U.S. patent application number 13/973700 was filed with the patent office on 2014-11-27 for methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects.
This patent application is currently assigned to XenoPort, Inc.. The applicant listed for this patent is XenoPort, Inc.. Invention is credited to Kenneth C. Cundy, Sami Karaborni, Peter A. Virsik.
Application Number | 20140350018 13/973700 |
Document ID | / |
Family ID | 49115589 |
Filed Date | 2014-11-27 |
United States Patent
Application |
20140350018 |
Kind Code |
A9 |
Cundy; Kenneth C. ; et
al. |
November 27, 2014 |
Methods of Administering Monomethyl Fumarate and Prodrugs Thereof
Having Reduced Side Effects
Abstract
Methods of reducing undesirable side effects during therapeutic
treatment using monomethyl fumarate and prodrugs of monomethyl
fumarate are disclosed.
Inventors: |
Cundy; Kenneth C.; (Redwood
City, CA) ; Karaborni; Sami; (Cupertino, CA) ;
Virsik; Peter A.; (Portola Valley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XenoPort, Inc. |
Santa Clara |
TX |
US |
|
|
Assignee: |
XenoPort, Inc.
Santa Clara
CA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20140057917 A1 |
February 27, 2014 |
|
|
Family ID: |
49115589 |
Appl. No.: |
13/973700 |
Filed: |
August 22, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61692168 |
Aug 22, 2012 |
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61692174 |
Aug 22, 2012 |
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61713897 |
Oct 15, 2012 |
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61713961 |
Oct 15, 2012 |
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61733234 |
Dec 4, 2012 |
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61769513 |
Feb 26, 2013 |
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61800132 |
Mar 15, 2013 |
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61837796 |
Jun 21, 2013 |
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61841513 |
Jul 1, 2013 |
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Current U.S.
Class: |
514/239.2 ;
514/547 |
Current CPC
Class: |
A61P 37/02 20180101;
A61P 25/00 20180101; A61P 17/06 20180101; A61K 9/2846 20130101;
A61K 31/5375 20130101; A61P 43/00 20180101; A61K 9/2866 20130101;
A61P 25/02 20180101; A61K 31/225 20130101; A61P 21/00 20180101;
A61K 9/2886 20130101; A61P 29/00 20180101 |
Class at
Publication: |
514/239.2 ;
514/547 |
International
Class: |
A61K 31/225 20060101
A61K031/225; A61K 31/5375 20060101 A61K031/5375 |
Claims
1. A method of systemically administering a therapeutically
effective amount of a compound selected from (i) monomethyl
fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a
combination thereof, to treat a disease in each patient of a
population of patients in need of such treatment, comprising
administering the compound(s) to each patient to achieve across the
population a maximum average concentration of monomethyl fumarate
in the blood plasma of the patients of less than 500 ng/ml.
2. The method of claim 1, wherein the maximum average concentration
of monomethyl fumarate in the blood plasma of the patients is less
than 400 ng/ml.
3. A method of systemically administering a therapeutically
effective amount of a compound selected from (i) monomethyl
fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a
combination thereof, to treat a disease in each patient of a
population of patients in need of such treatment, comprising
administering the compound(s) to each patient to achieve across the
population an average Cmax of monomethyl fumarate in the blood
plasma of the patients of less than 1100 ng/ml.
4. The method of claim 3, wherein the average Cmax of monomethyl
fumarate in the blood plasma of the patients is less than 600
ng/ml.
5. A method of systemically administering a therapeutically
effective amount of a compound selected from (i) monomethyl
fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a
combination thereof, to treat a disease in each patient of a
population of patients in need of such treatment, comprising
administering the compound(s) to each patient to achieve across the
population an average maximum rate of rise in monomethyl fumarate
concentration in the blood plasma of the patients of less than 0.25
wt % ng-eq of MMF dosed/ml/hr.
6. The method of claim 5, wherein the average maximum rate of rise
in monomethyl fumarate concentration in the blood plasma of the
patients is less than 0.20 wt % ng-eq of MMF dosed/ml/hr or is less
than 0.15 wt % ng-eq of MMF dosed/ml/hr.
7. The method of claim 5, wherein the average maximum rate of rise
in monomethyl fumarate concentration in the blood plasma of the
patients is less than 0.10 wt % ng-eq of MMF dosed/ml/hr
8. The method of claim 5, wherein the average maximum rate of rise
in monomethyl fumarate concentration is less than 500 ng/mL/hr.
9. The method of claim 5, wherein the average maximum rate of rise
in monomethyl fumarate concentration is less than 400 ng/mL/hr.
10. The method of claim 1, wherein incidence of flushing in the
population of patients is reduced.
11. The method of claim 1, wherein the disease is selected from
multiple sclerosis and psoriasis.
12. The method of claim 1, wherein the disease is selected from
adrenal leukodystrophy, AGE-induced genome damage, Alexanders
Disease, Alper's Disease, Alzheimer's disease, amyotrophic lateral
sclerosis, angina pectoris, arthritis, asthma, balo concentric
sclerosis, Canavan disease, cardiac insufficiency including left
ventricular insufficiency, central nervous system vasculitis,
Charcott-Marie-Tooth Disease, childhood ataxia with central nervous
system hypomyelination, chronic idiopathic peripheral neuropathy,
chronic obstructive pulmonary disease, Crohn's disease, diabetic
retinopathy, graft versus host disease, hepatitis C viral
infection, herpes simplex viral infection, human immunodeficiency
viral infection, Huntington's disease, irritable bowel disorder,
ischemia, Krabbe Disease, lichen planus, macular degeneration,
mitochondrial encephalomyopathy, monomelic amyotrophy, multiple
sclerosis, myocardial infarction, neurodegeneration with brain iron
accumulation, neuromyelitis optica, neurosarcoidosis, NF-.kappa.B
mediated diseases, optic neuritis, pareneoplastic syndromes,
Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateral
sclerosis, progressive supranuclear palsy, psoriasis, reperfusion
injury, retinopathia pigmentosa, Schilders Disease, subacute
necrotizing myelopathy, susac syndrome, transplantation rejection,
transverse myelitis, a tumor, ulcerative colitis, Zellweger's
syndrome, granulomas including annulaire, pemphigus, bollus
pemphigoid, behcet's, contact dermatitis, acute dermatitis, chronic
dermatitis, alopecia areata (totalis and universalis), sarcoidosis,
cutaneous sarcoidosis, pyoderma gangrenosum, cutaneous lupus,
Crohn's disease and cutaneous Crohn's disease.
13. The method of claim 1, wherein the compound comprises
monomethyl fumarate.
14. The method of claim 1, wherein the compound comprises a prodrug
of monomethyl fumarate.
15. The method of claim 14, wherein the compound comprises a
compound of Formula (I): ##STR00013## or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is C.sub.1-6 alkyl.
16. The method of claim 15, wherein the compound comprises dimethyl
fumarate.
17. The method of claim 1, wherein the compound is a compound of
Formula (II): ##STR00014## or a pharmaceutically acceptable salt
thereof, wherein: R.sup.2 and R.sup.3 are independently chosen from
hydrogen, C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl; R.sup.4
and R.sup.5 are independently chosen from hydrogen, C.sub.1-6
alkyl, substituted C.sub.1-6 alkyl, C.sub.1-6 alkoxy, substituted
C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl, substituted C.sub.1-6
alkoxycarbonyl, C.sub.1-6 heteroalkyl, substituted C.sub.1-6
heteroalkyl, C.sub.4-12 cycloalkylalkyl, substituted C.sub.4-12
cycloalkylalkyl, C.sub.7-12 arylalkyl, and substituted C.sub.7-12
arylalkyl; or R.sup.4 and R.sup.5 together with the nitrogen to
which they are bonded form a ring chosen from a C.sub.5-10
heteroaryl, substituted C.sub.5-10 heteroaryl, C.sub.5-10
heterocycloalkyl, and substituted C.sub.5-10 heterocycloalkyl;
wherein each substituent group is independently chosen from
halogen, --OH, --CN, --CF.sub.3, .dbd.O, --NO.sub.2, benzyl,
--C(O)NR.sup.11.sub.2, --R.sup.11, --OR.sup.11, --C(O)R.sup.11,
--COOR.sup.11, and --NR.sup.11.sub.2 wherein each R.sup.11 is
independently chosen from hydrogen and C.sub.1-4 alkyl.
18. The method of claim 17, wherein the compound is chosen from:
(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate; and
pharmaceutically acceptable salts thereof.
19. The method of claim 1, wherein the compound is a compound of
Formula (III): ##STR00015## or a pharmaceutically acceptable salt
thereof, wherein: R.sup.6 is chosen from C.sub.1-6 alkyl,
substituted C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, substituted
C.sub.1-6 heteroalkyl, C.sub.3-8 cycloalkyl, substituted C.sub.3-8
cycloalkyl, C.sub.6-8 aryl, substituted C.sub.6-8 aryl, and
--OR.sup.10 wherein R.sup.10 is chosen from C.sub.1-6 alkyl,
substituted C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, substituted
C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and substituted C.sub.6-10
aryl; R.sup.7 and R.sup.8 are independently chosen from hydrogen,
C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl; and wherein each
substituent group is independently chosen from halogen, --OH, --CN,
--CF.sub.3, .dbd.O, --NO.sub.2, benzyl, --C(O)NR.sup.11.sub.2,
--R.sup.11, --OR.sup.11, --C(O)R.sup.11, --COOR.sup.11,
N(R.sup.11)C(O)C(R.sup.11).sub.2NR.sup.11.sub.2, and
--NR.sup.11.sub.2 wherein each R.sup.11 is independently chosen
from hydrogen and C.sub.1-4 alkyl.
20. The method of claim 19, wherein the compound is chosen from:
1-(ethoxycarbonyloxy)ethyl methyl (2E)but-2-ene-1,4-dioate; methyl
1-(methylethoxycarbonyloxy)ethyl (2E)but-2-ene-1,4-dioate; methyl
1-(2-methylpropanoyloxy)ethyl (2E)but-2-ene-1,4-dioate; methyl
1-(phenylcarbonyloxy)ethyl (2E)but-2-ene-1,4-dioate;
cyclohexylcarbonyloxybutyl methyl (2E)but-2-ene-1,4-dioate;
[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl
(2E)but-2-ene-1,4-dioate; 1-(cyclohexyloxycarbonyloxy)ethyl methyl
(2E)but-2-ene-1,4-dioate; methyl 2-methyl-1-phenylcarbonyloxypropyl
(2E)but-2-ene-1,4-dioate;
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-am-
inopropanoic acid;
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-am-
inopropanoic acid;
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-
-aminoacetylamino)propanoic acid;
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-(a-
minoacetylamino)propanoic acid;
3-1-{{[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethoxycarbonyl}}(2S)-2-ami-
nopropanoic acid; and a pharmaceutically acceptable salt of any of
the foregoing.
21. The method of claim 1, wherein the compound is a compound of
Formula (IV): ##STR00016## or a pharmaceutically acceptable salt
thereof, wherein n is an integer from 2 to 6.
22. The method of claim 21, wherein the compound is chosen from:
methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1,4-dioate; methyl
3-morpholin-4-ylpropyl (2E)but-2-ene-1,4-dioate; methyl
4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and a
pharmaceutically acceptable salt of any of the foregoing.
23. A method of systemically administering a therapeutically
effective amount of a compound selected from (i) monomethyl
fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and (iii) a
combination thereof, to treat a disease in a patient in need of
such treatment, comprising one of a) or b): a) orally administering
to the patient, at a dosing frequency of not more than twice per
day, an enteric-coated oral sustained release dosage form
containing a therapeutically effective dose of the compound(s),
wherein the dosage form, when subjected to an in vitro dissolution
test employing as a dissolution medium 750 mL of 0.1 N hydrochloric
acid, at pH 1.2, for a period of 2 hours, followed by addition of
250 mL of 200 mM tribasic sodium phosphate buffer resulting in an
adjustment of the pH of the dissolution medium to 6.8, the
dissolution medium being maintained at 37.degree. C. and stirred at
100 rpm, releases: (i) less than 10 wt % of the dose over an
initial 2 hours of the in vitro dissolution test; (ii) at least 90
wt % of the dose over not less than an initial 8 hours of the in
vitro dissolution test; (iii) no more than 30 wt % of the dose in
any one hour during the in vitro dissolution test; and (iv) no more
than 40 wt % of the dose in any consecutive two hours during the in
vitro dissolution test; or b) orally administering to the patient,
at a frequency of not more than twice per day, a non-enteric-coated
oral sustained release dosage form containing a therapeutically
effective dose of the compound(s), wherein the dosage form, when
subjected to an in vitro dissolution test employing as a
dissolution medium 750 mL of 0.1 N hydrochloric acid, at pH 1.2,
for a period of 2 hours, followed by addition of 250 mL of 200 mM
tribasic sodium phosphate buffer resulting in an adjustment of the
pH of the dissolution medium to 6.8, releases (i) at least 90 wt %
of the dose over not less than an initial 8 hours of the in vitro
dissolution test; (ii) no more than 30 wt % of the dose in any one
hour during the in vitro dissolution test; and (iii) no more than
40 wt % of the dose in any consecutive two hours during the in
vitro dissolution test.
24. The method of claim 23, wherein the dosing frequency is twice
per day.
25. The method of claim 23, wherein the dosing frequency is once
per day.
26. The method of claim 25, wherein the dosage form releases at
least 90 wt % of the dose over not less than an initial 10 hours of
the in vitro dissolution test.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Application Ser. Nos. 61/800,132,
filed Mar. 15, 2013; 61/692,168, filed Aug. 22, 2012; 61/713,897,
filed Oct. 15, 2012; 61/733,234, filed Dec. 4, 2012; 61/769,513,
filed Feb. 26, 2013; 61/841,513, filed Jul. 1, 2013; 61/692,174,
filed Aug. 22, 2012; 61/713,961, filed Oct. 15, 2012; and
61/837,796, filed Jun. 21, 2013; the contents of each of which are
incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] Disclosed herein are methods of reducing patient flushing
while administering monomethyl fumarate and/or a prodrug thereof
during the treatment of diseases such as multiple sclerosis and
psoriasis.
BACKGROUND
[0003] Fumaric acid esters (FAEs) are approved in Germany for the
treatment of psoriasis, are being evaluated in the United States
for the treatment of psoriasis and multiple sclerosis, and have
been proposed for use in treating a wide range of immunological,
autoimmune, and inflammatory diseases and conditions.
[0004] FAEs and other fumaric acid derivatives have been proposed
for use in treating a wide-variety of diseases and conditions
involving immunological, autoimmune, and/or inflammatory processes
including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat.
No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1),
43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26,
522-526); asthma and chronic obstructive pulmonary diseases (Joshi
et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency
including left ventricular insufficiency, myocardial infarction and
angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US
2007/0027076); mitochondrial and neurodegenerative diseases such as
Parkinson's disease, Alzheimer's disease, Huntington's disease,
retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi
and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No.
6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423);
transplantation (Joshi and Strebel, WO 2002/055063, US
2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and
U.S. Pat. No. 7,157,423; and Lehmann et al., Arch Dermatol Res
2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO
2002/055063, U.S. Pat. No. 6,509,376, U.S. Pat. No. 7,157,423, and
US 2006/0205659) including multiple sclerosis (MS) (Joshi and
Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and
Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology
2006, 13, 604-610; and Schilling et al., Clin Experimental
Immunology 2006, 145, 101-107); ischemia and reperfusion injury
(Joshi et al., US 2007/0027076); AGE-induced genome damage
(Heidland, WO 2005/027899); inflammatory bowel diseases such as
Crohn's disease and ulcerative colitis; arthritis; and others
(Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO
2007/042034).
[0005] Fumaderm.RTM., an enteric coated tablet containing a mixture
of salts of monoethyl fumarate and dimethyl fumarate was approved
in Germany in 1994 for the treatment of psoriasis. Dimethyl
fumarate (DMF) is rapidly metabolized in vivo to monomethyl
fumarate (MMF), and hence DMF is considered to be a prodrug of
MMF.
##STR00001##
[0006] Fumaderm.RTM. is dosed three times per day with 1-2
grams/day administered for the treatment of psoriasis.
Fumaderm.RTM. exhibits a high degree of interpatient variability
with respect to drug absorption and food strongly reduces
bioavailability. Absorption is thought to occur in the small
intestine with peak levels achieved 5-6 hours after oral
administration. Significant side effects occur in 70-90% of
patients (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32,
246-49; and Hoelhagel et al., Br J Dermatology 2003, 149, 363-369).
Side effects of current FAE therapy include gastrointestinal upset
including nausea, vomiting, and diarrhea; and transient flushing of
the skin. In particular, significant flushing incidences have been
reported in patients with psoriasis after administration of BG00012
(DMF) (Artuc et al., Br J Dermatology Preprint, 2006, 154, 21).
Artuc et al. found flushing incidences in 18 of 24 patients dosed.
They also observed increases in PGD.sub.2, PGF.sub.2, and serotonin
plasma levels. The skin flushing side effect of FAEs is thought to
be the result of interactions with the hydroxy-carboxylic acid
receptor, HCA.sub.2, on keratinocytes, as well as on Langerhans
cells in the skin (Blad et al., Biological and Pharmacological
Roles of HCA Receptors, Advances in Pharmacology, 2011, 62,
219-250).
[0007] Fumaric acid derivatives (Joshi and Strebel, WO 2002/055063,
US 2006/0205659, and U.S. Pat. No. 7,157,423 (amide compounds and
protein-fumarate conjugates); Joshi et al., WO 2002/055066 and
Joshi and Strebel, U.S. Pat. No. 6,355,676 (mono and dialkyl
esters); Joshi and Strebel, WO 2003/087174 (carbocyclic and
oxacarbocylic compounds); Joshi et al., WO 2006/122652
(thiosuccinates); Joshi et al., US 2008/0233185 (dialkyl and diaryl
esters); Nielsen and Bundgaard, J Pharm Sci 1988, 77(4), 285-298
(glycolamide ester prodrugs); and Nilsson et al., US 2008/0004344
(salts)) have been developed in an effort to overcome the
deficiencies of current FAE therapy. Controlled release
pharmaceutical compositions comprising fumaric acid esters are
disclosed by Nilsson and Muller, WO 2007/042034; by Nilsson and
Rupp, US 2012/0034274 and US 2012/0034303. These last two
publications describe FAE formulations exhibiting reduced flushing
in patients.
SUMMARY
[0008] Disclosed herein are methods of systemically administering a
therapeutically effective amount of a compound selected from (i)
monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate,
and (iii) a combination thereof, to treat a disease in each patient
of a population of patients in need of such treatment. The methods
comprise administering the compound(s) to each patient to achieve
across the population of patients a maximum average concentration,
as defined herein, of monomethyl fumarate in the blood plasma of
the patients of less than 500 ng/ml. In certain aspects, the
maximum average concentration of monomethyl fumarate in the blood
plasma of the patients is maintained at less than 400 ng/ml.
[0009] The methods further comprise administering the compound(s)
to each patient to achieve, across the population of patients, an
average Cmax, as defined herein, of monomethyl fumarate in the
blood plasma of the patients of less than 1100 ng/ml. In certain
aspects, the average Cmaxof monomethyl fumarate in the blood plasma
of the patients is maintained at less than 600 ng/ml. In other
aspects, the average Cmaxof monomethyl fumarate in the blood plasma
of the patients is maintained at less than 400 ng/ml.
[0010] The methods are effective in reducing the
incidence/frequency of flushing across the population of
patients.
[0011] Also disclosed herein are methods of systemically
administering a therapeutically effective amount of a compound
selected from (i) monomethyl fumarate (MMF), (ii) a prodrug of
monomethyl fumarate, and (iii) a combination thereof, to treat a
disease in each patient in a population of patients in need of such
treatment. The methods comprise administering the compound(s) to
each patient to achieve across the population of patients: an
average maximum rate of rise in monomethyl fumarate concentration
in the blood plasma of the patients of less than 0.25 wt % ng-eq of
MMF dosed/ml/hr. In certain aspects, the average maximum rate of
rise in monomethyl fumarate concentration is less than 0.20 wt %
ng-eq of MMF dosed/ml/hr. In other aspects, the average maximum
rate of rise in monomethyl fumarate concentration is less than 0.15
wt % ng-eq of MMF dosed/ml/hr. In other aspects, the average
maximum rate of rise in monomethyl fumarate concentration is less
than 500 ng/mL/hr. In other aspects, the average maximum rate of
rise in monomethyl fumarate concentration is less than 400
ng/mL/hr. In other aspects, the average maximum rate of rise in
monomethyl fumarate concentration is less than 250 ng/mL/hr. In
other aspects, the average maximum rate of rise in monomethyl
fumarate concentration is less than 200 ng/mL/hr. In other aspects,
the average maximum rate of rise in monomethyl fumarate
concentration is less than 180 ng/mL/hr. In other aspects, the
average maximum rate of rise in monomethyl fumarate concentration
is less than 140 ng/mL/hr.
[0012] In some embodiments, the methods comprise administering the
compound(s) to each patient in a population of patients to achieve
across the population an average maximum rate of rise in monomethyl
fumarate concentration in the blood plasma of the patients of less
than 0.25 wt % ng-eq of MMF dosed/ml/hr, and an average monomethyl
fumarate concentration in the blood plasma of the patients,
measured at a time of said maximum rate of rise, of less than 250
ng/ml. In another embodiment, the average maximum rate of rise in
monomethyl fumarate concentration in the blood plasma of the
patients is less than 0.15 wt % ng-eq of MMF dosed/ml/hr, and an
average monomethyl fumarate concentration in the blood plasma of
the patients, measured at a time of said maximum rate of rise, is
less than 200 ng/ml. In yet another embodiment, the average maximum
rate of rise in monomethyl fumarate concentration in the blood
plasma of the patients is less than 0.10 wt % ng-eq of MMF
dosed/ml/hr, and an average monomethyl fumarate concentration in
the blood plasma of the patients, measured at a time of said
maximum rate of rise, is less than 140 ng/ml.
[0013] Also disclosed herein are methods of systemically
administering a therapeutically effective amount of a compound
selected from (i) monomethyl fumarate (MMF), (ii) a prodrug of
monomethyl fumarate, and (iii) a combination thereof, to treat a
disease in a patient in need of such treatment, comprising one of:
(a) orally administering to the patient, at a dosing frequency of
not more than twice per day, an enteric-coated oral or a
non-enteric-coated sustained release dosage form containing a
therapeutically effective dose of the compound(s), wherein the
dosage form, when subjected to an in vitro dissolution test
employing as a dissolution medium 750 mL of 0.1 N hydrochloric
acid, at pH 1.2, for a period of 2 hours, followed by addition of
250 mL of 200 mM tribasic sodium phosphate buffer resulting in an
adjustment of the pH of the dissolution medium to 6.8, the
dissolution medium being maintained at 37.degree. C. and stirred at
100 rpm, releases: (i) less than 10 wt % of the dose over an
initial 2 hours of the in vitro dissolution test; (ii) at least 90
wt % of the dose over not less than an initial 8 hours of the in
vitro dissolution test; (iii) no more than 30 wt % of the dose in
any one hour during the in vitro dissolution test; and (iv) no more
than 40 wt % of the dose in any consecutive two hours during the in
vitro dissolution test; or (b) orally administering to the patient,
at a frequency of not more than twice per day, a non-enteric-coated
oral sustained release dosage form containing a therapeutically
effective dose of the compound(s), wherein the dosage form, when
subjected to an in vitro dissolution test employing as a
dissolution medium 750 mL of 0.1 N hydrochloric acid, at pH 1.2,
for a period of 2 hours, followed by addition of 250 mL of 200 mM
tribasic sodium phosphate buffer resulting in an adjustment of the
pH of the dissolution medium to 6.8, releases (i) at least 90 wt %
of the dose over not less than an initial 8 hours of the in vitro
dissolution test; (ii) no more than 30 wt % of the dose in any one
hour during the in vitro dissolution test; and (iii) no more than
40 wt % of the dose in any consecutive two hours during the in
vitro dissolution test.
[0014] The therapeutic treatments disclosed herein can be used to
treat any number of diseases for which FAEs are known or thought to
be therapeutically effective. In certain embodiments, the
therapeutic treatments disclosed herein can be used to treat
adrenal leukodystrophy, AGE-induced genome damage, Alexanders
Disease, Alper's Disease, Alzheimer's disease, amyotrophic lateral
sclerosis, angina pectoris, arthritis, asthma, balo concentric
sclerosis, Canavan disease, cardiac insufficiency including left
ventricular insufficiency, central nervous system vasculitis,
Charcott-Marie-Tooth Disease, childhood ataxia with central nervous
system hypomyelination, chronic idiopathic peripheral neuropathy,
chronic obstructive pulmonary disease, Crohn's disease, diabetic
retinopathy, graft versus host disease, hepatitis C viral
infection, herpes simplex viral infection, human immunodeficiency
viral infection, Huntington's disease, irritable bowel disorder,
ischemia, Krabbe Disease, lichen planus, macular degeneration,
mitochondrial encephalomyopathy, monomelic amyotrophy, multiple
sclerosis, myocardial infarction, neurodegeneration with brain iron
accumulation, neuromyelitis optica, neurosarcoidosis, NF-.kappa.B
mediated diseases, optic neuritis, pareneoplastic syndromes,
Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateral
sclerosis, progressive supranuclear palsy, psoriasis, reperfusion
injury, retinopathia pigmentosa, Schilders Disease, subacute
necrotizing myelopathy, susac syndrome, transplantation rejection,
transverse myelitis, a tumor, ulcerative colitis, Zellweger's
syndrome, granulomas including annulaire, pemphigus, bollus
pemphigoid, behcet's, contact dermatitis, acute dermatitis, chronic
dermatitis, alopecia greata (totalis and universalis), sarcoidosis,
cutaneous sarcoidosis, pyoderma gangrenosum, cutaneous lupus,
Crohn's disease or cutaneous Crohn's disease. In some embodiments,
the therapeutic treatments disclosed herein can be used for the
treatment of multiple sclerosis and psoriasis.
[0015] In a first aspect, the compound being administered comprises
monomethyl fumarate.
[0016] In a second aspect, the compound being administered
comprises a prodrug of monomethyl fumarate.
[0017] In a third aspect, the prodrug of monomethyl fumarate
comprises a compound of Formula (I):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is
chosen from a C.sub.1 to C.sub.6 alkyl.
[0018] In a fourth aspect, the prodrug of monomethyl fumarate
comprises a compound of Formula (II):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0019] R.sup.2 and R.sup.3 are independently chosen from hydrogen,
C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl;
[0020] R.sup.4 and R.sup.5 are independently chosen from hydrogen,
C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
substituted C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl, substituted
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 heteroalkyl, substituted
C.sub.1-6 heteroalkyl, C.sub.4-12 cycloalkylalkyl, substituted
C.sub.4-12 cycloalkylalkyl, C.sub.7-12 arylalkyl, and substituted
C.sub.7-12 arylalkyl; or R.sup.4 and R.sup.5 together with the
nitrogen to which they are bonded form a ring chosen from a
C.sub.5-10 heteroaryl, substituted C.sub.5-10 heteroaryl,
C.sub.5-10 heterocycloalkyl, and substituted C.sub.5-10
heterocycloalkyl; and
[0021] wherein each substituent group is independently chosen from
halogen, --OH, --CN, --CF.sub.3, .dbd.O, --NO.sub.2, benzyl,
--C(O)NR.sup.11.sub.2, --R.sup.11, OR.sup.11, C(O)R.sup.11,
--COOR.sup.11, and --NR.sup.11.sub.2 wherein each R.sup.11 is
independently chosen from hydrogen and C.sub.1-4 alkyl.
[0022] In a fifth aspect, the prodrug of monomethyl fumarate
comprises a compound of Formula (III):
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein:
[0023] R.sup.6 is chosen from C.sub.1-6 alkyl, substituted
C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, substituted C.sub.1-6
heteroalkyl, C.sub.3-8 cycloalkyl, substituted C.sub.3-8
cycloalkyl, C.sub.6-8 aryl, substituted C.sub.6-8 aryl, and
--OR.sup.10 wherein R.sup.10 is chosen from C.sub.1-6 alkyl,
substituted C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, substituted
C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and substituted C.sub.6-10
aryl;
[0024] R.sup.7 and R.sup.8 are independently chosen from hydrogen,
C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl; and
[0025] wherein each substituent group is independently chosen from
halogen, --OH, --CN, --CF.sub.3, .dbd.O, --NO.sub.2, benzyl,
--C(O)NR.sup.11.sub.2, --R.sup.11, --OR.sup.11, --C(O)R.sup.11,
--COOR.sup.11, --N(R.sup.11)C(O)C(R.sup.11).sub.2NR.sup.11.sub.2,
and --NR.sup.11.sub.2 wherein each R.sup.11 is independently chosen
from hydrogen and C.sub.1-4 alkyl.
[0026] In a sixth aspect, the prodrug of monomethyl fumarate
comprises a compound of Formula (IV):
##STR00005##
or a pharmaceutically acceptable salt thereof, wherein n is an
integer from 2 to 6.
FIGURES
[0027] FIG. 1 shows the in vitro release profile of an
enteric-coated sustained released tablet according to Example
1.
[0028] FIG. 2 shows the mean plasma concentration of MMF following
the oral dosing of an enteric-coated sustained released tablet
according to Example 1.
[0029] FIG. 3 shows the percent of prodrug released from the
Example 5 dosage forms over time.
[0030] FIG. 4 shows the mean plasma concentration of MMF following
oral dosing of a formulation prepared according to Example 6 to
fasted and fed healthy adult patients.
[0031] FIG. 5 shows the percent of prodrug released from the
Example 8 dosage forms over time.
[0032] FIG. 6 shows the percent of prodrug released from the
Example 9 dosage forms over time.
[0033] FIG. 7 shows the percent of prodrug released from the
Example 10 dosage forms over time.
[0034] FIG. 8 shows the percent of prodrug released from the two
Example 12 dosage forms over time.
[0035] FIG. 9 shows the percent of prodrug released from the two
Example 13 dosage forms over time.
[0036] FIG. 10 shows the percent of prodrug released from the
Example 14 dosage form over time.
[0037] FIG. 11 shows the percent of prodrug released from the
Example 15 dosage form over time.
[0038] FIG. 12 shows the mean plasma concentration of MMF following
oral dosing of a formulation prepared according to Example 10 to
fasted and fed healthy adult patients.
[0039] FIG. 13 shows the % flushing incidences as a function of
mean MMF Cmax (maximum average concentration) (ng/mL) over patient
populations for DMF and Compound 1 (a prodrug of MMF).
[0040] FIG. 14 shows the % flushing incidences as a function of
mean of individual MMF Cmax (average Cmax) (ng/mL) for DMF and
Compound 1 (a prodrug of MMF).
[0041] FIG. 15 shows the % flushing incidences as a function of
maximum MMF slope (% MMF ng-eq dose/mL/hr) for DMF and Compound 1
(a prodrug of MMF).
[0042] FIG. 16 shows the % flushing incidences as a function of
maximum MMF slope (ng/mL/hr) for DMF and Compound 1 (a prodrug of
MMF).
[0043] The curves in the above figures, where applicable, were
fitted using a Hill E.sub.max model.
DEFINITIONS
[0044] A dash ("-") that is not between two letters or symbols is
used to indicate a point of attachment for a moiety or substituent.
For example, --CONH.sub.2 is bonded through the carbon atom.
[0045] "Alkyl" refers to a saturated or unsaturated, branched, or
straight-chain, monovalent hydrocarbon radical derived by the
removal of one hydrogen atom from a single carbon atom of a parent
alkane, alkene, or alkyne. Examples of alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl, and
ethynyl; propyls such as propan-1-yl, propan-2-yl, prop-1-en-1-yl,
prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl,
but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,
but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,
but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the
like.
[0046] The term "alkyl" is specifically intended to include groups
having any degree or level of saturation, i.e., groups having
exclusively single carbon-carbon bonds, groups having one or more
double carbon-carbon bonds, groups having one or more triple
carbon-carbon bonds, and groups having combinations of single,
double, and triple carbon-carbon bonds. Where a specific level of
saturation is intended, the terms alkanyl, alkenyl, and alkynyl are
used. In certain embodiments, an alkyl group can have from 1 to 20
carbon atoms (C.sub.1-20) in certain embodiments, from 1 to 10
carbon atoms (C.sub.1-10), in certain embodiments from 1 to 8
carbon atoms (C.sub.1-8), in certain embodiments, from 1 to 6
carbon atoms (C.sub.1-6), in certain embodiments from 1 to 4 carbon
atoms (C.sub.1-4), and in certain embodiments, from 1 to 3 carbon
atoms (C.sub.1-3).
[0047] "Aryl" refers to a monovalent aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Aryl encompasses benzene;
bicyclic ring systems wherein at least one ring is carbocyclic and
aromatic, for example, naphthalene, indane, and tetralin; and
tricyclic ring systems wherein at least one ring is carbocyclic and
aromatic, for example, fluorene. Aryl encompasses multiple ring
systems having at least one carbocyclic aromatic ring fused to at
least one carbocyclic aromatic ring, cycloalkyl ring, or
heterocycloalkyl ring. For example, aryl includes a phenyl ring
fused to a 5- to 7-membered heterocycloalkyl ring containing one or
more heteroatoms chosen from N, O, and S. For such fused, bicyclic
ring systems wherein only one of the rings is a carbocyclic
aromatic ring, the radical carbon atom may be at the carbocyclic
aromatic ring or at the heterocycloalkyl ring. Examples of aryl
groups include, but are not limited to, groups derived from
aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene,
hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane,
indene, naphthalene, octacene, octaphene, octalene, ovalene,
penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,
rubicene, triphenylene, trinaphthalene, and the like. In certain
embodiments, an aryl group can have from 6 to 20 carbon atoms
(C.sub.6-20), from 6 to 12 carbon atoms (C.sub.6-12), from 6 to 10
carbon atoms (C.sub.6-10), and in certain embodiments from 6 to 8
carbon atoms (C.sub.6-8).
[0048] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl group. Examples
of arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,
2-naphthophenylethan-1-yl and the like. Where specific alkyl
moieties are intended, the nomenclature arylalkanyl, arylalkenyl,
or arylalkynyl is used. In certain embodiments, an arylalkyl group
is C.sub.7-30 arylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the arylalkyl group is C.sub.1-10 and the aryl moiety is
C.sub.6-20, in certain embodiments, an arylalkyl group is
C.sub.6-18 arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety
of the arylalkyl group is C.sub.1-8 and the aryl moiety is
C.sub.6-10. In certain embodiments, an arylalkyl group is
C.sub.7-12 arylalkyl.
[0049] "Compounds" of Formulae (I)-(IV) disclosed herein include
any specific compounds within these formulae. Compounds may be
identified either by their chemical structure and/or chemical name.
Compounds are named using Chemistry 4-D Draw Pro, version 7.01c
(ChemInnovation Software, Inc., San Diego, Calif.). When the
chemical structure and chemical name conflict, the chemical
structure is determinative of the identity of the compound. The
compounds described herein may comprise one or more chiral centers
and/or double bonds and therefore may exist as stereoisomers such
as double-bond isomers (i.e., geometric isomers), enantiomers, or
diastereomers. Accordingly, any chemical structures within the
scope of the specification depicted, in whole or in part, with a
relative configuration are deemed to encompass all possible
enantiomers and stereoisomers of the illustrated compounds
including the stereoisomerically pure form (e.g., geometrically
pure, enantiomerically pure, or diastereomerically pure) and
enantiomeric and stereoisomeric mixtures. Enantiomeric and
stereoisomeric mixtures may be resolved into their component
enantiomers or stereoisomers using separation techniques or chiral
synthesis techniques well known to the skilled artisan. Compounds
selected from monomethyl fumarate, or a prodrug of monomethyl
fumarate such as dimethyl fumarate or a compound of Formulae
(I)-(IV), include, but are not limited to, optical isomers thereof,
racemates thereof, and other mixtures thereof. In such embodiments,
a single enantiomer or diastereomer, i.e., optically active form
can be obtained by asymmetric synthesis or by resolution of the
racemates. Resolution of the racemates may be accomplished, for
example, by conventional methods such as crystallization in the
presence of a resolving agent, or chromatography using, for
example, chiral stationary phases. Notwithstanding the foregoing,
in compounds selected from monomethyl fumarate, or a prodrug of
monomethyl fumarate such as dimethyl fumarate or a compound of
Formulae (I)-(IV), the configuration of the illustrated double bond
is only in the E configuration (i.e. trans configuration).
[0050] Compounds selected from monomethyl fumarate, or a prodrug of
monomethyl fumarate such as dimethyl fumarate or a compound of
Formulae (I)-(IV), may also exist in several tautomeric forms
including the enol form, the keto form, and mixtures thereof.
Accordingly, the chemical structures depicted herein encompass all
possible tautomeric forms of the illustrated compounds. Compounds
selected from monomethyl fumarate, or a prodrug of monomethyl
fumarate such as dimethyl fumarate or a compound of Formulae
(I)-(IV), also include isotopically labeled compounds where one or
more atoms have an atomic mass different from the atomic mass
conventionally found in nature. Examples of isotopes that may be
incorporated into the compounds disclosed herein include, but are
not limited to, .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, .sup.17O, etc. Compounds may exist in
unsolvated forms as well as solvated forms, including hydrated
forms and as N-oxides. In general, compounds as referred to herein
may be free acid, hydrated, solvated, or N-oxides. Certain
compounds may exist in multiple crystalline, co-crystalline, or
amorphous forms. Compounds selected from monomethyl fumarate, or a
prodrug of monomethyl fumarate such as dimethyl fumarate or a
compound of Formulae (I)-(IV), include pharmaceutically acceptable
salts thereof, or pharmaceutically acceptable solvates of the free
acid form of any of the foregoing, as well as crystalline forms of
any of the foregoing.
[0051] Compounds selected from monomethyl fumarate, or a prodrug of
monomethyl fumarate such as dimethyl fumarate or a compound of any
of Formulae (I)-(IV), also include solvates. A solvate refers to a
molecular complex of a compound with one or more solvent molecules
in a stoichiometric or non-stoichiometric amount. Such solvent
molecules are those commonly used in the pharmaceutical art, which
are known to be innocuous to a patient, e.g., water, ethanol, and
the like. A molecular complex of a compound or moiety of a compound
and a solvent can be stabilized by non-covalent intra-molecular
forces such as, for example, electrostatic forces, van der Waals
forces, or hydrogen bonds. The term "hydrate" refers to a solvate
in which the one or more solvent molecules is water.
[0052] Further, when partial structures of the compounds are
illustrated, an asterisk (*) indicates the point of attachment of
the partial structure to the rest of the molecule.
[0053] "Cycloalkyl" refers to a saturated or partially unsaturated
cyclic alkyl radical. Where a specific level of saturation is
intended, the nomenclature cycloalkanyl or cycloalkenyl is used.
Examples of cycloalkyl groups include, but are not limited to,
groups derived from cyclopropane, cyclobutane, cyclopentane,
cyclohexane, and the like. In certain embodiments, a cycloalkyl
group is C.sub.3-15 cycloalkyl, C.sub.3-12 cycloalkyl, and in
certain embodiments, C.sub.3-8 cycloalkyl.
[0054] "Cycloalkylalkyl" refers to an acyclic alkyl radical in
which one of the hydrogen atoms bonded to a carbon atom, typically
a terminal or sp.sup.3 carbon atom, is replaced with a cycloalkyl
group. Where specific alkyl moieties are intended, the nomenclature
cycloalkylalkanyl, cycloalkylalkenyl, or cycloalkylalkynyl is used.
In certain embodiments, a cycloalkylalkyl group is C.sub.4-30
cycloalkylalkyl, e.g., the alkanyl, alkenyl, or alkynyl moiety of
the cycloalkylalkyl group is C.sub.1-10 and the cycloalkyl moiety
is C.sub.3-20, and in certain embodiments, a cycloalkylalkyl group
is C.sub.3-20 cycloalkylalkyl, e.g., the alkanyl, alkenyl, or
alkynyl moiety of the cycloalkylalkyl group is C.sub.1-8 and the
cycloalkyl moiety is C.sub.3-12. In certain embodiments, a
cycloalkylalkyl group is C.sub.4-12 cycloalkylalkyl.
[0055] "Dimethyl fumarate" refers to the dimethyl ester of fumaric
acid. The compound has the formula H.sub.3COOCCH.dbd.CHCOOCH.sub.3,
and has a molecular weight of 144.13 daltons. This compound is also
known by the names Dimethyl (E)-butenedioate (IUPAC),
trans-1,2-Ethylenedicarboxylic acid dimethyl ester and
(E)-2-Butenedioic acid dimethyl ester. The compound is also
referred to herein by the acronym DMF.
[0056] "Disease" refers to a disease, disorder, condition, or
symptom of any of the foregoing.
[0057] "Drug" as defined under 21 U.S.C. .sctn.321(g)(1) means "(A)
articles recognized in the official United States Pharmacopoeia,
official Homeopathic Pharmacopoeia of the United States, or
official National Formulary, or any supplement to any of them; and
(B) articles intended for use in the diagnosis, cure, mitigation,
treatment, or prevention of disease in man or other animals; and
(C) articles (other than food) intended to affect the structure or
any function of the body of man or other animals.
[0058] "Flushing" refers to a transient erythema or redness of the
skin, together with a sensation of warmth or burning, typically
over the face and/or neck and less frequently on the upper trunk
and abdomen. A flush is usually temporary and is caused by
medications or other substances that cause widening of the
capillaries, such as niacin. A more detailed description of
flushing can be found in Champion R. H., et al, eds.
Rook/Wilkinson/Ebling Textbook of Dermatology, 6th ed., vol. 3.,
Oxford, UK: Blackwell Scientific, 1998; "Flushing and Flushing
Syndromes, Rosacea and Perioral Dermatitis", pp. 2099-2104.
[0059] "Halogen" refers to a fluoro, chloro, bromo, or iodo group.
In certain embodiments, halogen refers to a chloro group.
[0060] "Heteroalkyl" by itself or as part of another substituent
refers to an alkyl group in which one or more of the carbon atoms
(and certain associated hydrogen atoms) are independently replaced
with the same or different heteroatomic groups. Examples of
heteroatomic groups include, but are not limited to, --O--, --S--,
O--O--, --S--S--, --O--S--, --NR.sup.13, .dbd.N--N.dbd.,
--N.dbd.N--, --N.dbd.N--NR.sup.13--, --PR.sup.13--, --P(O).sub.2--,
--POR.sup.13--, --O--P(O).sub.2--, --SO--, --SO.sub.2--,
--Sn(R.sup.13).sub.2--, and the like, where each R.sup.13 is
independently chosen from hydrogen, C.sub.1-6 alkyl, substituted
C.sub.1-6 alkyl, C.sub.6-12 aryl, substituted C.sub.6-12 aryl,
C.sub.7-18 arylalkyl, substituted C.sub.7-18 arylalkyl, C.sub.3-7
cycloalkyl, substituted C.sub.3-7 cycloalkyl, C.sub.3-7
heterocycloalkyl, substituted C.sub.3-7 heterocycloalkyl, C.sub.1-6
heteroalkyl, substituted C.sub.1-6 heteroalkyl, C.sub.6-12
heteroaryl, substituted C.sub.6-12 heteroaryl, C.sub.7-18
heteroarylalkyl, or substituted C.sub.7-18 heteroarylalkyl.
Reference to, for example, a C.sub.1-6 heteroalkyl, means a
C.sub.1-6 alkyl group in which at least one of the carbon atoms
(and certain associated hydrogen atoms) is replaced with a
heteroatom. For example C.sub.1-6 heteroalkyl includes groups
having five carbon atoms and one heteroatom, groups having four
carbon atoms and two heteroatoms, etc. In certain embodiments, each
R.sup.13 is independently chosen from hydrogen and C.sub.1-3 alkyl.
In certain embodiments, a heteroatomic group is chosen from --O--,
--S--, --NH--, --N(CH.sub.3)--, and --SO.sub.2--; and in certain
embodiments, the heteroatomic group is --O--.
[0061] "Heteroaryl" refers to a monovalent heteroaromatic radical
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Heteroaryl encompasses multiple
ring systems having at least one heteroaromatic ring fused to at
least one other ring, which can be aromatic or non-aromatic. For
example, heteroaryl encompasses bicyclic rings in which one ring is
heteroaromatic and the second ring is a heterocycloalkyl ring. For
such fused, bicyclic heteroaryl ring systems wherein only one of
the rings contains one or more heteroatoms, the radical carbon may
be at the aromatic ring or at the heterocycloalkyl ring. In certain
embodiments, when the total number of N, S, and O atoms in the
heteroaryl group exceeds one, the heteroatoms are not adjacent to
one another. In certain embodiments, the total number of
heteroatoms in the heteroaryl group is not more than two.
[0062] Examples of heteroaryl groups include, but are not limited
to, groups derived from acridine, arsindole, carbazole,
.beta.-carboline, chromane, chromene, cinnoline, furan, imidazole,
indazole, indole, indoline, indolizine, isobenzofuran, isochromene,
isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,
phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,
tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,
thiazolidine, oxazolidine, and the like. In certain embodiments, a
heteroaryl group is from 4- to 20-membered heteroaryl (C.sub.4-20),
and in certain embodiments from 4- to 12-membered heteroaryl
(C.sub.4-10). In certain embodiments, heteroaryl groups are those
derived from thiophene, pyrrole, benzothiophene, benzofuran,
indole, pyridine, quinoline, imidazole, oxazole, or pyrazine. For
example, in certain embodiments, C.sub.5 heteroaryl can be furyl,
thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,
isoxazolyl.
[0063] "Heterocycloalkyl" refers to a saturated or unsaturated
cyclic alkyl radical in which one or more carbon atoms (and certain
associated hydrogen atoms) are independently replaced with the same
or different heteroatom; or to a parent aromatic ring system in
which one or more carbon atoms (and certain associated hydrogen
atoms) are independently replaced with the same or different
heteroatom such that the ring system no longer contains at least
one aromatic ring. Examples of heteroatoms to replace the carbon
atom(s) include, but are not limited to, N, P, O, S, Si, etc.
Examples of heterocycloalkyl groups include, but are not limited
to, groups derived from epoxides, azirines, thiiranes,
imidazolidine, morpholine, piperazine, piperidine, pyrazolidine,
pyrrolidine, quinuclidine, and the like. In certain embodiments, a
heterocycloalkyl group is C.sub.5-10 heterocycloalkyl, C.sub.5-8
heterocycloalkyl, and in certain embodiments, C.sub.5-6
heterocycloalkyl.
[0064] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry, i.e., an atom or a group
capable of being displaced by a nucleophile and includes halogen
such as chloro, bromo, fluoro, and iodo, acyloxy (alkoxycarbonyl)
such as acetoxy and benzoyloxy, aryloxycarbonyl, mesyloxy,
tosyloxy, trifluoromethanesulfonyloxy, aryloxy such as
2,4-dinitrophenoxy, methoxy, N,O-dimethylhydroxylamino,
p-nitrophenolate, imidazolyl, and the like.
[0065] "Monomethyl fumarate" refers to the monomethyl ester of
fumaric acid. The compound has the formula
HOOCCH.dbd.CHCOOCH.sub.3, and has a molecular weight of 130.10
daltons. The compound is also commonly referred to as
2(E)-Butenedioic acid 1-methyl ester,
(2E)-4-Methoxy-4-oxobut-2-enoic acid; Fumaric acid hydrogen
1-methyl ester; (2E)-2-Butenedioic acid 1-methyl ester;
(E)-2-Butenedioic acid monomethyl ester; Monomethyl
trans-ethylene-1,2-dicarboxylate; and methyl hydrogen fumarate. The
compound is also referred to herein and elsewhere by the acronyms
MMF and/or MHF.
[0066] "Parent aromatic ring system" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated .pi. (pi)
electron system. Included within the definition of "parent aromatic
ring system" are fused ring systems in which one or more of the
rings are aromatic and one or more of the rings are saturated or
unsaturated, such as, for example, fluorene, indane, indene,
phenalene, etc. Examples of parent aromatic ring systems include,
but are not limited to, aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene,
coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene,
as-indacene, s-indacene, indane, indene, naphthalene, octacene,
octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, and the like.
[0067] "Parent heteroaromatic ring system" refers to an aromatic
ring system in which one or more carbon atoms (and any associated
hydrogen atoms) are independently replaced with the same or
different heteroatom in such a way as to maintain the continuous
.pi.-electron system characteristic of aromatic systems and a
number of out-of-plane .pi.-electrons corresponding to the Huckel
rule (4n+2). Examples of heteroatoms to replace the carbon atoms
include, but are not limited to, N, P, O, S, and Si, etc.
Specifically included within the definition of "parent
heteroaromatic ring systems" are fused ring systems in which one or
more of the rings are aromatic and one or more of the rings are
saturated or unsaturated, such as, for example, arsindole,
benzodioxan, benzofuran, chromane, chromene, indole, indoline,
xanthene, etc. Examples of parent heteroaromatic ring systems
include, but are not limited to, arsindole, carbazole,
.beta.-carboline, chromane, chromene, cinnoline, furan, imidazole,
indazole, indole, indoline, indolizine, isobenzofuran, isochromene,
isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,
phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,
tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,
thiazolidine, oxazolidine, and the like.
[0068] "Patient" refers to a mammal, for example, a human.
[0069] "Pharmaceutically acceptable" refers to approved or
approvable by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly
in humans.
[0070] "Pharmaceutically acceptable salt" refers to a salt of a
compound, which possesses the desired pharmacological activity of
the parent compound. Such salts include acid addition salts, formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; and salts formed when an acidic proton present
in the parent compound is replaced by a metal ion, e.g., an alkali
metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine, and the like.
In certain embodiments, a pharmaceutically acceptable salt is the
hydrochloride salt. In certain embodiments, a pharmaceutically
acceptable salt is the sodium salt.
[0071] "Pharmaceutically acceptable vehicle" refers to a
pharmaceutically acceptable diluent, a pharmaceutically acceptable
adjuvant, a pharmaceutically acceptable excipient, a
pharmaceutically acceptable carrier, or a combination of any of the
foregoing with which a compound provided by the present disclosure
may be administered to a patient and which does not destroy the
pharmacological activity thereof and which is non-toxic when
administered in doses sufficient to provide a therapeutically
effective amount of the compound.
[0072] "Pharmaceutical composition" refers to a compound selected
from monomethyl fumarate, or a prodrug of monomethyl fumarate such
as dimethyl fumarate or a compound of Formulae (I)-(IV), and at
least one pharmaceutically acceptable vehicle, with which the
compound is administered to a patient.
[0073] "Substituted" refers to a group in which one or more
hydrogen atoms are independently replaced with the same or
different substituent group(s). In certain embodiments, each
substituent group is independently chosen from halogen, --OH, --CN,
--CF.sub.3, .dbd.O, --NO.sub.2, benzyl, --C(O)NH.sub.2, --R.sup.11,
--OR.sup.11, --C(O)R.sup.11, --COOR.sup.11, and --NR.sup.11.sub.2
wherein each R.sup.11 is independently chosen from hydrogen and
C.sub.1-4 alkyl. In certain embodiments, each substituent group is
independently chosen from halogen, --OH, --CN, --CF.sub.3,
--NO.sub.2, benzyl, --R.sup.11, --OR.sup.11, and --NR.sup.11.sub.2
wherein each R.sup.11 is independently chosen from hydrogen and
C.sub.1-4 alkyl. In certain embodiments, each substituent group is
independently chosen from halogen, --OH, --CN, --CF.sub.3, .dbd.O,
--NO.sub.2, benzyl, --C(O)NR.sup.11.sub.2, --R.sup.11, --OR.sup.11,
--C(O)R.sup.11, --COOR.sup.11, and --NR.sup.11.sub.2 wherein each
R.sup.11 is independently chosen from hydrogen and C.sub.1-4 alkyl.
In certain embodiments, each substituent group is independently
chosen from --OH, C.sub.1-4 alkyl, and --NH.sub.2.
[0074] "Systemic administration" and "systemically administering"
shall each mean a route of administration of a compound (as defined
herein) into the circulatory system of a patient in a
therapeutically effective amount (as defined herein). In some
non-limiting embodiments, administration can take place via enteral
administration (absorption of the medication through the
gastrointestinal tract) or parenteral administration (generally
injection, infusion, or implantation). These terms are in contrast
with topical and other types of local administration where a
therapeutically effective amount is not in the circulatory system.
In some embodiments, systemic administration is oral
administration. In some embodiments, systemic administration is
parenteral administration by injection.
[0075] "Treating" or "treatment" of any disease refers to
reversing, alleviating, arresting, or ameliorating a disease or at
least one of the clinical symptoms of a disease, reducing the risk
of acquiring at least one of the clinical symptoms of a disease,
inhibiting the progress of a disease or at least one of the
clinical symptoms of the disease or reducing the risk of developing
at least one of the clinical symptoms of a disease. "Treating" or
"treatment" also refers to inhibiting the disease, either
physically, (e.g., stabilization of a discernible symptom),
physiologically, (e.g., stabilization of a physical parameter), or
both, and to inhibiting at least one physical parameter that may or
may not be discernible to the patient. In certain embodiments,
"treating" or "treatment" refers to protecting against or delaying
the onset of at least one or more symptoms of a disease in a
patient.
[0076] "Therapeutically effective amount" refers to the amount of a
compound that, when administered to a subject for treating a
disease, or at least one of the clinical symptoms of a disease, is
sufficient to affect such treatment of the disease or symptom
thereof. The "therapeutically effective amount" may vary depending,
for example, on the compound, the disease and/or symptoms of the
disease, severity of the disease and/or symptoms of the disease or
disorder, the age, weight, and/or health of the patient to be
treated, and the judgment of the prescribing physician. An
appropriate amount in any given instance may be ascertained by
those skilled in the art or capable of determination by routine
experimentation.
[0077] "Therapeutically effective dose" refers to a dose that
provides effective treatment of a disease or disorder in a patient.
A therapeutically effective dose may vary from compound to
compound, and from patient to patient, and may depend upon factors
such as the condition of the patient and the route of delivery. A
therapeutically effective dose may be determined in accordance with
routine pharmacological procedures known to those skilled in the
art.
[0078] "Average Cmax" refers to the average of two or more
individual Cmax values determined across a group of multiple
subjects. For example, if multiple subjects are dosed as described
herein they can each have a different individual Cmax value. The
calculated mean of these different Cmax values is the "Average
Cmax" for the group.
[0079] "Maximum Average Concentration" refers to the observed Cmax
of an average plot of MMF concentration versus time for a group of
subjects, constructed as a single curve using the calculated
average MMF concentration across all subjects at each time point.
For example, if a group comprising multiple subjects is dosed as
described herein each subject can each have different MMF
concentrations at any given time point. The observed Cmax value
obtained from the single curve constructed by plotting the average
concentration values at each time point is the "Maximum Average
Concentration". The "Maximum Average Concentration" value may not
be the same as the "Average Cmax" value for the same group of
individuals.
[0080] "Average maximum rate of rise" refers to the average of all
of the individual maximum rates of rise determined across all
subjects.
DETAILED DESCRIPTION
[0081] Reference is now made in detail to certain embodiments of
the methods for reducing flushing in patients during administration
of a compound selected from: (i) monomethyl fumarate, (ii) a
prodrug of monomethyl fumarate, and/or (iii) a combination thereof.
The disclosed embodiments are not intended to be limiting of the
claims. To the contrary, the claims are intended to cover all
alternatives, modifications, and equivalents.
Methods
In Vitro Measurement of MMF or MMF Prodrug Release from a Dosage
Form
[0082] A 2-stage dissolution test in which the dosage form to be
tested is first placed in a low pH solution for 2 hours, followed
by placement in a near neutral pH solution for the remainder of the
test period. This dissolution test is used to better approximate
the pH conditions experienced by a dosage form after swallowing by
a patient, i.e., low pH of the stomach followed by near neutral pH
of the intestines. The dosage forms are first placed into a
dissolution vessel (USP, Type I, basket) containing 750 mL of 0.1 N
hydrochloric acid (pH 1.2). After 2 hours, 250 mL of 200 mM
tribasic sodium phosphate is added to the vessel resulting in a pH
adjustment from 1.2 to 6.8. The dissolution medium is kept at
37.degree. C. and is agitated at 100 rpm. Samples are taken at each
sampling time point and analyzed by reverse phase HPLC using a C18
column for the compound being tested. The HPLC parameters are set
as follows: a 7 minute gradient method according to Table 4
(Example 2) where Mobile Phase A is water/0.1% H.sub.3PO.sub.4 and
Mobile Phase B is water/acetonitrile/H.sub.3PO.sub.4 (10/90/0.1 by
volume) with UV detection at 210 nm.
[0083] Individual patients exhibit varying susceptabilities to
flushing caused by exposure to MMF. Thus, at identical MMF
exposures, certain patients exhibit no flushing while other
patients exhibit flushing. For this reason, in the present context,
a reduction of flushing is intended to denote a decrease in the
incidence/frequency among a given treated patient population of
flushing observed after administration of the compound(s) according
to the disclosures herein. The incidence/frequency of flushing
observed after administration of the same compound(s) but at
pharmacokinetic parameters (i.e., Cmax and slopes of the MMF blood
plasma concentration versus time curves) exceeding those set forth
herein is used as the basis for comparison. The incidence/frequency
of flushing in a patient population can be measured, e.g., as
described by O'toole et al. Cancer 2000, 88(4), 770-776. Typically,
the incidence/frequency of flushing is measured and expressed as
the percentage of patients within a test group who experience
flushing.
[0084] In the context of treating multiple sclerosis by
systemically administering MMF and/or an MMF prodrug, the only
reported incidences of flushing reported to date have been in
connection with the clinical testing of Biogen Idec's BG-12
product, which is a delayed release (i.e., enteric coated
microtablets) oral dosage form of the MMF prodrug dimethyl
fumarate; see, e.g., Sheikh et al., Safety Tolerability and
Pharmacokinetics of BG-12 Administered with and without Aspirin,
Key Findings from a Randomized, Double-blind, Placebo-controlled
Trial in Healthy Volunteers, Poster PO4.136 presented at the
64.sup.th Annual Meeting of the American Academy of Neurology, Apr.
21-28, 2012, New Orleans, La.; Dawson et al., Bioequivalence of
BG-12 (Dimethyl Fumarate) Administered as a Single 240 mg Capsule
and Two 120 mg Capsules: Findings from a Randomized, Two-period
Crossover Study, Poster P913 presented at the 28th Congress of the
European Committee for Treatment and Research in Multiple
Sclerosis, Oct. 10-13, 2012, Lyon, France; and Woodworth et al.,
Pharmacokinetics of Oral BG-12 Alone Compared with BG-12 and
Interferon .beta.-1a or Glatiramer Acetate Administered Together,
Studied in Health Volunteers, Poster PO4.207 presented at the
62.sup.nd Annual Meeting of the American Academy of Neurology, Apr.
10-17, 2010, Toronto, Ontario, Canada. In these publications,
Sheikh reported flushing incidences of 83% and 100% for patients
taking BG-12 only, BID and TID, respectively; Dawson reported
flushing incidences of 84% and 86% for two different BG-12 dosage
forms; and Woodward reported flushing incidences of 50% and 76% in
treatment groups receiving BG-12 alone. Thus, the reported
incidences of flushing in patients taking BG-12 averages to 80%
across multiple patient populations.
[0085] In one aspect, in the context of systemic treatment of
multiple sclerosis by systemic administration of MMF and/or an MMF
prodrug, a reduction in flushing according to the methods disclosed
herein is construed as a flushing incidence of less than 50% of a
treated patient population. In another aspect, the incidence of
flushing is less than 40% of a treated patient population. In
another aspect the incidence of flushing is less than 30% of a
treated patient population. The reduction of flushing
incidence/frequency, as described above, can be monitored in a
clinical trial setting.
[0086] In the context of treating psoriasis by systemically
administering MMF and/or an MMF prodrug, the only reported
incidences of flushing published to date have been in connection
with the clinical testing of Fumapharm's Fumaderm product, which is
a delayed release (i.e., enteric coated tablet) oral dosage form of
the MMF prodrug dimethyl fumarate together with several different
salts of monoethyl fumarate. Monoethyl fumarate and salts thereof
are not MMF prodrugs. Mrowietz et al. (Treatment of Psoriasis with
Fumaric Acid Esters: Results of a prospective Multicenter Study,
British Journal of Dermatology, 1998, 138(3), 456-460) report
flushing incidence of 31%. Other reported flushing incidence in
psoriasis patients taking Fumaderm of about 30% and one-third of
patients are common.
[0087] In one aspect, in the context of systemic treatment of
psoriasis by systemic administration of MMF and/or an MMF prodrug,
a reduction in flushing according to the methods disclosed herein
is construed as a flushing incidence of less than 20% of a treated
patient population. In another aspect, the incidence of flushing is
less than 15% of a treated patient population. In another aspect
the incidence of flushing is less than 10% of a treated patient
population. The reduction of flushing incidence/frequency, as
described above, can be monitored in a clinical trial setting.
[0088] In accordance with a first aspect of the presently disclosed
treatment methods, the MMF and/or MMF prodrug is systemically
administered in therapeutic amounts using a dosage form and a
dosing frequency that achieves across a population of patients
receiving said treatment a maximum average concentration, as
defined herein, of monomethyl fumarate in the blood plasma of the
patients of less than 500 ng/ml. In one embodiment, the maximum
average concentration of monomethyl fumarate in the blood plasma of
the patients is less than 400 ng/ml. In another embodiment, the
maximum average concentration of monomethyl fumarate in the blood
plasma of the patients is less than 350 ng/ml. In yet another
embodiment, the maximum average concentration of monomethyl
fumarate in the blood plasma of the patients is less than 300
ng/ml. In yet another embodiment, the maximum average concentration
of monomethyl fumarate in the blood plasma of the patients is less
than 250 ng/ml. In yet another embodiment, the maximum average
concentration of monomethyl fumarate in the blood plasma of the
patients is less than 200 ng/ml. In yet another embodiment, the
maximum average concentration of monomethyl fumarate in the blood
plasma of the patients is less than 150 ng/ml. In yet another
embodiment, the maximum average concentration of monomethyl
fumarate in the blood plasma of the patients is less than 100
ng/ml.
[0089] In another aspect, the average Cmax, as defined herein, of
monomethyl fumarate in the blood plasma of the patients is less
than 1100 ng/ml. In certain aspects, the average Cmax of monomethyl
fumarate in the blood plasma of the patients is maintained at less
than 600 ng/ml. In yet another aspect, the average Cmax of
monomethyl fumarate in the blood plasma of the patients is
maintained at less than 500 ng/ml. In yet another aspect, the
average Cmax of monomethyl fumarate in the blood plasma of the
patients is maintained at less than 400 ng/ml. In yet another
aspect, the average Cmax of monomethyl fumarate in the blood plasma
of the patients is maintained at less than 300 ng/ml. In yet
another aspect, the average Cmax of monomethyl fumarate in the
blood plasma of the patients is maintained at less than 200 ng/ml.
In yet another aspect, the average Cmax of monomethyl fumarate in
the blood plasma of the patients is maintained at less than 100
ng/ml.
[0090] The following table and FIGS. 13-14 show flushing incidence
as a function of MMF Cmax (maximum average concentration and
average Cmax) over patient populations for DMF and an MMF prodrug
of Formula (II). The curves in the figures were fitted using a Hill
E.sub.max model.
TABLE-US-00001 TABLE 1 Flushing Incidence as a Function of MMF Cmax
MMF Dosing Cmax Mean of Compound, Fre- of Indi- Flush- Formu- mg-
quency/ Mean vidual ing lation*, Dose eq of Dose Plot** MMF Inci-
(mg) and MMF Interval (ng/ Cmax*** dence Source fed or fasted dosed
(hrs) mL) (ng/mL) (%) Dawson.sup.+ DMF, BG- 218 BID/12 1250 2340 84
12, 240, fasted Sheikh.sup.+ DMF, BG- 218 BID/12 738 1335 83 12,
240, fed Study 1 Compound 212 BID/12 649 1290 83 (1).sup.++
Formulation 1, 400, fasted Study 2 Compound 106 Single 439 975 67
(1), Dose Formulation 1, 200, fasted Study 2 Compound 106 Single
302 529 58 (1), Dose Formulation 1, 200, fasted Study 2 Compound
106 Single 185 366 42 (1), Dose Formulation 1, 200, fed Study 2
Compound 106 Single 139 217 8 (1), Dose Formulation 2, 200, fed
Study 2 Compound 106 Single 129 95 8 (1), Dose Formulation 3, 200,
fasted Study 2 Compound 106 Single 124 143 0 (1), Dose Formulation
2, 200, fasted Study 2 Compound 106 Single 93 106 9 (1), Dose
Formulation 4, 200, fed Study 2 Compound 106 Single 63 80 8 (1),
Dose Formulation 3, 200, fed Study 2 Compound 106 Single 50 64 17
(1), Dose Formulation 4, 200, fast *Formulation 2 is the dosage
form described in Example 10; Formulation 3 is the dosage form
described in Example 3; Formulation 4 is the dosage form described
in Example 5; **maximum average Concentration; ***average Cmax;
.sup.+Poster (see above); .sup.++Compound (1) referred to in the
above table is an MMF prodrug of Formula (II);
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate having
the following chemical structure: ##STR00006##
[0091] The fifth column of the above table lists the values of MMF
Cmax of the mean plot (maximum average concentration) in decreasing
order. As shown in Table 1, as the mean MMF Cmax (maximum average
concentration) drops from 649 to 439 ng/ml, the flushing incidence
drops below the rates reported previously in the literature for the
BG-12 DMF product. The sixth column of the above table lists the
corresponding mean of individual MMF Cmax (Average Cmax) values. As
shown in Table 1, as the mean MMF Cmax (Average Cmax) drops below
1100 ng/ml, the flushing incidence drops below the rates reported
previously in the literature for the BG-12 DMF product.
[0092] In accordance with a second aspect of the presently
disclosed treatment methods, the MMF and/or MMF prodrug is
systemically administered in therapeutic amounts using a dosage
form and a dosing frequency that achieves across a population of
patients receiving said treatment an average maximum rate of rise
in MMF concentration in the blood plasma of the patients of less
than 0.25 wt % ng-eq of MMF dosed/ml/hr. In one embodiment, the
average maximum rate of rise in MMF concentration in the blood
plasma of the patients is less than 0.20 wt % ng-eq of MMF
dosed/ml/hr. In another embodiment, the average maximum rate of
rise in MMF concentration in the blood plasma of the patients is
less than 0.15 wt % ng-eq of MMF dosed/ml/hr. In yet another
embodiment, the average maximum rate of rise in MMF concentration
in the blood plasma of the patients is less than 0.10 wt % ng-eq of
MMF dosed/ml/hr.
[0093] In one embodiment, the methods comprise controlling
administration of the compound(s) to the patient to achieve across
a population of patients receiving said controlled administration
of compound(s), an average maximum rate of rise in monomethyl
fumarate concentration in the blood plasma of the patients of less
than 0.25 wt % ng-eq of MMF dosed/ml/hr, and an average monomethyl
fumarate concentration in the blood plasma of the patients,
measured at a time of said maximum rate of rise, of less than 200
ng/ml. In another embodiment, the average maximum rate of rise in
monomethyl fumarate concentration in the blood plasma of the
patients is less than 0.15 wt % ng-eq of MMF dosed/ml/hr, and an
average monomethyl fumarate concentration in the blood plasma of
the patients, measured at a time of said maximum rate of rise, is
less than 180 ng/ml. In yet another embodiment, the average maximum
rate of rise in monomethyl fumarate concentration in the blood
plasma of the patients is less than 0.10 wt % ng-eq of MMF
dosed/ml/hr, and an average monomethyl fumarate concentration in
the blood plasma of the patients, measured at a time of said
maximum rate of rise, is less than 140 ng/ml.
[0094] The maximum slope values (% dose and ng) for different
dosage treatments are given in Table 2. The FIGS. 15-16 show plots
of maximum MMF slope vs flushing incidence. The curves in the
figures were fitted using a Hill E.sub.max model.
TABLE-US-00002 TABLE 2 Compound, Flushing Formulation*, Dose Max
Slope Max slope Incidence Source (mg), food % dose/mL/h (ng/mL/hr)
(%) Dawson DMF, BG-12, 240 mg, 0.5005 1084.3 84 fed Sheikh DMF,
BG-12, 240 mg, 0.2885 625.0 83 fed Study 1 Compound (1), 0.3689
789.1 83 Compound (1), Formulation 1 400 mg fast Study 1 Compound
(1), 0.3128 669.2 67 Formulation 1 200 mg fast Study 2 Compound
(1), 0.3448 368.9 58 Formulation 1 200 mg fast Study 2 Compound
(1), 0.0680 72.7 42 Formulation 1 200 mg fed Study 2 Compound (1),
0.0647 69.3 8 Formulation 2 200 mg fed Study 2 Compound (1), 0.0718
76.8 0 Formulation 2 200 mg fast Study 2 Compound (1), 0.0542 57.9
8 Formulation 3 200 mg fast Study 2 Compound (1), 0.0334 35.7 8
Formulation 3 200 mg fed Study 2 Compound (1), 0.0448 47.9 17
Formulation 4 200 mg fast Study 2 Compound (1), 0.0787 84.2 9
Formulation 4 200 mg fed *Formulation 2 is the dosage form
described in Example 10; Formulation 3 is the dosage form described
in Example 3; Formulation 4 is the dosage form described in Example
5.
[0095] In order to achieve the pharmacokinetic values of (i) a
maximum average concentration of monomethyl fumarate in the blood
plasma of the patients of less than 500 ng/ml, and/or (ii) an
average maximum rate of rise in MMF concentration in the blood
plasma of the patients of less than 0.25 wt % ng-eq of MMF
dosed/ml/hr, it is necessary to control the introduction of MMF
and/or MMF prodrug into the patients' bloodstream. For systemic
oral delivery, this generally means an oral sustained release
dosage form. While sustained and delayed-sustained release dosage
forms of MMF prodrugs of Formula I, and most typically sustained
release dosage forms of DMF, have been disclosed in the literature
for reducing flushing, we have discovered that such dosage forms in
fact offer little improvement in reducing patient flushing, either
because they achieve too high of a maximum average concentration of
monomethyl fumarate in the blood plasma of the patients, and/or too
high of an average maximum rate of rise in MMF concentration in the
blood plasma of the patients. Specifically, Nilsson et al. in US
Patent Publication Nos. 2012/0034274 and 2012/0034303 disclose oral
sustained release and oral delayed sustained release dosage forms
of DMF, the latter dosage forms being enteric coated. Although the
Nilsson dosage forms purport to reduce the incidence of flushing in
patients, they present their flushing incidence as a percentage of
the patients who flush upon administration of Fumaderm which
contains DMF as a primary active ingredient (see Tables II in both
Nilsson publications) and at least some of the reported reductions
in the incidence of flushing (23% and 35% reductions compared to
Fumaderm) may well be within the range of experimental error or
variability within small patient populations. Of the many dosage
forms disclosed in these two publications, the slowest
DMF-releasing dosage forms are in Example 2 of US 2012/0034274 and
Examples 16 and 23 of US 2012/0034303. The Example 2 dosage form is
shown to release: (i) about 90% of the DMF dose over a period of 3
hours, (ii) about 43% of the DMF dose in the third hour of in vitro
release, and (iii) about 65% of the DMF loading over the second and
third hours of in vitro release. The Example 16 dosage form, which
is enteric coated and therefore exhibits little to no release
during the first 2 hours of the in vitro test at low pH conditions,
is shown to release (i) about 90% of the DMF dose over a period of
3.5 hours marked from the start of the near-neutral pH portion of
the test, and (ii) about 50-55% of its DMF loading over the second
and third hours of in vitro release. The Example 23 dosage form is
shown to release (i) about 90% of the DMF dose over a period of 4
hours, and (ii) about 65% of its DMF loading over the third and
fourth hours of in vitro release. Thus, all of the Nilsson dosage
forms release the majority (90%) of their DMF dose in periods of 4
hours or less, measured from the start of DMF release.
[0096] In contrast to the Nilsson et al. dosage forms, the dosage
forms disclosed herein release MMF and/or MMF prodrug at a slower
rate and over longer time periods than the Nilsson dosage forms.
The oral dosage forms disclosed herein can be characterized as
either enteric-coated, and therefore not designed to release much
of the compound in the low pH environment of a patient's stomach,
or non-enteric coated, in which release of compound in the stomach
is not necessarily prohibited.
[0097] Thus, for oral enteric-coated dosage forms disclosed herein,
the dosage forms contain a therapeutically effective dose of the
MMF and/or MMF prodrug and are designed to be administered to each
patient in a population of patients at a dosing frequency of not
more than twice per day. The dosage forms, when subjected to the in
vitro dissolution test employing pH 1.2 for the first 2 hours, and
pH 6.8 thereafter, releases the dose of MMF and/or MMF prodrug as
follows: (i) less than 10 wt % of the dose over the first 2 hours
of the in vitro dissolution test; (ii) at least 90 wt % of the dose
over not less than the first 8 hours of the in vitro dissolution
test; (iii) no more than 30 wt % of the dose in any one hour during
the in vitro dissolution test; and (iv) no more than 40 wt % of the
dose in any consecutive two hours during the in vitro dissolution
test.
[0098] For oral non-enteric-coated dosage forms disclosed herein,
the dosage forms contain a therapeutically effective dose of the
MMF and/or MMF prodrug and are designed to be administered to each
patient in a population of patients at a dosing frequency of not
more than twice per day. The dosage forms, when subjected to the in
vitro dissolution test employing pH 1.2 for the first 2 hours, and
pH 6.8 thereafter, releases the dose of MMF and/or MMF prodrug as
follows: (i) at least 90 wt % of the dose over not less than the
first 8 hours of the in vitro dissolution test; (ii) no more than
30 wt % of the dose in any one hour during the in vitro dissolution
test; and (iii) no more than 40 wt % of the dose in any consecutive
two hours during the in vitro dissolution test.
[0099] Suitable sustained release oral dosage forms that achieve
the above described in vitro release profiles are disclosed in
Examples 1 and 3 (enteric-coated sustained release tablets), 5
(enteric-coated pellets in a Vcaps plus capsule) and 8-15
(non-enteric-coated, compression coated tablets) herein.
Compounds
[0100] Certain embodiments of the methods disclosed herein utilize
a compound of Formula (I):
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is
chosen from a C.sub.1 to C.sub.6 alkyl.
[0101] In certain embodiments, R.sup.1 is C.sub.2 to C.sub.6
alkyl.
[0102] In certain embodiments, R.sup.1 is methyl.
[0103] In certain embodiments, R.sup.1 is ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, pentyl-2-yl,
2-methylbutyl, isopentyl, 3-methylbutan-2-yl, neopentyl,
tert-pentyl, n-hexyl, hexan-2-yl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 3-methylpentan-2-yl, 4-methylpentan-2-yl,
2,3-dimethylbutyl, or 3,3-dimethylbutyl.
[0104] Examples of compounds of Formula (I) include
dimethylfumarate, diethylfumarate, dipropylfumarate,
dibutylfumarate, dipentylfumarate, methyl-ethylfumarate,
methyl-propylfumarate, methyl-butylfumarate, methyl-pentylfumarate,
monoethylfumarate, monopropylfumarate, monobutylfumarate and
monopentylfumarate, and/or pharmaceutically acceptable salts of any
of the foregoing. In certain embodiments, the compounds of Formula
(I) include dimethyl fumarate, methyl ethyl fumarate, methyl
n-propyl fumarate and methyl i-propyl fumarate, including
pharmaceutically acceptable salts thereof. Pharmaceutically
acceptable salts thereof comprise metal salts, such as a salt
selected from alkali metal salts and alkaline earth metal salts
including sodium, potassium, calcium, magnesium, strontium or zinc
salts, amino acid salts etc.
[0105] Certain embodiments of the methods disclosed herein utilize
a compound of Formula (II):
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein:
[0106] R.sup.2 and R.sup.3 are independently chosen from hydrogen,
C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl;
[0107] R.sup.4 and R.sup.5 are independently chosen from hydrogen,
C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
substituted C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl, substituted
C.sub.1-6 alkoxycarbonyl, C.sub.1-6 heteroalkyl, substituted
C.sub.1-6 heteroalkyl, C.sub.4-12 cycloalkylalkyl, substituted
C.sub.4-12 cycloalkylalkyl, C.sub.7-12 arylalkyl, and substituted
C.sub.7-12 arylalkyl; or R.sup.4 and R.sup.5 together with the
nitrogen to which they are bonded form a ring chosen from a
C.sub.5-10 heteroaryl, substituted C.sub.5-10 heteroaryl,
C.sub.5-10 heterocycloalkyl, and substituted C.sub.5-10
heterocycloalkyl; and
[0108] wherein each substituent group is independently chosen from
halogen, --OH, --CN, --CF.sub.3, .dbd.O, --NO.sub.2, benzyl,
--C(O)NR.sup.11.sub.2, --R.sup.11, --OR.sup.11, --C(O)R.sup.11,
--COOR.sup.11, and --NR.sup.11.sub.2 wherein each R.sup.11 is
independently chosen from hydrogen and C.sub.1-4 alkyl.
[0109] In certain embodiments of a compound of Formula (II), each
substituent group is independently chosen from halogen, --OH, --CN,
--CF.sub.3, --R.sup.11, --OR.sup.11, and --NR.sup.11.sub.2 wherein
each R.sup.11 is independently chosen from hydrogen and C.sub.1-4
alkyl. In certain embodiments, each substituent group is
independently chosen from --OH, and --COOH.
[0110] In certain embodiments of a compound of Formula (II), each
substituent group is independently chosen from .dbd.O, C.sub.1-4
alkyl, and --COOR.sup.11 wherein R.sup.11 is chosen from hydrogen
and C.sub.1-4 alkyl.
[0111] In certain embodiments of a compound of Formula (II), each
of R.sup.2 and R.sup.3 is hydrogen.
[0112] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is C.sub.1-4 alkyl.
[0113] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, and tert-butyl.
[0114] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is methyl.
[0115] In certain embodiments of a compound of Formula (II),
R.sup.4 and R.sup.5 are independently chosen from hydrogen and
C.sub.1-6 alkyl.
[0116] In certain embodiments of a compound of Formula (II),
R.sup.4 and R.sup.5 are independently chosen from hydrogen and
C.sub.1-4 alkyl.
[0117] In certain embodiments of a compound of Formula (II),
R.sup.4 and R.sup.5 are independently chosen from hydrogen, methyl,
and ethyl.
[0118] In certain embodiments of a compound of Formula (II), each
of R.sup.4 and R.sup.5 is hydrogen; in certain embodiments, each of
R.sup.4 and R.sup.5 is methyl; and in certain embodiments, each of
R.sup.4 and R.sup.5 is ethyl.
[0119] In certain embodiments of a compound of Formula (II),
R.sup.4 is hydrogen; and R.sup.5 is chosen from C.sub.1-4 alkyl,
substituted C.sub.1-4 alkyl wherein the substituent group is chosen
from .dbd.O, --OR.sup.11, --COOR.sup.11, and --NR.sup.11.sub.2,
wherein each R.sup.11 is independently chosen form hydrogen and
C.sub.1-4 alkyl.
[0120] In certain embodiments of a compound of Formula (II),
R.sup.4 is hydrogen; and R.sup.5 is chosen from C.sub.1-4 alkyl,
benzyl, 2-methoxyethyl, carboxymethyl, carboxypropyl,
1,3,4-thiadiazolyl, methoxy, 2-methoxycarbonyl,
2-oxo(1,3-oxazolidinyl), 2-(methylethoxy)ethyl, 2-ethoxyethyl,
(tert-butyloxycarbonyl)methyl, (ethoxycarbonyl)methyl,
carboxymethyl, (methylethyl)oxycarbonylmethyl, and
ethoxycarbonylmethyl.
[0121] In certain embodiments of a compound of Formula (II),
R.sup.4 and R.sup.5 together with the nitrogen to which they are
bonded form a ring chosen from a C.sub.5-6 heterocycloalkyl,
substituted C.sub.5-6 heterocycloalkyl, C.sub.5-6 heteroaryl, and
substituted C.sub.5-6 heteroaryl ring. In certain embodiments of a
compound of Formula (II), R.sup.4 and R.sup.5 together with the
nitrogen to which they are bonded form a ring chosen from a C.sub.5
heterocycloalkyl, substituted C.sub.5 heterocycloalkyl, C.sub.5
heteroaryl, and substituted C.sub.5 heteroaryl ring. In certain
embodiments of a compound of Formula (II), R.sup.4 and R.sup.5
together with the nitrogen to which they are bonded form a ring
chosen from a C.sub.6 heterocycloalkyl, substituted C.sub.6
heterocycloalkyl, C.sub.6 heteroaryl, and substituted C.sub.6
heteroaryl ring. In certain embodiments of a compound of Formula
(II), R.sup.4 and R.sup.5 together with the nitrogen to which they
are bonded form a ring chosen from piperazine, 1,3-oxazolidinyl,
pyrrolidine, and morpholine ring.
[0122] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is C.sub.1-6 alkyl; R.sup.4 is hydrogen; and R.sup.5 is
chosen from hydrogen, C.sub.1-6 alkyl, and benzyl.
[0123] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is C.sub.1-6 alkyl; R.sup.4 is methyl; and R.sup.5 is
chosen from hydrogen, C.sub.1-6 alkyl, and benzyl.
[0124] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from hydrogen and C.sub.1-6 alkyl; and each of
R.sup.4 and R.sup.5 is C.sub.1-6 alkyl.
[0125] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from hydrogen and C.sub.1-6 alkyl; and each of
R.sup.4 and R.sup.5 is C.sub.1-6 alkyl. In certain embodiments of a
compound of Formula (II), each of R.sup.2 and R.sup.3 is hydrogen;
and each of R.sup.4 and R.sup.5 is C.sub.1-6 alkyl.
[0126] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from hydrogen and C.sub.1-4 alkyl; R.sup.4 is
hydrogen; and R.sup.5 is chosen from C.sub.1-4 alkyl and
substituted C.sub.1-4 alkyl, wherein the substituent group is
chosen from .dbd.O, --OR.sup.11, --COOR.sup.11, and
--NR.sup.11.sub.2, wherein each R.sup.11 is independently chosen
form hydrogen and C.sub.1-4 alkyl. In certain embodiments of a
compound of Formula (II), one of R.sup.2 and R.sup.3 is hydrogen
and the other of R.sup.2 and R.sup.3 is methyl; R.sup.4 is
hydrogen; and R.sup.5 is chosen from C.sub.1-4 alkyl and
substituted C.sub.1-4 alkyl, wherein the substituent group is
chosen from .dbd.O, --OR.sup.11, --COOR.sup.11, and
--NR.sup.11.sub.2, wherein each R.sup.11 is independently chosen
form hydrogen and C.sub.1-4 alkyl. In certain embodiments of a
compound of Formula (II), each of R.sup.2 and R.sup.3 is hydrogen;
R.sup.4 is hydrogen; and R.sup.5 is chosen from C.sub.1-4 alkyl and
substituted C.sub.1-4 alkyl, wherein the substituent group is
chosen from .dbd.O, --OR.sup.11, --COOR.sup.11, and
--NR.sup.11.sub.2, wherein each R.sup.11 is independently chosen
form hydrogen and C.sub.1-4 alkyl.
[0127] In certain embodiments of a compound of Formula (II),
R.sup.4 and R.sup.5 together with the nitrogen to which they are
bonded form a C.sub.5-10 heterocycloalkyl ring.
[0128] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from hydrogen and C.sub.1-6 alkyl; and R.sup.4
and R.sup.5 together with the nitrogen to which they are bonded
form a ring chosen from a C.sub.5-6 heterocycloalkyl, substituted
C.sub.5-6 heterocycloalkyl, C.sub.5-6 heteroaryl, and substituted
C.sub.5-6 heteroaryl ring. In certain embodiments of a compound of
Formula (II), one of R.sup.2 and R.sup.3 is hydrogen and the other
of R.sup.2 and R.sup.3 is methyl; and R.sup.4 and R.sup.5 together
with the nitrogen to which they are bonded form a ring chosen from
a C.sub.5-6 heterocycloalkyl, substituted C.sub.5-6
heterocycloalkyl, C.sub.5-6 heteroaryl, and substituted C.sub.5-6
heteroaryl ring. In certain embodiments of a compound of Formula
(II), each of R.sup.2 and R.sup.3 is hydrogen; and R.sup.4 and
R.sup.5 together with the nitrogen to which they are bonded form a
ring chosen from a C.sub.5-6 heterocycloalkyl, substituted
C.sub.5-6 heterocycloalkyl, C.sub.5-6 heteroaryl, and substituted
C.sub.5-6 heteroaryl ring.
[0129] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from hydrogen and C.sub.1-6 alkyl; and R.sup.4
and R.sup.5 together with the nitrogen to which they are bonded
form a ring chosen from morpholine, piperazine, and N-substituted
piperazine.
[0130] In certain embodiments of a compound of Formula (II), one of
R.sup.2 and R.sup.3 is hydrogen and the other of R.sup.2 and
R.sup.3 is chosen from hydrogen and C.sub.1-6 alkyl; and R.sup.4
and R.sup.5 together with the nitrogen to which they are bonded
form a ring chosen from morpholine, piperazine, and N-substituted
piperazine.
[0131] In certain embodiments of a compound of Formula (II),
R.sup.2 is hydrogen, and in certain embodiments, R.sup.3 is
hydrogen.
[0132] In certain embodiments of a compound of Formula (II),
R.sup.4 and R.sup.5 are independently chosen from hydrogen,
C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, C.sub.6-10 aryl,
substituted C.sub.6-10 aryl, C.sub.4-12 cycloalkylalkyl,
substituted C.sub.4-12 cycloalkylalkyl, C.sub.7-12 arylalkyl,
substituted C.sub.7-12 arylalkyl, C.sub.1-6 heteroalkyl,
substituted C.sub.1-6 heteroalkyl, C.sub.6-10 heteroaryl,
substituted C.sub.6-10 heteroaryl, C.sub.4-12
heterocycloalkylalkyl, substituted C.sub.4-12
heterocycloalkylalkyl, C.sub.7-12 heteroarylalkyl, substituted
C.sub.7-12 heteroarylalkyl; or R.sup.4 and R.sup.5 together with
the nitrogen to which they are bonded form a ring chosen from a
C.sub.5-10 heteroaryl, substituted C.sub.5-10 heteroaryl,
C.sub.5-10 heterocycloalkyl, and substituted C.sub.5-10
heterocycloalkyl.
[0133] In certain embodiments, the Formula (II) compound is chosen
from: [0134] (N,N-diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0135] methyl[N-benzylcarbamoyl]methyl
(2E)but-2-ene-1,4-dioate; [0136] methyl 2-morpholin-4-yl-2-oxoethyl
(2E)but-2-ene-1,4-dioate; [0137] (N-butylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0138]
[N-(2-methoxyethyl)carbamoyl]methyl methyl
(2E)but-2-ene-1,4-dioate; [0139]
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic
acid; [0140]
4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic
acid; [0141] methyl (N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl
(2E)but-2-ene-1,4-dioate; [0142] (N,N-dimethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate; [0143]
(N-methoxy-N-methylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0144]
bis-(2-methoxyethylamino)carbamoyl]methyl methyl
(2E)but-2-ene-1,4-dioate; [0145]
[N-(methoxycarbonyl)carbamoyl]methyl methyl
(2E)but-2ene-1,4-dioate; [0146]
4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic
acid, sodium salt; [0147] methyl 2-oxo-2-piperazinylethyl
(2E)but-2-ene-1,4-dioate; [0148] methyl
2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl (2E)but-2-ene-1,4-dioate;
[0149] {N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl
(2E)but-2-ene-1,4 dioate; [0150] methyl
2-(4-methylpiperazinyl)-2-oxoethyl (2E)but-2-ene-1,4-dioate; [0151]
methyl {N-[(propylamino)carbonyl]carbamoyl}methyl
(2E)but-2-ene-1,4-dioate; [0152] 2-(4-acetylpiperazinyl)-2-oxoethyl
methyl (2E)but-2-ene-1,4-dioate; [0153]
{N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl methyl
(2E)but-2-ene-1,4-dioate; [0154] methyl
2-(4-benzylpiperazinyl)-2-oxoethyl (2E)but-2-ene-1.4-dioate; [0155]
[N,N-bis(2-ethoxyethyl)carbamoyl]methyl methyl
(2E)but-2-ene-1,4-dioate; [0156]
2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl methyl
(2E)but-2ene-1,4-dioate; [0157]
1-{2-{(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetyl}(2S)pyrrolidine-2-ca-
rboxylic acid; [0158]
(N-{[tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0159]
{N-(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl methyl
(2E)but-2-ene-1,4-dioate; [0160] methyl
1-methyl-2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate;
[0161] (1S)--[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0162] (1S)--(N,N-dimethylcarbamoyl)ethyl
methyl (2E)but-2-ene-1,4-dioate; [0163]
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxyl]-N-methylacetylamino}aceti-
c acid; [0164] (N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate; [0165] methyl
(N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl
(2E)but-2-ene-1,4-dioate; [0166]
{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl
(2E)but-2-ene-1,4-dioate; [0167]
1-{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl methyl
(2E)but-2-ene-1,4-dioate; [0168]
1-{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl methyl
(2E)but-2-ene-1,4-dioate; [0169]
(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl methyl
(2E)but-2-ene-1,4-dioate; [0170]
(1S)-1-[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0171] (1R)-1-(N,N-diethylcarbamoyl)ethyl
methyl (2E)but-2-ene-1,4-dioate; and pharmaceutically acceptable
salts of any of the foregoing.
[0172] In certain embodiments of a compound of Formula (II), the
compound is chosen from: [0173] (N,N-diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0174] methyl[N-benzylcarbamoyl]methyl
(2E)but-2-ene-1,4-dioate; [0175] methyl 2-morpholin-4-yl-2-oxoethyl
(2E)but-2-ene-1,4-dioate; [0176] (N-butylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0177]
[N-(2-methoxyethyl)carbamoyl]methyl methyl
(2E)but-2-ene-1,4-dioate; [0178]
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic
acid; [0179]
{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic
acid; [0180] Methyl (N-(1,3,4-thiadiazol-2yl)carbamoyl)methyl
(2E)but-2ene-1,4-dioate; [0181] (N,N-dimethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate; [0182]
(N-methoxy-N-methylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0183]
bis-(2-methoxyethylamino)carbamoyl]methyl methyl
(2E)but-2-ene-1,4-dioate; [0184]
[N-(methoxycarbonyl)carbamoyl]methyl methyl
(2E)but-2ene-1,4-dioate; [0185] methyl 2-oxo-2-piperazinylethyl
(2E)but-2-ene-1,4-dioate; [0186] methyl
2-oxo-2-(2-oxo(1,3-oxazolidin-3yl)ethyl (2E)but-2ene-1,4-dioate;
[0187] {N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl
(2E)but-2ene-1,4 dioate; [0188]
(N-[(methoxycarbonyl)ethyl]carbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate; [0189]
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}propanoic
acid; and
[0190] pharmaceutically acceptable salts of any of the
foregoing.
[0191] In certain embodiments of a compound of Formula (II), the
compound is selected from (N,N-diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate:
##STR00009##
[0192] or a pharmaceutically acceptable salt thereof;
[0193] and (methyl 2-morpholin-4-yl-2-oxoethyl
(2E)but-2-ene-1,4-dioate:
##STR00010##
[0194] or a pharmaceutically acceptable salt thereof.
[0195] Certain embodiments of the methods disclosed herein utilize
a compound of Formula (III):
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein:
[0196] R.sup.6 is chosen from C.sub.1-6 alkyl, substituted
C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, substituted C.sub.1-6
heteroalkyl, C.sub.3-8 cycloalkyl, substituted C.sub.3-8
cycloalkyl, C.sub.6-8 aryl, substituted C.sub.6-8 aryl, and
--OR.sup.10 wherein R.sup.10 is chosen from C.sub.1-6 alkyl,
substituted C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, substituted
C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and substituted C.sub.6-10
aryl; and
[0197] R.sup.7 and R.sup.8 are independently chosen from hydrogen,
C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl;
[0198] wherein each substituent group is independently chosen from
halogen, --OH, --CN, --CF.sub.3, .dbd.O, --NO.sub.2, benzyl,
--C(O)NR.sup.11.sub.2, --R.sup.11, --OR.sup.11, --C(O)R.sup.11,
--COOR.sup.11, N(R.sup.11)C(O)C(R.sup.11).sub.2NR.sup.11.sub.2, and
--NR.sup.11.sub.2 wherein each R.sup.11 is independently chosen
from hydrogen and C.sub.1-4 alkyl.
[0199] In certain embodiments of a compound of Formula (III), each
substituent group is independently chosen from halogen, --OH, --CN,
--CF.sub.3, --R.sup.11, --OR.sup.11, and --NR.sup.11.sub.2 wherein
each R.sup.11 is independently chosen from hydrogen and C.sub.1-4
alkyl.
[0200] In certain embodiments of a compound of Formula (III), each
substituent group is independently chosen from .dbd.O, C.sub.1-4
alkyl, and --COOR.sup.11 wherein R.sup.11 is chosen from hydrogen
and C.sub.1-4 alkyl.
[0201] In certain embodiments of a compound of Formula (III), one
of R.sup.7 and R.sup.8 is hydrogen and the other of R.sup.7 and
R.sup.8 is C.sub.1-6 alkyl. In certain embodiments of a compound of
Formula (II), one of R.sup.7 and R.sup.8 is hydrogen and the other
of R.sup.7 and R.sup.8 is C.sub.1-4 alkyl.
[0202] In certain embodiments of a compound of Formula (III), one
of R.sup.7 and R.sup.8 is hydrogen and the other of R.sup.7 and
R.sup.8 is chosen from methyl, ethyl, n-propyl, and isopropyl. In
certain embodiments of a compound of Formula (III), each of R.sup.7
and R.sup.8 is hydrogen.
[0203] In certain embodiments of a compound of Formula (III),
R.sup.6 is C.sub.1-6 alkyl; one of R.sup.7 and R.sup.8 is hydrogen
and the other of R.sup.7 and R.sup.8 is C.sub.1-6 alkyl.
[0204] In certain embodiments of a compound of Formula (III),
R.sup.6 is --OR.sup.10.
[0205] In certain embodiments of a compound of Formula (III),
R.sup.10 is chosen from C.sub.1-4 alkyl, cyclohexyl, and
phenyl.
[0206] In certain embodiments of a compound of Formula (III),
R.sup.6 is chosen from methyl, ethyl, n-propyl, and isopropyl; one
of R.sup.7 and R.sup.8 is hydrogen and the other of R.sup.7 and
R.sup.8 is chosen from methyl, ethyl, n-propyl, and isopropyl.
[0207] In certain embodiments of a compound of Formula (III),
R.sup.6 is substituted C.sub.1-2 alkyl, wherein each of the one or
more substituent groups are chosen from --COOH,
--NHC(O)CH.sub.2NH.sub.2, and --NH.sub.2.
[0208] In certain embodiments of a compound of Formula (III),
R.sup.6 is chosen from ethoxy, methylethoxy, isopropyl, phenyl,
cyclohexyl, cyclohexyloxy, --CH(NH.sub.2)CH.sub.2COOH,
--CH.sub.2CH(NH.sub.2)COOH,
--CH(NHC(O)CH.sub.2NH.sub.2)--CH.sub.2COOH, and
--CH.sub.2CH(NHC(O)CH.sub.2NH.sub.2)--COOH.
[0209] In certain embodiments of a compound of Formula (III), one
of R.sup.7 and R.sup.8 is hydrogen and the other of R.sup.7 and
R.sup.8 is chosen from hydrogen, methyl, ethyl, n-propyl, and
isopropyl; and R.sup.6 is chosen from C.sub.1-3 alkyl and
substituted C.sub.1-3 alkyl, wherein each of the one or more
substituent groups are chosen from --COOH,
--NHC(O)CH.sub.2NH.sub.2, and --NH.sub.2, --OR.sup.10 wherein
R.sup.10 is chosen from C.sub.1-3 alkyl and cyclohexyl, phenyl, and
cyclohexyl.
[0210] In certain embodiments of a compound of Formula (III), the
compound is chosen from: [0211] [1-(ethoxycarbonyloxy)]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0212]
methyl[1-(methylethoxycarbonyloxy)]ethyl (2E)but-2-ene-1,4-dioate;
[0213] [1-(cyclohexyloxycarbonyloxy)]ethyl methyl
(2E)but-2-ene-1,4-dioate; and
[0214] pharmaceutically acceptable salts of any of the
foregoing.
[0215] In certain embodiments of a compound of Formula (III), the
compound is chosen from: [0216] methyl (2-methylpropanoyloxy)ethyl
(2E)but-2-ene-1,4-dioate; [0217] methyl[1-(phenylcarbonyloxy)]ethyl
(2E)but-2-ene-1,4-dioate; [0218] [1-(cyclohexylcarbonyloxy)]butyl
methyl (2E)but-2-ene-1,4-dioate; [0219]
1-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0220] methyl
2-methyl-1-phenylcarbonyloxypropyl (2E)but-2-ene-1,4-dioate;
and
[0221] pharmaceutically acceptable salts of any of the
foregoing.
[0222] In certain embodiments of a compound of Formula (III), the
compound is chosen from: [0223] [1-(ethoxycarbonyloxy)]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0224]
methyl[1-(methylethoxycarbonyloxy)]ethyl (2E)but-2-ene-1,4-dioate;
[0225] methyl[1-(2-methylpropanoyloxy)]ethyl
(2E)but-2-ene-1,4-dioate; [0226] methyl[1-phenylcarbonyloxy]ethyl
(2E)but-2-ene-1,4-dioate; [0227] [1-cyclohexylcarbonyloxy]butyl
methyl (2E)but-2-ene-1,4-dioate; [0228]
[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0229]
[1-(cyclohexyloxycarbonyloxy)]ethyl methyl
(2E)but-2-ene-1,4-dioate; [0230] methyl
2-methyl-1-phenylcarbonyloxypropyl (2E)but-2-ene-1,4-dioate; [0231]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-am-
inopropanoic acid; [0232]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-am-
inopropanoic acid; [0233]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-
-aminoacetylamino)propanoic acid; [0234]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-(2-a-
minoacetylamino)propanoic acid;
[0235] and
[0236] pharmaceutically acceptable salts of any of the
foregoing.
[0237] In certain embodiments of a compound of Formula (III), the
compound is chosen from: [0238]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-am-
inopropanoic acid, 2,2,2-trifluoroacetic acid salt; [0239]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-am-
inopropanoic acid, 2,2,2-trifluoroacetic acid salt; [0240]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-
-aminoacetylamino)propanoic acid, 2,2,2-trifluoroacetic acid salt;
[0241]
3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-(2-a-
minoacetylamino)propanoic acid, 2,2,2-trifluoroacetic acid salt;
[0242]
3-{{1-{[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]}ethoxycarbonyl}}(2S)-2-a-
minopropanoic acid, hydrochloride salt; and
[0243] pharmaceutically acceptable salts of any of the
foregoing.
[0244] Certain embodiments of the methods disclosed herein utilize
a compound of Formula (IV):
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein n is an
integer from 2 to 6.
[0245] In certain embodiments of a compound of Formula (IV), n is
2, n is 3, n is 4, n is 5, and in certain embodiments, n is 6.
[0246] In certain embodiments of a compound of Formula (IV), the
compound is a pharmaceutically acceptable salt.
[0247] In certain embodiments of a compound of Formula (IV), the
compound is the hydrochloride salt.
Synthesis of Compounds
[0248] MMF can be synthesized according to the methods described in
Dymicky, Preparation of Monomethyl Fumarate, Organic Preparations
and Procedures International: The New Journal for Organic
Synthesis, Vol 14, Issue 4, 1983; and Spatz et al., J. Org. Chem.,
1958, 23 (10), 1559-1560.
[0249] DMF can be synthesized according to the methods described in
Chinese Patent Publication CN 101318901A, the disclosures of which
are incorporated herein by reference.
[0250] Compounds of Formula (I) can be synthesized according to the
methods described in Speiser et al., U.S. Pat. No. 5,424,332, at
column 3, line 33 through column 4, line 2, the disclosures of
which are incorporated herein by reference.
[0251] Compounds of Formula (II) can be synthesized according to
the methods described in Gangakhedkar et al., U.S. Pat. No.
8,148,414, at column 23, line 44 through column 26, line 55 and
column 28, line 10 through column 29, line 34, the disclosures of
which are incorporated herein by reference.
[0252] Compounds of Formula (III) can be synthesized according to
the methods described in Gangakhedkar et al., U.S. Pat. No.
8,148,414, at column 29, line 43 through column 31, line 13, the
disclosures of which are incorporated herein by reference.
[0253] Compounds of Formula (IV) can be synthesized according to
the methods described in Cundy et al., U.S. patent application Ser.
No. 13/761,864, filed Feb. 7, 2013, at page 34, line 21 through
page 41, line 3, the disclosures of which are incorporated herein
by reference.
Pharmaceutical Compositions
[0254] Pharmaceutical compositions provided by the present
disclosure may comprise a therapeutically effective amount of MMF
and/or a prodrug of MMF together with a suitable amount of one or
more pharmaceutically acceptable vehicles so as to provide a
composition for proper administration to a patient. Suitable
pharmaceutical vehicles are described in the art.
[0255] In certain embodiments, MMF and/or a compound of Formulae
(I)-(IV) may be incorporated into pharmaceutical compositions to be
administered orally. Oral administration of such pharmaceutical
compositions may result in uptake of MMF and/or a compound of
Formulae (I)-(IV) throughout the intestine and entry into the
systemic circulation. Such oral compositions may be prepared in a
manner known in the pharmaceutical art and comprise MMF and/or a
compound of Formulae (I)-(IV) and at least one pharmaceutically
acceptable vehicle. Oral pharmaceutical compositions may include a
therapeutically effective amount of MMF and/or a compound of
Formulae (I)-(IV) and a suitable amount of a pharmaceutically
acceptable vehicle, so as to provide an appropriate form for
administration to a patient.
[0256] MMF and/or a compound of Formulae (I)-(IV) may be
incorporated into pharmaceutical compositions to be administered by
any other appropriate route of systemic administration including
intramuscular, intravenous and oral.
[0257] Pharmaceutical compositions comprising MMF and/or a compound
of Formulae (I)-(IV) and may be manufactured by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping, or lyophilizing
processes. Pharmaceutical compositions may be formulated in a
conventional manner using one or more physiologically acceptable
carriers, diluents, excipients, or auxiliaries, which facilitate
processing of MMF and/or a compound of Formulae (I)-(IV) or
crystalline forms thereof and one or more pharmaceutically
acceptable vehicles into formulations that can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen. Pharmaceutical compositions provided by the
present disclosure take the form of sustained-release formulations
suitable for administration to a patient.
[0258] Pharmaceutical compositions provided by the present
disclosure may be formulated in a unit dosage form. A unit dosage
form refers to a physically discrete unit suitable as a unitary
dose for patients undergoing treatment, with each unit containing a
predetermined quantity of MMF and/or a compound of Formulae
(I)-(IV) calculated to produce an intended therapeutic effect. A
unit dosage form may be for a single daily dose, for administration
2 times per day, or one of multiple daily doses, e.g., 3 or more
times per day. When multiple daily doses are used, a unit dosage
form may be the same or different for each dose. One or more dosage
forms may comprise a dose, which may be administered to a patient
at a single point in time or during a time interval.
[0259] In certain embodiments, an oral dosage form provided by the
present disclosure may be a controlled release dosage form.
Controlled delivery technologies can improve the absorption of a
drug in a particular region or regions of the gastrointestinal
tract. Controlled drug delivery systems may be designed to deliver
a drug in such a way that the drug level is maintained within a
therapeutically effective window and effective and safe blood
levels are maintained for a period as long as the system continues
to deliver the drug with a particular release profile in the
gastrointestinal tract. Controlled drug delivery may produce
substantially constant blood levels of a drug over a period of time
as compared to fluctuations observed with immediate release dosage
forms. For some drugs, maintaining a constant blood and tissue
concentration throughout the course of therapy is the most
desirable mode of treatment. Immediate release of drugs may cause
blood levels to peak above the level required to elicit a desired
response, which may waste the drug and may cause or exacerbate
toxic side effects. Controlled drug delivery can result in optimum
therapy, and not only can reduce the frequency of dosing, but may
also reduce the severity of side effects. Examples of controlled
release dosage forms include dissolution controlled systems,
diffusion controlled systems, ion exchange resins, osmotically
controlled systems, erodable matrix systems, pH independent
formulations, gastric retention systems, and the like.
[0260] An appropriate oral dosage form for a particular
pharmaceutical composition provided by the present disclosure may
depend, at least in part, on the gastrointestinal absorption
properties of MMF and/or a compound of Formulae (I)-(IV) the
stability of MMF and/or a compound of Formulae (I)-(IV) in the
gastrointestinal tract, the pharmacokinetics of MMF and/or a
compound of Formulae (I)-(IV) and the intended therapeutic profile.
An appropriate controlled release oral dosage form may be selected
for a particular compound. For example, gastric retention oral
dosage forms may be appropriate for compounds absorbed primarily
from the upper gastrointestinal tract, and sustained release oral
dosage forms may be appropriate for compounds absorbed primarily
from the lower gastrointestinal tract. Certain compounds are
absorbed primarily from the small intestine. In general, compounds
traverse the length of the small intestine in about 3 to 5 hours.
For compounds that are not easily absorbed by the small intestine
or that do not dissolve readily, the window for active agent
absorption in the small intestine may be too short to provide a
desired therapeutic effect.
[0261] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may be practiced with dosage forms
adapted to provide sustained release of MMF and/or a compound of
Formulae (I)-(IV) upon oral administration. Sustained release oral
dosage forms may be used to release drugs over a prolonged time
period and are useful when it is desired that a drug or drug form
be delivered to the lower gastrointestinal tract, including the
colon. Sustained release oral dosage forms include any oral dosage
form that maintains therapeutic concentrations of a drug in a
biological fluid such as the plasma, blood, cerebrospinal fluid, or
in a tissue or organ for a prolonged time period. Sustained release
oral dosage forms include diffusion-controlled systems such as
reservoir devices and matrix devices, dissolution-controlled
systems, osmotic systems, and erosion-controlled systems. Sustained
release oral dosage forms and methods of preparing the same are
well known in the art.
[0262] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any systemic dosage form of
the MMF and/or a prodrug of MMF, and wherein, when administered to
a patient, the maximum average concentration of MMF in the blood
plasma of the patient is less than 500 ng/ml. In one embodiment,
the maximum average concentration is less than 400 ng/ml. In
another embodiment, the maximum average concentration is less than
350 ng/ml. In another embodiment, the maximum average concentration
is less than 300 ng/ml. In another embodiment, the maximum average
concentration is less than 250 ng/ml. In another embodiment, the
maximum average concentration is less than 200 ng/ml. In another
embodiment, the maximum average concentration is less than 150
ng/ml. In some embodiments, the prodrug of MMF is a compound of
Formulae (I)-(IV).
[0263] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any systemic dosage form of
the MMF and/or a prodrug of MMF, and wherein, when administered to
a patient, the average maximum rate of rise in MMF concentration in
the blood plasma of the patients is less than 0.25 wt % ng-eq of
MMF dosed/ml/hr. In one embodiment, the average maximum rate of
rise is less than 0.20 wt % ng-eq of MMF dosed/ml/hr. In one
embodiment, the average maximum rate of rise is less than 0.15 wt %
ng-eq of MMF dosed/ml/hr. In one embodiment, the average maximum
rate of rise is less than 0.10 wt % ng-eq of MMF dosed/ml/hr.
[0264] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any systemic dosage form of
the MMF and/or a prodrug of MMF, and wherein, when administered to
a patient, the average maximum rate of rise in MMF concentration in
the blood plasma of the patients is less than 0.25 wt % ng-eq of
MMF dosed/ml/hr; and an average MMF concentration in the blood
plasma of the patients, measured at a time of said maximum rate of
rise, is less than 200 ng/ml.
[0265] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any systemic dosage form of
the MMF and/or a prodrug of MMF, and wherein, when administered to
a patient, the average maximum rate of rise in MMF concentration in
the blood plasma of the patients is less than 0.20 wt % ng-eq of
MMF dosed/ml/hr; and an average MMF concentration in the blood
plasma of the patients, measured at a time of said maximum rate of
rise, is less than 200 ng/ml or less than 150 ng/ml.
[0266] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any systemic dosage form of
the MMF and/or a prodrug of MMF, and wherein, when administered to
a patient, the average maximum rate of rise in MMF concentration in
the blood plasma of the patients is less than 0.15 wt % ng-eq of
MMF dosed/ml/hr; and an average MMF concentration in the blood
plasma of the patients, measured at a time of said maximum rate of
rise, is less than 180 ng/ml.
[0267] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any systemic dosage form of
the MMF and/or a prodrug of MMF, and wherein, when administered to
a patient, the average maximum rate of rise in MMF concentration in
the blood plasma of the patients is less than 0.10 wt % ng-eq of
MMF dosed/ml/hr; and an average MMF concentration in the blood
plasma of the patients, measured at a time of said maximum rate of
rise, is less than 140 ng/ml.
[0268] In another embodiment, the prodrug of MMF is a compound of
Formulae (I)-(IV).
[0269] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any enteric-coated sustained
release oral dosage form of the MMF and/or a prodrug of MMF, and
wherein, when subjected to an in vitro dissolution test employing
as a dissolution medium 750 mL of 0.1 N hydrochloric acid, at pH
1.2, for a period of 2 hours, followed by addition of 250 mL of 200
mM tribasic sodium phosphate buffer resulting in an adjustment of
the pH of the dissolution medium to 6.8, the dissolution medium
being maintained at 37.degree. C. and stirred at 100 rpm, the
dosage form releases: [0270] (i) less than 10 wt % of the dose over
an initial 2 hours of the in vitro dissolution test; (ii) at least
90 wt % of the dose over not less than an initial 8 hours of the in
vitro dissolution test; [0271] (iii) no more than 30 wt % of the
dose in any one hour during the in vitro dissolution test; and
[0272] (iv) no more than 40 wt % of the dose in any consecutive two
hours during the in vitro dissolution test.
[0273] In one embodiment, the prodrug of MMF is a compound of
Formulae (I)-(IV). In another embodiment, the enteric-coated oral
dosage form is administered to a patient at a dosing frequency of
not more than twice per day.
[0274] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any non-enteric-coated
sustained release oral dosage form of the MMF and/or a prodrug of
MMF, and wherein, when subjected to an in vitro dissolution test
employing as a dissolution medium 750 mL of 0.1 N hydrochloric
acid, at pH 1.2, for a period of 2 hours, followed by addition of
250 mL of 200 mM tribasic sodium phosphate buffer resulting in an
adjustment of the pH of the dissolution medium to 6.8, the
dissolution medium being maintained at 37.degree. C. and stirred at
100 rpm, the dosage form releases: [0275] (i) at least 90 wt % of
the dose over not less than an initial 8 hours of the in vitro
dissolution test; [0276] (ii) no more than 30 wt % of the dose in
any one hour during the in vitro dissolution test; and [0277] (iii)
no more than 40 wt % of the dose in any consecutive two hours
during the in vitro dissolution test.
[0278] In one embodiment, the prodrug of MMF is a compound of
Formulae (I)-(IV). In another embodiment, the non-enteric-coated
oral dosage form is administered to a patient at a dosing frequency
of not more than twice per day.
[0279] In certain embodiments, pharmaceutical compositions provided
by the present disclosure may include any suitable dosage forms
that achieve the above described in vitro release profiles. Such
dosage forms may be any systemic dosage forms, including sustained
release enteric-coated oral dosage form and sustained release
non-enteric-coated oral dosage form. Examples of suitable dosage
forms are described herein. Those skilled in the formulation art
can develop any number of acceptable dosage forms given the dosage
forms described in the examples as a starting point.
[0280] An appropriate dose of MMF and/or a compound of Formulae
(I)-(IV) or pharmaceutical composition comprising MMF and/or a
compound of Formulae (I)-(IV) may be determined according to any
one of several well-established protocols. For example, animal
studies such as studies using mice, rats, dogs, and/or monkeys may
be used to determine an appropriate dose of a pharmaceutical
compound. Results from animal studies may be extrapolated to
determine doses for use in other species, such as for example,
humans.
Uses
[0281] Compounds of Formulae (I)-(IV) are prodrugs of MMF. Thus,
compounds of Formulae (I)-(IV) and pharmaceutical compositions
thereof may be administered to a patient suffering from diseases,
disorders, conditions, and symptoms of any of the foregoing for
which alkyl hydrogen fumarates, such as MMF, are known to provide
or are later found to provide therapeutic benefit. MMF and/or a
compound of Formulae (I)-(IV) can be used to treat a disease chosen
from adrenal leukodystrophy, AGE-induced genome damage, Alexanders
Disease, Alper's Disease, Alzheimer's disease, amyotrophic lateral
sclerosis, angina pectoris, arthritis, asthma, balo concentric
sclerosis, Canavan disease, cardiac insufficiency including left
ventricular insufficiency, central nervous system vasculitis,
Charcott-Marie-Tooth Disease, childhood ataxia with central nervous
system hypomyelination, chronic idiopathic peripheral neuropathy,
chronic obstructive pulmonary disease, Crohn's disease, diabetic
retinopathy, graft versus host disease, hepatitis C viral
infection, herpes simplex viral infection, human immunodeficiency
viral infection, Huntington's disease, irritable bowel disorder,
ischemia, Krabbe Disease, lichen planus, macular degeneration,
mitochondrial encephalomyopathy, monomelic amyotrophy, multiple
sclerosis, myocardial infarction, neurodegeneration with brain iron
accumulation, neuromyelitis optica, neurosarcoidosis, NF-.kappa.B
mediated diseases, optic neuritis, pareneoplastic syndromes,
Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateral
sclerosis, progressive supranuclear palsy, psoriasis, reperfusion
injury, retinopathia pigmentosa, Schilders Disease, subacute
necrotizing myelopathy, susac syndrome, transplantation rejection,
transverse myelitis, a tumor, ulcerative colitis, Zellweger's
syndrome, granulomas including annulaire, pemphigus, bollus
pemphigoid, behcet's, contact dermatitis, acute dermatitis, chronic
dermatitis, alopecia greata (totalis and universalis), sarcoidosis,
cutaneous sarcoidosis, pyoderma gangrenosum, cutaneous lupus,
Crohn's disease or cutaneous Crohn's disease.
[0282] Methods of treating a disease in a patient provided by the
present disclosure comprise administering to a patient in need of
such treatment a therapeutically effective amount of MMF and/or a
compound of Formulae (I)-(IV). These compounds, and pharmaceutical
compositions thereof, provide therapeutic or prophylactic plasma
and/or blood concentrations of MMF following administration to a
patient. MMF and/or a compound of Formulae (I)-(IV) may be
administered in an amount and using a dosing schedule as
appropriate for treatment of a particular disease. Daily doses of
MMF and/or a compound of Formulae (I)-(IV) may range from about
0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 50
mg/kg, from about 1 mg/kg to about 50 mg/kg, and in certain
embodiments, from about 5 mg/kg to about 25 mg/kg. In certain
embodiments, MMF and/or a compound of Formulae (I)-(IV) may be
administered at a dose over time from about 1 mg to about 5 g per
day, from about 10 mg to about 4 g per day, and in certain
embodiments from about 20 mg to about 2 g per day. An appropriate
dose of MMF and/or a compound of Formulae (I)-(IV) may be
determined based on several factors, including, for example, the
body weight and/or condition of the patient being treated, the
severity of the disease being treated, the incidence and/or
severity of side effects, the manner of administration, and the
judgment of the prescribing physician. Appropriate dose ranges may
be determined by methods known to those skilled in the art.
[0283] MMF and the compounds of Formulae (I)-(IV) may be assayed in
vitro and in vivo for the desired therapeutic or prophylactic
activity prior to use in humans. In vivo assays, for example using
appropriate animal models, may also be used to determine whether
administration of MMF and/or a compound of Formulae (I)-(IV) is
therapeutically effective.
[0284] In certain embodiments, a therapeutically effective dose of
MMF and/or a compound of Formulae (I)-(IV) may provide therapeutic
benefit without causing substantial toxicity including adverse side
effects. Toxicity of MMF and/or a compound of Formulae (I)-(IV)
and/or metabolites thereof may be determined using standard
pharmaceutical procedures and may be ascertained by those skilled
in the art. The dose ratio between toxic and therapeutic effect is
the therapeutic index. A dose of MMF and/or a compound of Formulae
(I)-(IV) may be within a range capable of establishing and
maintaining a therapeutically effective circulating plasma and/or
blood concentration of MMF and/or a compound of Formulae (I)-(IV)
that exhibits little or no toxicity.
[0285] MMF and compounds of Formulae (I)-(IV) may be used to treat
a disease chosen from adrenal leukodystrophy, AGE-induced genome
damage, Alexanders Disease, Alper's Disease, Alzheimer's disease,
amyotrophic lateral sclerosis, angina pectoris, arthritis, asthma,
balo concentric sclerosis, Canavan disease, cardiac insufficiency
including left ventricular insufficiency, central nervous system
vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia with
central nervous system hypomyelination, chronic idiopathic
peripheral neuropathy, chronic obstructive pulmonary disease,
Crohn's disease, diabetic retinopathy, graft versus host disease,
hepatitis C viral infection, herpes simplex viral infection, human
immunodeficiency viral infection, Huntington's disease, irritable
bowel disorder, ischemia, Krabbe Disease, lichen planus, macular
degeneration, mitochondrial encephalomyopathy, monomelic
amyotrophy, multiple sclerosis, myocardial infarction,
neurodegeneration with brain iron accumulation, neuromyelitis
optica, neurosarcoidosis, NF-.kappa.B mediated diseases, optic
neuritis, pareneoplastic syndromes, Parkinson's disease,
Pelizaeus-Merzbacher disease, primary lateral sclerosis,
progressive supranuclear palsy, psoriasis, reperfusion injury,
retinopathia pigmentosa, Schilders Disease, subacute necrotizing
myelopathy, susac syndrome, transplantation rejection, transverse
myelitis, a tumor, ulcerative colitis, Zellweger's syndrome,
granulomas including annulaire, pemphigus, bollus pemphigoid,
behcet's, contact dermatitis, acute dermatitis, chronic dermatitis,
alopecia greata (totalis and universalis), sarcoidosis, cutaneous
sarcoidosis, pyoderma gangrenosum, cutaneous lupus, Crohn's disease
or cutaneous Crohn's disease. The underlying etiology of any of the
foregoing diseases being treated may have a multiplicity of
origins. Further, in certain embodiments, a therapeutically
effective amount of MMF and/or the compound of Formulae (I)-(IV)
may be administered to a patient, such as a human, as a
preventative measure against the foregoing diseases and disorders.
Thus, a therapeutically effective amount of MMF and/or a compound
of Formulae (I)-(IV) may be administered as a preventative measure
to a patient having a predisposition for and/or history of adrenal
leukodystrophy, AGE-induced genome damage, Alexanders Disease,
Alper's Disease, Alzheimer's disease, amyotrophic lateral
sclerosis, angina pectoris, arthritis, asthma, balo concentric
sclerosis, Canavan disease, cardiac insufficiency including left
ventricular insufficiency, central nervous system vasculitis,
Charcott-Marie-Tooth Disease, childhood ataxia with central nervous
system hypomyelination, chronic idiopathic peripheral neuropathy,
chronic obstructive pulmonary disease, Crohn's disease, diabetic
retinopathy, graft versus host disease, hepatitis C viral
infection, herpes simplex viral infection, human immunodeficiency
viral infection, Huntington's disease, irritable bowel disorder,
ischemia, Krabbe Disease, lichen planus, macular degeneration,
mitochondrial encephalomyopathy, monomelic amyotrophy, multiple
sclerosis, myocardial infarction, neurodegeneration with brain iron
accumulation, neuromyelitis optica, neurosarcoidosis, NF-.kappa.B
mediated diseases, optic neuritis, pareneoplastic syndromes,
Parkinson's disease, Pelizaeus-Merzbacher disease, primary lateral
sclerosis, progressive supranuclear palsy, psoriasis, reperfusion
injury, retinopathia pigmentosa, Schilders Disease, subacute
necrotizing myelopathy, susac syndrome, transplantation rejection,
transverse myelitis, a tumor, ulcerative colitis, Zellweger's
syndrome, granulomas including annulaire, pemphigus, bollus
pemphigoid, behcet's, contact dermatitis, acute dermatitis, chronic
dermatitis, alopecia greata (totalis and universalis), sarcoidosis,
cutaneous sarcoidosis, pyoderma gangrenosum, cutaneous lupus,
Crohn's disease and/or cutaneous Crohn's disease.
Administration
[0286] MMF and/or a prodrug of MMF and pharmaceutical compositions
thereof may be administered orally or by any other appropriate
route suitable for systemic, as opposed to local, administration.
For example, systemic administration can be by infusion or bolus
injection, by absorption through epithelial or mucocutaneous
linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.).
Other suitable routes of systemic administration include, but are
not limited to, intradermal, intramuscular, intraperitoneal,
intravenous, subcutaneous, intranasal, epidural, oral, sublingual
and inhalation.
[0287] The amount of MMF and/or a prodrug of MMF that will be
effective in the treatment of a disease in a patient will depend,
in part, on the nature of the condition and can be determined by
standard clinical techniques known in the art. In addition, in
vitro or in vivo assays may be employed to help identify optimal
dosage ranges. A therapeutically effective amount of MMF and/or a
prodrug of MMF to be administered may also depend on, among other
factors, the subject being treated, the weight of the subject, the
severity of the disease, the manner of administration, and the
judgment of the prescribing physician. In the case of an MMF
prodrug, for which MMF is the pharmacologically active metabolite,
the amount of prodrug to be administered is generally determined by
calculating the weight of any pharmacologically inactive promoiety
that is cleaved during metabolism of the prodrug and then
administering a MMF equivalent amount of the prodrug.
[0288] For systemic administration, a therapeutically effective
dose may be estimated initially from in vitro assays. For example,
a dose may be formulated in animal models to achieve a beneficial
circulating composition concentration range. Initial doses may also
be estimated from in vivo data, e.g., animal models, using
techniques that are known in the art. Such information may be used
to more accurately determine useful doses in humans. One having
ordinary skill in the art may optimize administration to humans
based on animal data.
[0289] A dose may be administered in a single dosage form or in
multiple dosage forms. When multiple dosage forms are used the
amount of compound contained within each dosage form may be the
same or different. The amount of MMF and/or a prodrug of MMF
contained in a dose may depend on the route of administration and
whether the disease in a patient is effectively treated by acute,
chronic, or a combination of acute and chronic administration.
[0290] In certain embodiments an administered dose is less than a
toxic dose. Toxicity of the compositions described herein may be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., by determining the LD.sub.50 (the
dose lethal to 50% of the population) or the LD.sub.100 (the dose
lethal to 100% of the population). The dose ratio between toxic and
therapeutic effect is the therapeutic index. In certain
embodiments, MMF and/or a prodrug of MMF may exhibit a high
therapeutic index. The data obtained from these cell culture assays
and animal studies may be used in formulating a dosage range that
is not toxic for use in humans. A dose of MMF and/or a prodrug of
MMF provided by the present disclosure may be within a range of
circulating concentrations in for example the blood, plasma, or
central nervous system, that include the effective dose and that
exhibits little or no toxicity. A dose may vary within this range
depending upon the dosage form employed and the route of
administration utilized. In certain embodiments, an escalating dose
may be administered.
Combination Therapy
[0291] Methods provided by the present disclosure further comprise
administering one or more pharmaceutically active compounds in
addition to MMF and/or a prodrug of MMF. Such compounds may be
provided to treat the same disease or a different disease than the
disease being treated with the MMF and/or MMF prodrug.
[0292] In certain embodiments, MMF and/or an MMF prodrug may be
used in combination with at least one other therapeutic agent. In
certain embodiments, MMF and/or a MMF prodrug may be administered
to a patient together with another compound for treating diseases
and conditions including: adrenal leukodystrophy, Alexanders
Disease, Alper's Disease, balo concentric sclerosis, Canavan
disease, central nervous system vasculitis, Charcott-Marie-Tooth
Disease, childhood ataxia with central nervous system
hypomyelination, diabetic retinopathy, graft versus host disease,
hepatitis C viral infection, herpes simplex viral infection, human
immunodeficiency viral infection, Krabbe Disease, lichen planus,
macular degeneration, monomelic amyotrophy, neurodegeneration with
brain iron accumulation, neuromyelitis optica, neurosarcoidosis,
optic neuritis, pareneoplastic syndromes, Pelizaeus-Merzbacher
disease, primary lateral sclerosis, progressive supranuclear palsy,
Schilders Disease, subacute necrotizing myelopathy, susac syndrome,
transverse myelitis, a tumor and Zellweger's syndrome.
[0293] MMF and/or an MMF prodrug and the at least one other
therapeutic agent may act additively or, and in certain
embodiments, synergistically. The at least one additional
therapeutic agent may be included in the same dosage form as MMF
and/or the MMF prodrug or may be provided in a separate dosage
form. Methods provided by the present disclosure can further
include, in addition to administering MMF and/or an MMF prodrug,
administering one or more therapeutic agents effective for treating
the same or different disease than the disease being treated by MMF
and/or the MMF prodrug. Methods provided by the present disclosure
include administration of MMF and/or an MMF prodrug and one or more
other therapeutic agents provided that the combined administration
does not inhibit the therapeutic efficacy of the MMF and/or the MMF
prodrug and/or does not typically produce significant and/or
substantial adverse combination effects.
[0294] In certain embodiments, dosage forms comprising MMF and/or a
prodrug of MMF may be administered concurrently with the
administration of another therapeutic agent, which may be part of
the same dosage form as, or in a different dosage form than that
comprising MMF and/or a prodrug of MMF. MMF and/or a prodrug of MMF
may be administered prior or subsequent to administration of
another therapeutic agent. In certain embodiments of combination
therapy, the combination therapy may comprise alternating between
administering MMF and/or a prodrug of MMF and a composition
comprising another therapeutic agent, e.g., to minimize adverse
drug effects associated with a particular drug. When MMF and/or a
prodrug of MMF is administered concurrently with another
therapeutic agent that potentially may produce an adverse drug
effect including, but not limited to, toxicity, the other
therapeutic agent may advantageously be administered at a dose that
falls below the threshold at which the adverse drug reaction is
elicited.
[0295] In certain embodiments, dosage forms comprising MMF and/or a
prodrug of MMF may be administered with one or more substances to
enhance, modulate and/or control release, bioavailability,
therapeutic efficacy, therapeutic potency, stability, and the like
of MMF and/or a prodrug of MMF. For example, to enhance the
therapeutic efficacy of a MMF and/or a prodrug of MMF, the MMF
and/or a prodrug of MMF may be co-administered with or a dosage
form comprising MMF and/or a prodrug of MMF may comprise one or
more active agents to increase the absorption or diffusion of MMF
and/or a prodrug of MMF from the gastrointestinal tract to the
systemic circulation, or to inhibit degradation of the MMF and/or a
prodrug of MMF in the blood of a patient. In certain embodiments,
MMF and/or a prodrug of MMF may be co-administered with an active
agent having pharmacological effects that enhance the therapeutic
efficacy of a MMF and/or a prodrug of MMF.
EXAMPLES
[0296] The following examples illustrate various aspects of the
disclosure. It will be apparent to those skilled in the art that
many modifications, both to materials and methods, may be practiced
without departing from the scope of the disclosure.
Example 1
Preparation of Sustained Release Dosage Form
Enteric Coated, 15% HPMC in Core, with Barrier Layer
[0297] Delayed sustained release tablets containing an MMF prodrug
were made having the ingredients shown in Table 3:
TABLE-US-00003 TABLE 3 Composition of Enteric Coated Sustained
Release Tablet (15% HPMC in Core) Quantity Quantity Component
Manufacturer Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Clara,
Drug substance 200.00 66.74 Diethylcarbamoyl)methyl CA) methyl
(2E)but-2-ene-1,4- dioate [Compound (1)] Hydroxypropyl Cellulose
Ashland (Hopewell, Binder 6.19 2.06 VA) Lactose Monohydrate
Foremost (Rothschild, Filler 44.95 15.00 WI) Hypromellose 2208 Dow
Chemical Sustained release 44.95 15.00 (Midland, MI) agent Silicon
Dioxide Cabot (Tuscola, IL) Glidant 0.60 0.20 Magnesium Stearate
Mallinckrodt (St. Lubricant 3.00 1.00 Louis, MO) Total Core 299.69
100.00 Opadry 03O19184 Colorcon (West Point, Barrier coat 7.13 2.38
PA) Total Barrier 7.13 2.38 Coating Methacrylic Acid Co- Evonik
Industries Enteric polymer 24.20 8.08 polymer Dispersion (Essen,
Germany) Triethyl Citrate Vertellus (Greensboro, Plasticizer 1.25
0.42 NC) PlasACRYL .TM. T20 Emerson Resources Anti-tacking 2.41
0.80 (Norristown, PA) agent Total Enteric 27.87 9.30 Coating Total
Tablet 334.69 111.68
[0298] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation was performed in two batches at 456 g per batch.
Compound (1) and hydroxypropyl cellulose were passed through a
conical mill with a 610 micron round holed screen. Compound (1) and
hydroxypropyl cellulose were then combined in a Key KG-5 granulator
bowl and mixed with water addition for approximately 7 minutes. The
wet granules were dried in a Glatt GPCG-1 fluid bed dryer at
40.degree. C. The two portions of dried granules were sized by
passing through a conical mill with an approximately 1300 micron
grater type screen. The milled granules were blended with the
hypromellose 2208, silicon dioxide, and lactose monohydrate for 10
minutes in an 8 quart (7.61) V-blender. This blend was passed
through an 850 micron mesh screen. The magnesium stearate was
passed through a 600 micron mesh screen and blended with the
additional core materials in the V-blender for 5 minutes. Core
tablets (299.69 mg) were compressed using a GlobePharma Minipress
II rotary tablet press with 8.6 mm round concave tooling. The core
tablets had a final mean hardness of approximately 12 kp. For the
coating, an aqueous suspension was prepared by mixing with an
impeller 63.8 g Opadry 03O19184 with 770.7 g of purified water. The
water contained in the suspension is removed during the film
coating process and therefore not included in the final formulation
in Table 3. The tablets were coated with the aqueous suspension in
an O'Hara Technologies Labcoat M coater with a 12'' (30.5 cm)
diameter perforated pan until the desired weight gain of barrier
coat was achieved. The coating process occurred at an inlet
temperature of approximately 52.degree. C. and an outlet
temperature of 36.degree. C. After coating, the tablets were dried
for 2 hours at 40.degree. C. An aqueous suspension was prepared by
mixing with an impeller 405.1 g methacrylic acid copolymer
dispersion, 6.3 g triethyl citrate, 60.6 g PlasACRYL.TM. T20 with
228.1 g water. The water contained in the methacrylic acid
copolymer dispersion and the PlasACRYL.TM. T20 is removed during
the film coating process and therefore not included in the final
formulation in Table 3. The tablets were coated with the aqueous
suspension in the O'Hara Technologies Labcoat M coater until the
desired weight gain of enteric film was achieved. The coating
process occurred at an inlet temperature of approximately
40.degree. C. and an outlet temperature of 30.degree. C. After
coating, the tablets were dried for 2 hours at 40.degree. C.
Example 2
In Vitro Dissolution Profile of Example 1 Dosage Form
[0299] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Example 1. The 2-stage dissolution test was used to better
approximate the pH conditions experienced by a dosage form after
swallowing by a patient, i.e., low pH of the stomach followed by
near neutral pH of the intestines. The dosage forms were first
placed into a dissolution vessel (USP, Type I, basket) containing
750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL
of 200 mM tribasic sodium phosphate was added to the vessel
resulting in a pH adjustment from 1.2 to 6.8. The dissolution
medium was kept at 37.degree. C. and was agitated at 100 rpm.
[0300] For the Example 1 dosage forms, samples of the dissolution
medium were withdrawn after 1 and 2 hours in the low pH stage, and
at 0.5, 2, 4, 7, 10, and 14 hours following buffer addition. The
released amount of the MMF prodrug in the samples was determined by
reverse phase HPLC using a C18 column and a 7 minute gradient
method according to Table 4 where Mobile Phase A is water/0.1%
H.sub.3PO.sub.4 and Mobile Phase B is
water/acetonitrile/H.sub.3PO.sub.4 (10/90/0.1 by volume) with UV
detection at 210 nm.
TABLE-US-00004 TABLE 4 HPLC Gradient Conditions Time (minute) %
Mobile Phase A % Mobile Phase B 0 85 15 5 35 65 5.5 85 15 7 85
15
[0301] As shown in FIG. 1, for dosage forms prepared according to
Example 1, drug release is delayed for approximately 2 hours,
followed by sustained release reaching>90% at 12 hours.
Example 3
Preparation of Delayed Sustained Release Dosage Form
Enteric Coated, 15% HPMC in Core, without Barrier Layer
[0302] Delayed sustained release tablets containing compound (1)
were made having the ingredients shown in Table 5:
TABLE-US-00005 TABLE 5 Composition of Enteric Coated Sustained
Release Tablet (15% HPMC in Core, without Barrier Layer) Quantity
Quantity Component Manufacturer Role (mg/tablet) (% w/w) (N,N-
XenoPort (Santa Drug 200.00 66.74 Diethylcarbamoyl)methyl Clara,
CA) substance methyl (2E)but-2-ene- 1,4-dioate [Compound 1]
Hydroxypropyl Cellulose Ashland Binder 6.18 2.06 (Hopewell, VA)
Lactose Monohydrate Foremost Filler 44.95 15.00 (Rothschild, WI)
Hypromellose 2208 Dow Chemical Sustained 44.95 15.00 (Midland, MI)
release agent Silicon Dioxide Cabot (Tuscola, Glidant 0.60 0.20 IL)
Magnesium Stearate Mallinckrodt (St. Lubricant 3.00 1.00 Louis, MO)
Total Core 299.68 100.00 Methacrylic Acid Co- Evonik Industries
Enteric 23.42 7.82 polymer Dispersion (Essen, Germany) polymer
Triethyl Citrate Vertellus Plasticizer 1.21 0.41 (Greensboro, NC)
PlasACRYL .TM. T20 Emerson Anti-tacking 2.33 0.78 Resources agent
(Norristown, PA) Total Coat 27.90 9.00 Total Tablet 327.59
109.00
[0303] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation was performed in two batches at 463.9 g per batch.
Compound (1) and hydroxypropyl cellulose were passed through a
conical mill with a 610 micron round holed screen. Compound (1) and
hydroxypropyl cellulose were then combined in a Key KG-5 granulator
bowl and mixed with water addition for approximately 10 minutes.
The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at
40.degree. C. The two portions of dried granules were blended with
silicon dioxide and sized by passing through a conical mill with an
approximately 1300 micron grater type screen. The milled granules
were blended with the hypromellose 2208 and lactose monohydrate for
10 minutes in an 8 quart (7.61) V-blender. This blend was passed
through an 850 micron mesh screen. The magnesium stearate was
passed through a 600 micron mesh screen and blended with the
additional core materials in the V-blender for 5 minutes. Core
tablets (299.68 mg) were compressed using a GlobePharma Minipress
II rotary tablet press with 11/32'' round concave tooling. The core
tablets had a final mean hardness of approximately 11 kp. For the
coating, an aqueous suspension was prepared by mixing with an
impeller 578.7 g methacrylic acid copolymer dispersion, 9.0 g
triethyl citrate, 86.5 g PlasACRYL.TM. T20 with 325.8 g water. The
water contained in the methacrylic acid copolymer dispersion and
the PlasACRYL.TM. T20 is removed during the film coating process
and therefore not included in the final formulation in Table 4. The
tablets were coated with the aqueous suspension in the O'Hara
Technologies Labcoat M coater until the desired weight gain of
enteric film was achieved. The coating process occurred at an inlet
temperature of approximately 41.degree. C. and an outlet
temperature of 31.degree. C. After coating, the tablets were dried
for 2 hours at 40.degree. C.
Example 4
Safety, Tolerability, and Pharmacokinetics of Example 3 Dosage
Form
[0304] A randomized, double-blind crossover, food effect,
single-dose study of the safety, tolerability, and pharmacokinetics
of an oral dosage form of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate in healthy adult subjects was conducted.
Twenty-four healthy adult volunteers (males and females)
participated in the study. Twelve of the subjects received a dosage
form of Example 3, once in a fed condition and once in a fasted
condition, with a two-week washout between treatments. The fasted
dosing was achieved by dosing the subject following an overnight
fast while the fed dosing was achieved by dosing the subject after
consuming a high fat-content breakfast. The tested dosage forms
contained 200 mg of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate (107 mg equivalents of methyl hydrogen
fumarate).
[0305] Blood samples were collected from all subjects prior to
dosing, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24,
30, 36, 48, 60, 72, 84, 96, 108 and 120 hours after dosing. Urine
samples were collected from all subjects prior to dosing, and
complete urine output was obtained at the 0-4, 4-8, 8-12, 12-24,
24-36, 36-48, 48-72, 72-96 and 96-120 hour intervals after dosing.
Blood samples were quenched immediately with acetonitrile and
frozen. Sample aliquots were prepared for analysis of (i) methyl
hydrogen fumarate, (ii) (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, (iii) N,N diethyl-2-hydroxy acetamide and
(iv)
(2S,3S,4S,5R,6R)-6-[(N,N-diethylcarbamoyl)methoxy]-3,4,5-trihydroxy-2H-3,-
4,5,6-tetrahydropyran-2-carboxylic acid, the latter two being other
potential metabolites of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, using sensitive and specific LC/MS/MS
methods.
[0306] The plasma concentration of MMF following oral dosing of the
formulation prepared according to Example 3 to fasted and fed
healthy adult patients is shown in FIG. 2. Table 6 shows the
preliminary mean (SD) pharmacokinetic data for
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
[Compound (1)] in fed and fasted patients.
TABLE-US-00006 TABLE 6 PK Data for Compound (1) Average C.sub.max
T.sub.max AUC.sub.inf N Food (ng/mL) (hr) (ng hr/mL) 12*/8** Fasted
95* 4.17* 400** (26) (0.84) (166) 12*/5*** Fed 80* 9.92* 377***
(39) (5.50) (132) *Cmax and Tmax measured in all 12 subjects,
**based on 8 out of 12 subjects with a defined terminal phase,
***based on 5 out of 12 subjects with a defined terminal phase
[0307] The formulation produced mean (SD) maximum MMF
concentrations (average Cmax) of 95 (26) ng/mL fasted and 80 (39)
ng/mL fed. MMF AUC was 400 (160) ng*h/mL fasted and 377 (132)
ng*h/mL fed. The time to peak concentration (Tmax) was 4.17 (0.84)
hr fasted and 9.92 (5.50) hr fed. Promoiety was cleared from blood
with a half-life around 3 hours.
[0308] (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
was well tolerated during the trial. All 12 subjects completed the
dosing period. All adverse events were mild. One subject in the
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate fed
group reported flushing more frequently than in the fed placebo
group. No subjects in the fasted (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate group reported flushing, and no
subjects in either the fed or fasted (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate groups reported feeling hot more
than for placebo. A comparison of these adverse events of the
formulation to placebo is shown in Table 7.
TABLE-US-00007 TABLE 7 Comparison of Adverse Events Flushing
Feeling Hot Fasted Fed Fasted Fed Placebo 0 1 0 0 Example 3 1 1 0 0
Formulation
Example 5
Preparation of VCaps Plus Capsule Dosage Form
[0309] Size 00 VCaps Plus capsules containing 477 mg of
extended-release (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate-containing pellets were manufactured with
the formulation shown in Table 8:
TABLE-US-00008 TABLE 8 Composition of VCaps Plus Capsule Quantity
Quantity Component Manufacturer Role (mg/tablet) (% w/w) (N,N-
Cambridge Drug substance 200.00 60.00 Diethylcarbamoyl)methyl
(Germantown, WI) methyl (2E)but-2-ene-1,4- dioate Microcrystalline
Cellulose FMC Filler 133.33 40.00 (Newark, DE) Total Pellet 333.33
100.00 Core Ethylcellulose Ashland Water-insoluble 20.56 6.17
(Hopewell VA) coating agent Hydroxypropyl Cellulose Ashland Water
soluble 5.00 1.50 (Hopewell VA) coating agent Talc Luzenac
Anti-tacking 5.00 1.50 (Houston TX) agent Dibutyl sebacate
Vertellus Plasticizer 2.78 0.83 (Greensboro, NC) Total Barrier/
33.33 10.00 Sustained Release Coating Methacrylic Acid Co- Evonik
Enteric coating 88.55 24.15 polymer Dispersion (Darmstadt, agent
Germany) Triethyl Citrate Vertellus Plasticizer 14.30 3.90
(Greensboro, NC) PlasACRYL T20 Emerson Anti tacking 7.15 1.95
(Norristown, PA) agent Total Enteric 110.00 30.00 Coating VCaps
Plus Size 00 Capsugel Capsule 111-125 23.29-26.22 Capsule (Puebla,
Mexico)
[0310] The capsules were manufactured according to the following
process. An extrusion/spheronization process was selected for the
manufacture of the core pellets for the capsules. The
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate was
first screened then mixed with microcrystalline cellulose. This
blend was then formed into a wet mass with the addition of aqueous
acetate buffer (pH 3.5) and the mass then extruded through a 1.0 mm
screen and the extrudates were spheronized (at 1200 rpm for 3
minutes) to form the core pellets. These core pellets are then
classed to retain the pellets within 0.85 mm to 1.4 mm before the
next processing step. The pellets were then coated with the target
amount of the sustained release membrane using a hydroalcoholic
mixture of ethylcellulose and hydroxypropyl cellulose. This coating
was performed in a Wurster-type coater (product temperature at
30.degree. C. and spray rate at 10 g/minute). The overall coating
time was approximately 2 hours. The coated pellets were dried
further in an oven to remove any residual solvent. The dried
sustained release film-coated pellets were then enteric coated to
the target amount by aqueous film coating in a Wurster-type coater
(product temperature at 30.degree. C. and a spray rate at 10
g/min). The overall coating time was approximately 2 hours. The
capsules were then filled with the appropriate amount of pellets to
achieve the desired dose strength.
Example 6
In Vitro Dissolution Profile of VCaps Plus Capsule Dosage Form
[0311] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Example 5 in order to mimic the conditions of a dosage form as it
transits the gastrointestinal tract. Thus, the dosage forms were
first placed into a dissolution medium having a pH of 1.2, to mimic
the conditions of the stomach, and then placed into a dissolution
medium of pH 6.8, to mimic the conditions of the intestines. The
dissolution vessel (USP, Type I, basket) initially contained 750 mL
of 0.1 N hydrochloric acid (pH 1.2). After 2 hours of dissolution,
250 mL of 200 mM tribasic sodium phosphate was added to the vessel
resulting in a pH adjustment from 1.2 to 6.8. The dissolution
medium was kept at 37.degree. C. and was agitated at 100 rpm.
[0312] Samples of the dissolution medium were withdrawn at 1 and 2
hours following the start of the low pH stage, and at 0.5, 2, 4, 7,
10, and 14 hours following start of the near-neutral pH stage. The
concentration of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate in solution was determined using reverse
phase HPLC using a C18 column and a phosphoric
acid/acetonitrile/water isocratic mobile phase with photodiode
detection at 210 nm.
[0313] The percent of prodrug released from the Example 5 dosage
forms over time is shown in FIG. 3. These dosage forms showed no
prodrug release in the first 2 hours (acid stage) of testing. Slow
prodrug release was observed after the dissolution medium pH was
adjusted to 6.8. Full prodrug release was achieved after about 20
hours in pH 6.8.
Example 7
Safety, Tolerability, and Pharmacokinetics of Capsule Dosage
Form
[0314] A randomized, double-blind crossover, food effect,
single-dose study of the safety, tolerability, and pharmacokinetics
of a sustained release oral dosage form of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in
healthy adult subjects was conducted. Twelve healthy adult
volunteers (males and females) participated in the study. All
twelve subjects received a dosage form of Example 5, once in a fed
condition and once in a fasted condition, with a two-week washout
between treatments. The fasted dosing was achieved by dosing the
subject following an overnight fast while the fed dosing was
achieved by dosing the subject after consuming a high fat-content
breakfast. The dosage form contains 200 mg of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (107
mg equivalents of methyl hydrogen fumarate).
[0315] Blood samples were collected from all subjects prior to
dosing, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24,
30, 36, 48, 60, 72, 84, 96, 108 and 120 hours after dosing. Urine
samples were collected from all subjects prior to dosing, and
complete urine output was obtained at the 0-4, 4-8, 8-12, 12-24,
24-36, 36-48, 48-72, 72-96 and 96-120 hour intervals after dosing.
Blood samples were quenched immediately with acetonitrile and
frozen. Sample aliquots were prepared for analysis of (i) methyl
hydrogen fumarate, (ii) (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, (iii) N,N diethyl-2-hydroxy acetamide and
(iv)
(2S,3S,4S,5R,6R)-6-[(N,N-diethylcarbamoyl)methoxy]-3,4,5-trihydroxy-2H-3,-
4,5,6-tetrahydropyran-2-carboxylic acid, the latter two being other
potential metaboliltes of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, using sensitive and specific LC/MS/MS
methods.
[0316] The plasma concentration of MMF following oral dosing of the
formulation prepared according to Example 5 to fasted and fed
healthy adult patients is shown in FIG. 4. Table 9 shows the
preliminary mean (SD) pharmacokinetic data for
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in fed
and fasted patients.
TABLE-US-00009 TABLE 9 PK Data for Capsule Dosage Form Average
C.sub.max T.sub.max AUC.sub.inf N Food (ng/mL) (hr) (ng hr/mL)
12*/10** Fasted 64* 3.08* 257** (34) (0.79) (116) 12 Fed 106 6.42
398 (37) (1.98) (123) *Cmax and Tmax measured in all 12 subjects,
**based on 10 out of 12 subjects with a defined terminal phase
[0317] The formulation produced mean (SD) maximum MMF
concentrations (average Cmax) of 64 (34) ng/mL fasted and 106 (37)
ng/mL fed. MMF AUC was 257 (116) ng*h/mL fasted and 398 (123)
ng*h/mL fed. The time to peak concentration (Tmax) was 3.08 (0.79)
hr fasted and 6.42 (1.98) hr fed. Promoiety was cleared from blood
with a half-life around 3 hours. (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate was well tolerated during the
trial. All 12 subjects completed the dosing period. All adverse
events were mild. Two subjects in the (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate fed group reported flushing more
frequently than in the fed placebo group. No subjects in the fasted
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate group
reported flushing, and no subjects in either the fed or fasted
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate groups
reported feeling hot more than for placebo. A comparison of these
adverse events of the formulation to placebo is shown in Table
10.
TABLE-US-00010 TABLE 10 Comparison of Adverse Events Flushing
Feeling Hot Fasted Fed Fasted Fed Placebo 0 1 0 0 Example 5 2 0 0 0
Formulation
Example 8
Preparation of Compression Coated Tablet Dosage Form (Non-Enteric
Coated, 8% HPMC in Core)
[0318] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 11:
TABLE-US-00011 TABLE 11 Composition of CCT Dosage Form (Non-Enteric
Coated, 8% HPMC in Core) Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Clara, Drug
substance 100.00 29.19 Diethylcarbamoyl)methyl CA) methyl
(2E)but-2-ene-1,4- dioate Hydroxypropyl Cellulose Aqualon
(Hopewell, Binder 3.12 0.91 VA) Hypromellose 2208 Dow Chemical
Sustained Release 9.14 2.67 (100000 mPa s) (Midland, MI) Polymer
Silicon Dioxide Cabot (Tuscola, IL) Glidant 0.23 0.06 Magnesium
Stearate Mallinckrodt (St. Louis, Lubricant 1.71 0.50 MO) Total
Core 114.20 33.33 Lactose Hydrate Foremost (Rothschild, Filler
157.60 46.00 WI) Hypromellose 2208 Dow Chemical Sustained Release
68.52 20.00 (100 mPa s) (Midland, MI) Polymer Magnesium Stearate
Mallinckrodt (St. Louis, Lubricant 2.28 0.67 MO) Total Mantle
228.40 66.67 Total Tablet 342.60 100.00
[0319] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation batch size was 680 g. (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate was passed through the Quadro Comil
U5 with an 813 micron screen at 2000 rpm. Hydroxypropyl cellulose
was passed through a 600 micron mesh screen.
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
hydroxypropyl cellulose were granulated with purified water using a
Diosna P1/6 equipped with a 4 L bowl. The wet granules were
screened through an 1180 micron mesh screen and dried on trays in
an oven at 30.degree. C. for 6 hours.
[0320] The core blend batch size was 5 g. The dried granules,
hydroxypropylmethylcellulose (i.e., hypromellose 2208 having 100000
mPas viscosity), and the silicon dioxide were then passed through a
600 micron mesh screen, combined in a glass jar and blended in a
Turbula mixer for 5 minutes. Magnesium stearate was passed through
a 250 micron screen and added to the blend before blending an
additional 1.5 minutes. Core tablets (114.2 mg) were compressed
using a Carver Press with 1/4 inch (6.35 mm) round standard concave
tooling at 0.4 metric ton (MT) force. The core tablets had a final
hardness of approximately 7.6 kp (.about.74 Newtons).
[0321] The mantle blend was prepared using a direct compression
process and a batch size of 10 g. The hypromellose 2208 (100 MPas
viscosity) and lactose hydrate were passed through a 600 micron
mesh screen, combined in a glass jar and blended in a Turbula mixer
for 5 minutes. Magnesium stearate was passed through a 250 micron
screen and added to the blend and blended an additional 1.5
minutes. The mantle blend was then applied to the core tablets
using the Carver Press with 3/8 inch (9.53 mm) round standard
concave tooling. Half the mantle blend (114.2 mg) was weighed out,
added to the die, and tamped slightly to flatten. Then, the core
tablet was placed into the die and pressed down gently into the
mantle blend. The second half of the mantle blend (114.2 mg) was
then added on top of the core tablet and the mantle was compressed
using 1.5 MT force. The final compression coated tablets had a
total weight of 342.6 mg with a (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate loading of 100 mg (29.19%). The tablets
had a final hardness around 14.7 kp (.about.144 Newtons).
Example 9
Preparation of Compression Coated Tablet Dosage Form
Non-Enteric Coated, 30% HPMC in Mantle
[0322] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 12:
TABLE-US-00012 TABLE 12 Composition of CCT Dosage Form (Non-Enteric
Coated, 30% HPMC in Mantle) Quantity Quantity Component
Manufacturer Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Clara,
Drug substance 100.00 31.78 Diethylcarbamoyl)methyl CA) methyl
(2E)but-2-ene-1,4- dioate Hydroxypropyl Cellulose Aqualon
(Hopewell, Binder 3.12 0.99 VA) Silicon Dioxide Cabot (Tuscola, IL)
Glidant 0.21 0.06 Magnesium Stearate Mallinckrodt (St. Louis,
Lubricant 1.57 0.50 MO) Total Core 104.90 33.33 Lactose Hydrate
Foremost (Rothschild, Filler 144.76 46.00 WI) Hypromellose 2208 Dow
Chemical Sustained Release 62.94 20.00 (100000 mPa s) (Midland, MI)
Polymer Magnesium Stearate Mallinckrodt (St. Louis, Lubricant 2.10
0.67 MO) Total Mantle 209.80 66.67 Total Tablet 314.70 100.00
[0323] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation batch size was 680 g. (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate was passed through the Quadro Comil
U5 with an 813 micron screen at 2000 rpm. Hydroxypropyl cellulose
was passed through a 600 micron mesh screen.
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
hydroxypropyl cellulose were granulated with purified water using a
Diosna P1/6 equipped with a 4 L bowl. The wet granules were
screened through an 1180 micron mesh screen and dried on trays in
an oven at 30.degree. C. for 6 hours.
[0324] The core blend batch size was 5 g. The dried granules and
the silicon dioxide were then passed through a 600 micron mesh
screen, combined in a glass jar and blended in a Turbula mixer for
5 minutes. Magnesium stearate was passed through a 250 micron
screen and added to the blend before blending an additional 1.5
minutes. Core tablets (104.9 mg) were compressed using a Carver
Press with 1/4 inch (6.35 mm) round standard concave tooling at 0.4
metric ton (MT) force. The core tablets had a final hardness of
approximately 6.1 kp (.about.60 Newtons).
[0325] The mantle blend was prepared using a direct compression
process and a batch size of 100 g. The hydroxypropylmethylcellulose
(i.e., hypromellose 2208 having 100000 MPas viscosity) and lactose
hydrate were passed through a 600 micron mesh screen, combined in a
1 quart (0.95 l) V-blender and blended for 10 minutes. Magnesium
stearate was passed through a 250 micron screen and added to the
blend and blended an additional 4 minutes. The mantle blend was
then applied to the core tablets using the Carver Press with 3/8
inch (9.53 mm) round standard concave tooling. Half the mantle
blend (104.9 mg) was weighed out, added to the die, and tamped
slightly to flatten. Then, the core tablet was placed into the die
and pressed down gently into the mantle blend. The second half of
the mantle blend (104.9 mg) was then added on top of the core
tablet, and the mantle was compressed using 1.5 MT force. The final
compression coated tablets had a total weight of 314.7 mg with a
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
loading of 100 mg (31.78%). The tablets had a final hardness around
13.1 kp (.about.128 Newtons).
Example 10
Composition of CCT Dosage Form (Non-Enteric Coated, 8% HPMC in
Core)
[0326] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 13:
TABLE-US-00013 TABLE 13 Composition of CCT Dosage Form (Non-Enteric
Coated, 8% HPMC in Core) Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- Cambridge Major Drug substance 100.0
27.59 Diethylcarbamoyl)methyl (Germantown, WI) methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose Aqualon
(Hopewell, Binder 3.1 0.86 VA) Hypromellose 2208 Dow Chemical
Sustained Release 9.1 2.51 (100000 mPa s) (Midland, MI) Polymer
Silicon Dioxide Evonik (Rheinfelden, Glidant 0.6 0.17 Germany)
Magnesium Stearate Mallinckrodt (St. Lubricant 1.7 0.47 Louis, MO)
Total Core 114.5 31.59 Lactose Hydrate Foremost Filler 164.8 45.47
(Rothschild, WI) Hypromellose 2208 Dow Chemical Sustained Release
80.6 22.24 (100 mPa s) (Midland, MI) Polymer Magnesium Stearate
Mallinckrodt (St. Lubricant 2.5 0.69 Louis, MO) Total Mantle 247.9
68.41 Total Tablet 362.4 100.00
[0327] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation was performed in 2 batches at 494.88 g each.
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate was
passed through a 1.0 mm mesh screen. Hydroxypropyl cellulose was
passed through a 600 micron mesh screen.
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
hydroxypropyl cellulose were combined in a 3 L bowl and mixed for
10 minutes using the Quintech granulator. The mixture was then
transferred to a 2 L bowl granulated with purified water using the
Quintech granulator. The wet granules were screened through a 2000
micron mesh screen and dried on trays in an oven at 30.degree. C.
for 4 hours 20 minutes. The dried granules were then passed through
an 850 micron screen.
[0328] The core blend batch size was 1099.2 g. The
hydroxypropylmethyl-cellulose (i.e., Hypromellose 2208 having
100000 mPas viscosity) and the silicon dioxide were combined,
passed through a 600 micron mesh screen, and added to the dry
granules in a 5 L cube blender and blended for 10 minutes at 25
rpm. Magnesium stearate was passed through a 600 micron screen and
added to the blend before blending an additional 4 minutes at 25
rpm. Core tablets (114.5 mg) were compressed using a Manesty F3
tablet press with 6.0 mm round concave tooling. The core tablets
had a final mean hardness between 8.1 to 10.2 kp (79-100
Newtons).
[0329] The mantle blend was prepared using a direct compression
process and a batch size of 5.0 kg. The hypromellose 2208 (100 MPas
viscosity) and lactose hydrate were combined and passed through a
600 micron mesh screen, placed in and blended on the Tumblemix 18 L
Bin Blender for 8.5 minutes at 30 rpm. Magnesium stearate was
passed through a 600 micron screen and added to the blend and
blended an additional 3.5 minutes. The mantle blend was then
applied to the core tablets using a Kikusui tablet press (Kikusui
Seisakusho Ltd., Kyoto, Japan) specially designed for the
manufacture of compression coated tablets. Compression was
completed using 9.5 mm round concave tooling and approximately 1000
kp force. The final compression coated tablets had a total weight
of 362.4 mg with a (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate loading of 100 mg (27.59%). The
compression coated tablets had a final mean hardness between 10.9
to 14.0 kp (107-137 Newtons).
Example 11
In Vitro Dissolution Profile of Compression Coated Tablet Dosage
Forms
[0330] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Examples 8, 9, and 10 in order to mimic the conditions of a dosage
form as it transits the gastrointestinal tract. Thus, the dosage
forms were first placed into a dissolution medium having a pH of
1.2, to mimic the conditions of the stomach, and then placed into a
dissolution medium of pH 6.8, to mimic the conditions of the
intestines. The dissolution vessel (USP, Type I, basket) initially
contained 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours
of dissolution, 250 mL of 200 mM tribasic sodium phosphate was
added to the vessel resulting in a pH adjustment from 1.2 to 6.8.
The dissolution medium was kept at 37.degree. C. and was agitated
at 100 rpm.
[0331] For the tested dosage forms, samples of the dissolution
medium were withdrawn at the indicated time points shown in the
respective figures. The amount of (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate in the dissolution medium samples
was determined by reverse phase HPLC using a C18 column and a 7
minute gradient method according to Table 14 where Mobile Phase A
is water/0.1% H.sub.3PO.sub.4 and Mobile Phase B is
water/acetonitrile/H.sub.3PO.sub.4 (10/90/0.1 by volume) with UV
detection at 210 nm.
TABLE-US-00014 TABLE 14 HPLC Gradient Conditions Time (minute) %
Mobile Phase A % Mobile Phase B 0 85 15 5 35 65 5.5 85 15 7 85
15
[0332] As shown in FIG. 5, for dosage forms prepared according to
Example 8, drug release is delayed for approximately 2 hours, and
thereafter the drug is released gradually, reaching more than 90%
released at 16 hours.
[0333] As shown in FIG. 6, for dosage forms prepared according to
Example 9, drug release is delayed for approximately 2 hours,
followed by near zero order release, reaching more than 90%
released at 24 hours.
[0334] As shown in FIG. 7, for dosage forms prepared according to
Example 10, drug release is delayed for approximately 2 hours, and
thereafter the drug is released gradually, reaching more than 90%
released at 16 hours.
Example 12
Preparation of Compression Coated Tablet Dosage Form
Non-Enteric Coated, 10% HPMC in the Core
[0335] To demonstrate the effect of increasing the percentage of
sustained release polymer in the core on the in vitro dissolution
profile, two different tablet formulations were made according to
the procedure outlined in Example 8, but with differing levels of
hypromellose 2208 (100000 MPas viscosity) in the core, i.e.,
compared to the Example 8 tablets. Thus, the Example 8 tablets
contained 8 wt % HPMC in the core while the Example 12 tablets
contained 10 wt % HPMC in the core, respectively. The tablet
formulations, including the Example 8 tablet formulation for
reference, are shown in Table 15.
TABLE-US-00015 TABLE 15 Composition of CCT Dosage Forms
(Non-Enteric Coated, 8% and 10% HPMC in Core) Quantity Quantity
(mg/ Quantity (mg/ Quantity tablet) (% w/w) tablet) (% w/w)
Component Example 8 Example 12 (N,N- 100.00 29.19 100.00 28.55
Diethylcarbamoyl)methyl methyl (2E)but-2- ene-1,4-dioate
Hydroxypropyl Cellulose 3.12 0.91 3.10 0.88 Hypromellose 2208 9.14
2.67 11.67 3.33 (100000 mPa s) Silicon Dioxide 0.23 0.06 0.23 0.07
Magnesium Stearate 1.71 0.50 1.75 0.50 Total Core 114.20 33.33
116.75 33.33 Lactose Hydrate 157.60 46.00 161.12 46.00 Hypromellose
2208 68.52 20.00 70.05 20.00 (100 mPa s) Magnesium Stearate 2.28
0.67 2.33 0.67 Total Mantle 228.40 66.67 233.50 66.67 Total Tablet
342.60 100.00 350.25 100.00
[0336] The dissolution profiles from the three compression coated
tablets were measured according to the method described in Example
11. FIG. 8 shows that the MHF prodrug release rate slows with
increasing percentage of hypromellose 2208 (100000 mPas) in the
core, but the initial delay before the start of prodrug release
stays the same at approximately 2 hours, likely due to the
unchanged mantle layer.
Example 13
Preparation of Sustained Release Tablet Dosage Forms (Non-Enteric
Coated)
[0337] To demonstrate the effect of increasing the viscosity of
sustained release polymer in the mantle on the in vitro dissolution
profile, tablets were made with hypromellose 2208 of different
viscosities in the mantle: Example 13a (4000 mPas), and Example 13b
(a combination of 100 mPas and 4000 mPas to give an effective
viscosity of .about.2000 mPas). The formulation details are shown
in Table 16.
TABLE-US-00016 TABLE 16 Composition of Sustained Release Tablet
Dosage Forms (Non-Enteric Coated) Quantity Quantity Quantity
Quantity (mg/tablet) (% w/w) (mg/tablet) (% w/w) Component Example
13a Example 13b (N,N-Diethylcarbamoyl)methyl methyl 200.00 32.00
200.00 32.00 (2E)but-2-ene-1,4-dioate Hydroxypropyl Cellulose 6.20
1.00 6.20 1.00 Magnesium Stearate 2.10 0.30 2.10 0.30 Total Core
208.30 33.30 208.30 33.30 Lactose Hydrate 308.30 49.30 308.30 49.30
Hypromellose 2208 0.00 0.00 52.05 8.35 (100 mPa s) Hypromellose
2208 104.10 16.70 52.05 8.35 (4000 mPa s) Magnesium Stearate 4.20
0.70 4.20 0.70 Total Mantle 416.60 66.70 416.60 66.70 Total Tablet
624.90 100.00 624.90 100.00
[0338] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation batch size was 170 g. (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate was passed through the Quadro Comil
U5 with an 813 micron screen at 2000 rpm. Hydroxypropyl cellulose
was passed through a 500 micron mesh screen.
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
hydroxypropyl cellulose were granulated with purified water using a
Diosna P1/6 equipped with a 1 L bowl. The wet granules were
screened through an 1180 micron mesh screen and dried on trays in
an oven at 30.degree. C. for 3 hours 48 minutes.
[0339] The core blend batch size was 20.0 g. The dried granules and
magnesium stearate were combined in a glass bottle and blended in a
Turbula mixer for 2 minutes. Core tablets (208.3 mg) were
compressed using a Manesty FlexiTab single station tablet press
with 5/16 inch (7.9 mm) round standard concave tooling at forces
ranging from 9.9 to 14.0 kN. The core tablets had a final mean
hardness of 8.4 kp (.about.82 Newtons).
[0340] The mantle blend was prepared using a direct compression
process and a batch size of either 10 g (Example 13b) or 20 g
(Example 13a). The hypromellose 2208 and lactose hydrate were
passed through a 600 micron mesh screen, combined in a glass bottle
and blended in a Turbula mixer for either 10 (Example 13a), or 5
(Example 13b) minutes. In each case, magnesium stearate was passed
through a 250 micron screen and added to the blend and blended an
additional 1.5 minutes. The mantle blend was then applied to the
core tablets using the Carver Press with 7/16 inch (11.1 mm) round
standard concave tooling. Half the mantle blend (208.3 mg) was
weighed out, added to the die, and tamped slightly to flatten.
Then, the core tablet was placed into the die and pressed down
gently into the mantle blend. The second half of the mantle blend
(208.3 mg) was then added on top of the core tablet and the mantle
was compressed using 2.0 metric ton (MT) force. The final
compression coated tablets had a total weight of 624.9 mg with a
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
loading of 200 mg (32.00%). The tablets had a final hardness of
about 18.3 to 19.5 kp (.about.179 to 191 Newtons).
[0341] The dissolution profiles from the two compression coated
tablets were measured according to the method described in Example
11. FIG. 9 shows that the MHF prodrug release rate slows with
increasing hypromellose viscosity and the delay time increases
slightly with increasing hypromellose viscosity.
Example 14
Preparation of Sustained Release Tablet Dosage Forms
Non-Enteric Coated with 5 wt % Hypromellose 2208 (100000 mPas) in
the Core and 40% Hypromellose 2208 (100 mPas) in the Mantle
[0342] To demonstrate the effect of increasing the percentage of
hypromellose 2208 (100 mPas viscosity) in the mantle on the in
vitro dissolution profile and reducing the amount of hypromellose
2208 (100000 mPas) in the core, tablets were made according to the
procedure outlined in Example 8, but with 5 wt % hypromellose 2208
(100000 mPas) in the core and 40% of hypromellose 2208 (100 MPas)
in the mantle: The tablet formulation is shown in Table 17.
TABLE-US-00017 TABLE 17 Composition of SR Tablet Dosage Forms
[Non-Enteric Coated with 5 wt % hypromellose 2208 (100000 mPa s) in
the core and 40% hypromellose 2208 (100 MPa s) in the mantle]
Quantity Quantity (mg/tablet) (% w/w) Component Example 14
(N,N-Diethylcarbamoyl)methyl methyl(2E)but- 100.00 30.17
2-ene-1,4-dioate Hydroxypropyl Cellulose 3.10 0.93 Hypromellose
2208 5.52 1.66 (100000 mPa s) Silicon Dioxide 0.22 0.07 Magnesium
Stearate 1.66 0.50 Total Core 110.50 33.33 Lactose Hydrate 130.39
39.33 Hypromellose 2208 88.40 26.67 (100 mPa s) Magnesium Stearate
2.21 0.67 Total Mantle 221.00 66.67 Total Tablet 331.50 100.00
[0343] The dissolution profile from the Example 14 compression
coated tablets was measured according to the method described in
Example 11. FIG. 10 shows that the delay to drug release is
increased with increasing percentage of hypromellose 2208 (100
mPas) in the mantle, and the rate of MHS prodrug increases slightly
with decreasing percentage of hypromellose 2208 (100000 mPas) in
the core.
Example 15
Preparation of Sustained Release Tablet Dosage Forms
Non-Enteric Coated Formulation with No Hypromellose in the Core and
Thin Mantle
[0344] To demonstrate the effect of decreasing the thickness of the
mantle on the in vitro dissolution profile, the mantle to core
weight ratio was decreased from 2 to 1.5. The tablet formulation is
shown in Table 18.
TABLE-US-00018 TABLE 18 Composition of SR Tablet Dosage Form
(Non-Enteric Coated) Quantity Quantity (mg/tablet) (% w/w)
Component Example 15 (N,N-Diethylcarbamoyl)methyl methyl(2E)but-
100.00 38.37 2-ene-1,4-dioate Hydroxypropyl Cellulose 3.06 1.17
Silicon Dioxide 0.10 0.04 Magnesium Stearate 1.04 0.40 Total Core
104.20 40.00 Lactose Hydrate 107.8 41.40 Hypromellose 2208 46.9
18.00 (100000 mPa s) Magnesium Stearate 1.56 0.60 Total Mantle
156.40 66.70 Total Tablet 260.60 100.00
[0345] The tablets were made according to the following steps. The
core tablets were prepared using a wet granulation process. The
granulation batch size was 680 g. (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate was passed through the Quadro Comil
U5 with an 813 micron screen at 2000 rpm. Hydroxypropyl cellulose
was passed through a 600 micron mesh screen.
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
hydroxypropyl cellulose were granulated with purified water using a
Diosna P1/6 equipped with a 4 L bowl. The wet granules were
screened through an 1180 micron mesh screen and dried on trays in
an oven at 30.degree. C. for 6 hours.
[0346] The core blend batch size was 30.0 g. The dried granules and
the silicon dioxide were then passed through a 600 micron mesh
screen, combined in a glass jar and blended in a Turbula mixer for
2 minutes. Magnesium stearate was passed through a 250 micron
screen and added to the blend before blending an additional 1.5
minutes. Core tablets (104.2 mg) were compressed using a Manesty
FlexiTab single station tablet press with 1/4 inch (6.35 mm) round
standard concave tooling at approximately 3 kN force. The core
tablets had a final hardness of 6.2 to 7.0 kp (about 61 to 69
Newtons).
[0347] The mantle blend was prepared using a direct compression
process and a batch size of 10 g. The hypromellose 2208 (100000
MPas) and lactose hydrate were passed through a 600 micron mesh
screen, combined in a glass bottle and blended for 5 minutes in a
Turbula mixer. Magnesium stearate was passed through a 250 micron
screen and added to the blend and blended an additional 1.5
minutes. The mantle blend was then applied to the core tablets
using the Carver Press with 5/16 inch (7.94 mm) round standard
concave tooling. Half the mantle blend (78.2 mg) was weighed out,
added to the die, and tamped slightly to flatten. Then, the core
tablet was placed into the die and pressed down gently into the
mantle blend. The second half of the mantle blend (78.2 mg) was
then added on top of the core tablet and the mantle was compressed
using 1.1 metric ton (MT) force. The final compression coated
tablets had a total weight of 260.6 mg with a
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
loading of 100 mg (38.37%). The tablets had a final hardness
ranging from 13.1 to 14.0 kp (about 128 to 137 Newtons).
[0348] The dissolution profile from the compression coated tablets
was measured according to the method described in Example 11. FIG.
11 shows that the release of drug substance from the tablet
increases with decreasing mantle to core weight ratio (compare with
Example 9 and FIG. 6).
Example 16
Safety, Tolerability, and Pharmacokinetics of Example 10 Dosage
Form
[0349] A randomized, double-blind crossover, food effect,
single-dose study of the safety, tolerability, and pharmacokinetics
of an oral dosage form of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate in healthy adult subjects was conducted.
Twelve healthy adult volunteers (males and females) participated in
the study. All twelve subjects received a dosage form of Example
10, once in a fed condition and once in a fasted condition, with a
two-week washout between treatments. The fasted dosing was achieved
by dosing the subject following an overnight fast while the fed
dosing was achieved by dosing the subject after consuming a high
fat-content breakfast. The dosage form contained 100 mg of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (54 mg
equivalents of methyl hydrogen fumarate).
[0350] Blood samples were collected from all subjects prior to
dosing, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24,
30, 36, 48, 60, 72, 84, 96, 108 and 120 hours after dosing. Urine
samples were collected from all subjects prior to dosing, and
complete urine output was obtained at the 0-4, 4-8, 8-12, 12-24,
24-36, 36-48, 48-72, 72-96 and 96-120 hour intervals after dosing.
Blood samples were quenched immediately with acetonitrile and
frozen. Sample aliquots were prepared for analysis of (i) methyl
hydrogen fumarate, (ii) (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, (iii) N,N diethyl-2-hydroxy acetamide and
(iv)
(2S,3S,4S,5R,6R)-6-[(N,N-diethylcarbamoyl)methoxy]-3,4,5-trihydroxy-2H-3,-
4,5,6-tetrahydropyran-2-carboxylic acid, the latter two being other
potential metaboliltes of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, using sensitive and specific LC/MS/MS
methods.
[0351] The plasma concentration of MMF following oral dosing of the
formulation prepared according to Example 10 to fasted and fed
healthy adult patients is shown in FIG. 12. Table 19 shows the
preliminary mean (SD) pharmacokinetic data for
(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in fed
and fasted patients.
TABLE-US-00019 TABLE 19 PK Data for Example 10 Dosage Form Average
C.sub.max AUC.sub.inf N Food (ng/mL) (ng hr/mL) 12 Fasted 143 625
(61.1) (216) 12 Fed 217 750 (88.5) (242)
[0352] MMF release from the formulation was sustained and minimally
affected by food. The formulation produced mean (SD) maximum MMF
concentrations (average Cmax) 143 (61) ng/mL fasted and 217 (89)
ng/mL fed. MMF AUC was 625 (216) ngh/mL fasted and 750 (242) ngh/mL
fed. Promoiety was cleared from blood with a half-life around 3
hours. (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
was well tolerated during the trial. All 12 subjects completed the
dosing period. All adverse events were mild. Adverse events that
were reported in more than one subject and that were more
frequently for (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate than for placebo were flushing and feeling
hot. A comparison of these adverse events to placebo is shown in
Table 20.
TABLE-US-00020 TABLE 20 Comparison of Adverse Events Flushing
Feeling Hot Fasted Fed Fasted Fed Placebo 0 1 0 0 Formulation 0 1 0
0
[0353] Finally, it should be noted that there are alternative ways
of implementing the embodiments disclosed herein. Accordingly, the
present embodiments are to be considered as illustrative and not
restrictive, and the claims are not to be limited to the details
given herein, but may be modified within the scope and equivalents
thereof.
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