutical bead composition comprises sucrose or starch;
the binder in the second pharmaceutical bead composition is HPMC;
the enteric coating in the second pharmaceutical bead composition
comprises a copolymer of methacrylic acid and methyl methacrylate
and the ratio of methacrylic acid to methyl methacrylate in the
copolymer is 1:1; and the functional coating in the second
pharmaceutical bead composition comprises of a mixture of
ethylcellulose (EC) and hydroxypropyl cellulose (HPC) and the
weight ratio of ethylcellulose (EC) to hydroxypropyl cellulose
(HPC) is 65:35.
[0481] In embodiment (208), for the pharmaceutical composition of
embodiment (207), the enteric coating in the second pharmaceutical
bead composition further comprises triethyl citrate and the weight
ratio of the copolymer of methacrylic acid and methyl methacrylate
to triethyl citrate is 5:1; and the functional coating in the
second pharmaceutical bead composition comprises a mixture of
ETHOCEL.TM. 10 (ethylcellulose polymer with viscosity in the range
of 9-11 cP for 5% weight solution in 80% toluene and 20% ethanol)
and JF Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity
in the range of 150-400 cP for 5% by weight solution in water),
wherein the weight ratio of ETHOCEL.TM. 10 to JF Klucel.RTM. is
65:35.
[0482] In embodiment (209), for the pharmaceutical composition of
any one of embodiments (198)-(206), wherein the inert core in the
second pharmaceutical bead composition comprises sucrose or starch;
the binder in the second pharmaceutical bead composition is HPMC;
the enteric coating in the second pharmaceutical bead composition
comprises a copolymer of methacrylic acid and methyl methacrylate
and the ratio of methacrylic acid to methyl methacrylate in the
copolymer is 1:1; and the functional coating in the second
pharmaceutical bead composition comprises of a mixture of
ethylcellulose (EC) and hydroxypropyl cellulose (HPC) and the
weight ratio of ethylcellulose (EC) to hydroxypropyl cellulose
(HPC) is 60:40.
[0483] In embodiment (210), for the pharmaceutical composition of
embodiment (209), the enteric coating in the second pharmaceutical
bead composition further comprises triethyl citrate and the weight
ratio of the copolymer of methacrylic acid and methyl methacrylate
to triethyl citrate is 5:1; and the functional coating in the
second pharmaceutical bead composition comprises a mixture of
ETHOCEL.TM. 10 (ethylcellulose polymer with viscosity in the range
of 9-11 cP for 5% weight solution in 80% toluene and 20% ethanol)
and JF Klucel.RTM. (hydroxypropyl cellulose polymer with viscosity
in the range of 150-400 cP for 5% by weight solution in water),
wherein the weight ratio of ETHOCEL.TM. 10 to JF Klucel.RTM. is
60:40.
[0484] In embodiment (211), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0485] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0486] an enteric coating surrounding the core, wherein the weight
percentage of the enteric coating is 11%-13% of the total weight of
the core; and
[0487] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.5%-5.5% of the total weight of the core,
[0488] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0489] In embodiment (212), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0490] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0491] an enteric coating surrounding the core, wherein the weight
percentage of the enteric coating is 11%-13% of the total weight of
the core; and
[0492] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
5.0%-6.0% of the total weight of the core,
[0493] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0494] In embodiment (213), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0495] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0496] an enteric coating surrounding the core, wherein the weight
percentage of the enteric coating is 11%-13% of the total weight of
the core; and
[0497] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
11.5%-12.5% of the total weight of the core,
[0498] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0499] In embodiment (214), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0500] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0501] an enteric coating surrounding the core, wherein the weight
percentage of the enteric coating is 11%-13% of the total weight of
the core; and
[0502] a functional coating surrounding the enteric coating,
wherein the weight percentage of the functional coating is
4.0%-5.0% of the total weight of the core,
[0503] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0504] In embodiment (215), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0505] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0506] a functional coating surrounding the core, wherein the
weight percentage of the functional coating is 4.5%-5.5% of the
total weight of the core,
[0507] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11%-13% of
the total weight of the core; and
[0508] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0509] In embodiment (216), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0510] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0511] a functional coating surrounding the core, wherein the
weight percentage of the functional coating is 5.0%-6.0% of the
total weight of the core,
[0512] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11%-13% of
the total weight of the core; and
[0513] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0514] In embodiment (217), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0515] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0516] a functional coating surrounding the core, wherein the
weight percentage of the functional coating is 11.5%-12.5% of the
total weight of the core,
[0517] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11%-13% of
the total weight of the core; and
[0518] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0519] In embodiment (218), for the pharmaceutical composition of
any one of embodiments (1)-(81), wherein the second pharmaceutical
bead composition comprises:
[0520] a core comprising an active substance, wherein the active
substance is dimethyl fumarate;
[0521] a functional coating surrounding the core, wherein the
weight percentage of the functional coating is 4.0%-5.0% of the
total weight of the core,
[0522] an enteric coating surrounding the functional coating,
wherein the weight percentage of the enteric coating is 11%-13% of
the total weight of the core; and
[0523] wherein the weight percentage of dimethyl fumarate is
60%-80% of the total weight the core.
[0524] In embodiment (219), for the pharmaceutical composition of
any one of embodiments (211)-(218), the enteric coating in the
second pharmaceutical bead composition comprises a copolymer of
methacrylic acid and methyl methacrylate and the ratio of
methacrylic acid to methyl methacrylate in the copolymer is 1:1;
and the functional coating comprises of a mixture of ethylcellulose
(EC) and hydroxypropyl cellulose (HPC) and the weight ratio of
ethylcellulose (EC) to hydroxypropyl cellulose (HPC) is 65:35.
[0525] In embodiment (220), for the pharmaceutical composition of
embodiment (219), the enteric coating in the second pharmaceutical
bead composition further comprises triethyl citrate and the weight
ratio of the copolymer of methacrylic acid and methyl methacrylate
to triethyl citrate is 5:1; and the functional coating comprises a
mixture of ETHOCEL.TM. 10 (ethylcellulose polymer with viscosity in
the range of 9-11 cP for 5% weight solution in 80% toluene and 20%
ethanol) and JF Klucel.RTM. (hydroxypropyl cellulose polymer with
viscosity in the range of 150-400 cP for 5% by weight solution in
water), wherein the weight ratio of ETHOCEL.TM. 10 to JF
Klucel.RTM. is 65:35.
[0526] In embodiment (221), for the pharmaceutical composition of
any one of embodiments (211)-(218), the enteric coating in the
second pharmaceutical bead composition comprises a copolymer of
methacrylic acid and methyl methacrylate and the ratio of
methacrylic acid to methyl methacrylate in the copolymer is 1:1;
and the functional coating comprises of a mixture of ethylcellulose
(EC) and hydroxypropyl cellulose (HPC) and the weight ratio of
ethylcellulose (EC) to hydroxypropyl cellulose (HPC) is 60:40.
[0527] In embodiment (222), for the pharmaceutical composition of
embodiment (221), the enteric coating in the second pharmaceutical
bead composition further comprises triethyl citrate and the weight
ratio of the copolymer of methacrylic acid and methyl methacrylate
to triethyl citrate is 5:1; and the functional coating comprises a
mixture of ETHOCEL.TM. 10 (ethylcellulose polymer with viscosity in
the range of 9-11 cP for 5% weight solution in 80% toluene and 20%
ethanol) and JF Klucel.RTM. (hydroxypropyl cellulose polymer with
viscosity in the range of 150-400 cP for 5% by weight solution in
water), wherein the weight ratio of ETHOCEL.TM. 10 to JF
Klucel.RTM. is 60:40.
[0528] In embodiment (223), for the pharmaceutical composition of
any one of embodiments (32)-(55) and (60)-(81), the diameter of the
core in the first pharmaceutical bead composition is in the range
of 0.5 mm to 2.0 mm.
[0529] In embodiment (224), for the pharmaceutical composition of
embodiment (223), the diameter of the core in the first
pharmaceutical bead composition is in the range of 0.6 mm to 2.0
mm.
[0530] In embodiment (225), for the pharmaceutical composition of
embodiment (223), the diameter of the core in the first
pharmaceutical bead composition is in the range of 0.5 mm to 1.5
mm.
[0531] In embodiment (226), for the pharmaceutical composition of
any one of embodiments (127)-(197) and (211)-(225), the diameter of
the core in the second pharmaceutical bead composition is in the
range of 0.5 mm to 2.0 mm.
[0532] In embodiment (227), for the pharmaceutical composition of
embodiment (226), the diameter of the core in the second
pharmaceutical bead composition is in the range of 0.6 mm to 2.0
mm.
[0533] In embodiment (228), for the pharmaceutical composition of
embodiment (226), the diameter of the core in the second
pharmaceutical bead composition is in the range of 0.5 mm to 1.5
mm.
[0534] The controlled-release pharmaceutical bead compositions
(i.e., the second pharmaceutical bead composition) of the present
invention provide extended release of the active substance dimethyl
fumarate when subjected to a dissolution test. The dissolution test
can be carried out according to standard procedures published by
USP-NF.
[0535] In one embodiment, the dissolution profile of the
pharmaceutical composition of the present invention is determined
by subjecting the pharmaceutical composition 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 USP Simulated
Intestinal Fluid (SIF) without pancreatin as dissolution medium in
a USP Apparatus II (paddle apparatus) (Test 1). Alternatively, the
dissolution profile is determined by subjecting the pharmaceutical
composition of the present invention to an in vitro dissolution
test employing USP Simulated Gastric Fluid (SGF) without pepsin as
dissolution medium during the first 2 hours of the test and then
USP Simularted Intestinal Fluid (SIF) without pancreatin as
dissolution medium in a USP Apparatus IV (flow-through cell) (Test
2). In yet another alternative, the dissolution profile is
determined by subjecting the pharmaceutical composition of the
present invention to an in vitro dissolution test employing USP
Simularted Intestinal Fluid (SIF) without pancreatin in a USP
Apparatus IV (flow-through cell) (Test 3). USP SIF ans SGF
solutions can be prepared according to according to procedures
described in USP35-NF30.
[0536] In certain embodiments, when subjected to dissolution Test
1, the pharmaceutical bead composition of the present invention has
the following dissolution profile:
[0537] within the first 2 hours of the test, less than 10% by
weight of the active substance in the tablet is released;
[0538] within the first 4 hours of the test, 10-70% by weight of
the active substance in the tablet is released; and
[0539] within the first 7 hours of the test, 50-100% by weight of
the active substance in the tablet is released.
[0540] In certain embodiments, when subjected to dissolution Test
1, the tablet composition of the present invention has the
following dissolution profile:
[0541] within the first 2 hours of the test, less than 10% by
weight of the active substance in the tablet is released; and
[0542] within the first 4 hours of the test, 90-100% by weight of
the active substance in the tablet is released.
[0543] In certain embodiments, when subjected to dissolution Test
2, the bead composition of the present invention has the following
dissolution profile:
[0544] within the first 2 hours of the test, less than 10% by
weight of the active substance in the tablet is released;
[0545] within the first 4 hours of the test, 10-70% by weight of
the active substance in the tablet is released; and
[0546] within the first 9 hours of the test, 50-100% by weight of
the active substance in the table is released.
[0547] In certain embodiments, when subjected to dissolution Test
2, the bead composition of the present invention has the following
dissolution profile:
[0548] within the first 2 hours of the test, less than 10% by
weight of the active substance in the tablet is released;
[0549] within the first 4 hours of the test, 70-90% by weight of
the active substance in the tablet is released; and
[0550] within the first 9 hours of the test, 90-100% by weight of
the active substance in the table is released.
[0551] In certain embodiments, The controlled-release
pharmaceutical bead compositions (i.e., the second pharmaceutical
bead composition) of the present invention releases 80% of dimethyl
fumarate from the composition within 3-10 hours, preferably within
4-8 hours, more preferably within 4-6 hours in an in vivo
pharmacokinetic study described herein. In particular, dogs were
administered with the pharmaceutical composition of the present
invention containing 240 mg of DMF.
[0552] In certain embodiments, the pharmaceutical composition of
the present invention is in the form of a capsule, wherein the
first pharmaceutical bead composition and the second pharmaceutical
composition are encapsulated in the capsule. Any type of capsules
known in the art can be used in the present invention. In one
embodiment, the capsule is a hard capsule. In another embodiment,
the capsule is a soft capsule. In yet another embodiment, the
capsule is a gelatin capsule. In another embodiment, the capsule is
a hard gelatin capsule. More specifically, the capsule is a size 0
hard gelatin capsule.
[0553] The present invention also provides a method of treating a
subject having multiple sclerosis (e.g., relapsing-remitting MS,
secondary progressive MS, primary progressive MS, progressive
relapsing MS) comprising administering to the subject an effective
amount of a pharmaceutical composition described herein. In one
embodiment, the method of the present invention is for treating
relapsing-remitting MS.
[0554] As used herein, the term "treating" or "treatment" refers to
obtaining desired pharmacological and/or physiological effect. The
effect can be therapeutic, which includes achieving, partially or
substantially, one or more of the following results: partially or
totally reducing the extent of the disease, disorder or syndrome;
ameliorating or improving a clinical symptom or indicator
associated with the disorder; or delaying, inhibiting or decreasing
the likelihood of the progression of the disease, disorder or
syndrome.
[0555] As used herein, the term "subject" and the term "patient"
can be used interchangeable and they refer to a mammal in need of
treatment, e.g., companion animals (e.g., dogs, cats, and the
like), farm animals (e.g., cows, pigs, horses, sheep, goats and the
like) and laboratory animals (e.g., rats, mice, guinea pigs and the
like). Typically, the subject is a human in need of treatment.
[0556] The effective amount or therapeutic dosage of the
pharmaceutical compositions described herein that is administered
to treat a patient depends on a number of factors, which include,
but are not limited to, weight and age of the patient, route of
administration, the underlying causes of the disease to be treated,
and the severity of the disease to be treated. In one embodiment,
the effective dosage can range from 1 mg/kg to 50 mg/kg (e.g., from
2.5 mg/kg to 20 mg/kg or from 2.5 mg/kg to 15 mg/kg). In one
embodiment, an effective amount of DMF to be administered to a
subject, for example orally, can be from 0.1 g to 1 g per day, for
example, from 200 mg to 800 mg per day (e.g., from 240 mg to 720 mg
per day; or from 480 mg to 720 mg per day; or 480 mg per day; or
720 mg per day).
[0557] The daily dose can range, but is not limited to, a total
amount of 60 mg to 800 mg, 60 mg to 720 mg, 60 mg to 500 mg, 60 mg
to 480 mg, 60 mg to 420 mg, 60 mg to 360 mg, 60 mg to 240 mg, 60 mg
to 220 mg, 60 mg to 200 mg, 60 mg to 180 mg, 60 mg to 160 mg, 60 mg
to 140 mg, 60 mg to 120 mg, 60 mg to 100 mg, 60 mg to 80 mg, 80 mg
to 480 mg, 100 mg to 480 mg, 120 mg to 480 mg, 140 mg to 480 mg,
160 mg to 480 mg, 180 mg to 480 mg, 200 mg to 480 mg, 220 mg to 480
mg, 240 mg to 480 mg, 300 mg to 480 mg, 360 mg to 480 mg, 400 mg to
480 mg, 450 mg to 500 mg, 480 mg to 500 mg, 80 to 400 mg, 100 to
300 mg, 120 to 180 mg, or 140 mg to 160 mg.
[0558] In one embodiment, the daily dosage is 240 mg.
Alternatively, the daily dosage is 480 mg.
[0559] The daily dose(s) of DMF may be administered in a single
administration or in separate administrations of 2, 3, 4, or 6
equal doses. In one embodiment, the effective daily dose is 480 mg
per day and is administered in one dose to a subject in need
thereof. In another embodiment, the effective daily dose is 240 mg
per day and is administered in one dose to a subject in need
thereof.
[0560] In one embodiment, the pharmaceutical composition of the
present invention is administered at least one hour before or after
food is consumed by the subject in need thereof. In case the
subject experiences side effects (e.g., flushing or GI discomfort),
the subject can consume food shortly (e.g., 30 mins to an hour)
before administered the pharmaceutical composition.
[0561] In one embodiment, the subject administered the
pharmaceutical compositions of the present invention may take one
or more non-steroidal anti-inflammatory drugs (e.g., aspirin)
before (for example, 10 minutes to an hour, e.g., 30 minutes
before) taking the pharmaceutical composition. In one embodiment,
the subject administered the pharmaceutical composition takes the
one or more non-steroidal anti-inflammatory drugs (e.g., aspirin)
to control side effects (e.g., flushing). In another embodiment,
the one or more non-steroidal anti-inflammatory drugs is selected
from a group consisting of aspirin, ibuprofen, naproxen,
ketoprofen, celecoxib, MK-0524, and combinations thereof. The one
or more non-steroidal anti-inflammatory drugs can be administered
in an amount of 50 mg to 500 mg before taking the dosage form
described above. In one embodiment, a subject takes 325 mg aspirin
before taking each dosage form described above.
[0562] In one embodiment, the subject in need of the treatment is
administered a first dose of the pharmaceutical compositions
described herein for a first dosing period; and administered a
second dose of the pharmaceutical compositions described herein for
a second dosing period. In one embodiment, the first dose is lower
than the second dose (e.g., the first dose is half of the second
dose). In one embodiment, the first dosing period is at least one
week (e.g., 1-4 weeks). In one embodiment, the first dose of the
pharmaceutical compositions comprises 240 mg of DMF and the
pharmaceutical composition is administered to the subject once
daily for the first dosing period. In one embodiment, the second
dose of the pharmaceutical composition comprises 480 mg of DMF and
the pharmaceutical composition is administered to the subject once
daily for the second dosing period. In one embodiment, if the
subject, after being administered the dose at the second dosing
period, experiences more than expected level of side effects (e.g.,
flushing or a gastrointestinal disturbance), the subject can use a
lower dose (e.g., the dose at the first dosing period) for a period
(e.g., 1-4 weeks or more) sufficient to allow the side effects to
decrease before returning to the dose at the second dosing
period.
[0563] In one embodiment, the first dose of the pharmaceutical
composition comprises 240 mg of DMF and the pharmaceutical
composition is administered to the subject once daily for at least
one week, and the second dose of the pharmaceutical composition
comprises 480 mg of DMF and the pharmaceutical composition is
administered to the subject once daily for at least two weeks.
[0564] In one embodiment, the subject is administered a first dose
for one week and a second dose for a second dosing period of at
least 48 weeks. In another embodiment, the subject is administered
a first dose for one week and a second dose for a second dosing
period of at least two years. In another embodiment, the subject is
administered a first dose for one week and a second dose until the
subject does not require treatment.
[0565] In certain embodiments, the methods of treating a subject
having multiple sclerosis described herein further comprises
administering to the subject a second therapeutic agent.
[0566] In one embodiment, the second therapeutic agents is a
disease modifying agent. In one embodiment, the second therapeutic
agents alleviate the side effects of dimethyl fumarate. For
example, the second therapeutic agent can be a therapeutic agent
that can reduce the flushing (e.g., aspirin) or GI disturbance
(e.g., loperamide).
[0567] In another embodiment, the second therapeutic agent is a
Nrf-2 modulator.
[0568] In yet another embodiment, the second therapeutic agents can
be, e.g., interferon beta-1a (Avonex.RTM., Rebif.RTM.), glatiramer
(Copaxone.RTM.), modafinil, azathioprine, predisolone,
mycophenolate, mofetil, mitoxantrone, natalizumab (Tysabri.RTM.),
sphinogosie-1 phosphate modulator e.g., fingolimod (Gilenya.RTM.),
and other drugs useful for MS treatment such as teriflunornide
(Aubagio.RTM.), piroxicam, and phenidone.
[0569] The pharmaceutical DMF compositions of the present invention
and the second therapeutic agent may be administered concurrently
(as separate compositions or together in a single dosage form) or
consecutively over overlapping or non-overlapping intervals. In the
sequential administration, the DMF composition and the second
therapeutic agent can be administered in any order. In some
embodiments, the length of an overlapping interval is more than 2,
4, 6, 12, 24, 48 weeks or longer.
[0570] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
EXAMPLES
Example 1. Methods for Preparing Pharmaceutical Bead Compositions
of the Present Invention
[0571] The following coating processes were conducted using a fluid
bed granulator with a Wurster insert. API dimethyl fumarate was
first layered onto the surface of sugar spheres by spraying a DMF
containing solution (Table 1) onto the sugar spheres in a fluid
bed.
TABLE-US-00001 TABLE 1 DMF solution formulation Ingredients Weight
% DMF 21% HPMC (HPMC E5) 2% Ethanol (96% v/v) 62% DI Water 15%
TOTAL 100%
The API layered spheres were then enteric coated for acid
protection.
TABLE-US-00002 TABLE 2 Enteric coat formulation Ingredients Weight
% Eudragit L100 6.5% (Methacylic acid- methyl methacrylate
copolymer) IPA 90.7% Water 1.5% Triethyl citrate 1.3% TOTAL
100%
A sustained release functional coating (Tables 3, 4, 5 and 6) was
then applied to the enteric coated spheres.
TABLE-US-00003 TABLE 3 Coating solution formulation for EC/HPC
65/35 Ingredients Weight % EC (Ethocel 10) 3.9 HPC (Klucel JF) 2.1
Water 11.3 IPA 82.7 TOTAL 100%
TABLE-US-00004 TABLE 4 Coating solution formulation for EC/HPC
70/30 Ingredients Weight % EC (Ethocel 10) 4.2 HPC (Klucel JF) 1.8
Water 11.3 IPA 82.7 TOTAL 100%
TABLE-US-00005 TABLE 5 Coating solution formulation for RS/RL 75/25
Ingredients Weight % Eudragit RS 4.5 Eudragit RL 1.5 Water 11.3 IPA
82.7 TOTAL 100%
TABLE-US-00006 TABLE 6 Coating solution formulation for RS/RL 80/20
Ingredients Weight % Eudragit RS 4.8 Eudragit RL 1.2 Water 11.3 IPA
82.7 TOTAL 100%
[0572] Specifically, Formulation D is prepared according to the
general procedure described above using DMF solution described in
Table 1 and enteric coating solution described in Table 2.
Formulation D has no functional coating. Formulations E and F are
prepared according to the procedures for Formulation D and is
further coated with functional coating solution described in Table
3. The weight percentages of the functional coating in Formulation
E is 2.5% of the total weight of the sugar sphere and DMF layer.
The weight percentages of the functional coating in Formulation F
is 5.0% of the total weight of the sugar sphere and DMF layer.
Formulations D, E and F are beads having a diameter of 1-1.2
mm.
[0573] Formulation A is prepared according to the general procedure
described above using DMF solution described in Table 1, enteric
coating solution described in Table 2 and functional coating
solution described in Table 3a below.
TABLE-US-00007 TABLE 3a Coating solution formulation for EC/HPC
60/40 Ingredients Weight % EC (Ethocel 10) 3.6 HPC (Klucel JF) 2.4
Water 11.3 IPA 82.7 TOTAL 100%
[0574] The weight percentage of each ingredients in Formulation A
is as follows:
[0575] Sugar core--19% of the total weight of the sugar sphere and
the DMF layer;
[0576] DMF--74% of the total weight of the sugar sphere and the DMF
layer;
[0577] Binder--7% of the total weight of the sugar sphere and the
DMF layer;
[0578] Enteric coating--12% of the total weight of the sugar sphere
and the DMF layer; and
[0579] Functional coating--4.5% of the total weight of the sugar
sphere and DMF layer.
[0580] Formulation B is prepared according to the general procedure
described above using DMF solution described in Table 1 and enteric
coating solution described in Table 2. Formulation B has no
functional coating. The weight percentage of each ingredients in
Formulation B is as follows:
[0581] Sugar core--19% of the total weight of the sugar sphere and
the DMF layer;
[0582] DMF--74% of the total weight of the sugar sphere and the DMF
layer;
[0583] Binder--7% of the total weight of the sugar sphere and the
DMF layer; and
[0584] Enteric coating--12% of the total weight of the sugar sphere
and the DMF layer.
Example 2. Preparation of Pharmaceutical Composition of the Present
Invention (Mixed Beads Formulation)
[0585] A mixed beads formulation was prepared by combining and
encapsulating the first pharmaceutical bead composition
(Formulation B described above) and the second pharmaceutical bead
composition (Formulation A described above) in size 0 hard gelatin
capsules with a white opaque body and a white opaque cap using an
encapsulator with two inputs, with each input for each type of
beads. The weight ratio of the first pharmaceutical bead
composition (Formulation B) and the second pharmaceutical bead
composition (Formulation A) is 3:1.
Example 3. Dissolution Profiles for Mixed Beads Formulations
[0586] The dissolution profiles for various bead formulations with
different weight ratios between the first pharmaceutical bead
composition and the second pharmaceutical bead composition were
determined according to methods described below, which are standard
procedures published by USP-NF using USP apparatus II and IV.
[0587] Test 1. The pharmaceutical compositions of the present
invention were 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 USP Simulated Intestinal Fluid (SIF)
without pancreatin as dissolution medium in a USP Apparatus II
(paddle apparatus).
[0588] Test 2. The pharmaceutical compositions of the present
invention were subjected to an in vitro dissolution test employing
USP Simulated Gastric Fluid (SGF) without pepsin as dissolution
medium during the first 2 hours of the test and then USP Simulated
Intestinal Fluid (SIF) without pancreatin as dissolution medium in
a USP Apparatus IV (flow-through cell).
[0589] Test 3. The pharmaceutical compositions of the present
invention were subjected to an in vitro dissolution test employing
USP Simularted Intestinal Fluid (SIF) without pancreatin as
dissolution medium in a USP Apparatus IV (flow-through cell).
[0590] USP SIF solution can be prepared according to according to
procedures described in USP35-NF30. For 1 L scale, the SIF solution
can be prepared by dissolving 6.8 g of monobasic potassium
phosphate in 250 mL of water followed by mixing. 77 mL of 0.2 N
sodium hydroxide and 500 mL of water are added sequentially. The pH
of the resulting solution is adjusted with either 0.2 N sodium
hydroxide or 0.2 N hydrochloric acid to a pH of 6.8.+-.0.1 followed
by dilution with water to 1000 mL. USP SGF solution can be prepared
according to procedures described in USP35-NF30. For 1 L scale, the
SGF solution can be prepared by dissolving 2.0 g of sodium chloride
(NaCl) in 7.0 mL of hydrochloric acid (HCl) and sufficient water to
make 1000 mL.
[0591] Formulation 1 contains a mixture of bead Formulation B and
bead Formulation A, wherein the weight ratio of Formulation B and
Formulation A is 3:1. Formulation 2 contains a mixture of bead
Formulation B and bead Formulation A, wherein the weight ratio of
Formulation B and Formulation A is 1:3. Formulation 3 contains only
bead Formulation A. The dissolution profiles for Formulations 1, 2
and 3 are shown in FIG. 1 (using Test 1) and FIG. 2 (using Test
2).
Example 4. Methods of Preparing Bead Formulations by Extrusion
Spheronization
[0592] Alternatively, the beads formulation can be prepared using
extrusion spheronization. DMF is first mixed with excipients and
solvent into a wet mass. The wet mass is then forced through an
extruder to form cylindrical pellets. The diameter of the pellets
ranges from 0.6 mm to 2 mm depending on the equipment setting. The
extruded pellets will then be spheronized in a spheronizer with a
rotating disk. The diameter of the spheres can range from 0.6 to 2
mm depending on the initial cylindrical pellet size. Tables 7 and 8
below list exemplary formulations.
TABLE-US-00008 TABLE 7 Exemplary Formulations for Extrusion
Spheronization DMF 65% 65% Microcrystalline cellulose 11% / (Avicel
PH101) Microcrystalline cellulose / 15% (Avicel PH102) Lactose
Monohydrate Fast Flo / 10% Starch 1500 4% / Ac-Di-Sol 10% 10% PEO
10% / PEO 4000 / /
TABLE-US-00009 TABLE 8 Exemplary Formulations for Extrusion
Spheronization DMF 75% 75% Microcrystalline Cellulose 14% 14%
(Avicel PH101) Starch 1500 4% 4% Ac-Di-Sol 5% Explotab 5% TEC 2%
2%
The DMF spheres are then coated with the enteric coating and the
functional coating described above.
Example 5. Methods of Preparing Bead Formulations by Fluid Bed
Spheronization
[0593] The bead formulations of the present invention can also be
prepared utilizing the Glatt's CPS unit to spheronize dimethyl
fumarate and excipients (MCC and disintegrant) with solvents
(water, ethanol or API) into spheres with size ranging from 500 um
to 1.5 mm.
* * * * *