U.S. patent application number 17/327395 was filed with the patent office on 2022-01-13 for compositions and methods for treating multiple sclerosis.
The applicant listed for this patent is Vitalis LLC. Invention is credited to Joseph Habboushe.
Application Number | 20220008441 17/327395 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-13 |
United States Patent
Application |
20220008441 |
Kind Code |
A1 |
Habboushe; Joseph |
January 13, 2022 |
COMPOSITIONS AND METHODS FOR TREATING MULTIPLE SCLEROSIS
Abstract
Provided are compositions and methods for treating multiple
sclerosis (MS). One embodiment of the disclosed method entails
orally administering to a MS patient a first amount of aspirin and
a second amount of fumaric acid or an ester or a salt thereof. In
some embodiments, the aspirin is administered at from about 80 mg
to about 500 mg per day and the fumaric acid or ester or salt
thereof is administered at about 360 mg per day.
Inventors: |
Habboushe; Joseph; (New
York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vitalis LLC |
New York |
NY |
US |
|
|
Appl. No.: |
17/327395 |
Filed: |
May 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16523916 |
Jul 26, 2019 |
11013751 |
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17327395 |
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15922729 |
Mar 15, 2018 |
10398712 |
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16523916 |
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62594493 |
Dec 4, 2017 |
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62473080 |
Mar 17, 2017 |
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International
Class: |
A61K 31/616 20060101
A61K031/616; A61K 31/225 20060101 A61K031/225; A61P 25/00 20060101
A61P025/00; A61K 9/50 20060101 A61K009/50; A61K 31/194 20060101
A61K031/194 |
Claims
1-11. (canceled)
12. A capsule comprising a dosage form comprising an effective
amount of aspirin and an effective amount a fumaric acid or an
ester or a salt thereof, wherein the aspirin and fumaric acid or an
ester or a salt thereof are each individually formulated as
enterically coated microspheres contained within a capsule
shell.
13. The capsule of claim 12, wherein the capsule is coated with a
second dose of aspirin formulated to dissolve in an oral cavity of
a subject.
14. The capsule of claim 13, comprising from about 20 mg to about
500 mg of aspirin.
15. A method of treating multiple sclerosis (MS) in a human patient
in need thereof, comprising orally administering to the patient a
dosage form comprising aspirin and fumaric acid or an ester or a
salt thereof, wherein the aspirin is administered at from about 150
mg to about 650 mg per day and the fumaric acid or ester or salt
thereof is administered at about 300 mg to about 450 mg per
day.
16. The method of claim 15, wherein at least a portion of the
aspirin is formulated to dissolve in an oral cavity of a
subject.
17. The method of claim 15 or 16, wherein the fumaric acid or ester
or salt thereof is formulated for dissolving in stomach,
intestines, or further distal in the gastrointestinal tract of the
subject.
18. The method of claim 15, wherein the pharmaceutical composition
is in the form of a capsule.
19. A method of treating multiple sclerosis (MS) , psoriasis, a
motor neuron disease, a neurodegenerative disease, an autoimmune
disease, an inflammatory disease, sepsis, or a skin disease in a
human patient in need thereof, comprising orally administering to
the patient one or more tablets each comprising a first portion
comprising a first amount of aspirin and a second portion
comprising a second amount of fumaric acid or an ester or a salt
thereof, wherein the first portion is formulated to dissolve in an
oral cavity of a subject, wherein the second portion is formulated
for dissolving in stomach, intestines, or further distal in the
gastrointestinal tract of the subject, and wherein the aspirin is
administered at from about 150 mg to about 650 mg per day and the
fumaric acid or ester or salt thereof is administered at about 300
mg to about 450 mg per day.
20. The method of claim 19, wherein the patient suffers from
relapse-remitting MS (RRMS).
21. The method of claim 19, wherein the patient has a history of
non-compliance with a medication due to cutaneous flush or a
gastrointestinal side effect.
22. The method of claim 19, wherein the second amount of the
fumaric acid or ester or salt thereof is about 180 mg.
23. The method of claim 22, wherein the first amount of aspirin is
from about 80 mg to about 250 mg.
24. The method of claim 22, wherein the second portion further
comprises a third amount of aspirin.
25. The method of claim 24, wherein the first amount of aspirin and
the second amount of aspirin each is from about 20 mg to about 120
mg or from about 80 mg to about 120 mg.
26. The method of claim 22, wherein the second portion is enclosed
in an enteric coating.
27. The method of claim 19, wherein the ester is dimethyl fumarate,
monomethyl fumarate or combination thereof.
28-48. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/523,916 filed Jul. 26, 2019, which is a continuation of U.S.
application Ser. No. 15/922,729 filed Mar. 15, 2018, which claims
the benefit under 35 U.S.C. .sctn. 119(e) of U.S. Provisional
Application Ser. No. 62/473,080 filed Mar. 17, 2017, and
Provisional Application Ser. No. 62/594,493, filed Dec. 4, 2017,
the contents of which are incorporated by reference in its entirety
into the present disclosure.
BACKGROUND
[0002] Multiple sclerosis (MS) is the most common autoimmune
disorder affecting the central nervous system. In 2013, about 2.3
million people were affected globally with rates varying widely in
different regions and among different populations. About 20,000
people died from MS in 2013, up from 12,000 in 1990. The disease
usually begins between the ages of 20 and 50 and is twice as common
in women as in men.
[0003] Multiple sclerosis was first described in 1868 by
Jean-Martin Charcot. The name multiple sclerosis refers to the
numerous scars that develop on the white matter of the brain and
spinal cord. MS is a demyelinating disease in which the insulating
covers of nerve cells in the brain and spinal cord are damaged.
This damage disrupts the ability of parts of the nervous system to
communicate, resulting in a range of signs and symptoms, including
physical, mental, and sometimes psychiatric problems. Specific
symptoms can include double vision, blindness in one eye, muscle
weakness, trouble with sensation, or trouble with coordination. MS
takes several forms, with new symptoms either occurring in isolated
attacks (relapsing forms) or building up over time (progressive
forms). Between attacks, symptoms may disappear completely;
however, permanent neurological problems often remain, especially
as the disease advances.
[0004] While the cause is not clear, the underlying mechanism is
thought to be either destruction by the immune system or failure of
the myelin-producing cells. Proposed causes for this include
genetics and environmental factors such as being triggered by a
viral infection. MS is usually diagnosed based on the presenting
signs and symptoms and the results of supporting medical tests.
[0005] There is no known cure for multiple sclerosis. Treatments
attempt to improve function after an attack and prevent new
attacks. Medications used to treat MS, while modestly effective,
can have side effects and be poorly tolerated. Physical therapy can
help with a patient's ability to function.
[0006] It has been shown that dimethyl fumarate (DMF) and its
metabolite, monomethyl fumarate (MMF), are effective treatments for
relapse-remitting multiple sclerosis (RMMS). Both DMF and MMF
activate the nuclear-factor-E2-related factor-2 (Nrf2)
transcriptional pathway, which induces anti-inflammatory and
neuroprotective modalities in RMMS patients. About 30% to 40% of
treated individuals, however, suffer from cutaneous flush which is
associated with both DMF and MMF. Such adverse effects, therefore,
limit the use of DMF and MMF in treating MS.
SUMMARY
[0007] The present disclosure provides treatment regimens for
diseases that can be suitably treated with fumaric acid of its
ester or salt, such as dimethyl fumarate (DMF), monomethyl fumarate
(MMF), or the combination thereof. Examples of such diseases
include multiple sclerosis (MS), psoriasis, necrobiosis lipoidica,
granuloma annulare, sarcoidosis, granulomatous and inflammatory
skin disorders, lichen planus pityriasis rubra pilaris, chronic
discoid lupus erythematosus, necrobiosis lipoidica, cheilitis
granulomatosa, annular elastotic giant cell granuloma, malign
melanoma, lupus erythematosus, aplopecia areata, hidradenitis
suppurativa, other granulomatous and inflammatory skin disorders,
other inflammatory disorders such as colitis, DNA damage in tumor,
gastrointestinal ulceration, collagen type II degradation, and
other immune modulated diseases. In some embodiments, the treatment
methods enable the effective use of a daily dose of fumaric acid or
an ester or salt thereof that is lower than their recommended use
(e.g., 480 mg per day), without compromise of the treatment
outcome.
[0008] It is discovered surprisingly that the methods and
pharmaceutical compositions described herein may increase the
bioavailability of the fumaric acid or an ester or salt thereof
(e.g., dimethyl fumarate) such that a significantly lower dose can
be administered (e.g., 420, 400 or 360 mg per day), without
compromise of the treatment outcome. In addition, in some
embodiments, the treatment methods allow a patient to tolerate a
higher dose of fumaric acid or an ester or salt thereof, which
higher dose may be required given the condition and other
requirements of the patient.
[0009] In one embodiment, provided is a method of treating multiple
sclerosis (MS) in a human patient in need thereof, comprising
orally administering to the patient aspirin and fumaric acid or an
ester or a salt thereof, wherein the aspirin is administered at
from about 150 mg to about 650 mg (or from about 300 mg to about
500 mg) per day and the fumaric acid or ester or salt thereof is
administered at about 300 mg to about 450 mg per day (or from about
340 mg to about 380 mg per day). The aspirin and the fumaric acid
or ester or a salt thereof can be administered separately or
together, concurrently or sequentially.
[0010] In some embodiments, the aspirin is formulated to dissolve
in an oral cavity of a subject. In some embodiments, the fumaric
acid or ester or salt thereof is formulated for dissolving in
stomach, intestines, or further distal in the gastrointestinal
tract of the subject.
[0011] Also provided, in one embodiment, is a method of treating
multiple sclerosis (MS) in a human patient in need thereof,
comprising orally administering to the patient one or more tablets
each comprising a first portion comprising a first amount of
aspirin and a second portion comprising a second amount of fumaric
acid or an ester or a salt thereof, wherein the first portion is
formulated to dissolve in an oral cavity of a subject, wherein the
second portion is formulated for dissolving in stomach, intestines,
or further distal in the gastrointestinal tract of the subject, and
wherein the aspirin is administered at from about 150 (or 160, 170,
180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300,
310, 320, 330, 340, 350, 360, 370, 380, 390 or 400) mg to about 650
(or 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520,
530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, or 640) mg
per day and the fumaric acid or ester or salt thereof is
administered at about 300 (or 300, 310, 320, 330, 340, 350, or 360)
mg to about 450 (or 360, 370, 380, 390, 400, 410, 420, 430, 440, or
450) mg per day.
[0012] In some embodiments, the patient suffers from
relapse-remitting MS (RRMS). In some embodiments, the patient has a
history of non-compliance with a medication due to cutaneous flush
or a gastrointestinal side effect.
[0013] In some embodiments, the second amount of the fumaric acid
or ester or salt thereof is about 180 mg. In some embodiments, the
first amount of aspirin is from about 80 mg to about 250 mg. In
some embodiments, the second portion further comprises a third
amount of aspirin. In some embodiments, the first amount of aspirin
and the second amount of aspirin each is from about 40 mg to about
120 mg. In some embodiments, the second portion is enclosed in an
enteric coating.
[0014] In some embodiments, the ester is dimethyl fumarate,
monomethyl fumarate or combination thereof.
[0015] Pharmaceutical compositions are also provided. In some
embodiments, the pharmaceutical composition is a fixed dose
combination comprising aspirin and a fumaric acid or an ester or a
salt thereof. In some embodiments, the pharmaceutical composition
is a fixed dose combination comprising aspirin and dimethyl
fumarate, optionally in combination with an additional fumaric acid
or an ester or a salt thereof.
[0016] In some embodiments, the pharmaceutical composition
comprises about 40 (or 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,
150, 160, 170, 180, or 190) mg to about 250 (or 210, 220, 230, or
240) mg of aspirin and about 150 (or 160, 165, 170, 175, 180, or
185) mg to about 190 (or 180, 185, 195, 200, 210, 220, 225, or 230)
mg of fumaric acid or an ester or a salt thereof. In some
embodiments, the pharmaceutical composition comprises about 300 (or
310, 320, 330, 340, 350, 360, 370, 380, 390 or 400) mg to about 500
(or 410, 420, 430, 440, 450, 460, 470, 480, or 490) mg of aspirin
and about 340 (or 300, 310, 320, 330, 350, or 360) mg to about 380
(or 360, 370, 380, 390, 400, 410, 420, 430, 440, or 450) mg of
fumaric acid or an ester or a salt thereof.
[0017] In some embodiments, the pharmaceutical compositions
described herein are formulated as a tablet. In some embodiments,
the pharmaceutical compositions described herein are formulated as
a capsule comprising the aspirin and a fumaric acid or an ester or
a salt thereof. In some embodiments, the pharmaceutical
compositions described herein are formulated as a capsule
comprising the aspirin and a fumaric acid or an ester or a salt
thereof, wherein the aspirin and fumaric acid or an ester or a salt
thereof are each formulated as a microsphere. In some embodiments,
the aspirin is present in a first portion formulated to dissolve in
an oral cavity of a subject, and the fumaric acid or ester or salt
thereof is present in a second portion formulated for dissolving in
stomach, intestines, or further distal in the gastrointestinal
tract of the subject.
[0018] In some embodiments, the aspirin is present in a first
portion formulated to dissolve in an oral cavity of a subject, and
a second portion formulated for dissolving in stomach, intestines,
or further distal in the gastrointestinal tract of the subject. In
some embodiments, the pharmaceutical compositions described herein
are formulated as a capsule comprising the aspirin and a fumaric
acid or an ester or a salt thereof, wherein the aspirin and fumaric
acid or an ester or a salt thereof are each formulated as a
microsphere contained within a capsule shell, and a second portion
of aspirin is present as a coating on the capsule shell and is
formulated to dissolve in an oral cavity of a subject. By
administering this particular dosage form, it is contemplated that
the effective dose of DMF can be reduced, thus reducing and/or
relieving one or more side effects of DMF.
[0019] In one embodiment, provided is a method of treating multiple
sclerosis (MS) in a human patient in need thereof, comprising
orally administering to the patient aspirin and fumaric acid or an
ester or a salt thereof, wherein the aspirin is administered at
from about 300 mg to about 500 mg per day and the fumaric acid or
ester or salt thereof is administered at about 580 mg to about 620
mg per day. In some embodiments, the aspirin is formulated to
dissolve in an oral cavity of a subject. In some embodiments, the
fumaric acid or ester or salt thereof is formulated for dissolving
in stomach, intestines, or further distal in the gastrointestinal
tract of the subject. In some embodiments, the aspirin and the
fumaric acid or ester or salt thereof are administered
concurrently.
[0020] Also provided, in one embodiment, is a method of treating
multiple sclerosis (MS) in a human patient in need thereof,
comprising orally administering to the patient one or more tablets
each comprising a first portion comprising a first amount of
aspirin and a second portion comprising a second amount of fumaric
acid or an ester or a salt thereof, wherein the first portion is
formulated to dissolve in an oral cavity of a subject, wherein the
second portion is formulated for dissolving in stomach, intestines,
or further distal in the gastrointestinal tract of the subject, and
wherein the aspirin is administered at from about 150 mg to about
650 mg per day and the fumaric acid or ester or salt thereof is
administered at about 570 mg to about 630 mg per day, or about 300
to about 450 mg per day, or about 300 to about 400 mg per day, or
about 350 to about 400 mg per day, or about 360 mg per day.
[0021] In some embodiments, the patient suffers from
relapse-remitting MS (RRMS). In some embodiments, the patient
suffers from secondary progressive multiple sclerosis (SPMS).
[0022] Also provided, in one embodiment, is a method of treating
psoriasis in a human patient in need thereof, comprising orally
administering to the patient one or more tablets each comprising a
first portion comprising a first amount of aspirin and a second
portion comprising a second amount of fumaric acid or an ester or a
salt thereof, wherein the first portion is formulated to dissolve
in an oral cavity of a subject, wherein the second portion is
formulated for dissolving in stomach, intestines, or further distal
in the gastrointestinal tract of the subject, and wherein the
aspirin is administered at from about 150 mg to about 650 mg per
day and the fumaric acid or ester or salt thereof is administered
at about 570 mg to about 630 mg per day, or about 300 to about 450
mg per day, or about 300 to about 400 mg per day, or about 350 to
about 400 mg per day, or about 360 mg per day.
[0023] In addition to multiple sclerosis and psoriasis, fumaric
acid or ester or salt thereof can also be used for treating other
diseases and conditions such as motor neuron disease,
neurodegenerative diseases, autoimmune diseases, inflammatory
diseases, sepsis, and skin diseases or conditions.
[0024] A motor neuron disease a neurological condition that
selectively affects motor neurons. Examples include amyotrophic
lateral sclerosis (ALS), hereditary spastic paraplegia (HSP),
primary lateral sclerosis (PLS), progressive muscular atrophy
(PMA), progressive bulbar palsy (PBP) and pseudobulbar palsy.
[0025] Neurodegenerative diseases are results of progressive loss
of structure or function of neurons, including death of neurons.
Examples include amyotrophic lateral sclerosis, Parkinson's,
Alzheimer's, and Huntington's, which occur as a result of
neurodegenerative processes.
[0026] Non-limiting examples of autoimmune or inflammatory disease
include Parkinson's disease, arthritis, rheumatoid arthritis,
multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's
disease, inflammatory bowel disease, ulcerative colitis, lupus,
systemic lupus erythematous, juvenile rheumatoid arthritis,
juvenile idiopathic arthritis, Grave's disease, Hashimoto's
thyroiditis, Addison's disease, celiac disease, dermatomyositis,
multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren
syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis and
ankylosing spondylitis.
[0027] Skin diseases are various skin problems, from small red
bumps on the skin to widespread rashes. Some skin conditions can be
unsightly but harmless, while others may be contagious. Many skin
conditions are also itchy or painful. The presently disclosed
compositions and methods are suitable for treating these diseases
and the symptoms. Non-limiting examples of symptoms include itch,
swelling, redness, rash, flaky, scaly skin, blisters, oozing and
bumps or growths.
[0028] In some embodiments, the second amount of the fumaric acid
or ester or salt thereof is about 300 mg. In some embodiments, the
first amount of aspirin is from about 80 mg to about 250 mg. In
some embodiments, the second portion further comprises a third
amount of aspirin. In some embodiments, the first amount of aspirin
and the second amount of aspirin each is from about 80 mg to about
120 mg. In some embodiments, the first portion further comprises a
water-soluble sugar or sugar substitute. In some embodiments, the
second portion is enclosed in an enteric coating. In some
embodiments, the ester is dimethyl fumarate, monomethyl fumarate or
combination thereof. In some embodiments, the monomethyl fumarate
is hydrogen monomethyl fumarate or a salt thereof (e.g., Na.sup.+,
K.sup.+, Ca.sup.2+, Zn.sup.2+, Mg.sup.2+, Fe.sup.2+). In some
embodiments, the monomethyl fumarate is hydrogen monomethyl
fumarate.
[0029] Pharmaceutical compositions are also provided, for example,
suitable for once daily, twice daily, or three times daily
administration. In one embodiment, the composition comprises about
100 (or 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200) mg to
about 250 (or 200, 210, 220, 230, or 240) mg of aspirin and about
170 (or 175, 180, 185, or 190) mg to about 220 (or 185, 190, 195,
200, 205, 210, or 215) mg of fumaric acid or an ester or a salt
thereof. In one embodiment, the composition comprises about 150 (or
160, 170, 180, or 190) mg to about 250 (or 210, 220, 230, or 240)
mg of aspirin and about 285 (or 270, 270, 280, 290, 295, or 300) mg
to about 315 (or 300, 305, 310, 320, or 325) mg of fumaric acid or
an ester or a salt thereof. In one embodiment, the composition
comprises about 300 (or 310, 320, 330, 340, 350, 360, 370, 380, 390
or 400) mg to about 500 (or 410, 420, 430, 440, 450, 460, 470, 480,
or 490) mg of aspirin and about 570 (or 560, 565, 575, 580, 590 or
595) mg to about 630 (or 605, 610, 515, 620, 625, 635, or 640) mg
of fumaric acid or an ester or a salt thereof. In one embodiment,
the composition comprises about 40 (or 20, 30, 40, 50, 60, 70, 80,
90, 100 or 120) mg to about 500 (or 410, 420, 430, 440, 450, 460,
470, 480, or 490) mg of aspirin and about 120 (or 130, 140, 150,
160, 170, 180, 190, 200, 210 or 220) mg to about 240 (or or 210,
220, 230, or 240) mg of fumaric acid or an ester or a salt
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 is an example of the scale that was used to rate the
assessment of Question 1 in Example 4.
[0031] FIG. 2 is an example of the scale that was used to rate the
assessment of Questions 2 and 3 in Example 4.
DETAILED DESCRIPTION
[0032] The following description sets forth exemplary embodiments
of the present technology. It should be recognized, however, that
such description is not intended as a limitation on the scope of
the present disclosure but is instead provided as a description of
exemplary embodiments.
[0033] As used in the present specification, the following words,
phrases and symbols are generally intended to have the meanings as
set forth below, except to the extent that the context in which
they are used indicates otherwise.
[0034] As used herein, "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Except insofar as any conventional media
or agent is incompatible with the active ingredient, its use in the
therapeutic compositions is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
[0035] "Relapse-remitting multiple sclerosis," or RRMS, is a type
of MS of which symptoms can appear suddenly and be severe and can
then go quiet for months or years. Between flare-ups, the disease
tends not to progress or progresses relatively slowly, and symptoms
may disappear.
[0036] "Secondary-progressive multiple sclerosis," or SPMS, is a MS
condition in which the disease tends to progress steadily. This can
happen with or without relapses. Many patients with RRMS may
transition to SPMS at some point in the course of their
disease.
[0037] "Fumaric acid" is the chemical compound with the formula
HO.sub.2CCH.dbd.CHCO.sub.2H. The "salts and esters" of fumaric acid
are known as fumarates, and include any ester (e.g., mono ester
hydrogen fumarate or salt thereof or diester of fumaric acid), such
as dimethyl fumarate (DMF) and monomethyl fumarate (MMF). The
fumaric acid can comprise a mixture of DMF, also three monoethyl
hydrogen fumarates or salt thereof (calcium, magnesium, and zinc
salts) (e.g.,) Fumaderm.RTM.). The fumaric acid can comprise ALKS
8700 ("a MMF molecule" which is a prodrug to MMF).
[0038] Dimethyl fumarate (DMF) is the dimethyl ester of fumaric
acid, having a chemical name of dimethyl (E)-butenedioate. DMF and
its metabolite, monomethyl fumarate (MMF), were initially
recognized as effective hypoxic cell radiosensitizers. They are
also used as oral therapy for psoriasis. Other diseases, such as
necrobiosis lipoidica, granuloma annulare, and sarcoidosis may also
be suitably treated with DMF and MMF.
[0039] In a non-medical setting, DMF is applied as a biocide to
prevent growths of mold during storage or transport in a humid
climate. However, due to incidences of allergic reactions after
skin contact the European Union banned DMF in consumer products
since 1998, and since January 2009 the import of products
containing DMF was also banned. Medical use of DMF also is known to
come with associated side effects, such as progressive multifocal
leukoencephalopathy, which can be serious. Another side effect
associated with the use of DMF or MMF is the flushing, which has
been reported to cause non-compliance of patients.
[0040] A commercial form of DMF for treating MS is Tecfidera.RTM..
According to the drug label, the starting dose for Tecfidera.RTM.
is 120 mg twice a day orally. After 7 days, the dose should be
increased to the maintenance dose of 240 mg twice a day orally.
Temporary dose reductions to 120 mg twice a day may be considered
for individuals who do not tolerate the maintenance dose. Higher
doses of Tecfidera.RTM. are not recommended.
[0041] It is a surprising and unexpected discovery of the instant
inventor that administration of both aspirin and fumaric acid or
its ester or salt such as DMF and MMF achieves increased treatment
efficacy and reduced side effects as compared to the fumarate
alone. Such a dual administration, therefore, makes it possible to
use a lower dose (e.g., 420, 400 or 360 mg per day) of fumaric acid
of the ester or salt thereof, as compared to the conventional
commercial dose (e.g., 480 mg per day), to achieve the same
efficacy as the conventional dose would but with greatly reduced
side effects.
[0042] The impact of aspirin on the bioavailability of DMF has been
evaluated previously and acknowledged by the US FDA. In Sheikh et
al., Clin Ther. 2013;35:1582-94, for example, the authors observed
that pretreatment with 325 mg aspirin for 4 days reduced flushing
incidence and intensity but did not affect gastrointestinal events
or the pharmacokinetic profile of DMF (abstract). In other words,
aspirin pretreatment did not change the bioavailability of the DMF.
Accordingly, the present discovery that concomitant administration
of aspirin increased the bioavailability of DMF by about 5% is
necessarily surprising and unexpected.
[0043] Such a surprising and unexpected discovery that the dual
administration increases the bioavailability of the fumarate (e.g.,
DMF) makes it possible to use a lower dose (e.g., 420, 400 or 360
mg per day) while achieving the same or substantially similar
efficacy as compared to the conventional commercial dose (e.g., 480
mg per day) , to achieve the same efficacy as the conventional
dose. On the other hand, this dual formulation allows
administration of a higher dose (e.g., 600 mg per day) of fumaric
acid of the ester or salt thereof so that patients who desire such
high doses can avoid or suffer reduced undesirable side effects
such as flushing. The dual administration can be sequential
administration or concurrent administration of two or more separate
compositions, or administration of a composition that includes two
or more different ingredients.
[0044] In some embodiments, a co-formulation is disclosed. In some
aspects, the aspirin and fumaric acid of the ester or salt thereof
are in separate portions in the co-formulation, such as a tablet.
In some aspects, the separate portions are formulated similarly and
in other aspects, the aspirin portion is formulated in a
dissolvable fashion (dissolvable portion) and the fumaric acid
portion is formulated as a swallowable fashion (swallowable
portion). In some aspects, the swallowable portion also contains an
amount of aspirin, which is shown to further enhance the effect of
the dissolvable aspirin in a synergistic fashion.
[0045] In some embodiments, a similarly structured co-formulation
is disclosed that includes aspirin and therapeutic agent having a
niacin-mediated flushing side effect. The term "therapeutic agent
having a niacin-mediated flushing side effect," as used herein,
refers to a group of drugs that activate the nicotinic acid
receptor GPR109a, resulting in flushing symptoms commonly observed
for patients taking niacin. Sometimes, such agents are also
referred to as "nicotinic acid receptor agonists" or "GPR109a
agonists." Non-limiting examples of such therapeutic agents include
niacin, nicotyinyl alcohol, acipimox, acifran, newer GPR109a
agonists, hydroxybutyrate, and fumarates (e.g., dimethyl fumarate,
mono-ethyl fumarate, diethyl fumarate).
[0046] Structure-activity studies have shown common structural
features of GPR109a agonists. Some of the GPR109a agonists have a
carcoxyl group, like in niacin. Another group are anthranilic acid
analogs. More of such structural elements are discussed in Boatman
et al. J. Med. Chem. 2008; 51(24):7653-62.
[0047] In some embodiments, aspirin can be substituted with a
non-steroidal anti-inflammation drug (NSAID). Non-limiting examples
of NSAIDs include aspirin, celecoxib, diclofenac, diflunisal,
etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac,
nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac,
and tolmetin.
[0048] A "dissolvable portion" as used herein refers to a portion
of a drug form that is formulated to dissolve in an oral cavity of
a subject. A dissolvable portion, in one embodiment, is
pulverizable which can be dispersed in the oral cavity by
masticating, sucking, dissolving or other common means, thereby
releasing its active ingredient into the oral cavity where it
enters the circulatory system by traversing the buccal mucosa.
Other embodiments of dissolvable portions are also provided below
in the present disclosure.
[0049] A "swallowable portion" is relative to the dissolvable
portion and can be harder than the dissolvable portion. Therefore,
the swallowable portion is more readily swallowed by the subject
and releases the active ingredient by dissolving it in stomach,
intestines, or further distal in the gastrointestinal (GI) tract of
the subject.
[0050] The dissolvable portion and the swallowable portion, in some
embodiments, are side by side in a tablet but with different
physical or chemical properties. In some embodiments, the intraoral
is placed outside of the swallowable portion to form a bi-layer
tablet.
[0051] In the context of the present disclosure, the use of the
term hard or swallowable in reference to the dissolvable portion is
used to connote that the swallowable portion is not pulverized by
the force and can withstand the force of masticating or chewing
that effectively pulverizes the outer layer of the pharmaceutical
composition of the present disclosure. In one embodiment, the
swallowable portion is chew-resistant. Further, in referring to the
swallowable portion as being ingestible, it is meant that the
swallowable portion is capable of being taken up and absorbed by
one or more portions of the gastrointestinal tract, stomach,
intestines or a further distal of the gastrointestinal tract. The
swallowable portion of the combination tablet may be conventionally
covered with one or more layers of coatings to permit a timed
release of the active contained therein following ingestion by a
subject. The present disclosure contemplates a release profile of
the ingested core particle of from 30 minutes to 24 hours.
[0052] In the context of the present disclosure, the term
pulverizable or easily pulverizable refers to a portion of a
material that is ground or dispersed into small particles within
the oral cavity by gentle pressure generated by chewing or
masticating the layer to be ground. There is no intent to imply any
particular size or fineness of the resulting particles, as it is
contemplated herein that it is only required that the pulverized
material release a therapeutic agent within the oral cavity.
[0053] The term masticating or chewing, in the context of the
present disclosure, is meant to signify that the pulverizing or
grinding is being performed by a patient's or subject's teeth, or
gums. A specific embodiment of the combination pill may cause the
first bite(s) to rupture or dislodge the outer layer thereby
releasing it from the central core and can then be chewed. There is
no intent to signify any particular degree of force required or
generated by the masticating teeth or gums. The requirement is that
the force actually used to produce the pulverized granules,
particles, powder and the like, is sufficient to disrupt the
dissolvable portion of the present disclosure while leaving the
swallowable portion intact.
[0054] The term sucking, dissolving or other common means, in the
context of the present disclosure, is meant to signify that the
intraoral or pulverizable portion can be absorbed in the oral
cavity through use of the tongue, gums, cheeks, saliva and
combinations thereof, over a period of time. A specific embodiment
of the combination pill causes the intraoral or pulverizable
portion to dissolve in the oral cavity over a period of 5 minutes,
while the combination pill is held in the oral cavity, through
interaction with saliva. The requirement is that interaction with
the tongue, gums, cheeks, saliva and combinations thereof by
sucking, dissolving or other common means, is sufficient to disrupt
the outer layer of the pharmaceutical composition of the present
disclosure while leaving the swallowable portion intact.
[0055] For the purpose of this description, the term intact does
not require that the swallowable portion remain in one piece.
Instead, it signifies that at least 50% of the swallowable portion
is swallowed, but preferably that 75% of the swallowable portion
material is swallowed; even more preferably that approximately 75%
to about 85% of the swallowable portion material is swallowed, and
most preferably, from about 85% to about 95% of the swallowable
portion material is swallowed, and most particularly, that greater
than 95% of the swallowable portion material is swallowed.
[0056] The buccal mucosa is meant to refer to the epithelium lining
the oral cavity, including the sublingual region. The buccal mucosa
further includes the sub-epithelial tissue; i.e., the tissue and
macromolecular layers that accumulate underneath the epithelium.
The sub-epithelial tissue includes, inter alia, connective tissue
cells (fibroblasts, adipocytes, lymphocytes, and the like),
extracellular matrix, basement membrane, smooth muscle, and
vascular elements, etc. The buccal mucosa is a highly vascular
tissue, and therefore a desirable route of entry into the general
circulation.
[0057] In one embodiment, the present disclosure provides a method
of treating multiple sclerosis (MS) in a human patient in need
thereof. In some embodiments, the disease or condition being
treated is one or more of psoriasis, necrobiosis lipoidica,
granuloma annulare, sarcoidosis, granulomatous and inflammatory
skin disorders, lichen planus pityriasis rubra pilaris, chronic
discoid lupus erythematosus, necrobiosis lipoidica, cheilitis
granulomatosa, annular elastotic giant cell granuloma, malign
melanoma, lupus erythematosus, aplopecia areata, hidradenitis
suppurativa, other granulomatous and inflammatory skin disorders,
other inflammatory disorders such as colitis, DNA damage in tumor,
gastrointestinal ulceration, collagen type II degradation, and
other immune modulated diseases.
[0058] The method entails, in one embodiment, orally administering
to the patient a first amount of aspirin and a second amount of
fumaric acid or an ester or a salt thereof. In some embodiments,
the aspirin is administered at from about 300 mg to about 500 mg
per day and the fumaric acid or ester or salt thereof is
administered at about 340 mg to about 380 mg per day.
[0059] The method entails, in one embodiment, orally administering
to the patient one or more tablets each comprising a first portion
comprising a first amount of aspirin and a second portion
comprising a second amount of fumaric acid or an ester or a salt
thereof, wherein the first portion is formulated to dissolve in an
oral cavity of a subject, wherein the second portion is formulated
for dissolving in stomach, intestines, or further distal in the
gastrointestinal tract of the subject, and wherein the aspirin is
administered at from about 300 mg to about 500 mg per day and the
fumaric acid or ester or salt thereof is administered at about 340
mg to about 380 mg per day.
[0060] In some embodiments, the daily dose of the fumaric acid or
ester or salt thereof is about 350 mg to about 370 mg, or about 355
mg to about 365 mg, or about 360 mg.
[0061] In some aspects, the daily administration is twice daily,
and each administration is with one or two tablets. In one aspect,
the second portion of each tablet, also referred to as the
swallowable portion, contains about 170 mg to about 190 mg fumaric
acid or an ester or salt thereof. In one aspect, the second portion
of each tablet, also referred to as the swallowable portion,
contains about 175 mg to about 185 mg fumaric acid or an ester or
salt thereof. In one aspect, the second portion of each tablet,
also referred to as the swallowable portion, contains about 180 mg
fumaric acid or an ester or salt thereof.
[0062] In one aspect, the first portion of each tablet, also
referred to as the dissolvable portion, contains about 150 mg to
about 250 mg aspirin, or alternatively about 175 mg to about 225 mg
aspirin, or about 200 mg aspirin. In some embodiments, the first
portion contains about 75 mg to about 125 mg aspirin, or
alternatively about 90 mg to about 110 mg aspirin, or about 100 mg
aspirin, and meanwhile the second portion further contains about 75
mg to about 125 mg aspirin, or alternatively about 90 mg to about
110 mg aspirin, or about 100 mg aspirin, such that the total amount
of aspirin in each tablet can still be about 150 mg to about 250
mg.
[0063] In some embodiments, the patient suffers from
relapse-remitting MS (RRMS), a relatively common form of MS. In
some embodiments, the patient has a history of non-compliance with
a medication due to cutaneous flush or a gastrointestinal side
effect. "Non-compliance" as used herein refers to a patient's
failure, of at least one time, to take the DMF/MMF medication due
to complaint of flushing. In some embodiments, the patient has
suspended taking DMF/MMF for at least 1 week, 2 weeks, 1 month, 2
months, 3 months, or 6 months.
[0064] In one embodiment, the present disclosure provides a method
of treating multiple sclerosis (MS) in a human patient in need
thereof.
[0065] In some embodiments, the disease or condition being treated
is one or more of psoriasis, necrobiosis lipoidica, granuloma
annulare, sarcoidosis, granulomatous and inflammatory skin
disorders, lichen planus pityriasis rubra pilaris, chronic discoid
lupus erythematosus, necrobiosis lipoidica, cheilitis
granulomatosa, annular elastotic giant cell granuloma, malign
melanoma, lupus erythematosus, aplopecia areata, hidradenitis
suppurativa, other granulomatous and inflammatory skin disorders,
other inflammatory disorders such as colitis, DNA damage in tumor,
gastrointestinal ulceration, collagen type II degradation, and
other immune modulated diseases.
[0066] The method entails, in one embodiment, orally administering
to the patient a first amount of aspirin and a second amount of
fumaric acid or an ester or a salt thereof. In some embodiments,
the aspirin is administered at from about 300 mg to about 500 mg
per day and the fumaric acid or ester or salt thereof is
administered at about 570 mg to about 630 mg per day.
[0067] The method entails, in one embodiment, orally administering
to the patient one or more tablets each comprising a first portion
comprising a first amount of aspirin and a second portion
comprising a second amount of fumaric acid or an ester or a salt
thereof, wherein the first portion is formulated to dissolve in an
oral cavity of a subject, wherein the second portion is formulated
for dissolving in stomach, intestines, or further distal in the
gastrointestinal tract of the subject, and wherein the aspirin is
administered at from about 300 mg to about 500 mg per day and the
fumaric acid or ester or salt thereof is administered at about 570
(or 575, 580, 585, 590, or 595) mg to about 630 (or 605, 610, 615,
620 or 625) mg per day.
[0068] In some embodiments, the daily dose of the fumaric acid or
ester or salt thereof is about 590 mg to about 610 mg, or about 595
mg to about 605 mg, or about 600 mg.
[0069] In some aspects, the daily administration is once, twice or
three times daily, and each administration is with one or two
tablets. In one aspect, the second portion of each tablet, also
referred to as the swallowable portion, contains about 290 mg to
about 310 mg fumaric acid or an ester or salt thereof. In one
aspect, the second portion of each tablet, also referred to as the
swallowable portion, contains about 295 mg to about 305 mg fumaric
acid or an ester or salt thereof. In one aspect, the second portion
of each tablet, also referred to as the swallowable portion,
contains about 300 mg fumaric acid or an ester or salt thereof.
[0070] In one aspect, the first portion of each tablet, also
referred to as the dissolvable portion, contains about 150 mg to
about 250 mg aspirin, or alternatively about 175 mg to about 225 mg
aspirin, or about 200 mg aspirin. In some embodiments, the first
portion contains about 75 mg to about 125 mg aspirin, or
alternatively about 90 mg to about 110 mg aspirin, or about 100 mg
aspirin, and meanwhile the second portion further contains about 75
mg to about 125 mg aspirin, or alternatively about 90 mg to about
110 mg aspirin, or about 100 mg aspirin, such that the total amount
of aspirin in each tablet can still be about 150 mg to about 250
mg.
[0071] In some embodiments, the patient has been treated with
fumaric acid or an ester or salt thereof but the treatment is
considered inadequate. In some embodiments, the patient suffers
from relapse-remitting MS (RRMS). In some embodiments, the patient
suffers from secondary progressive multiple sclerosis (SPMS).
Example Co-Formulations
[0072] Pharmaceutical formulations are provided, in some
embodiments. The formulations may include aspirin at a suitable
dose and form and a fumaric acid or an ester or a salt thereof at a
suitable dose and form. In some embodiments, the formulation
includes at last about 20, 30, 40, 50, 60, 70, 80, 90, 100, 105,
110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170,
175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235,
240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300
mg aspirin. In some embodiments, the formulation includes not more
than about 500, 490, 480, 470, 460, 450, 440, 430, 420, 410, 400,
390, 380, 370, 360, 350, 340, 330, 325, 320, 315, 310, 305, 300,
295, 290, 285, 280, 275, 260, 255, 250, 245, 240, 235, 230, 225,
220, 215, 210, 205, 200, 190, 180, 170, 160, or 150 mg aspirin.
[0073] In some embodiments, the formulation includes at least about
80, 90, 100, 120, 125, 150, 155, 160, 165, 170, 175, 180, 185, 190,
195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255,
260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320,
325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385,
390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450,
455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 510, 520, 530,
540, 550, 560, 570, 580, 590, or 600 mg of a fumaric acid or an
ester or a salt thereof. In some embodiments, the formulation
include not more than about 600, 590, 580, 570, 560, 55, 540, 530,
520, 510, 500, 490, 480, 470, 460, 450, 440, 430, 420, 410, 400,
390, 380, 370, 360, 350, 340, 330, 325, 320, 315, 310, 305, 300,
295, 290, 285, 280, 275, 260, 255, 250, 245, 240, 235, 230, 225,
220, 215, 210, 205, 200, 195, 190, 185, 180, 175, 170, 165, 160,
155, or 150 mg of a fumaric acid or an ester or a salt thereof.
[0074] In some embodiments, the fumaric acid or an ester or a salt
thereof is dimethyl fumarate, optionally in combination with an
additional fumaric acid or an ester or a salt thereof. In some
embodiments, the additional fumaric acid or an ester or a salt
thereof is monomethyl fumarate or a salt thereof (e.g., Na.sup.+,
K.sup.+, Ca.sup.2+, Zn.sup.2+, Fe.sup.2+). In some embodiments, the
monomethyl fumarate is hydrogen monomethyl fumarate. In some
embodiments, the pharmaceutical composition consists essentially of
an effective amount of aspirin and an effective amount of dimethyl
fumarate.
[0075] In some embodiments, the pharmaceutical composition
comprises from about 80 mg to about 380 mg of the fumaric acid or
ester or salt thereof. In some embodiments, the pharmaceutical
composition comprises from about 80 mg to about 380 mg of the
dimethyl fumarate. In some embodiments, the pharmaceutical
composition comprises from about 30 mg to about 500 mg of aspirin.
In some embodiments, the pharmaceutical composition comprises from
about 150 mg to about 500 mg of aspirin. In some embodiments, the
pharmaceutical composition comprises from about 30 mg to about 500
mg of aspirin and from about 80 mg to about 380 mg of a fumaric
acid or an ester or a salt thereof. In some embodiments, the
pharmaceutical composition comprises from about 150 mg to about 500
mg of aspirin and from about 80 mg to about 380 mg of a fumaric
acid or an ester or a salt thereof.
[0076] In some embodiments, the pharmaceutical compositions
described herein are formulated as a capsule comprising aspirin and
a fumaric acid or an ester or a salt thereof, wherein the aspirin
and fumaric acid or an ester or a salt thereof are each formulated
as a microsphere contained within a capsule shell, and a second
portion of aspirin is present as a coating on the capsule shell and
is formulated to dissolve in an oral cavity of a subject.
[0077] In some embodiments, the pharmaceutical composition, or
dosage form, provided herein comprises aspirin and a fumaric acid
or an ester or a salt thereof, wherein the aspirin and fumaric acid
or an ester or a salt thereof are each individually formulated as
enterically coated microspheres which are contained within a
capsule shell. In some embodiments, the capsule may also be coated
with a second portion of aspirin formulated to dissolve in an oral
cavity of a subject. In some embodiments, the total dose of aspirin
of the capsule (i.e., the combined amount present within the
capsule in combination with the aspirin present as a coating on the
capsule shell) is about 20 mg to about 500 mg, or about 20 mg to
about 325 mg, or about 20 mg, or about 25 mg, or about 30 mg, or
about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or
about 75 mg, or about 80 mg, or about 90 mg, or about 100 mg, or
about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or
about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or
about 190 mg, or about 200 mg, or about 210 mg, or about 220 mg, or
about 230 mg, or about 240 mg, or about 250 mg, or about 260 mg, or
about 270 mg, or about 280 mg, or about 290 mg, or about 300 mg, or
about 310 mg, or about 315 mg, or about 320 mg, or about 325
mg.
[0078] In some embodiments, the total dose of aspirin of the
capsule is present in about a 1:1 ratio between the aspirin
microspheres within the capsule and the aspirin present as a
coating on the capsule shell. In some embodiments, the dose of
aspirin present as microspheres within the capsule is about 20 mg,
or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or
about 70 mg, or about 75 mg, or about 80 mg. In some embodiments,
the dose of aspirin present as a coating on the capsule shell is
about 20 mg, or about 25 mg, or about 30 mg, or about 40 mg, or
about 50 mg, or about 60 mg, or about 70 mg, or about 75 mg, or
about 80 mg.
[0079] The microspheres described herein may also include
non-spherical microparticles, such as oblong or cylindrical
microparticles.
[0080] In some embodiments, the microspheres described herein have
an average particle size of less than about 7 mm, or less than
about 6 mm, or less than about 5 mm, or less than about 4 mm, or
less than about 3 mm, or less than about 2 mm, or less than about
1.7 mm, or less than about 1.6 mm, or less than about 1.5 mm, or
less than about 1.4 mm, or less than about 1.3 mm, or less than
about 1.2 mm, or less than about 1.1 mm, or less than about 1.0 mm,
or less than about 900 .mu.m, or less than about 850 .mu.m, or less
than about 800 .mu.m, or less than about 750 .mu.m, or less than
about 700 .mu.m, or less than about 650 .mu.m, or less than about
600 .mu.m, or less than about 550 .mu.m, or less than about 500
.mu.m, or less than about 450 .mu.m, or less than about 300 .mu.m.
In some embodiments, the particle size ranges from about 900 .mu.m
to about 2,000 .mu.m, or from about 850 .mu.m to about 1.7 mm, or
from about 1.0 mm to 1.5 mm.
[0081] In some embodiments, the microspheres comprise an enteric
coating such that the API (aspirin or fumaric acid or an ester or a
salt thereof (e.g., DMF)) is released in the gastrointestinal tract
(e.g., the small intestine). In some embodiments, the enteric
coating on the microspheres is formulated or applied such that the
aspirin is released in the gastrointestinal tract (e.g., the small
intestine) at substantially the same time as the fumaric acid or an
ester or a salt thereof (e.g., DMF). In some embodiments, the
enteric coating on the microspheres is formulated or applied such
that the aspirin is released in the gastrointestinal tract (e.g.,
the small intestine) just prior to (e.g., 1-5, 1-10, 1-15, or 1-20
minutes) the fumaric acid or an ester or a salt thereof (e.g.,
DMF). Accordingly, in some embodiments, the enteric coating on the
aspirin microspheres is thinner than the enteric coating on the
fumaric acid or an ester or a salt thereof (e.g., DMF)
microspheres.
[0082] It is contemplated that by co-administering the aspirin and
fumaric acid or an ester or a salt thereof (e.g., DMF) to the
patient in such a way that the aspirin is absorbed within less than
about 5 minutes (or less than about 10 minutes, 15 minutes, 20
minutes, 25 minutes or 30 minutes) of, or substantially
simultaneously to, the fumaric acid or an ester or a salt thereof
(e.g., DMF), the bioavailability of the fumaric acid or an ester or
a salt thereof (e.g., DMF) will be enhanced such that the
therapeutically effective dose is about 480 mg/day or less, or at
least about 360 mg/day, or about 360 mg/day, or about 380 mg/day,
or about 400 mg/day, or about 410 mg/day, or about 420 mg/day, or
between about 360 mg/day and 420 mg/day, or between about 360
mg/day and 480 mg/day.
[0083] In some embodiments, the microspheres described herein
comprise about 80% w/w, or about 75% w/w, or about 70% w/w, or
about 65% w/w active ingredient (i.e., aspirin or fumaric acid or
an ester or a salt thereof).
[0084] In one embodiment, an example co-formulation has a chewable
outer layer as the dissolvable portion, such that it can be
absorbed quickly. This chewable layer may be adhered directly to
the inner layer (the swallowable portion), or it may be such
designed that when it is bitten lightly (e.g. with minimal force,
such as the force needed to chew a banana), this outer chewable
layer breaks off into many pieces within the mouth, and can be
chewed and thus absorbed, leaving the hard inner layers in the
mouth to be swallowed. By making the chewable layer "crumble" in
such a way, the patient will avoid biting hard through the hard
inner layer of the tablet, which could be uncomfortable if the
inner tablet is very hard, or could damage the integrity of the
inner tablet, allowing it to be absorbed earlier than desired.
[0085] This may be similar to eating a cherry, where one bites the
outer layer off and eats it, but does not bite too hard to chip
their tooth on the hard inner pit. However, in the inventive tablet
the patient would then swallow the inner tablet, instead of
spitting out the cherry pit.
[0086] The outer chewable layer can be formulated, e.g., with a
water soluble sugar and/or a sugar substitutes. Suitable
water-soluble sugars and/or sugar substitutes are glucose, maltose,
sucrose, dextrose, fructose, sorbitol, mannitol or other types of
natural or artificial sweeteners. Mixtures of various sugars or
sugar substitutes are also suitable.
[0087] The chewable layer can also be formulated with, e.g., a gel
forming agent. Examples of such suitable gel formers are xanthan
gum, methylcelluloses such as sodium carboxymethylcellulose or
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, alginates, tragacanth or edible starch.
These substances are all commercially available and usually meet
the purity requirements and quality regulations for pharmaceutical
products. All such gel formers and coatings contemplated are GRAS
(generally regarded as safe).
[0088] Wetting agents and lubricants such as sodium lauryl sulfate,
as well as coloring agents, flavoring agents, sweetening agents
(including other nonnutritive sweeteners), tableting agents,
stabilizers, antioxidants, cooling agents, and preservatives, can
also be present.
[0089] A binding agent can also be present such as cellulose,
cellulosic derivatives, polyvinyl pyrrolidone, starch, modified
starch, and mixtures thereof, and, in particular, microcrystalline
cellulose.
[0090] One example of a manufacturing technique to formulate the
chewable component over the solid dosage form is compression
coating. The compression coating can be prepared by, e.g., a
Manesty Dry-Cota press, which consists of two side by side
interconnected tablet presses where the core is made on one press
then mechanically transferred to the next press for compression
coating. Each "press" has an independent powder feed mechanism so
that core blend is loaded on one machine and coating blend on the
other. Mechanical transfer arms rotate between the machines to
remove cores from one press and transfer them to the coating press.
Other and more modern types of presses which may be used (e.g.
Elizabeth Hata HT-AP44-MSU-C, Killian RUD, Fette PT 4090) have a
dual feed system for coating blend and pre-made cores. This
configuration is more flexible, in that cores can be pan coated
with a functional or cosmetic coating before compression coating.
However, any conventional, art-recognized manufacturing technique
that permits the formulation of a chewable component over a solid
dosage form will be readily appreciated by the skilled artisan and
is contemplated by the present disclosure.
[0091] A similar embodiment would not only have an outer chewable
layer, but also a thin shell outside of the chewable layer. This
would be similar to the thin candy shell of an M&M candy. With
this thin outer shell helping to hold the tablet together, the
chewable layer can be designed to more easily crumble and dissolve
than if there was no outer shell, e.g., by reducing the amount of
binder or by reducing the compression to that which will minimally
hold the chewable component together until the outer shell is
applied.
[0092] The outer shell can be a sugar coating or a polymer coating
such as hydroxypropylmethylcelluose or polyvinylalcohol or
combinations thereof, for example.
[0093] Another embodiment contemplated by the present disclosure is
an outer layer made from liquid, within a thin outer skin or shell.
When the patient bites lightly on the tablet, this outer skin would
fracture, allowing the liquid (or gel) of a fast-absorbing
medication to release into the mouth and thus be absorbed quickly,
starting at the mouth's mucous membranes. There are several
possible embodiments of this outer layer, including viscous
liquids, gels, quick absorbable substances, powder within a
breakable skin, substances that "melt" in the mouth (quickly
absorb) and more. In another embodiment of this example, the liquid
can be comprised of two or more substances and can also include
solid particles which can be comprised of one or more substances.
In this embodiment, the solid particles would be suspended in the
liquid. The solid particles could also dissolve over time into the
liquid.
[0094] When the outer layer is manufactured to absorb quickly, the
drug can be formulated with a water soluble excipient such as a
sugar, sugar alcohol, polyethylene glycol (PEG), or polyethylene
oxide. The preferred water-soluble excipients are the sugar
alcohols including, but not limited to sorbitol, mannitol,
maltitol, reduced starch saccharide, xylitol, reduced paratinose,
erythritol, and combinations thereof. The preferred sugar is
glucose. Other suitable water-soluble excipients include gelatin,
partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate
and mixtures thereof. A disintigrating agent such as sodium starch
"meltable" formulation can be readily determined by one of skill in
the art.
[0095] When the outer layer contains a liquid within an outer skin,
the outer skin can be gelatin and the drug can be mixed with water
or miscible solvents such as propylene glycol; PEG's and ethanol,
or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive
oil.
[0096] Another embodiment has an outer layer which rapidly
dissolves when sucked on. When the inner layer is reached, the
patient would swallow the tablet. This embodiment can be designed
such that the outer surface of the inner, hard layer has a texture
that is easily recognized by the tongue, so that it is clear to the
patient when the outer layer is fully dissolved, and thus when it
is time to swallow the inner layer. This would be similar to a
Tootsie Pop.RTM., in that the Tootsie Roll.RTM. center is easily
recognized by the tongue as feeling very different than the outer
dissolvable candy.
[0097] In such an embodiment, the dissolvable portion can be
formulated in a dissolvable matrix material. The dissolvable matrix
may include carbohydrates, fats, proteins, waxes (natural and
synthetic), hydrocarbons, and other materials which safely and
rapidly dissolve in the mouth.
[0098] The inner, swallowable "slow absorb" or "extended release"
layer contemplated by the present disclosure can have any number of
art-recognized constituencies. In one embodiment, the inner layer
is designed similar to a standard tablet. In another embodiment,
the inner layer is enteric coated, further slowing the release of
the medication. In still another embodiment the inner layer can be
an extended release dosage form.
[0099] When the inner layer has an enteric coating, the coating can
be, e.g., a material selected from the group consisting of one or
more of the following: cellulose acetate phthalate, alginates,
alkali-soluble acrylic resins, hydroxypropyl methylcellulose
phthalate, methacrylate-methacrylic acid copolymers, polyvinyl
acetate phthalate and styrol maleic acid copolymers. The coating
can also be multilayered; i.e. one or more coatings are
contemplated to provide extended release kinetics which permit the
inner tablet to release over a period of from 15 minutes to 24
hours or more.
[0100] The extended release dosage form can be formulated with the
drug dispersed in a matrix or with an extended release coating.
Suitable materials form inclusion in an extended release matrix or
coating can be, e.g., a cellulosic material, an acrylic polymer, or
a combination thereof.
[0101] The contemplated inner layer can also be made of a substance
which is softer and more pliable than a standard hard tablet, e.g.
similar to a hard taffy. In this way, the patient could not chip
their teeth when biting the tablet, as the inner layer will absorb
some of the shock of the bite without breaking or dissolving. It
can then by swallowed to be absorbed in the GI system, after the
outer layer was absorbed in the mouth.
[0102] The "taffy" can be prepared, e.g., with an admixture of a
sugar melt having at least 40% sugar, such as fructose and a
surface active agent. However, the skilled artisan can readily
prepare alternative formulations of sugar-based substances to
achieve an inner core that absorbs the shock of the chewing force
exerted by an individual in the normal course of taking a chewable
medication.
[0103] In another example, the dissolvable portion can include two
or more discrete pulverizable portions or layers. All discrete
pulverizable layers will be dispersed in the oral cavity by
masticating, thereby releasing the layers from the hard inner
core.
[0104] Compounds which may be included in the two or more discrete
pulverizable portions or layers include sodium lauryl sulfate, as
well as coloring agents, flavoring agents, sweetening agents
(including other nonnutritive sweeteners), tableting agents,
stabilizers, antioxidants, cooling agents, and preservatives,
suitable water-soluble sugars and/or sugar substitutes including
glucose, maltose, sucrose, dextrose, fructose, sorbitol, mannitol
or other types of natural or artificial sweeteners, gel forming
agents including xanthan gum, methylcelluloses such as sodium
carboxymethylcellulose or hydroxypropylmethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, alginates,
tragacanth and soluble starch, binding agents including cellulose,
cellulosic derivatives, polyvinyl pyrrolidone, starch, modified
starch, and microcrystalline cellulose, water soluble excipients
such as a sugar, sugar alcohol, polyethylene glycol (PEG), or
polyethylene oxide, sorbitol, mannitol, maltitol, reduced starch
saccharide, xylitol, reduced paratinose, erythritol, gelatin,
partially hydrolyzed gelatin, hydrolyzed dextran, dextrin,
alginate, naproxen sodium (sodium
(2S)-2-(6-methoxynaphthalen-2-yl)propanoate) and ibuprofen
(2-[4-(2-methylpropyl)phenyl]propanoic acid), aspirin, a COX
inhibitor, COX-2 specific inhibitors such as colecoxib
(Celebrex.TM.)
(4-[5-(4-methylphenyl-3-)trifluoromethyl)pyrazol-1-yl]benzenesulfonamide)
and rofecoxib (Vioxx.TM.)
(4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one), Percocet.TM.
(combination of acetaminophen and oxycodone), Tylenol.TM.
acetaminophen, an NSAID an anti-emetic, a sedative, an anesthetic,
an amnesiatic, acetaminophen, diclofenac, aspirin, laropiprant, or
vitamins such as Vitamin C, and more, or any combination of the
above. These discrete layers may also cover only a portion of the
hard inner core, or swallowable portion.
EXAMPLES
[0105] The following examples are included to demonstrate specific
embodiments of the disclosure. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques to function well in the practice
of the disclosure, and thus can be considered to constitute
specific modes for its practice. However, those of skill in the art
should, in light of the present disclosure, appreciate that many
changes can be made in the specific embodiments which are disclosed
and still obtain a like or similar result without departing from
the spirit and scope of the disclosure.
Example 1. Intraoral Administration of Aspirin Reduces
Fumarate-Induced Flush More Than Swallowed Aspirin
[0106] Seven human patients with multiple sclerosis who were
already taking dimethyl fumarate and had experienced flushing side
effects from dimethyl fumarate were recruited for this study. Each
patient did not have an allergy or reaction to aspirin or dimethyl
fumarate (DMF), had not been diagnosed with kidney disease or liver
disease, was not pregnant or planning to be pregnant within the
following two months, had not been breastfeeding within the
preceding two months, and had not used aspirin for the preceding 7
days.
[0107] In Period I, each patient was given their standard dose of
240 mg dimethyl fumarate orally. Each patient was asked to rate his
or her flush on the Global Flush Severity Scale (GFSS) (see Paolini
et al. Int. J. Clin. Pract. 62(6):896-904 (2008)), when the flush
completely resolved. The Global Flushing Severity Score measures,
overall, in the previous 24 hours, how each patient rates the
flushing symptoms, including redness, warmth, tingling, and
itchiness of the skin.
[0108] Period II did not start until at least two days upon
completion of Period I. At Period II, each patient orally swallowed
162 mg aspirin followed by 240 mg dimethyl fumarate. After the
flush completely resolved, then each patient recorded his or her
GFSS flush rating.
[0109] Not until at least two days later did Period III start. At
Period III, each patient was asked to not swallow the orally
administered aspirin (162 mg) but to allow the aspirin to be
absorbed through the oral mucosa. The aspirin was in powdered form
and the remaining aspirin in the mouth was washed out with water.
Afterwards, 240 mg of dimethyl fumarate was swallowed with a glass
of water. Still, the flush was rated (GFSS) after it was
resolved.
[0110] The patients during Period III suffered the least severe
flush than during any other Periods. Among Periods I through II,
the severity of flush was the lowest in Period III (a 52% reduction
as compared to Period I), second lowest in Period II (a 33%
reduction as compared to Period I) and the highest in Period I. As
the total amount of aspirin was the same between Period II and III,
this example therefore demonstrates that oral release of aspirin
greatly increased aspirin's anti-flushing effect for dimethyl
fumarate.
Example 2. Dose Ranging Study
[0111] Two hundred and twenty subjects will be recruited for the
purposes of this trial. Eligible patients must have a diagnosis of
release-remitting multiple sclerosis (RMMS), and at least one
relapse in the 12 months prior to randomization. The trial is a
randomized, double-blind, placebo-controlled, dose-ranging trial in
RMMS patients already taking DMF. The trial is scheduled to last 48
weeks. Prior to the 48 weeks of on-trial time, patients will be
randomly assigned, in a 1:1:1:1:1 allocation, to one of five
treatments: (i) DMF 180 mg/VTS-ASA (aspirin) 200 mg twice daily;
(ii) DMF 240 mg/VTS-ASA 200 mg twice daily; (iii) DMF 300
mg/VTS-ASA 200 mg twice daily; (iv) DMF 300 mg/VTS-ASA 200 mg once
daily; and (v) Placebo 240 mg twice daily. Both patients and
practitioners were will be blinded to the treatment regime. Study
participants will report to the clinical research unit (CRU) every
4 weeks during the study period for routine medical monitoring, and
every 4 weeks for the first 24 weeks for brain MRI scans.
[0112] Study participants will be evaluated for the following
primary endpoints; (i) Number of new GdE lesions in weeks 12-14;
(ii) Number of new GdE lesions in weeks 4-24; (iii) Number of new
GdE lesions per patient in weeks 12-24; (iv) ARR during weeks 0-24;
(v) ARR during weeks 25-48; (vi) ARR during weeks 0-48. Secondary
safety endpoints include; (i) headache; (ii) nasopharyngitis; (iii)
nausea; (iv) diarrhea; (v) abdominal pain; (vi) lower limb
fracture; (vii) pelvic inflammatory disease; (viii) phlebitis; (ix)
urinary retention; and (x) uterine leiomyoma.
[0113] In addition to the primary and secondary endpoints listed
above, the proposed trial will additionally investigate endpoints
that are specific to the inquiry of the effect of pretreatment of
aspirin with DMF. These endpoints include; (i) occurrence of flush;
(ii) occurrence of pruritus; (iii) occurrence of hot flush; (iv)
Global Flushing Severity Score (GFSS); (v) Fatigue Severity Score
(FSS); (vi) Number of new or enlarging T2-hyperintense lesions at
week 24, a metric of remyelination; (vii) Number of new
T1-hypointense lesions at week 24, a metric of remyelination; and
(viii) PHQ-9 Depression Score.
[0114] Clinically meaningful differences between treatment groups
will be evaluated at the end of the study period according to
intention to treat (ITT) principals.
Example 3. Bioequivalence Study
[0115] The bioequivalence study will be performed in two parts; a
pilot study (about 20 healthy subjects), followed by a Phase 1
study (about 125 subjects). The pilot study in healthy males and
females is designed to establish a pharmacokinetic (PK) profile
under fasting and fed conditions for the orally administered test
and reference products to compare the bioavailability in accordance
with Food and Drug Administration (FDA) and Center for Drug
Evaluation and Research (CDER) guidelines. Phase 1 subjects have a
diagnosis of release-remitting multiple sclerosis (RMMS), and at
least one relapse in the 12 months prior to randomization.
[0116] Subjects in both studies will be randomly assigned, in a
1:1:1:1 allocation, to one of four treatments: oral administration
of (i) aspirin only (control); (ii) DMF only; (iii) DMF/aspirin
combination in the fasted state; (iv) DMF/aspirin combination in
the fed state. Both patients and practitioners will be blinded to
the treatment regime.
Study Objectives
[0117] To investigate the PK profiles of the test product, DMF 180
mg/ASA 150 mg capsules and the reference products, DMF 240 mg
delayed-released capsules and Bayer Aspirin.RTM. 325 mg tablets,
and to determine the sample size for future studies.
[0118] For this purpose the PK profiles of DMF's metabolite,
monomethylfumarate (MMF), acetylsalicylic acid (ASA) and its active
metabolite, salicylic acid (SA) in plasma will be investigated
after administration of a single dose of the test and reference
formulations, under fasting and fed conditions.
[0119] These will be a single-dose, open-label, laboratory-blind,
randomized, four period crossover pilot study with orally
administered dimethylfumarate and aspirin conducted under fasting
and fed conditions.
[0120] The studies will comprise: [0121] Screening period of
maximum 21 days; [0122] Four treatment periods (each of which will
include a profile period of 12 hours separated by a wash-out period
of 3 calendar days (minimum number of days based on half-life of
the analyte/metabolites) to 7 calendar days (maximum number of days
based on logistical arrangements) between consecutive
administrations of the IMP, and [0123] A post-study visit within 72
hours of completion of the last treatment period of the study.
[0124] Procedures listed for the post-study visit will be performed
in the event of early withdrawal from the study. Subjects will be
assigned randomly to treatment sequence, before the first
administration of IMP.
[0125] The duration of this study is expected to be approximately
25 days (approximately 31/2 weeks) per subject (excluding the
screening period). The actual overall study duration and study
recruitment time may vary.
[0126] Along with other assessments during the screening period and
admission, during the treatment period the subjects vital signs
will be assessed and they will be assessed for adverse events and
concomitant medication and pharmacokinetic blood samples will be
collected at the following time points: at pre dose (0 hours), at
15 minutes (acetylsalicylic acid and salicylic acid only), 30
minutes, 45 minutes (acetylsalicylic acid and salicylic acid only)
and at 1 hour, 1 hour 30 minutes, 2 hours, 2 hours 30 minutes, 3
hours, 3 hours 30 minutes, 4 hours, 5 hours, 6 hours, 7 hours, 8
hours, 10 hours and 12 hours post dose (total: 17 samples per
treatment period). If applicable, the collection of PK blood
samples take precedence over other assessments at a scheduled
time-point.
[0127] Subjects will receive either the test or reference product,
according to the randomization schedule, under fasting and fed
conditions. Subjects will receive each product once.
TABLE-US-00001 Treatment A - DMF only fasting (Reference 1) API:
Dimethylfumarate (DMF) Dosage form and strength: 240 mg delayed
release capsule Study dose: 240 mg (1 capsule) Route of
administration: Oral
TABLE-US-00002 Treatment B - Aspirin only fasting (Reference 2)
API: Aspirin (acetylsalicylic acid [ASA]) Dosage form and strength:
325 mg tablet Study dose: 325 mg (1 tablet) Route of
administration: Oral
TABLE-US-00003 Treatment C - DMF/aspirin (ASA) fasting (Test 1)
API: DMF 180 mg/aspirin (ASA) 150 mg Dosage form and strength: DMF
180 mg/aspirin (ASA) 150 mg fixed dose combination capsule Study
dose: DMF 180 mg/aspirin (ASA) 150 mg capsule (1 capsule) Route of
administration: Oral (the outer layer of the fixed dose combination
capsule contains aspirin that dissolves in the mouth before the
remaining part of the capsule is then swallowed whole with
water)
TABLE-US-00004 Treatment D - DMF/aspirin (ASA) fed (Test 2) API:
DMF 180 mg/aspirin (ASA) 150 mg Dosage form and strength: DMF 180
mg/aspirin (ASA) 150 mg fixed dose combination capsule Study dose:
DMF 180 mg/aspirin (ASA) 150 mg capsule (1 capsule) Route of
administration: Oral (the outer layer of the fixed dose combination
capsule contains aspirin that dissolves in the mouth before the
remaining part of the capsule is then swallowed whole with
water)
[0128] For the fasting treatment periods, after an overnight fast
of at least 10 hours, subjects will receive either the reference or
the test product (according to the randomization schedule) with 240
mL water. The reference products must be swallowed whole with
water. The fixed dose combination capsule) must be kept in the
mouth until the outer layer (containing the aspirin) has dissolved
in the mouth before the capsule is then swallowed whole with water.
Specific details on the administration of the test product will be
provided in a separate document, if needed.
[0129] For fed treatment period, after an overnight fast of at
least 10 hours, subjects will receive a standardized high-fat,
high-calorie breakfast 30 minutes before administration of IMP. The
entire meal must be consumed within 30 minutes. After completion of
the breakfast subjects will receive either the reference or the
test product (according to the randomization schedule) with 240 mL
water. The reference products must be swallowed whole with water.
The fixed dose combination capsule) must be kept in the mouth until
the outer layer (containing the aspirin) has dissolved in the mouth
before the capsule is then swallowed whole with water.
[0130] Quantitative analysis of monomethylfumarate, acetylsalicylic
acid and salicylic acid in the collected plasma samples will be
performed by BASD using liquid chromatography with tandem mass
spectrometry (LC-MS/MS).
[0131] Calculation of the PK parameters will be made with
Phoenix.RTM. WinNonlin.RTM. 6.2 (or higher) (Certara, L. P., 1699
South Hanley Road, St Louis, Mo. 63144, USA). The PK parameters
will be calculated for each subject and treatment using
non-compartmental analysis and using the actual sampling time
intervals (relative to IMP administration).
[0132] Primary Pharmacokinetic Parameters for monomethylfumarate,
acetylsalicylic acid and salicylic acid: [0133] Maximum observed
plasma concentration (Cmax) [0134] Area under the plasma
concentration versus time curve, from time zero to t, where t is
the time of the last quantifiable concentration (AUC(.sub.0-t))
[0135] Area under the plasma concentration versus time curve, with
extrapolation to infinity (AUC(.sub.0-.infin.))
[0136] Secondary Pharmacokinetic Parameters for monomethylfumarate,
acetylsalicylic acid and salicylic acid [0137] Time to maximum
observed plasma concentration (t.sub.max) [0138] Terminal
elimination rate constant (.lamda..sub.z) [0139] Apparent terminal
elimination half-life (t.sub.1/2-z)
[0140] It is contemplated that this study will show that that by
co-administering DMF with aspirin as described herein, the
bioavailability of the DMF will be increased such that the
effective dose of DMF can be reduced to as low as about 360 mg/day,
or 480 mg/day or less, or about 400 mg/day, about 420 mg/day, or
from about 360 mg/day to about 420 mg/day.
Example 4. Pilot, Randomized, Open-Label, 2-Way Crossover
Comparative Bioavailability Study of Dimethyl
Fumarate-Acetylsalicylic Acid 180 mg-150 mg Delayed-Release Capsule
(vts-72) and Tecfidera 240 mg Delayed-Release Capsule (Reference)
Following a Single Dose in Healthy Subjects Under Fasting
Conditions
[0141] The objective of this example was to compare the rate and
extent of absorption of monomethyl fumarate from a dimethyl
fumarate-acetylsalicylic acid 180 mg-150 mg delayed-release capsule
(VTS-72) (Test; Treatment A) versus Tecfidera 240 mg
delayed-release capsule (Reference; Treatment B), administered as
1.times.180 mg-150 mg or 1.times.240 mg delayed-release capsule
under fasting conditions.
[0142] This was a single center, pilot, comparative
bioavailability, open-label, randomized, single-dose, 2-period,
2-sequence, crossover study under fasting conditions. A total of 12
healthy adult male or female volunteers were included in this pilot
study. For each period, subjects will be confined from at least 10
hours before dosing until 12 hours post-dose. There were a washout
of 7 days or more between doses. The washout period could be
increased for logistical considerations. Participation of each
subject in this study lasted approximately 9 days. Subjects were
administered each treatment according to the 2-period, 2-sequence,
block randomization scheme.
[0143] Treatment A: Subjects were required not to wear dentures or
to remove their tongue piercing at the time of dosing. The
delayed-release capsule were placed on the subject's tongue.
Subjects were instructed to suck the delayed-release capsule until
the acetylsalicylic acid coating was dissolved or up to a maximum
of 1 minute after the delayed-release capsule had been placed on
the subject's tongue. The delayed-release capsule should not be
chewed, bitten, or swallowed during that 1 minute period or until
the coating is dissolved; only the saliva could be swallowed. The
subject was instructed to give a hand sign once the acetylsalicylic
acid coating was dissolved (the capsule should feel and taste
different). Thereafter, or up to a maximum of 1 minute after the
delayed- release capsule was placed on the subject's tongue, 240 mL
of water was given to subjects to swallow the capsule. Time of
dosing was set to the time the capsule was placed on the tongue. A
hand and mouth check was performed to ensure consumption of the
medication.
[0144] Treatment B: Study medication was administered to each
subject and was swallowed whole with 240 mL of water without being
sucked, chewed or bitten, and a hand and mouth check was performed
to ensure consumption of the medication.
[0145] Flushing (including redness, warmth, tingling, and itchiness
of the skin) was assessed at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4
hours post-dose using the question and the rating scale presented
in Section--Flushing Assessment below. Half grades were not
assigned. Flushing symptoms were recorded as adverse events.
[0146] GI symptoms were assessed at 10 hours post-dose using the
questions and the rating scale presented in
Section--Gastrointestinal Symptoms Assessment below. Half grades
were not assigned. GI symptoms were recorded as adverse events.
Flushing Assessment
[0147] Flushing was assessed using the question below. The question
was asked by the clinical staff: [0148] Question 1: Overall, at
this moment, how would you rate your flushing symptoms (including
redness, warmth, tingling, and itchiness of the skin)? Score from 0
to 10 (none 0, mild 1 to 3, moderate 4 to 6, severe 7 to 9, extreme
10).
[0149] FIG. 1 is an example of the scale that was used to rate the
assessment of Question 1.
Gastrointestinal Symptoms Assessment
[0150] Gastrointestinal symptoms were assessed using the questions
below. Questions were asked by the clinical staff: [0151] Question
2: Overall, during the past 10 hours, how would you rate your GI
side effects(nausea, diarrhea, upper abdominal pain, lower
abdominal pain, vomiting, indigestion, constipation, bloating, and
flatulence)? [0152] Question 3: Overall, during the past 10 hours,
how bothersome were your GI side effects (nausea, diarrhea, upper
abdominal pain, lower abdominal pain, vomiting, indigestion,
constipation, bloating, and flatulence)?
[0153] FIG. 2 is an example of the scale that was used to rate the
assessment of Questions 2 and 3.
[0154] The flushing side effect reported by each of the subject is
summarized in Table 1 below. The total reduction of flushing from
15.9 to 7.9 was about 50.3%. When the doses of DMF were normalized
to 180 mg in both treatments, the reduction was still 33.6%.
Considering that, as shown below, aspirin increased the
bioavailability of DMF by about 5%, the reduction of the flushing
side effect is actually about 36.8%.Also interestingly, 6 of these
11 subjects had their flushes peak at least 30 mins earlier with
VTS-72 (only 2 were later) than with DMF alone.
TABLE-US-00005 TABLE 1 Summary of Flush Ratings Total Flush Rating*
Treatment A Treatment B (180 mg DMF + Subject # (240 mg DMF) 150 mg
Aspirin) 1 (drop out) (drop out) 2 26 5 3 8 8 4 18 14 5 26 13 6 14
6 7 36 13 8 8 2 9 11 9 10 9 0 11 8 15 12 11 2 Mean 15.9 7.9
Normalized Mean 11.9 7.9 *Flushes were scored from 0-10 every 30
mins, up to 4 hours post dose (8 total measurements per dose) and
added up
[0155] Table 2 below provides a descriptive statistics summary of
monomethyl fumarate plasma pharmacokinetic parameters.
TABLE-US-00006 TABLE 2 Descriptive Statistics Summary of Monomethyl
Fumarate Plasma Pharmacokinetic Parameters Parameter Treatment A
Treatment B (units) N Mean SD CV % N Mean SD CV % AUC.sub.0-t
(h*ng/mL) 11 3874.01 1213.13 31.31 11 4924.24 1550.02 31.48
AUC.sub.0-inf (h*ng/mL) 11 3885.63 1214.97 31.27 11 4958.99 1544.26
31.14 Residual area (%) 11 0.32 0.16 49.93 11 0.74 1.79 243.23
C.sub.max (ng/mL) 11 2034.02 599.26 29.46 11 2749.40 988.79 35.96
T.sub.1/2 el (h) 11 0.62 0.14 22.14 11 0.75 0.27 35.53 K.sub.el
(/h) 11 1.1618 0.2268 19.5244 11 1.0149 0.2926 28.8326 Correlation
11 -0.9978 0.0023 -0.2328 11 -0.9639 0.0689 -7.1439 K.sub.el Lower
(h) 11 4.768 0.959 20.105 11 5.364 1.002 18.687 K.sub.el Upper (h)
11 7.269 1.349 18.553 11 8.360 1.362 16.287
[0156] When the mean values in both treatments were normalized to
180 mg DMF, the mean values are summarized in Table 3.
Co-administration of aspirin did not have significant impact on the
C.sub.max of DMF. However, the co-administration of aspirin caused
an about 5% increase in AUC.sub.0-t and AUC.sub.0-inf. Also
surprisingly, the data showed very tight inter-subject variability
(confidence intervals).
TABLE-US-00007 TABLE 3 Statistics Summary after Dose Normalization
Treatment B Change % Treatment A (normalized) (A over B)
AUC.sub.0-t (h*ng/mL) 3874.01 3693.18 4.90% AUC.sub.0-inf (h*ng/mL)
3885.63 3719.2425 4.47% Residual area (%) 0.32 0.555 -4.23%
C.sub.max (ng/mL) 2034.02 2062.05 -1.36%
[0157] Also interestingly, even though the C.sub.max did not have a
significant change, the co-administration of aspirin shifted the
T.sub.max to about 20 minutes earlier (median). See Table 4.
TABLE-US-00008 TABLE 4 Summary Statistics of T.sub.max Parameter
Treatment A Treatment B (units) N Median Min Max N Median Min Max
T.sub.max (h) 11 2.330 1.327 4.499 11 2.661 0.747 4.994
[0158] This example demonstrates that co-administration of aspirin
increased the bioavailability of DMF by about 5% while at the same
time reducing the flushing side effect by more than 35%.
[0159] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
[0160] The disclosures illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," "containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the disclosure claimed.
[0161] Thus, it should be understood that although the present
disclosure has been specifically disclosed by preferred embodiments
and optional features, modification, improvement and variation of
the disclosures embodied therein herein disclosed may be resorted
to by those skilled in the art, and that such modifications,
improvements and variations are considered to be within the scope
of this disclosure. The materials, methods, and examples provided
here are representative of preferred embodiments, are exemplary,
and are not intended as limitations on the scope of the
disclosure.
[0162] The disclosure has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
disclosure. This includes the generic description of the disclosure
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[0163] In addition, where features or aspects of the disclosure are
described in terms of Markush groups, those skilled in the art will
recognize that the disclosure is also thereby described in terms of
any individual member or subgroup of members of the Markush
group.
[0164] All publications, patent applications, patents, and other
references mentioned herein are expressly incorporated by reference
in their entirety, to the same extent as if each were incorporated
by reference individually. In case of conflict, the present
specification, including definitions, will control.
[0165] It is to be understood that while the disclosure has been
described in conjunction with the above embodiments, that the
foregoing description and examples are intended to illustrate and
not limit the scope of the disclosure. Other aspects, advantages
and modifications within the scope of the disclosure will be
apparent to those skilled in the art to which the disclosure
pertains.
* * * * *