U.S. patent application number 13/973622 was filed with the patent office on 2014-11-27 for oral dosage forms of methyl hydrogen fumarate and prodrugs thereof.
This patent application is currently assigned to XenoPort, Inc.. The applicant listed for this patent is XenoPort, Inc.. Invention is credited to Laura Elizabeth Bauer, Ching Wah Chong, Sami Karaborni, Chen Mao, Peter A. Virsik, David J. Wustrow.
Application Number | 20140348915 13/973622 |
Document ID | / |
Family ID | 49085232 |
Filed Date | 2014-11-27 |
United States Patent
Application |
20140348915 |
Kind Code |
A9 |
Karaborni; Sami ; et
al. |
November 27, 2014 |
Oral Dosage Forms of Methyl Hydrogen Fumarate and Prodrugs
Thereof
Abstract
Improved oral dosage forms of methyl hydrogen fumarate and
prodrugs thereof are disclosed. Methods of treating diseases such
as multiple sclerosis and psoriasis using such dosage forms are
also disclosed.
Inventors: |
Karaborni; Sami; (Cupertino,
CA) ; Bauer; Laura Elizabeth; (Sunnyvale, CA)
; Mao; Chen; (Mountain View, CA) ; Chong; Ching
Wah; (Fremont, CA) ; Wustrow; David J.; (Los
Gatos, CA) ; Virsik; Peter A.; (Portola Valley,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XenoPort, Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
XenoPort, Inc.
Santa Clara
CA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20140056978 A1 |
February 27, 2014 |
|
|
Family ID: |
49085232 |
Appl. No.: |
13/973622 |
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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61692179 |
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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61837796 |
Jun 21, 2013 |
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61841513 |
Jul 1, 2013 |
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Current U.S.
Class: |
424/465 ;
514/239.2; 514/478; 514/547 |
Current CPC
Class: |
A61K 9/1652 20130101;
A61K 9/2826 20130101; A61K 9/146 20130101; A61K 9/2054 20130101;
A61P 17/06 20180101; A61P 25/28 20180101; A61P 21/02 20180101; A61K
9/4808 20130101; A61K 31/225 20130101; A61P 29/00 20180101; A61K
9/284 20130101; A61K 9/2886 20130101; A61P 1/04 20180101; A61P
25/00 20180101; A61K 31/215 20130101; A61P 25/16 20180101; A61P
19/02 20180101; A61K 9/2866 20130101; A61P 19/00 20180101; A61K
9/4866 20130101; A61K 31/27 20130101; A61P 17/02 20180101; Y02A
50/414 20180101; A61K 9/2095 20130101; A61P 25/14 20180101; Y02A
50/30 20180101; A61K 31/5375 20130101 |
Class at
Publication: |
424/465 ;
514/478; 514/547; 514/239.2 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 31/215 20060101 A61K031/215; A61K 31/5375 20060101
A61K031/5375; A61K 31/27 20060101 A61K031/27 |
Claims
1. An oral pharmaceutical tablet, comprising: (A) a tablet core
comprising (i) a compound selected from (a) methyl hydrogen
fumarate (MHF), (b) a prodrug of MHF, (c) pharmaceutically
acceptable salts of (a) or (b), and (d) combinations of any of the
foregoing, and (ii) one or more core tableting excipients; and (B)
a compressed coating layer surrounding said tablet core, the
coating layer comprising a material that is either (i) a
proton-donating acidic material having a pKa of greater than 8,
(ii) a proton-accepting basic material having a pKa of less than 2,
(iii) a natural gum or polysaccharide, (iv) a neutral polymer salt,
or (v) a lipid, the coating layer releasing no more than 20% of the
compound over a period of 2 hours after the tablet is placed in an
aqueous solution free of the compound.
2. The oral pharmaceutical tablet of claim 1, wherein the coating
layer material is a non-ionizable polymer substantially free of
carboxylic acid moieties.
3. The oral pharmaceutical tablet of claim 1, wherein the coating
layer material is selected from non-ionizable cellulosic polymers,
non-ionizable vinyl polymers, and non-ionizable polyvinyl alcohol
polymers.
4. The oral pharmaceutical tablet of claim 1, wherein the tablet
core comprises an immediate release formulation.
5. The oral pharmaceutical tablet of claim 1, wherein the tablet
core comprises a sustained release formulation.
6. The oral pharmaceutical tablet of claim 1, wherein at least one
of the tablet core and the coating layer comprises a sustained
release agent.
7. The oral pharmaceutical tablet of claim 6, wherein the sustained
release agent is selected from hydroxypropylmethyl cellulose and
ethyl cellulose.
8. The oral pharmaceutical tablet of claim 1, the tablet having a
core weight to: compressed coating weight ratio of 1:1 to 1:3.
9. The oral pharmaceutical tablet of claim 1, wherein the tablet
releases no more than 10% of the compound over a period of 2 hours
after the tablet is placed in the aqueous solution.
10. The oral pharmaceutical tablet of claim 1, wherein the coating
layer includes one or more excipients selected from binders,
fillers, glidants and lubricants.
11. The oral pharmaceutical tablet of claim 1, wherein the core
tableting excipients are selected from binders, fillers,
disintegrants, glidants and lubricants.
12. The oral dosage form of claim 1, wherein the coating layer
material has a pKa of greater than 10 or less than 0.
13. The oral pharmaceutical tablet of claim 1, wherein the compound
comprises methyl hydrogen fumarate.
14. The oral pharmaceutical tablet of claim 1, wherein the compound
comprises a prodrug of methyl hydrogen fumarate.
15. The oral pharmaceutical tablet of claim 14, wherein the prodrug
of methyl hydrogen fumarate is a compound of formula (I):
##STR00004## or a pharmaceutically acceptable salt thereof,
wherein: R.sup.1 and R.sup.2 are independently chosen from
hydrogen, C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl; R.sup.3
and R.sup.4 are independently chosen from hydrogen, C.sub.1-6
alkyl, substituted C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl,
substituted C.sub.1-6 heteroalkyl, C.sub.3-11 cycloalkyl,
substituted C.sub.3-11 cycloalkyl, 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.3 and R.sup.4 together
with the nitrogen to which they are bonded form a ring chosen from
a C.sub.4-10 heteroaryl, substituted C.sub.4-10 heteroaryl,
C.sub.4-10 heterocycloalkyl, and substituted C.sub.4-10
heterocycloalkyl; n is an integer from 0 to 4; and X is
independently chosen from a single oxygen atom and a pair of
hydrogen atoms; 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;
and wherein when X is a single oxygen atom, the oxygen atom is
connected to the carbon to which it is bonded by a double bond to
form a carboxyl group and when X is a pair of hydrogen atoms, each
hydrogen atom is connected to the carbon to which it is bonded to
by single bond.
16. The oral pharmaceutical tablet of claim 14, wherein the prodrug
of methyl hydrogen fumarate is a compound of formula (II):
##STR00005## or a pharmaceutically acceptable salt thereof,
wherein: n is an integer from 2 to 6; and R.sup.1 is methyl.
17. The oral pharmaceutical tablet of claim 15, wherein the prodrug
of MHF is selected from dimethyl fumarate,
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate,
(N,N-Dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, and
pharmaceutically acceptable salts thereof.
18. The oral pharmaceutical tablet of claim 17, wherein the prodrug
of MHF comprises (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate.
19. The oral pharmaceutical tablet of claim 16, wherein the
compound is selected from methyl 4-morpholin-4-ylbutyl
(2E)but-2-ene-1,4-dioate, methyl 5-morpholin-4-ylpentyl
(2E)but-2-ene-1,4-dioate HCl, and pharmaceutically acceptable salt
thereof.
20. The oral pharmaceutical tablet of claim 18, wherein the tablet
contains from 50 to 900 mg of the prodrug.
21. The oral pharmaceutical tablet of claim 18, wherein the tablet
contains from 100 to 400 mg of the prodrug.
22. The oral pharmaceutical tablet of claim 1, wherein the tablet
releases at least 80% of the compound within 3 hours after being
placed in the aqueous solution.
23. The oral pharmaceutical tablet of claim 1, wherein the tablet
releases at least 80% of the compound over a period of at least 6
hours after being placed in the aqueous solution.
24. A method of treating a disease in a patient, comprising orally
administering to a patient in need thereof the pharmaceutical
tablet of claim 1.
25. The method of claim 24, wherein the oral administration is
sufficient to obtain a therapeutic concentration of MHF in blood
plasma of the patient of at least 0.7 .mu.g/ml at a time within 24
hours after said oral administration.
26. The method of claim 24, wherein the oral administration is
sufficient to obtain an area under a concentration of methyl
hydrogen fumarate in blood plasma versus time curve (AUC) of at
least 12.0 .mu.ghr/ml over 24 hours after start of the oral
administration.
27. The method of claim 24, wherein the disease is multiple
sclerosis.
28. The method of claim 24, wherein the disease is psoriasis.
29. The method of claim 24, wherein the disease is selected from
Parkinson's disease, amyotrophic lateral sclerosis (ALS),
Huntington's disease, Alzheimer's disease, lupus, Crohn's disease,
psoriatic arthritis and alkylosing spondilitis.
Description
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Application Ser. No. 61/692,179
filed Aug. 22, 2012, Ser. No. 61/692,168, filed Aug. 22, 2012, Ser.
No. 61/713,897 filed Oct. 15, 2012, Ser. No. 61/733,234 filed Dec.
4, 2012, Ser. No. 61/769,513 filed Feb. 26, 2013, Ser. No.
61/841,513 filed Jul. 1, 2013, 61/692,174 filed Aug. 22, 2012, and
61/713,961 filed Oct. 15, 2012, 61/837,796 filed Jun. 21, 2013 the
contents of each of which are incorporated by reference in their
entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to oral dosage forms of
methyl hydrogen fumarate (MHF) and prodrugs of MHF which are useful
in treating conditions such as multiple sclerosis (MS) and/or
psoriasis.
BACKGROUND
[0003] Fumaric acid esters, i.e., dimethylfumarate (DMF) in
combination with salts of ethylhydrogenfumarate, have been used in
the treatment of psoriasis for many years. The combination product,
marketed under the trade name Fumaderm.RTM., is in the form of oral
tablets and is available in two different dosage strengths
(Fumaderm.RTM. initial and Fumaderm.RTM.):
TABLE-US-00001 Fumaderm .RTM. Fumaderm .RTM. Fumarate Compound
Initial (mg) (mg) Dimethylfumarate 30 120 Ethyl hydrogen fumarate,
calcium salt 67 87 Ethyl hydrogen fumarate, magnesium 5 5 salt
Ethyl hydrogen fumarate, zinc salt 3 3
[0004] The two strengths are intended to be applied in an
individually based dosing regimen starting with Fumaderm.RTM.
initial in an escalating dose, and then after, e.g., three weeks of
treatment, switching to Fumaderm.RTM.. Both Fumaderm.RTM. initial
and Fumaderm.RTM. are enteric coated tablets.
[0005] Another marketed composition is Fumaraat 120.RTM. containing
120 mg of DMF and 95 mg of calcium monoethyl fumarate (TioFarma,
Oud-Beijerland, Netherlands). The pharmacokinetic profile of
Fumaraat 120.RTM. in healthy subjects is described in Litjens et
al., Br. J. Clin. Pharmacol., 2004, vol. 58:4, pp. 429-432. The
results show that a single oral dose of Fumaraat 120.RTM. is
followed by a rise in serum MHF concentration and only negligible
concentrations of DMF and fumaric acid is observed. Thus, DMF is
thought to be a precursor or prodrug of MHF.
[0006] U.S. Pat. Nos. 6,277,882 and 6,355,676 disclose respectively
the use of alkyl hydrogen fumarates and the use of certain fumaric
acid monoalkyl ester salts for preparing microtablets for treating
psoriasis, psoriatic arthritis, neurodermatitis and enteritis
regionalis Crohn. U.S. Pat. No. 6,509,376 discloses the use of
certain dialkyl fumarates for the preparation of pharmaceutical
preparations for use in transplantation medicine or the therapy of
autoimmune diseases in the form of microtablets or micropellets.
U.S. Pat. No. 4,959,389 discloses compositions containing different
salts of fumaric acid monoalkyl esters alone or in combination with
a dialkyl fumarate. GB 1,153,927 relates to medical compositions
comprising dimethyl maleic anhydride, dimethyl maleate and/or
DMF.
[0007] Biogen Idec's BG12, an oral dosage form of DMF that is an
enteric coated capsule containing DMF in micropellet form, has been
in human clinical testing for the treatment of MS and has shown
promising results in reducing MS relapses and MS disability
progression. Unfortunately, DMF is highly irritating to the skin
and mucosal membranes with the result that oral administration of
DMF tends to cause serious digestive tract irritation with
attendant nausea, vomiting, abdominal pain and diarrhea. This
irritation problem is particularly problematic with the mucosal
tissue lining the stomach. For this reason, products such as
Fumaderm.RTM. and BG12 are made with enteric coatings that prevent
the DMF from being released from the dosage form until after the
dosage form passes out of the stomach and into the small
intestine.
[0008] More recently, MHF prodrugs including
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
(N,N-Dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate are
disclosed in Gangakhedkar et al. U.S. Pat. No. 8,148,414.
Additional MHF prodrugs are disclosed in Cundy et al. U.S. Patent
Application 61/595,835 filed Feb. 7, 2012. Both of these disclose
the use of MHF prodrugs for treating a number of medical
conditions, including MS and psoriasis.
SUMMARY
[0009] Disclosed herein are orally administered compression coated
tablet dosage forms of methyl hydrogen fumarate, or a prodrug of
methyl hydrogen fumarate, having improved prodrug stability and
shelf-life. The dosage forms are useful for treating conditions
such as multiple sclerosis and psoriasis.
[0010] Fumaric acid esters such as methyl hydrogen fumarate and
prodrugs of methyl hydrogen fumarate, e.g., dimethyl fumarate, have
certain physical and chemical properties that cause problems when
such compounds are used as therapeutic agents, particularly when
administered orally to a patient. First, such compounds have been
shown to cause skin irritation. Second, such compounds exhibit
degrees of chemical instability upon exposure to light, including
ultra violet light. Third, such compounds have been shown to cause
flushing in certain patients and/or at certain dosages. Fourth,
certain fumarate compounds (i.e., dimethyl fumarate) have been
shown to cause adverse interactions with the endothelial tissues
lining the stomach, causing severe tissue damage and attendant
gastrointestinal distress and symptoms such as nausea and abdominal
pain and diarrhea. Fifth, such compounds tend to be chemically less
stable at low pH levels (e.g., pH.ltoreq.2), compared to nearer
neutral pH levels (e.g., pH of 3 to 6) with the result that the
compounds can chemically break down into non-therapeutic
metabolites in the low pH environs of the stomach. While enteric
coatings have previously been proposed for certain fumarate dosage
forms, it has now been discovered that these fumarate compounds
tend to exhibit poor chemical stability in the presence of such
enteric coating materials.
[0011] These and other problems are solved by an oral
pharmaceutical tablet comprising a tablet core and a compressed
coating layer surrounding the tablet core. The tablet core contains
a compound selected from (i) methyl hydrogen fumarate (MHF), (ii) a
prodrug of MHF, pharmaceutically acceptable salts thereof and
combinations thereof, and (iii) one or more core tableting
excipients, such as a binder, a filler, a glidant and/or a
lubricant. The compressed coating layer comprises a material that
is either (i) a proton-donating acidic material having a pKa of
greater than 8, (ii) a proton-accepting basic material having a pKa
of less than 2, (iii) a natural gum or polysaccharide, (iv) a
neutral polymer salt, (v) a sugar, or (vi) a lipid. The coating
layer also remains intact and releases no more than 20% of the
compound over a period of 2 hours after the tablet is placed in an
aqueous solution free of the compound.
[0012] In certain embodiments, the coating layer material is a
non-ionizable polymer substantially free of carboxylic acid
moieties. In particular, the coating layer material may be selected
from non-ionizable cellulosic polymers, non-ionizable vinyl
polymers, and non-ionizable polyvinyl alcohol polymers. The coating
layer optionally includes one or more excipients selected from
binders, fillers, glidants and lubricants.
[0013] In certain embodiments, at least one of the tablet core and
the coating layer comprises a sustained release agent. In
particular, the sustained release agent may be selected from
hydroxypropyl methyl cellulose and ethyl cellulose.
[0014] In certain embodiments, the tablet has a core weight to
compressed coating weight ratio of 1:1 to 1:3. In other
embodiments, the tablet releases no more than 10% of the compound
over a period of 2 hours after the tablet is placed in an aqueous
solution free of the compound.
[0015] In certain embodiments, the compressed coating layer
comprises a material that is either (i) a proton-donating acidic
material having a pKa of greater than 10, or (ii) a
proton-accepting basic material having a pKa of less than 0.
[0016] In certain embodiments, the compound comprises methyl
hydrogen fumarate. In other embodiments, the compound comprises a
prodrug of methyl hydrogen fumarate. In still other embodiments,
the prodrug of methyl hydrogen fumarate is selected from dimethyl
fumarate, (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, (N,N-Dimethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, and combinations thereof.
[0017] In certain embodiments, the tablet core is a an immediate
release formulation and the compression coated tablet releases at
least 80% of the compound within 3 hours after being placed in an
aqueous solution free of the compound. In other embodiments, the
tablet core is a sustained release formulation and the compression
coated tablet releases at least 80% of the compound over a period
of at least 6 hours after being placed in an aqueous solution free
of the compound.
[0018] Also provided are methods of treating a disease in a
patient, comprising orally administering to a patient in need
thereof the pharmaceutical tablets disclosed herein. In particular,
the tablets disclosed herein can be used to treat multiple
sclerosis and/or psoriasis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 1, tested in accordance with Example 4;
[0020] FIG. 2 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 2, tested in accordance with Example 4;
[0021] FIG. 3 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 3, tested in accordance with Example 4;
[0022] FIG. 4 is a graph showing the concentration of MHF in the
blood of fasted monkeys following administration of the oral dosage
forms of Examples 1 and 2;
[0023] FIG. 5 is a graph showing the concentration of MHF in the
blood of fed monkeys following administration of the oral dosage
forms of Examples 1 and 2;
[0024] FIG. 6 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms as well as the uncoated cores of Example 3, tested in
accordance with Example 6;
[0025] FIG. 7 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms as well as the uncoated cores of Example 2, tested in
accordance with Example 7;
[0026] FIG. 8 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Examples 1 and 8, tested in accordance with Example 8;
[0027] FIG. 9 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 9, tested in accordance with Example 9;
[0028] FIG. 10 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Examples 8 and 10, tested in accordance with Example
10;
[0029] FIG. 11 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 11, tested in accordance with Example 11;
[0030] FIG. 12 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 12, tested in accordance with Example 12;
[0031] FIG. 13 is a graph showing the concentration of MMF in the
blood in fed and fasted healthy human patients following
administration of the oral dosage form of Example 3;
[0032] FIG. 14 is a graph showing the rate of degradation of DMF
and (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate as
a function of increased acetate concentration;
[0033] FIG. 15 is a graph showing the rate of formation of
degradation products for (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate as tested in Example 14;
[0034] FIG. 16 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Examples 15-18, tested in accordance with Example 21;
[0035] FIG. 17 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 19, tested in accordance with Example 22;
[0036] FIG. 18 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 20, tested in accordance with Example 23;
[0037] FIG. 19 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 26, tested in accordance with Example 28; and
[0038] FIG. 20 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the dosage
forms of Example 27, tested in accordance with Example 29.
DEFINITIONS
[0039] 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.
[0040] "Alkyl" refers to a saturated or unsaturated, branched,
cyclic, 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,
for example, 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, cyclopropyl,
cyclobutyl, cyclopentyl, etc.; and the like.
[0041] The term "alkyl" includes 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, or alkynyl are used. The term "alkyl" includes
cycloalkyl and cycloalkylalkyl groups. In certain embodiments, an
alkyl group can have from 1 to 10 carbon atoms (C.sub.1-10), 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), in
certain embodiments, from 1 to 3 carbon atoms (C.sub.1-3), and in
certain embodiments, from 1 to 2 carbon atoms (C.sub.1-2). In
certain embodiments, alkyl is methyl, in certain embodiments,
ethyl, and in certain embodiments, n-propyl or isopropyl.
[0042] "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.8-10. In certain embodiments, an arylalkyl group is
C.sub.7-12 arylalkyl.
[0043] "AUC" refers to the area under a curve on which time is
plotted on the X-axis and concentration of a substance (e.g., MHF)
in blood or blood plasma is plotted on the Y-axis over a particular
period of time (e.g., time zero to 24 hours). AUC is commonly
expressed in units of mghr/ml.
[0044] "Compounds" include MHF and MHF prodrugs. MHF products
include DMF and the compounds of Formula (I) or Formula (II)
including 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 those skilled in the art.
Compounds of Formula (I) or Formula (II) include, for example,
optical isomers of compounds of Formula (I) or Formula (II),
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 methods such as crystallization in the presence of a
resolving agent, or chromatography using, for example, chiral
stationary phases. Notwithstanding the foregoing, in compounds of
Formula (I) or Formula (II) the configuration of the illustrated
double bond is only in the E configuration (i.e., trans
configuration).
[0045] "Compressed coating layer" refers to the coating layer of a
tablet-in-tablet composition, which is produced by first preparing
a tablet "core" from a first component, and then applying a coating
layer by a subsequent compression step. The terms "shell" and
"mantle" are also sometimes used to describe the compressed coating
layer.
[0046] MHF and MHF prodrug compounds 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, for example, .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 disclosed
herein may be free acid, hydrated, solvated, or N oxides. Certain
compounds may exist in multiple crystalline, co-crystalline, or
amorphous forms. Compounds of Formula (I) or Formula (II) 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.
[0047] MHF and MHF prodrug compounds 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 include 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 are water.
[0048] 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.
[0049] "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.
[0050] "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.
[0051] "Disease" refers to a disease, disorder, condition, or
symptom of any of the foregoing.
[0052] "Dosage form" refers to a form of a formulation that
contains an amount of active agent or prodrug of an active agent,
e.g., the R-baclofen prodrug (1), which can be administered to a
patient to achieve a therapeutic effect. An oral dosage form is
intended to be administered to a patient via the mouth and
swallowed. Examples of oral dosage forms include capsules, tablets,
and liquid suspensions. A dose of a drug may include one or more
dosage forms administered simultaneously or over a period of
time.
[0053] "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 . . . "
[0054] "Heteroalkyl" by itself or as part of another substituent
refer 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--.
[0055] "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.
[0056] "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.4-10 heterocycloalkyl, C.sub.4-8
heterocycloalkyl, and in certain embodiments, C.sub.4-6
heterocycloalkyl.
[0057] "Immediate release" refers to formulations or dosage forms
that rapidly dissolve in vitro and in vivo and are intended to be
completely dissolved and absorbed in the stomach or upper
gastrointestinal tract. Immediate release formulations can release
at least 90% of the active ingredient or precursor thereof within
about 15 minutes, within about 30 minutes, within about one hour,
or within about two hours of administering an immediate release
dosage form.
[0058] "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, such as acetoxy
and benzoyloxy, alkoxycarbonylaryloxycarbonyl, mesyloxy, tosyloxy,
and trifluoromethanesulfonyloxy; aryloxy such as
2,4-dinitrophenoxy, methoxy, N,O-dimethylhydroxylamino,
p-nitrophenolate, imidazolyl, and the like.
[0059] "MHF" refers to methyl hydrogen fumarate, a compound having
the following chemical structure:
##STR00001##
[0060] This compound is also sometimes referred to as monomethyl
fumarate (MMF).
[0061] "MHF Prodrug" refers to a prodrug that is metabolized in
vivo to form methyl hydrogen fumarate as a pharmacologically active
metabolite.
[0062] "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, for example, 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, for
example, 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.
[0063] "Patient" refers to a mammal, for example, a human.
[0064] "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.
[0065] "Pharmaceutically acceptable salt" refers to a salt of a
compound that 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.
[0066] "Pharmaceutically acceptable excipient" refers to a
pharmaceutically acceptable filler, a pharmaceutically acceptable
adjuvant, a pharmaceutically acceptable vehicle, 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, 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 or a pharmacologically active
metabolite thereof.
[0067] "Prodrug" refers to a compound administered in a
pharmacologically inactive (or significantly less active) form.
Once administered, the compound is metabolized in vivo into an
active metabolite. Prodrugs may be designed to improve oral
bioavailability, particularly in cases where the metabolite
exhibits poor absorption from the gastrointestinal tract. Prodrugs
can be used to optimize the absorption, distribution, metabolism,
and excretion (ADME) of the active metabolite.
[0068] A composition or material that is "substantially free of
carboxylic acid moieties" is a composition or material that has
less than 2% w/w of carboxylic acid moieties. In certain
embodiments, a composition or material that is "substantially free
of carboxylic acid moieties" is a composition or material that has
less than 1% w/w of carboxylic acid moieties. In certain
embodiments, a composition or material that is "substantially free
of carboxylic acid moieties" is a composition or material that has
less than 0.01% w/w of carboxylic acid moieties.
[0069] "Substituent" refers to a group in which one or more
hydrogen atoms are independently replaced (or substituted) with the
same or 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.
[0070] "Sustained-release" refers to release of a drug from a
dosage form in which the drug release occurs over a period of time.
Sustained release can mean that release of the drug from the dosage
form is extended for longer than it would be in an
immediate-release dosage form, i.e., at least over several hours.
In some embodiments, in vivo release of the compound occurs over a
period of at least 2 hours, in some embodiments, over a period of
at least about 4 hours, in some embodiments, over a period of at
least about 8 hours, in some embodiments over a period of at least
about 12 hours, in some embodiments, over a period of at least
about 16 hours, in some embodiments, over a period of at least
about 20 hours, and in some embodiments, over a period of at least
about 24 hours.
[0071] "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.
[0072] "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 effect 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,
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 compound may be ascertained by those skilled in the art
and/or is capable of determination by routine experimentation.
[0073] "Therapeutically effective dose" refers to a dose that
provides effective treatment of a disease in a patient. A
therapeutically effective dose may vary from compound to compound
and/or from patient to patient, and may depend upon factors such as
the condition of the patient and the severity of the disease. A
therapeutically effective dose may be determined in accordance with
routine pharmacological procedures known to those skilled in the
art.
[0074] Reference is now made in detail to certain embodiments of
compounds, compositions, and methods. 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.
DETAILED DESCRIPTION
[0075] The oral pharmaceutical compositions disclosed herein are
so-called tablet-in-tablet compositions. In general, the
tablet-in-tablet compositions described herein are produced by
first preparing a tablet core from a first component, and then
applying during a subsequent compression step a compression coating
layer (which is sometimes referred to as a shell or mantle) of a
second component in a manner such that the finished formulation
comprises the core surrounded by the compression coating.
Tablet-in-tablet compositions are disclosed for example in U.S.
Pat. Nos. 8,148,393; 8,088,786; 8,067,033; 7,195,769; and
6,770,297.
A. Tablet Core
[0076] The dosage forms disclosed herein include a tablet core
containing a compound selected from (i) methyl hydrogen fumarate
(MHF), (ii) a prodrug of methyl hydrogen fumarate, (iii)
pharmaceutically acceptable salts of (i) and (ii), and (iv)
combinations thereof. Compressed tablet cores containing a fumarate
compound can be made using well-known techniques such as those
described in Remington: The Science and Practice of Pharmacy,
21.sup.st Edition, University of the Sciences in Philadelphia Ed.
(2005). Such tablet cores can contain one or more known tableting
excipients such as binders, fillers, disintegrants, glidants,
lubricants, surfactants, plasticizers, anti-adherents, buffers,
disintegrants, wetting agents, emulsifying agents, thickening
agents, coloring agents, sustained release agents, or combinations
of any of the foregoing. In certain embodiments, the excipient is
substantially free of carboxylic acid moieties.
[0077] Binders may be included in the tablet core to hold the
components of the core together. Examples of binders useful in the
present disclosure include, for example, polyvinylpyrrolidone,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
methylcellulose, hydroxyethyl cellulose, sugars, dextran,
cornstarch, and combinations of any of the foregoing. In certain
embodiments, the binder is hydroxypropyl cellulose.
[0078] Fillers may be added to increase the bulk to make dosage
forms. Examples of fillers useful in the present disclosure include
dibasic calcium phosphate, dibasic calcium phosphate dihydrate,
calcium sulfate, dicalcium phosphate, tricalcium phosphate,
lactose, cellulose including microcrystalline cellulose, mannitol,
sodium chloride, dry starch, pregelatinized starch, compressible
sugar, mannitol, and combinations of any of the foregoing. In
certain embodiments, the filler is lactose monohydrate. Fillers may
be water insoluble, water soluble, or combinations thereof.
Examples of useful water insoluble fillers include starch, dibasic
calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate,
tricalcium phosphate, powdered cellulose, microcrystalline
cellulose, and combinations of any of the foregoing. Examples of
water-soluble fillers include water soluble sugars and sugar
alcohols, such as lactose, glucose, fructose, sucrose, mannose,
dextrose, galactose, the corresponding sugar alcohols and other
sugar alcohols, such as mannitol, sorbitol, xylitol, and
combinations of any of the foregoing. In certain embodiments
wherein the filler is lactose, a tablet dosage form may comprise an
amount of filler ranging from about 25 wt % to about 60 wt %, and
in certain embodiments, from about 30 wt % to about 55 wt %.
[0079] Glidants may be included in the tablet core to reduce
sticking effects during processing, film formation, and/or drying.
Examples of useful glidants include talc, magnesium stearate,
glycerol monostearate, colloidal silicon dioxide, precipitated
silicon dioxide, fumed silicon dioxide, and combinations of any of
the foregoing. In certain embodiments, a glidant is colloidal
silicon dioxide. Tablet dosage forms may comprise less than about 3
wt % of a glidant, in certain embodiments, less than about 1 wt %
of a glidant as a flow aid.
[0080] Lubricants and anti-static agents may be included in a
pharmaceutically acceptable coating to aid in processing. Examples
of lubricants useful in coatings provided by the present disclosure
include calcium stearate, glycerol behenate, glyceryl monostearate,
magnesium stearate, mineral oil, polyethylene glycol, sodium
stearyl fumarate, sodium lauryl sulfate, stearic acid, talc,
vegetable oil, zinc stearate, and combinations of any of the
foregoing. In certain embodiments, the lubricant is magnesium
stearate. In certain embodiments, oral dosage forms may comprise an
amount of lubricant ranging from about 0.5 wt % to about 3 wt
%.
[0081] 1. Immediate Release Formulations in the Core
[0082] In various embodiments, the core contains an immediate
release formulation of the active compound. The immediate release
formulation can be any immediate release formulation known in the
art. Various immediate release formulations include uncoated active
compound, immediate release particles, granules or powders of the
compound, inert cores having a coating of the compound, and/or
granules or pellets of the compound coated with a highly soluble
immediate release coating.
[0083] In certain embodiments, immediate release particles may
comprise the compound and any appropriate vehicle, for example, any
of those disclosed herein. The compound is combined with any
tableting excipient known in the art to allow release of the
compound as an immediate release formulation.
[0084] Disintegrants may be included in the tablet core to cause a
tablet core to break apart, for example, by expansion of a
disintegrants when exposed to water. Examples of useful
disintegrants include water swellable substances such as
croscarmellose sodium, sodium starch glycolate, cross-linked
polyvinyl pyrrolidone, and combinations of any of the foregoing. In
various embodiments, the disintegrants can be selected to be
substantially free of carboxylic acid moieties.
[0085] In various embodiments, immediate release formulations can
include granules of the compound formed by granulation methods
known to those skilled in the art.
[0086] 2. Sustained Release in the Core
[0087] The tablet core may also be formulated in a sustained
release formulation. Examples of materials for effecting sustained
release include, but are not limited to, cellulosic polymers such
as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl
cellulose acetate succinate, hydroxypropyl methyl cellulose
phthalate, methylcellulose, ethyl cellulose, cellulose acetate,
cellulose acetate phthalate, cellulose acetate trimellitate, and
carboxymethylcellulose sodium; acrylic acid and methacrylic acid
copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cyanoethyl methacrylate, poly(acrylic acid),
poly(methacrylic acid), methacrylic acid alkylamide copolymer,
poly(methyl methacrylate), polymethacrylate, poly(methyl
methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate
copolymers, ammonioalkyl methacrylate copolymers, and methacrylic
resins commercially available under the tradename Eudragit.RTM.
including Eudragit.RTM. L, Eudragit.RTM. S, Eudragit.RTM.E,
Eudragit.RTM. RL, and Eudragit.RTM. RS; vinyl polymers and
copolymers such as polyvinylpyrrolidone, vinyl acetate,
vinylacetate phthalate, vinylacetate crotonic acid copolymer, and
ethylene-vinyl acetate copolymer; enzymatically degradable polymers
such as azo polymers, pectin, chitosan, amylase, and guar gum; and
shellac. Combinations of any of the foregoing polymers may also be
used to form sustained-release coatings.
[0088] 3. Compression Coated Core
[0089] The core can comprise one or more the components described
for the compression coating layer, infra. In such formulations, the
core reduces the amount of fumarate compound in the core from being
released. As such, the core can have any of the components and
properties of the compression coating layer as described herein. It
is understood that in such variations, the compression coating core
and compression coating layer may have the same or different
components.
B. Compression Coating Layer
[0090] A compression coating layer surrounds the core of the tablet
dosage form. The function of the coating layer is to reduce the
amount of the fumarate compound contained in the core being
released from the tablet while the dosage form remains in the
patient's stomach. Typically it takes from 1 to 3 hours, measured
from the time of swallowing, for the contents of the stomach to
pass into the small (upper) intestine. Thus, the coating layer
comprises a material that releases no more than 20% of the compound
over a period of 2 hours after the tablet is placed in an aqueous
solution free of the compound. In other embodiments, the coating
layer comprises a material that releases no more than 10% of the
compound over a period of 2 hours after the tablet is placed in an
aqueous solution free of the compound. In this way, the coating
layer reduces the amount of fumarate compound coming into contact
with the epithelial tissues lining the stomach.
[0091] The protective function of the compression coating layer is
achieved by appropriate selection of the coating layer material as
well as the thickness. Generally, the coating layer thickness can
be expressed as a weight percent of the total tablet, or as a
weight ratio of the tablet coating to the tablet core. In certain
aspects, the tablets can have a core weight to: compressed coating
weight ratio of 1:1 to 1:3. Similarly, in certain aspects the
tablets can have a compression coating that ranges from about 40 wt
% to about 75 wt % of the total tablet weight.
[0092] In various aspects, the oral pharmaceutical tablet is
configured to release at least 80% of the compound within 3 hours
after being placed in an aqueous solution free of the compound. In
further embodiments, the oral pharmaceutical tablet is configured
to release at least 80% of the compound over a period of at least 6
hours after being placed in an aqueous solution free of the
compound.
[0093] In various aspects, the rate of erosion of the compression
coating layer can be reduced by increasing the amount of erodible
material in the compression coating layer, and/or increasing the
viscosity of the erodible material. By increasing the amount of the
erodible material in the compression coating layer, the compression
coating layer requires more time to erode, and thereby releases
less active compound over time.
[0094] Likewise, the viscosity of erodible materials in the
compression coating layer can be increased. By increasing the
viscosity of the erodible material in the compression coating
layer, the compression coating layer requires more time to erode
and releases less active compound over time. Various erodible
materials have a range of viscosities depending on structural
properties such as polymer molecular weight, the degree of
crosslinking, etc. For example, polymers can be obtained with a
range of increasing viscosities. Viscosities of various materials
can be obtained from Rowe, Raymond C, Paul J. Sheskey, and Paul J.
Weller. Handbook of Pharmaceutical Excipients. London:
Pharmaceutical Press, 2003.
[0095] The oral pharmaceutical tablet can be configured to result
in a therapeutic concentration of MHF in blood plasma of the
patient of at least 0.7 .mu.g/ml at a time within 24 hours after
said oral administration. In further embodiments, the oral
pharmaceutical tablet is configured to result in an area under a
concentration of methyl hydrogen fumarate in blood plasma versus
time curve (AUC) of at least 12.0 .mu.ghr/ml over 24 hours after
start of the oral administration.
[0096] In certain embodiments, there is sufficient coating material
to cover the outer surface of the tablet core. In certain
embodiments, the tablet has a core weight to compressed coating
weight ratio of 1:1 to 1:3. The coating layer is sufficiently thick
such that the coating layer releases no more than 20% of the
compound over a period of 2 hours after the tablet is placed in an
aqueous free of the compound. The thickness can depend on the
material composition of the coating layer. In certain embodiments,
the coating layer thickness is equal to or greater than 0.5 mm. The
coating layer is sufficiently thick to cover the entire outer
surface of the tablet core.
Compression Coating Layer Materials
[0097] A compression coating layer surrounds the tablet core. It
will be understood that either the compression coating layer is in
direct contact with the tablet core, or that one or more
intermediate layers are disposed between the compression coating
layer and the tablet core. The compression coating comprises one or
more materials that will not cause premature breakdown of the
fumarate compound during product shelf life.
[0098] Surprisingly, MHF and MHF prodrugs have been found to have
poor stability when placed in contact with ionizable polymers
having carboxylic acid moieties of the type that are commonly used
in enteric coatings. Such enteric polymers include for example
hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl
methyl cellulose succinate, hydroxypropyl cellulose acetate
succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl
cellulose acetate succinate, hydroxypropyl methyl cellulose
phthalate, hydroxyethyl methyl cellulose acetate succinate,
hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl
cellulose, carboxymethyl cellulose, cellulose acetate phthalate,
methyl cellulose acetate phthalate, ethyl cellulose acetate
phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl
methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate
phthalate succinate, hydroxypropyl methyl cellulose acetate
succinate phthalate, hydroxypropyl methyl cellulose succinate
phthalate, cellulose propionate phthalate, hydroxypropyl cellulose
butyrate phthalate, cellulose acetate trimellitate, methyl
cellulose acetate trimellitate, ethyl cellulose acetate
trimellitate, hydroxypropyl cellulose acetate trimellitate,
hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl
cellulose acetate trimellitate succinate, cellulose propionate
trimellitate, cellulose butyrate trimellitate, cellulose acetate
terephthalate, cellulose acetate isophthalate, cellulose acetate
pyridinedicarboxylate, salicylic acid cellulose acetate,
hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid
cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose
acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic
acid cellulose acetate, and ethyl picolinic acid cellulose acetate.
Thus, in certain embodiments the compression coating is
substantially free of ionizable polymers having carboxylic acid
moieties of the types mentioned above.
[0099] Compression coating layers release no more than 20% of the
compound over a period of 2 hours after the tablet is placed in an
aqueous solution free of the compound.
[0100] 1. Non-Ionizable Polymers
[0101] As used herein, non-ionizable polymers are materials that
are either (i) a proton-donating acidic material having a pKa of
greater than 8, or (ii) a proton-accepting basic material having a
pKa of less than 2.
[0102] In some variations, the compression coating layer comprises
a material that is (i) a proton-donating acidic material having a
pKa of greater than 8, (ii) a proton-accepting basic material
having a pKa of less than 2, (iii) a natural gum or polysaccharide,
(iv) a neutral polymer salt, (v) a sugar, or (vi) a lipid. In
certain embodiments, the compression coating layer comprises a
material that is either (i) a proton-donating acidic material
having a pKa of greater than 10, or (ii) a proton-accepting basic
material having a pKa of less than 0. The pKa values for various
compounds may be calculated as is known in the art.
[0103] The compression coating layer can be comprised of one or
more non-ionizable polymers. Examples of suitable non-ionizable
polymers include non-ionizable cellulosic polymers, non-ionizable
vinyl and polyvinyl alcohol polymers, non-ionizable polymers that
are not cellulose or vinyl-based, natural gum and polysaccharides,
neutral polymer salts, readily ionizable polymers lacking
carboxylic acid moieties, and lipids.
[0104] a. Non-Ionizable Cellulosic Polymers
[0105] In some variations, the compression coating layer comprises
a non-ionizable cellulosic polymer. Specific examples of
non-ionizable cellulosic polymers include methylcellulose,
ethylcellulose, propylcellulose, butylcellulose, cellulose acetate,
cellulose propionate, cellulose butyrate, cellulose acetate
butyrate, cellulose acetate propionate, methyl cellulose, methyl
cellulose acetate, methyl cellulose propionate, methyl cellulose
butyrate, ethyl cellulose acetate, ethyl cellulose propionate,
ethyl cellulose butyrate, hydroxymethyl cellulose, hydroxyethyl
cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose,
hydroxybutyl cellulose, hydroxyethyl cellulose acetate, and
hydroxyethyl ethyl cellulose, low-substituted hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl
cellulose acetate, hydroxypropyl methyl cellulose propionate,
hydroxypropyl methyl cellulose butyrate, and corresponding salts
and esters. In general, such non-ionizable cellulosic polymers are
substantially free of carboxylic acid moieties.
[0106] b. Non-Ionizable Vinyl-Based Polymers
[0107] In some variations, the compression coating layer comprises
a non-ionizable vinyl-based polymer. Exemplary vinyl-based polymers
include polyvinvyl acetate, and polyvinylpyrrolidone. Exemplary
vinyl-containing polymers further include vinyl polymers and
copolymers having at least hydroxyl-containing repeat units,
alkylacyloxy-containing repeat units, or cyclicamido-containing
repeat units. Still further exemplary vinyl-containing polymers
also include polyvinyl alcohols that have at least a portion of
their repeat units in the unhydrolyzed (vinyl acetate) form,
polyvinylhydroxyethyl ether, polyvinyl alcohol polyvinyl acetate
copolymers, polyvinyl pyrrolidone,
polyvinylpyrrolidone-polyvinvylacetate copolymers, polyethylene
polyvinyl alcohol copolymers, and polyoxyethylene-polyoxypropylene
copolymers. In alternate embodiments, vinyl copolymers can include
a second polymer having (1) substantially carboxy-free
hydroxyl-containing repeat units and (2) hydrophobic repeat units.
In various embodiments, the preceding vinyl-based non-ionizable
polymers and co-polymers are substantially free of carboxylic acid
moieties.
[0108] In certain embodiments, the non-ionizable polyvinyl
materials show no degradation as an excipient. Non-limiting
examples of such materials include polyvinylpyrrolidone and
crospovidone.
[0109] c. Non-Ionizable Polymer that is Neither Cellulose Nor Vinyl
Based
[0110] In some variations, the compression coating layer comprises
non-cellulosic non-vinyl-based non-ionizable polymers. Examples of
such polymers include poly(lactide) poly(glycolide),
poly(.epsilon.-caprolactone), poly(lactide-co-glycolide),
poly(lactide-co-.epsilon.-caprolactone), poly(ethylene
oxide-co-.epsilon.-caprolactone), poly(ethylene oxide-co-lactide),
poly(ethylene oxide-co-lactide-co-glycolide),
poly(isobutyl)cyanoacrylate, and poly(hexyl)cyanoacrylate,
polyethylene oxide, and poly(ethyl acrylate-co-methyl methacrylate)
2:1 (Eudragit NE). In some variations, non-ionizable polymers such
as polyoxyethylene-polyoxypropylene block copolymers show no
degradation as an excipient. In certain variations, the
non-cellulosic non-vinyl based non-ionizable polymers are
substantially free of carboxylic acid moieties.
[0111] In further variations, non-vinyl non-cellulosic
non-ionizable polymers and co-polymers are functionalized with one
or more carboxyl or amine substituents. Such polymers and
co-polymers include carboxylic acid functionalized
polymethyacrylates, carboxylic acid functionalized polyacrylate,
amine-functionalized polyacrylates, amine-functionalized
polymethacrylates, proteins, and carboxylic acid functionalized
starches.
[0112] 2. Natural Gums and Polysaccharides
[0113] In some variations, the compression coating layer comprises
a natural gum or polysaccharides. Suitable examples of such natural
gums and polysaccharides include guar gum, tara gum, locust bean
gum, carrageenan, gellan gum, alginate, and xanthan gum.
[0114] In certain embodiments, the natural gums and polysaccharides
are substantially free of carboxylic acid moieties, including salts
thereof. Non-limiting examples of such materials include guar gum,
tara gum, locust bean gum, and carrageenan.
[0115] In certain embodiments, the natural gums and polysaccharides
have carboxylic acid moieties. Non-limiting examples of such
materials include gellan gum, Alginate, and xanthan gum.
[0116] 3. Neutral Polymer Salts
[0117] In some variations, the compression coating layer comprises
a neutral polymer salt. Non-limiting examples of such neutral
polymer salts include poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1, poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.2, crosslinked sodium carboxymethyl cellulose (croscarmellose
sodium), crosslinked sodium carboxymethyl cellulose (sodium starch
glycolate), salts of carboxymethyl cellulose, salts of carboxyethyl
cellulose, salts of carboxypropyl cellulose, salts of carboxybutyl
cellulose, salts of carboxymethyl starch, and salts of carboxyethyl
starch.
[0118] In certain embodiments, the neutral polymer salts are
substantially free of carboxylate moieties. Non-limiting examples
of such neutral polymer salts include poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1 and poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.2,
[0119] In certain additional embodiments, the neutral polymer salts
are salts of carboxylate moieties. Non-limiting examples of such
neutral polymer salts include crosslinked sodium carboxymethyl
cellulose (croscarmellose sodium), crosslinked sodium carboxymethyl
cellulose (sodium starch glycolate), salts of carboxymethyl
cellulose, salts of carboxyethyl cellulose, salts of carboxypropyl
cellulose, salts of carboxybutyl cellulose, salts of carboxymethyl
starch, and salts of carboxyethyl starch. In certain embodiments,
the neutral polymer salts do not degrade as excipients.
Non-limiting examples of such materials include poly(ethyl
acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride) 1:2:0.1 and poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.2, and croscarmellose sodium.
[0120] In certain embodiments, certain neutral polymer salts
include a carboxyl group that is neutralized with a counter ion.
For example, croscarmellose sodium includes a carboxyl group that
is neutralized with sodium.
[0121] In certain other embodiments, the readily ionizable polymers
do not contain carboxylic acid groups. Such materials include
poly(butyl methacrylate-co-(2-dimethylaminoethyl)
methacrylate-co-methyl methacrylate) 1:2:1 (Eudragit E), chitosan,
and methyl methacrylate diethylaminoethyl methacrylate copolymer.
Eudragit E has polymer free amino groups, and is neutral at pH>5
and protonated at pH<5. It is therefore soluble in an aqueous
solution at low pH and insoluble in an aqueous solution at high
pH.
[0122] In certain variations, the neutral polymer salts are
substantially free of carboxylic acid moieties.
[0123] 4. Lipids
[0124] In some variations, the compression coating layer comprises
a lipid. Examples of suitable lipids are glyceryl behenate, castor
oil, hydrogenated vegetable oil, hydrogenated carnauba wax. and
microcrystalline wax. In certain variations, the lipids are
substantially free of carboxylic acid moieties.
Fumarate Compounds; MHF and MHF Prodrugs
[0125] In certain embodiments, the active ingredient in the dosage
forms disclosed herein is methyl hydrogen fumarate or a
pharmaceutically acceptable salt thereof.
[0126] Alternatively, the active ingredient in the dosage forms
disclosed herein can be an MHF prodrug. One suitable MHF prodrug is
dimethyl fumarate. Other suitable MHF prodrugs are the compounds of
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0127] R.sup.1 and R.sup.2 are independently chosen from hydrogen,
C.sub.1-6 alkyl, and substituted C.sub.1-6 alkyl;
[0128] R.sup.3 and R.sup.4 are independently chosen from hydrogen,
C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl, C.sub.1-6
heteroalkyl, substituted C.sub.1-6 heteroalkyl, C.sub.3-11
cycloalkyl, substituted C.sub.3-11 cycloalkyl, 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.3 and
R.sup.4 together with the nitrogen to which they are bonded form a
ring chosen from a C.sub.4-10 heteroaryl, substituted C.sub.4-10
heteroaryl, C.sub.4-10 heterocycloalkyl, and substituted C.sub.4-10
heterocycloalkyl;
[0129] n is an integer from 0 to 4; and
[0130] X is independently chosen from a single oxygen atom and a
pair of hydrogen atoms;
[0131] 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;
[0132] and wherein when X is a single oxygen atom, the oxygen atom
is connected to the carbon to which it is bonded by a double bond
to form a carboxyl group and when X is a pair of hydrogen atoms,
each hydrogen atom is connected to the carbon to which it is bonded
to by single bond.
[0133] Compounds of Formula I are disclosed in (i) Gangakhedkar et
al., U.S. Pat. No. 8,148,414; and (ii) Virsik et al. U.S. Ser. No.
61/653,375, filed May 30, 2012, the disclosures of which are
incorporated herein by reference. The methods and schemes of
synthesis disclosed in Gangakhedkar et al., U.S. Pat. No. 8,148,414
are incorporated herein by reference.
[0134] In other embodiments, the MHF prodrug is dimethyl
fumarate.
[0135] In other embodiments, the MHF prodrug is a compound of
Formula (II):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0136] n is an integer from 2 to 6; and
[0137] R.sup.1 is methyl.
[0138] Compounds of Formula (II) are disclosed in Cundy et al.,
U.S. Patent Application No. 61/595,835 filed Feb. 7, 2012, the
disclosures of which are incorporated herein by reference.
Therapeutic Uses
[0139] The dosage forms disclosed herein may be administered to a
patient suffering from any disease including a disorder, condition,
or symptom for which MHF is known or hereafter discovered to be
therapeutically effective. Indications for which MHF has been
prescribed, and hence for which a dosage form disclosed herein is
also expected to be effective, include psoriasis. Other indications
for which the disclosed dosage forms may be therapeutically
effective include multiple sclerosis, an inflammatory bowel
disease, asthma, chronic obstructive pulmonary disease, and
arthritis.
[0140] Methods of treating a disease in a patient provided by the
present disclosure comprise administering to a patient in need of
such treatment a dosage form disclosed herein. The dosage forms
disclosed herein may provide therapeutic or prophylactic plasma
and/or blood concentrations of MHF following administration to a
patient.
[0141] The dosage forms disclosed herein may be administered in an
amount and using a dosing schedule as appropriate for treatment of
a particular disease. For example, daily doses of MHF or a MHF
prodrug 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, the MHF or MHF prodrug 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 MHF or a MHF prodrug 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.
[0142] MHF or a MHF prodrug 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 MHF
or a MHF prodrug is therapeutically effective.
[0143] In certain embodiments, a therapeutically effective dose of
MHF or a MHF prodrug may provide therapeutic benefit without
causing substantial toxicity including adverse side effects.
Toxicity of MHF or a MHF prodrug 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
MHF or a MHF prodrug may be within a range capable of establishing
and maintaining a therapeutically effective circulating plasma
and/or blood concentration of MHF or a MHF prodrug that exhibits
little or no toxicity.
[0144] The dosage forms disclosed herein may be used to treat
diseases, disorders, conditions, and symptoms of any of the
foregoing for which MHF is known to provide or is later found to
provide therapeutic benefit. MHF is known to be effective in
treating psoriasis, multiple sclerosis, an inflammatory bowel
disease, asthma, chronic obstructive pulmonary disease, and
arthritis. Hence, the dosage forms disclosed herein may be used to
treat any of the foregoing diseases and disorders. 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 MHF and/or a MHF prodrug may be
administered to a patient, such as a human, as a preventative
measure against various diseases or disorders. Thus, a
therapeutically effective amount of MHF or a MHF prodrug may be
administered as a preventative measure to a patient having a
predisposition for and/or history of immunological, autoimmune,
and/or inflammatory diseases including psoriasis, asthma and
chronic obstructive pulmonary diseases, cardiac insufficiency
including left ventricular insufficiency, myocardial infarction and
angina pectoris, mitochondrial and neurodegenerative diseases such
as Parkinson's disease, Alzheimer's disease, Huntington's disease,
retinopathia pigmentosa and mitochondrial encephalomyopathy,
transplantation rejection, autoimmune diseases including multiple
sclerosis, ischemia and reperfusion injury, AGE-induced genome
damage, inflammatory bowel diseases such as Crohn's disease and
ulcerative colitis; and NF-.kappa.B mediated diseases.
Psoriasis
[0145] Psoriasis is characterized by hyperkeratosis and thickening
of the epidermis as well as by increased vascularity and
infiltration of inflammatory cells in the dermis. Psoriasis
vulgaris manifests as silvery, scaly, erythematous plaques on
typically the scalp, elbows, knees, and buttocks. Guttate psoriasis
occurs as tear-drop size lesions.
[0146] Fumaric acid esters are recognized for the treatment of
psoriasis and dimethyl fumarate is approved for the systemic
treatment of psoriasis in Germany (Mrowietz and Asadullah, Trends
Mol Med 2005, 11(1), 43-48; and Mrowietz et al., Br J Dermatology
1999, 141, 424-429).
[0147] Efficacy of MHF or a MHF prodrug for treating psoriasis can
be determined using animal models and in clinical trials.
Inflammatory Arthritis
[0148] Inflammatory arthritis includes diseases such as rheumatoid
arthritis, juvenile rheumatoid arthritis (juvenile idiopathic
arthritis), psoriatic arthritis, and ankylosing spondylitis produce
joint inflammation. The pathogenesis of immune-mediated
inflammatory diseases including inflammatory arthritis is believed
to involve TNF and NK-.kappa.B signaling pathways (Tracey et al.,
Pharmacology & Therapeutics 2008, 117, 244-279). DMF has been
shown to inhibit TNF and inflammatory diseases including
inflammatory arthritis are believed to involve TNF and NK-.kappa.B
signaling and therefore may be useful in treating inflammatory
arthritis (Lowewe et al., J Immunology 2002, 168, 4781-4787).
[0149] The efficacy of MHF or a MHF prodrug for treating
inflammatory arthritis can be determined using animal models and in
clinical trials.
Multiple Sclerosis
[0150] Multiple sclerosis (MS) is an inflammatory autoimmune
disease of the central nervous system caused by an autoimmune
attack against the isolating axonal myelin sheets of the central
nervous system. Demyelination leads to the breakdown of conduction
and to severe disease with destruction of local axons and
irreversible neuronal cell death. The symptoms of MS are highly
varied with each individual patient exhibiting a particular pattern
of motor, sensible, and sensory disturbances. MS is typified
pathologically by multiple inflammatory foci, plaques of
demyelination, gliosis, and axonal pathology within the brain and
spinal cord, all of which contribute to the clinical manifestations
of neurological disability (see e.g., Wingerchuk, Lab Invest 2001,
81, 263-281; and Virley, NeuroRx 2005, 2(4), 638-649). Although the
causal events that precipitate MS are not fully understood,
evidence implicates an autoimmune etiology together with
environmental factors, as well as specific genetic predispositions.
Functional impairment, disability, and handicap are expressed as
paralysis, sensory and octintive disturbances spasticity, tremor, a
lack of coordination, and visual impairment, which impact on the
quality of life of the individual. The clinical course of MS can
vary from individual to individual, but invariably the disease can
be categorized in three forms: relapsing-remitting, secondary
progressive, and primary progressive.
[0151] Studies support the efficacy of FAEs for treating MS and are
undergoing phase II clinical testing (Schimrigk et al., Eur J
Neurology 2006, 13, 604-610; and Wakkee and Thio, Current Opinion
Investigational Drugs 2007, 8(11), 955-962).
[0152] Assessment of MS treatment efficacy in clinical trials can
be accomplished using tools such as the Expanded Disability Status
Scale and the MS Functional as well as magnetic resonance imaging
lesion load, biomarkers, and self-reported quality of life. Animal
models of MS shown to be useful to identify and validate potential
therapeutics include experimental autoimmune/allergic
encephalomyelitis (EAE) rodent models that simulate the clinical
and pathological manifestations of MS and nonhuman primate EAE
models.
Inflammatory Bowel Disease (Crohn's Disease, Ulcerative
Colitis)
[0153] Inflammatory bowel disease (IBD) is a group of inflammatory
conditions of the large intestine and in some cases, the small
intestine that includes Crohn's disease and ulcerative colitis.
Crohn's disease, which is characterized by areas of inflammation
with areas of normal lining in between, can affect any part of the
gastrointestinal tract from the mouth to the anus. The main
gastrointestinal symptoms are abdominal pain, diarrhea,
constipation, vomiting, weight loss, and/or weight gain. Crohn's
disease can also cause skin rashes, arthritis, and inflammation of
the eye. Ulcerative colitis is characterized by ulcers or open
sores in the large intestine or colon. The main symptom of
ulcerative colitis is typically constant diarrhea with mixed blood
of gradual onset. Other types of intestinal bowel disease include
collagenous colitis, lymphocytic colitis, ischaemic colitis,
diversion colitis, Behcet's colitis, and indeterminate colitis.
[0154] FAEs are inhibitors of NF-.kappa.B activation and therefore
may be useful in treating inflammatory diseases such as Crohn's
disease and ulcerative colitis (Atreya et al., J Intern Med 2008,
263(6), 59106).
[0155] The efficacy of MHF or a MHF prodrug for treating
inflammatory bowel disease can be evaluated using animal models and
in clinical trials. Useful animal models of inflammatory bowel
disease are known.
Asthma
[0156] Asthma is reversible airway obstruction in which the airway
occasionally constricts, becomes inflamed, and is lined with an
excessive amount of mucus. Symptoms of asthma include dyspnea,
wheezing, chest tightness, and cough. Asthma episodes may be
induced by airborne allergens, food allergies, medications, inhaled
irritants, physical exercise, respiratory infection, psychological
stress, hormonal changes, cold weather, or other factors.
[0157] As an inhibitor of NF-.kappa.B activation and as shown in
animal studies (Joshi et al., US 2007/0027076) FAEs may be useful
in treating pulmonary diseases such as asthma and chronic
obstructive pulmonary disorder.
[0158] The efficacy of MHF or a MHF prodrug for treating asthma can
be assessed using animal models and in clinical trials.
Chronic Obstructive Pulmonary Disease
[0159] Chronic obstructive pulmonary disease (COPD), also known as
chronic obstructive airway disease, is a group of diseases
characterized by the pathological limitation of airflow in the
airway that is not fully reversible, and includes conditions such
as chronic bronchitis, emphysema, as well as other lung disorders
such as asbestosis, pneumoconiosis, and pulmonary neoplasms (see,
e.g., Barnes, Pharmacological Reviews 2004, 56(4), 515-548). The
airflow limitation is usually progressive and associated with an
abnormal inflammatory response of the lungs to noxious particles
and gases. COPD is characterized by a shortness of breath the last
for months or years, possibly accompanied by wheezing, and a
persistent cough with sputum production. COPD is most often caused
by tobacco smoking, although it can also be caused by other
airborne irritants such as coal dust, asbestos, urban pollution, or
solvents. COPD encompasses chronic obstructive bronchiolitis with
fibrosis and obstruction of small airways, and emphysema with
enlargement of airspaces and destruction of lung parenchyma, loss
of lung elasticity, and closure of small airways.
[0160] The efficacy of administering MHF or a MHF prodrug for
treating chronic obstructive pulmonary disease may be assessed
using animal models of chronic obstructive pulmonary disease and in
clinical studies. For example, murine models of chronic obstructive
pulmonary disease are known.
Neurodegenerative Disorders
[0161] Neurodegenerative diseases such as Parkinson's disease,
Alzheimer's disease, Huntington's disease and amyoptrophic lateral
sclerosis are characterized by progressive dysfunction and neuronal
death. NF-.kappa.B inhibition has been proposed as a therapeutic
target for neurodegenerative diseases (Camandola and Mattson,
Expert Opin Ther Targets 2007, 11(2), 123-32).
Parkinson's Disease
[0162] Parkinson's disease is a slowly progressive degenerative
disorder of the nervous system characterized by tremor when muscles
are at rest (resting tremor), slowness of voluntary movements, and
increased muscle tone (rigidity). In Parkinson's disease, nerve
cells in the basal ganglia, e.g., substantia nigra, degenerate, and
thereby reduce the production of dopamine and the number of
connections between nerve cells in the basal ganglia. As a result,
the basal ganglia are unable to smooth muscle movements and
coordinate changes in posture as normal, leading to tremor,
incoordination, and slowed, reduced movement (bradykinesia)
(Blandini, et al., Mol. Neurobiol. 1996, 12, 73-94).
[0163] The efficacy of MHF or a MHF prodrug for treating
Parkinson's disease may be assessed using animal and human models
of Parkinson's disease and in clinical studies.
Alzheimer's Disease
[0164] Alzheimer's disease is a progressive loss of mental function
characterized by degeneration of brain tissue, including loss of
nerve cells and the development of senile plaques and
neurofibrillary tangles. In Alzheimer's disease, parts of the brain
degenerate, destroying nerve cells and reducing the responsiveness
of the maintaining neurons to neurotransmitters. Abnormalities in
brain tissue consist of senile or neuritic plaques, e.g., clumps of
dead nerve cells containing an abnormal, insoluble protein called
amyloid, and neurofibrillary tangles, twisted strands of insoluble
proteins in the nerve cell.
[0165] The efficacy of MHF or a MHF prodrug for treating
Alzheimer's disease may be assessed using animal and human models
of Alzheimer's disease and in clinical studies.
Huntington's Disease
[0166] Huntington's disease is an autosomal dominant
neurodegenerative disorder in which specific cell death occurs in
the neostriatum and cortex (Martin, N Engl J Med 1999, 340,
1970-80). Onset usually occurs during the fourth or fifth decade of
life, with a mean survival at age of onset of 14 to 20 years.
Huntington's disease is universally fatal, and there is no
effective treatment. Symptoms include a characteristic movement
disorder (Huntington's chorea), cognitive dysfunction, and
psychiatric symptoms. The disease is caused by a mutation encoding
an abnormal expansion of CAG-encoded polyglutamine repeats in the
protein, huntingtin.
[0167] The efficacy of MHF or a MHF prodrug for treating
Huntington's disease may be assessed using animal and human models
of Huntington's disease and in clinical studies.
Amyotrophic Lateral Sclerosis
[0168] Amyotrophic lateral sclerosis (ALS) is a progressive
neurodegenerative disorder characterized by the progressive and
specific loss of motor neurons in the brain, brain stem, and spinal
cord (Rowland and Schneider, N Engl J Med 2001, 344, 1688-1700).
ALS begins with weakness, often in the hands and less frequently in
the feet that generally progresses up an arm or leg. Over time,
weakness increases and spasticity develops characterized by muscle
twitching and tightening, followed by muscle spasms and possibly
tremors. The average age of onset is 55 years, and the average life
expectancy after the clinical onset is 4 years. The only recognized
treatment for ALS is riluzole, which can extend survival by only
about three months.
[0169] The efficacy MHF or a MHF prodrug for treating ALS may be
assessed using animal and human models of ALS and in clinical
studies.
Other Diseases
[0170] Other diseases and conditions for which MHF or a MHF prodrug
such as DMF or a compound of Formulae (I) or (II) can be useful in
treating include rheumatica, granuloma annulare, lupus, autoimmune
carditis, eczema, sarcoidosis, and autoimmune diseases including
acute disseminated encephalomyelitis, Addison's disease, alopecia
areata, ankylosing spondylitis, antiphospholipid antibody syndrome,
autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner
ear disease, bullous pemphigoid, Behcet's disease, celiac disease,
Chagas disease, chronic obstructive pulmonary disease, Crohn's
disease, dermatomyositis, diabetes mellitus type I, endometriosis,
Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome,
Hashimoto's disease, hidradenitis suppurativea, Kawasaki disease,
IgA neuropathy, idiopathic thrombocytopenic purpura, interstitial
cystitis, lupus erythematosus, mixed connective tissue disease,
morphea, multiple sclerosis, myasthenia gravis, narcolepsy,
neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis,
psoriatic arthritis, polymyositis, primary biliary cirrhosis,
rheumatoid arthritis, schizophrenia, scleroderma, Sjogren's
syndrome, stiff person syndrome, temporal arteritis, ulcerative
colitis, vasculitis, vitiligo, Wegener's granulomatosis, optic
neuritis, neuromyelitis optica, subacute necrotizing myelopathy,
balo concentric sclerosis, transverse myelitis, susac syndrome,
central nervous system vasculitis, neurosarcoidosis,
Charcott-Marie-Tooth Disease, progressive supranuclear palsy,
neurodegeneration with brain iron accumulation, pareneoplastic
syndromes, primary lateral sclerosis, Alper's Disease, monomelic
myotrophy, adrenal leukodystrophy, Alexanders Disease, Canavan
disease, childhood ataxia with central nervous system
hypomyelination, Krabbe Disease, Pelizaeus-Merzbacher disease,
Schilders Disease, Zellweger's syndrome, Sjorgren's Syndrome, human
immunodeficiency viral infection, hepatitis C viral infection,
herpes simplex viral infection and a tumor.
Dosing
[0171] The dosage forms disclosed herein, and their use for
therapeutic treatment, are not limited to any particular oral
dosing regimen as long as the dosing regimen achieves therapeutic
blood plasma concentration levels and AUC levels. MHF or a MHF
prodrug may be administered at dosage levels of about 0.001 mg/kg
to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from
about 0.1 mg/kg to about 10 mg/kg of subject body weight per day,
one, two, three, four or more times a day, to obtain the desired
concentrations and AUC for MHF in the blood plasma.
[0172] In various embodiments, the tablet can contain more than 50
mg of prodrug In further embodiments, the tablet can contain more
than 100 mg of prodrug. In further embodiments, the tablet can
contain more than 150 mg of prodrug. In further embodiments, the
tablet can contain more than 200 mg of prodrug. In further
embodiments, the tablet can contain more than 250 mg of prodrug. In
further embodiments, the tablet can contain more than 300 mg of
prodrug. In further embodiments, the tablet can contain more than
350 mg of prodrug.
[0173] In various embodiments, the oral pharmaceutical tablet can
contain equal to or less than 900 mg of prodrug. In further
embodiments, the tablet can contain less than 800 mg of prodrug. In
further embodiments, the tablet can contain less than 700 mg of
prodrug. In further embodiments, the tablet can contain less than
600 mg of prodrug. In further embodiments, the tablet can contain
less than 500 mg of prodrug. In further embodiments, the tablet can
contain less than 450 mg of prodrug. In further embodiments, the
tablet can contain less than 400 mg of prodrug. In further
embodiments, the tablet can contain less than 350 mg of prodrug. In
further embodiments, the tablet can contain less than 300 mg of
prodrug. In further embodiments, the tablet can contain less than
250 mg of prodrug.
[0174] For the treatment of multiple sclerosis and/or psoriasis,
blood plasma concentrations of MHF of at least 0.5 .mu.g/ml during
the course of dosing is desired. In other embodiments, blood plasma
concentrations of MHF of at least 0.7 .mu.g/ml during the course of
dosing is desired. In other embodiments, blood plasma
concentrations of MHF of at least 1.2 .mu.g/ml during the course of
dosing is desired.
[0175] Similarly, for the treatment of multiple sclerosis and/or
psoriasis, an area under a concentration of MHF in blood plasma
versus time curve (AUC) of at least 4.0 .mu.ghr/ml over 24 hours of
dosing is desired. In other embodiments, an area under a
concentration of MHF in blood plasma versus time curve (AUC) of at
least 4.8 .mu.ghr/ml over 24 hours of dosing is desired. In other
embodiments, an area under a concentration of MHF in blood plasma
versus time curve (AUC) of at least 6.0 .mu.ghr/ml over 24 hours of
dosing is desired. In other embodiments, an area under a
concentration of MHF in blood plasma versus time curve (AUC) of at
least 7.0 .mu.ghr/ml over 24 hours of dosing is desired. In other
embodiments, an area under a concentration of MHF in blood plasma
versus time curve (AUC) of at least 9.0 .mu.ghr/ml over 24 hours of
dosing is desired. In other embodiments, an area under a
concentration of MHF in blood plasma versus time curve (AUC) of at
least 10.5 .mu.ghr/ml over 24 hours of dosing is desired. In still
other embodiments, an area under a concentration of MHF in blood
plasma versus time curve (AUC) of at least 12.0 .mu.ghr/ml over 24
hours of dosing is desired.
[0176] The amount of MHF or a MHF prodrug 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 MHF or a MHF prodrug to be
administered may also depend on, among other factors, the subject
being treated, the weight of the subject, the severity of the
disease, and the judgment of the prescribing physician.
[0177] For oral 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.
[0178] 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 MHF or a MHF prodrug contained in
a dose may depend on whether the disease in a patient is
effectively treated by acute, chronic, or a combination of acute
and chronic administration.
[0179] 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 LD50 (the dose
lethal to 50% of the population) or the LD100 (the dose lethal to
100% of the population). The dose ratio between toxic and
therapeutic effect is the therapeutic index. In certain
embodiments, a MHF prodrug 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 MHF or a MHF prodrug 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. In certain embodiments, an escalating dose may be
administered.
EXAMPLES
[0180] 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
[0181] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 1:
TABLE-US-00002 TABLE 1 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Drug substance
100.00 29.19 Diethylcarbamoyl)methyl Clara, CA) methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose Aqualon
(Hopewell, Binder 3.12 0.91 VA) Hypromellose 2208 Dow Chemical
Sustained 9.14 2.67 (100000 mPa s) (Midland, MI) Release Polymer
Silicon Dioxide Cabot (Tuscola, IL) Glidant 0.23 0.06 Magnesium
Stearate Mallinckrodt (St. Lubricant 1.71 0.50 Louis, MO) Total
Core 114.20 33.33 Lactose Hydrate Foremost (Rothschild, Filler
157.60 46.00 WI) Hypromellose 2208 Dow Chemical Sustained 68.52
20.00 (100 mPa s) (Midland, MI) Release Polymer Magnesium Stearate
Mallinckrodt (St. Lubricant 2.28 0.67 Louis, MO) Total Mantle
228.40 66.67 Total Tablet 342.60 100.00
[0182] 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.
[0183] The core blend batch size was 5 g. The dried granules,
hydroxypropyl methyl cellulose (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 on 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).
[0184] 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 on 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 2
[0185] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 2:
TABLE-US-00003 TABLE 2 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Drug substance
100.00 31.78 Diethylcarbamoyl)methyl Clara, 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. Lubricant
1.57 0.50 Louis, MO) Total Core 104.90 33.33 Lactose Hydrate
Foremost (Rothschild, Filler 144.76 46.00 WI) Hypromellose 2208 Dow
Chemical Sustained 62.94 20.00 (100000 mPa s) (Midland, MI) Release
Polymer Magnesium Stearate Mallinckrodt (St. Lubricant 2.10 0.67
Louis, MO) Total Mantle 209.80 66.67 Total Tablet 314.70 100.00
[0186] 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.
[0187] 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 on 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).
[0188] The mantle blend was prepared using a direct compression
process and a batch size of 100 g. The hydroxypropyl methyl
cellulose (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 3
[0189] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 3:
TABLE-US-00004 TABLE 3 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 Binder
3.1 0.86 (Hopewell, VA) Hypromellose 2208 Dow Chemical Sustained
Release 9.1 2.51 (100000 mPa s) (Midland, MI) Polymer Silicon
Dioxide Evonik Glidant 0.6 0.17 (Rheinfelden, 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
[0190] 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.
[0191] The core blend batch size was 1099.2 g. The hydroxypropyl
methyl 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).
[0192] 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 4
[0193] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Examples 1, 2, and 3 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 0.1N 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.
[0194] 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 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-00005 TABLE 4 Time (minute) % Mobile Phase A % Mobile
Phase B 0 85 15 5 35 65 5.5 85 15 7 85 15
[0195] As shown in FIG. 1, for dosage forms prepared according to
Example 1, drug release is delayed for approximately 2 hours, and
thereafter the drug is released gradually, reaching more than 90%
released at 16 hours.
[0196] As shown in FIG. 2, for dosage forms prepared according to
Example 2, drug release is delayed for approximately 2 hours,
followed by near zero order release, reaching more than 90%
released at 24 hours.
[0197] As shown in FIG. 3, for dosage forms prepared according to
Example 3, drug release is delayed for approximately 2 hours, and
thereafter the drug is released gradually, reaching more than 90%
released at 16 hours.
Example 5
[0198] The concentration.+-.1 SD of MHF in the blood of
Cynomologous monkeys following oral dosing of delayed release
enteric coated tablets prepared according to Examples 1 and 2 is
shown in FIGS. 4 and 5. In these Figures, the MHF concentrations
following dosing with the Example 1 tablets are shown with symbols
and the MHF concentrations following dosing with the Example 2
tablets are shown with symbols. The data in FIG. 4 is from animals
dosed in a fasted state and the data in FIG. 5 is from animals
dosed in a fed state.
Administration Protocol
[0199] Tablets prepared according to Examples 1 and 2 (100 mg
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate per
tablet) were administered by oral dosing to groups of four adult
male Cynomologous (Macaca fascicularis) monkeys (each monkey
weighed about 4 to 5 kg). Each monkey was administered two tablets
in either a fasted state or a fed state. All animals were fasted
overnight before the study. For the fed leg, animals were
administered blended food via oral gavage in the morning 30 minutes
prior to administration of each test formulation. For the fasted
leg, the animals remained fasted for 4 hours post-dosing. Blood
samples (1.0 mL) were obtained from all animals via the femoral
vein at pre-dose and intervals over 24 hours after oral dosing.
Blood was collected in pre-chilled K.sub.2EDTA, quenched with
acetonitrile and stored at -50.degree. C. to -90.degree. C. until
analyzed. There was a minimum 7 day wash out period between dosing
sessions.
Sample Preparation for Absorbed Drug
[0200] 300 .mu.L of acetonitrile was added to 1.5 mL Eppendorf
tubes for the preparation of samples and standards.
[0201] Sample Preparation: Blood was collected at different time
points and immediately 100 .mu.L of blood was added into Eppendorf
tubes containing 300 .mu.L of methanol and mixed by vortexing.
[0202] Standard Preparation: One hundred .mu.L of blood was added
to 290 .mu.L of acetonitrile in Eppendorf tubes. 10 .mu.L of MMF
standard solution (0.2, 0.5, 1, 2.5, 5, 10, 25, 50 and 100
.mu.g/mL) was added to each tube to make up the final calibration
standards (0.02, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5 and 10
.mu.g/mL).
[0203] A 150 .mu.L aliquot of supernatant from quenched blood
standards, QCs and samples was transferred to a 96-well plate and
20 .mu.L of the internal standard solution was added to each well,
the plate was capped and vortexed well. The supernatant was
injected onto the API 4000 LC/MS/MS system for analysis
LC/MS/MS Analysis
[0204] The concentration of MMF in monkey blood was determined
using an API 4000 LC/MS/MS instrument equipped with Agilent Binary
pump and autosampler. The column was a Luna C8 (2) 4.6.times.150
mm, 5.mu. column operating at 2 to 8.degree. C. temperature. The
mobile phases were (A) 0.1% formic acid in water, and (B) 0.1%
formic acid in acetonitrile. The gradient condition was: 2% B for 1
min, increasing to 95% B in 3.5 min and maintained for 2 min, then
decreasing to 2% B in 5.6 min and maintained for 2.3 min. 30 .mu.L
of sample was injected into the column. A Turbo-Ion Spray source
was used, and was detected in negative ion mode for the MRM
transition of 128.95/84.8. Peaks were integrated using Analyst 1.5
quantitation software.
Example 6
[0205] To demonstrate the effect of the compression coating on the
in vitro dissolution profile from tablets made according to Example
3, the dissolution profile from the cores of the compression coated
tablets of Example 3 (i.e., the intermediate product before
application of the mantle) was tested according to the method
described in Example 4 and compared to the dissolution profile from
the finished compression coated tablets of Example 3. FIG. 6 shows
that the compression coating provides a 2 hour delay before drug
release as shown by comparing the profiles of the cores ( symbols)
and the compression coated tablets ( symbols).
Example 7
[0206] To demonstrate the effect of the compression coating on the
in vitro dissolution profile from tablets made according to Example
2, the dissolution profile from the cores of the compression coated
tablets of Example 2 (i.e., the intermediate product before
application of the mantle) was tested according to the method
described in Example 4 and compared to the dissolution profile from
the finished compression coated tablets of Example 2. FIG. 7 shows
that the compression coating provides a 2 hour delay and a near
zero order release profile as shown by comparing the profiles of
the cores ( symbols) and the compression coated tablets (
symbols).
Example 8
[0207] 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 1, but with significantly
differing levels of hypromellose 2208 (100000 MPas viscosity) in
the core, i.e., compared to the Example 1 tablets. Thus, the
Example 1 tablets contained 8 wt % HPMC while the two Example 8
tablets contained 5 wt % and 10 wt % HPMC, respectively. The tablet
formulations, including the Example 1 tablet formulation for
reference, are shown in Table 5.
TABLE-US-00006 TABLE 5 Quantity Quantity Quantity Quantity Quantity
Quantity (mg/tablet) (% w/w) (mg/tablet) (% w/w) (mg/tablet) (%
w/w) Component Example 1 Example 8a Example 8b (N,N- 100.00 29.19
100.00 30.17 100.00 28.55 Diethylcarbamoyl)methyl methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose 3.12 0.91 3.10
0.93 3.10 0.88 Hypromellose 2208 9.14 2.67 5.52 1.66 11.67 3.33
(100000 mPa s) Silicon Dioxide 0.23 0.06 0.22 0.07 0.23 0.07
Magnesium Stearate 1.71 0.50 1.66 0.50 1.75 0.50 Total Core 114.20
33.33 110.50 33.33 116.75 33.33 Lactose Hydrate 157.60 46.00 152.49
46.00 161.12 46.00 Hypromellose 2208 68.52 20.00 66.30 20.00 70.05
20.00 (100 mPa s) Magnesium Stearate 2.28 0.67 2.21 0.67 2.33 0.67
Total Mantle 228.40 66.67 221.00 66.67 233.50 66.67 Total Tablet
342.60 100.00 331.50 100.00 350.25 100.00
[0208] The dissolution profiles from the three compression coated
tablets were measured according to the method described in Example
4. 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 9
[0209] 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 9a (100 mPas), Example 9b (4000
mPas), and Example 9c (a combination of 100 mPas and 4000 mPas to
give an effective viscosity of .about.2000 mPas). The formulation
details are shown in Table 6.
TABLE-US-00007 TABLE 6 Quantity Quantity Quantity Quantity Quantity
Quantity (mg/tablet) (% w/w) (mg/tablet) (% w/w) (mg/tablet) (%
w/w) Component Example 9a Example 9b Example 9c (N,N- 200.00 32.00
200.00 32.00 200.00 32.00 Diethylcarbamoyl)methyl methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose 6.20 1.00 6.20
1.00 6.20 1.00 Magnesium Stearate 2.10 0.30 2.10 0.30 2.10 0.30
Total Core 208.30 33.30 208.30 33.30 208.30 33.30 Lactose Hydrate
308.30 49.30 308.30 49.30 308.30 49.30 Hypromellose 2208 104.10
16.70 0.00 0.00 52.05 8.35 (100 mPa s) Hypromellose 2208 0.00 0.00
104.10 16.70 52.05 8.35 (4000 mPa s) Magnesium Stearate 4.20 0.70
4.20 0.70 4.20 0.70 Total Mantle 416.60 66.7 221.00 66.70 233.50
66.70 Total Tablet 624.90 100.0 331.50 100.00 350.25 100.00
[0210] 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.
[0211] The core blend batch size was 20.0 g. The dried granules and
magnesium stearate were combined in a glass bottle and blended on 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).
[0212] The mantle blend was prepared using a direct compression
process and a batch size of either 10 g (Examples 9a and 9c) or 20
g (Example 9b). The hypromellose 2208 and lactose hydrate were
passed through a 600 micron mesh screen, combined in a glass bottle
and blended on a Turbula mixer for either 10 (Example 9b), 6
(Example 9a), or 5 (Example 9c) 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).
[0213] The dissolution profiles from the three compression coated
tablets were measured according to the method described in Example
4. FIG. 9 shows that the MHF prodrug release rate slows with
increasing hypromellose viscosity and the delay time increases with
increasing hypromellose viscosity.
Example 10
[0214] To demonstrate the effect of increasing the percentage of
hypromellose 2208 (100 mPas viscosity) in the mantle on the in
vitro dissolution profile, tablets were made according to the
procedure outlined in Example 1, but with 5 wt % hypromellose 2208
(100000 mPas) in the core and different levels of hypromellose 2208
(100 MPas) in the mantle: Example 8a (30% hypromellose in mantle)
and Example 10 (40% hypromellose in mantle). The tablet
formulations, including the Example 1 and Example 8a tablet
formulations for reference, are shown in Table 7.
TABLE-US-00008 TABLE 7 Quantity Quantity Quantity Quantity Quantity
Quantity (mg/tablet) (% w/w) (mg/tablet) (% w/w) (mg/tablet) (%
w/w) Component Example 1 Example 8a Example 10 (N,N- 100.00 29.19
100.00 30.17 100.00 30.17 Diethylcarbamoyl)methyl methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose 3.12 0.91 3.10
0.93 3.10 0.93 Hypromellose 2208 9.14 2.67 5.52 1.66 5.52 1.66
(100000 mPa s) Silicon Dioxide 0.23 0.06 0.22 0.07 0.22 0.07
Magnesium Stearate 1.71 0.50 1.66 0.50 1.66 0.50 Total Core 114.20
33.33 110.50 33.33 110.50 33.33 Lactose Hydrate 157.60 46.00 152.49
46.00 130.39 39.33 Hypromellose 2208 68.52 20.00 66.30 20.00 88.40
26.67 (100 mPa s) Magnesium Stearate 2.28 0.67 2.21 0.67 2.21 0.67
Total Mantle 228.40 66.67 221.00 66.67 221.00 66.67 Total Tablet
342.60 100.00 331.50 100.00 331.50 100.00
[0215] The dissolution profiles from the three compression coated
tablets were measured according to the method described in Example
4. FIG. 10 shows that the rate of MHS prodrug release slows and the
delay to drug release is increased with increasing percentage of
hypromellose 2208 (100 mPas) in the mantle.
Example 11
[0216] To demonstrate the effect of increasing the percentage of
hypromellose 2208 (100000 mPas) in the mantle on the in vitro
dissolution profile, tablets were made with two different levels of
hypromellose 2208 (100000 mPas) in the mantle: Example 11a (20%)
and Example 11b (30%). The tablet formulations are shown in Table
8.
TABLE-US-00009 TABLE 8 Quantity Quantity (mg/ Quantity (mg/
Quantity tablet) (% w/w) tablet) (% w/w) Component Example 11a
Example 11b (N,N- 100.00 38.37 100.00 38.37 Diethylcarbamoyl)methyl
methyl (2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose 3.06 1.17
3.06 1.17 Silicon Dioxide 0.10 0.04 0.10 0.04 Magnesium Stearate
1.04 0.40 1.04 0.40 Total Core 104.20 40.00 104.20 40.00 Lactose
Hydrate 107.92 41.41 92.28 35.40 Hypromellose 2208 46.92 18.01
62.56 24.00 (100000 mPa s) Magnesium Stearate 1.56 0.60 1.56 0.60
Total Mantle 156.40 60.00 156.40 66.70 Total Tablet 260.60 100.00
260.60 100.00
[0217] 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.
[0218] 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).
[0219] 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 on 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).
[0220] The dissolution profiles from the two compression coated
tablets were measured according to the method described in Example
4. FIG. 11 shows that the release slows with increasing percentage
of hypromellose 2208 (100000 mPas) in the mantle.
Example 12
[0221] A stability study was conducted on the
(N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate-containing compression coated tablets, 100
mg at 5.degree. C., 25.degree. C./60% RH, 30.degree. C./65% RH, and
40.degree. C./75% RH. The tablets used in the stability study had
the composition outlined in Table 9.
TABLE-US-00010 TABLE 9 Quantity Quantity (mg/tablet) (% w/w)
Component Example 12 (N,N- 99.74 27.63 Diethylcarbamoyl)methyl
methyl (2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose 3.08 0.85
Hypromellose 2208 9.07 2.51 (100000 mPa s) Silicon Dioxide 0.51
0.14 Magnesium Stearate 1.70 0.47 Total Core 114.10 31.60 Lactose
Hydrate 164.25 45.49 Hypromellose 2208 80.28 22.23 (100000 mPa s)
Magnesium Stearate 2.47 0.68 Total Mantle 247.00 68.40 Total Tablet
361.10 100.00
[0222] 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 2
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 in a Glatt Fluid Bed Drier at
40.degree. C. for 15 minutes, 39 sec. The dried granules were then
passed through an 800 micron screen.
[0223] The core blend batch size was 1095.36 g. The hypromellose
2208 (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 (114.1 mg) were compressed using a Manesty F3
tablet press with 6.0 mm round concave tooling. The core tablets
had a final mean hardness of 8.6 kp (about 84 Newtons).
[0224] 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 an 18 L Bin 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
specially designed for the manufacture of compression coated
tablets. Compression was completed using 9.5 mm round concave
tooling and approximately 1200 kp force. The final compression
coated tablets had a total weight of 361.1 mg with a
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
loading of 100 mg (27.63%). The compression coated tablets had a
final mean hardness of 15.3 kp (about 150 Newtons).
[0225] The final tablets were packaged for stability testing. The
packaging configuration was thirty tablets in a 0.02 inch (0.5 mm)
thick, 60 cm.sup.3 HDPE bottle with child-resistant screw cap and
foil induction seal, containing a 2 g silica gel canister. The
packaged tablets were placed on stability according to the protocol
outlined in Table 10. The stability results for the appearance,
assay/impurity, and water content are presented in Table 11. The
stability results for the dissolution are presented in FIG. 12.
TABLE-US-00011 TABLE 10 Stability Schedule Storage Condition T0 1 3
6 9 12 5.degree. C. X X X X X X 25.degree. C./60% RH X X X X X
30.degree. C./65% RH (X) X X 40.degree. C./75% RH X X X Testing
included: D = 2-stage dissolution (pH 1.2/6.8), n = 6 A =
Assay/impurity and Appearance, n = 5
TABLE-US-00012 TABLE 11 Assay Total Storage Time (% Degradants
Condition (month) Appearance w/w) (% w/w) Initial 0 White round
99.0 ND tablets 5.degree. C. 1 conforms 102.5 ND 3 conforms 99.4 ND
25.degree. C./60% RH 1 conforms 103.5 ND 3 conforms 101.2 ND
40.degree. C./75% RH 1 conforms 101.1 ND 3 conforms 99.2 ND ND =
not detected
Example 13
[0226] 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 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 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).
[0227] 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.
[0228] 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. 13. Table 12 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-00013 TABLE 12 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)
[0229] MMF release from the formulation was sustained and minimally
affected by food. The formulation produced mean (SD) maximum MMF
concentrations (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 13.
TABLE-US-00014 TABLE 13 Flushing Feeling Hot Fasted Fed Fasted Fed
Placebo 0 1 0 0 Formulation 0 1 0 0
Example 14
[0230] This example studied the degradation of MHF prodrugs
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
DMF in the presence of varying quantities of acetic acid. Each
prodrug was placed in a pH 6.0 phosphate buffer with multiple
concentrations of sodium acetate (0.0 M, 0.1 M, 0.5 M, 2.0 M, 3.0
M, and 4.0 M) at 40.degree. C. The presence of prodrug was measured
over time up to 42 hours. The rate of prodrug degradation can be
expressed according to the following formula: In (A)=ln
(A.sub.0)-K.sub.obst, wherein A is the prodrug concentration,
A.sub.0 is the prodrug concentration at time zero and K.sub.obs is
the observed slope of the curve plotting ln (A) versus time (t).
Thus, the higher the K.sub.obs, the more quickly the prodrug is
degrading. Thus, K.sub.obs is a measure of prodrug stability, with
prodrugs having a lower K.sub.obs being more stable than prodrugs
having a higher K.sub.obs. The K.sub.obs for
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
DMF are plotted as a function of acetate concentration in FIG.
14.
[0231] The amounts of the two primary degradation products for
prodrug (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate were measured after a 14.6 hour exposure
to acetate solutions of varying concentrations, all at pH 6.0 and
40.degree. C. The data are shown in FIG. 15. Thus, FIG. 15 depicts
the amount of each of the two primary degradation products of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate as a
mole % of the initial amount of prodrug, at the varying acetate
concentrations.
[0232] The degradation rates of each of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and
DMF increased with increasing concentrations of acetate. The effect
was more pronounced for the (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate prodrug than for DMF. For
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, the
formation rates of both primary degradation products increased with
increasing acetate concentration. This is consistent with the more
pronounced effect of acetate seen with (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate compared to DMF.
[0233] Without wishing to be limited to a specific mechanism or
mode of action, increased carboxyl concentration independent of pH
causes increased degradation of the MHF prodrugs. It is believed
that selection of pharmaceutical excipients in the core, and
compression coating layer components, that are substantially free
of carboxylic acid moieties reduces the degradation of the MHF
prodrugs.
Example 15
[0234] Compression coated tablets containing dimethyl fumarate were
made having the ingredients shown in Table 14:
TABLE-US-00015 TABLE 14 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) Dimethyl Fumarate TCI (Portland, OR) Drug
substance 120.00 28.96 Hydroxypropyl Cellulose Ashland (Wilmington,
Binder 3.63 0.88 DE) Hypromellose 2208 Dow Chemical Sustained 9.41
2.27 (100000 mPa s) (Midland, MI) Release Polymer Silicon Dioxide
Degussa (Parsippany, Glidant 0.67 0.16 NJ) Magnesium Stearate
Mallinckrodt (St. Lubricant 0.67 0.16 Louis, MO) Total Core 134.38
32.43 Lactose Hydrate Foremost (Rothschild, Filler 186.20 44.93 WI)
Hypromellose 2208 Dow Chemical Sustained 91.00 21.96 (100 mPa s)
(Midland, MI) Release Polymer Magnesium Stearate Mallinckrodt (St.
Lubricant 2.80 0.68 Louis, MO) Total Mantle 280.00 67.57 Total
Tablet 414.38 100.00
[0235] The tablets were made according to the following steps. The
core tablets were prepared using a direct compression process and a
batch size of 30 g. The dimethyl fumarate was passed through a 180
micron mesh screen and the hydroxypropyl cellulose, hypromellose
2208 (100000 MPas viscosity), and silicon dioxide were passed
through a 600 micron mesh screen, combined in a glass jar and
blended on a Turbula mixer for 5 minutes. Magnesium stearate was
passed through a 600 micron screen and added to the blend and
blended an additional 1.5 minutes. Core tablets (134.4 mg) were
compressed using a Carver Press with 6.00 mm round standard concave
tooling at 0.3 metric ton (MT) force.
[0236] The mantle blend was prepared using a direct blending
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 the Carver Press with 9.50 mm
round standard concave tooling. Half the mantle blend (140.0 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
(140.0 mg) was then added on top of the core tablet and the mantle
was compressed using 1.6 MT force. The final compression coated
tablets had a total weight of 414.4 mg with a dimethyl fumarate
loading of 120 mg (28.96%). The (axial.times.radial) dimensions of
the compression coated tablet were 5.92.times.9.54 mm. The mantle
layer was removed from the compression coated tablet exposing the
compressed core. The (axial.times.radial) dimensions of the
compressed core were 3.66.times.6.62 mm. The axial mantle thickness
was then calculated by taking half of the difference between the
axial measurements of the compression coated tablet and the
compressed core. The same was done for the radial mantle thickness
calculation. The axial and radial mantle thicknesses were
calculated to be 1.13 mm and 1.46 mm, respectively.
Example 16
[0237] Compression coated tablets containing dimethyl fumarate were
made having the ingredients shown in Table 15:
TABLE-US-00016 TABLE 15 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) Dimethyl Fumarate TCI (Portland, OR) Drug
substance 120.00 45.39 Hydroxypropyl Cellulose Ashland (Wilmington,
Binder 3.63 1.37 DE) Hypromellose 2208 Dow Chemical Sustained 9.41
3.56 (100000 mPa s) (Midland, MI) Release Polymer Silicon Dioxide
Degussa (Parsippany, Glidant 0.67 0.25 NJ) Magnesium Stearate
Mallinckrodt (St. Lubricant 0.67 0.25 Louis, MO) Total Core 134.38
50.83 Lactose Hydrate Foremost (Rothschild, Filler 86.45 32.70 WI)
Hypromellose 2208 Dow Chemical Sustained 42.25 15.98 (100 mPa s)
(Midland, MI) Release Polymer Magnesium Stearate Mallinckrodt (St.
Lubricant 1.30 0.49 Louis, MO) Total Mantle 130.00 49.17 Total
Tablet 264.38 100.00
[0238] The tablets were made according to the following steps. The
core tablets were prepared using the same equipment, procedures,
and material quantity as those described in Example 15.
[0239] The mantle blend was prepared using the same equipment and
procedures as those described in Example 15, but with the following
differences. The mantle blend was applied to the core tablets using
the Carver Press with 5/16 inch (7.94 mm) round standard concave
tooling. Half the mantle blend (65.0 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 (65.0 mg) was then added on top
of the core tablet and the mantle was compressed using 1.6 metric
ton (MT) force. The final compression coated tablets had a total
weight of 264.4 mg with a dimethyl fumarate loading of 120 mg
(45.39%). The (axial.times.radial) dimensions of the compression
coated tablet were 4.84.times.7.97 mm. The mantle layer was removed
from the compression coated tablet exposing the compressed core.
The (axial.times.radial) dimensions of the compressed core were
3.52.times.6.63 mm. The axial mantle thickness was then calculated
by taking half of the difference between the axial measurements of
the compression coated tablet and the compressed core. The same was
done for the radial mantle thickness calculation. The axial and
radial mantle thicknesses were calculated to be 0.66 mm and 0.67
mm, respectively.
Example 17
[0240] Compression coated tablets containing dimethyl fumarate were
made having the ingredients shown in Table 16:
TABLE-US-00017 TABLE 16 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) Dimethyl Fumarate TCI (Portland, OR) Drug
substance 120.00 28.96 Hydroxypropyl Cellulose Ashland (Wilmington,
Binder 3.63 0.88 DE) Hypromellose 2208 Dow Chemical Sustained 9.41
2.27 (100000 mPa s) (Midland, MI) Release Polymer Silicon Dioxide
Degussa (Parsippany, Glidant 0.67 0.16 NJ) Magnesium Stearate
Mallinckrodt (St. Lubricant 0.67 0.16 Louis, MO) Total Core 134.38
32.43 Lactose Hydrate Foremost (Rothschild, Filler 165.20 39.87 WI)
Hypromellose 2208 Dow Chemical Sustained 112.00 27.03 (100 mPa s)
(Midland, MI) Release Polymer Magnesium Stearate Mallinckrodt (St.
Lubricant 2.80 0.68 Louis, MO) Total Mantle 280.00 67.57 Total
Tablet 414.38 100.00
[0241] The tablets were made according to the following steps. The
core tablets were prepared using the same equipment, procedures,
and material quantity as those described in Example 15.
[0242] The mantle blend was prepared using a direct blending
process and a batch size of 60 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 on a Turbula mixer
for 5 minutes. Magnesium stearate was passed through a 600 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 9.50 mm round standard concave tooling.
Half the mantle blend (140.0 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 (140.0 mg) was then added on top of
the core tablet and the mantle was compressed using 1.6 metric ton
(MT) force. The final compression coated tablets had a total weight
of 414.4 mg with a dimethyl fumarate loading of 120 mg (28.96%).
The (axial.times.radial) dimensions of the compression coated
tablet were 6.10.times.9.52 mm. The mantle layer was removed from
the compression coated tablet exposing the compressed core. The
(axial.times.radial) dimensions of the compressed core were
3.65.times.6.53 mm. The axial mantle thickness was then calculated
by taking half of the difference between the axial measurements of
the compression coated tablet and the compressed core. The same was
done for the radial mantle thickness calculation. The axial and
radial mantle thicknesses were calculated to be 1.23 mm and 1.50
mm, respectively.
Example 18
[0243] Compression coated tablets containing dimethyl fumarate were
made having the ingredients shown in Table 17:
TABLE-US-00018 TABLE 17 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) Dimethyl Fumarate TCI (Portland, OR) Drug
substance 120.00 45.39 Hydroxypropyl Cellulose Ashland (Wilmington,
Binder 3.63 1.37 DE) Hypromellose 2208 Dow Chemical Sustained 9.41
3.56 (100000 mPa s) (Midland, MI) Release Polymer Silicon Dioxide
Degussa (Parsippany, Glidant 0.67 0.25 NJ) Magnesium Stearate
Mallinckrodt (St. Lubricant 0.67 0.25 Louis, MO) Total Core 134.38
50.83 Lactose Hydrate Foremost (Rothschild, Filler 76.70 29.01 WI)
Hypromellose 2208 Dow Chemical Sustained 52.00 19.67 (100 mPa s)
(Midland, MI) Release Polymer Magnesium Stearate Mallinckrodt (St.
Lubricant 1.30 0.49 Louis, MO) Total Mantle 130.00 49.17 Total
Tablet 264.38 100.00
[0244] The tablets were made according to the following steps. The
core tablets were prepared using the same equipment, procedures,
and material quantity as those described in Example 15.
[0245] The mantle blend was prepared using the same equipment and
procedures as those described in Example 17, but with the following
differences. The mantle blend was applied to the core tablets using
the Carver Press with 5/16 inch (7.94 mm) round standard concave
tooling. Half the mantle blend (65.0 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 (65.0 mg) was then added on top
of the core tablet and the mantle was compressed using 1.6 metric
ton (MT) force. The final compression coated tablets had a total
weight of 264.4 mg with a dimethyl fumarate loading of 120 mg
(45.39%). The (axial.times.radial) dimensions of the compression
coated tablet were 4.84.times.7.95 mm. The mantle layer was removed
from the compression coated tablet exposing the compressed core.
The (axial.times.radial) dimensions of the compressed core were
3.42.times.6.67 mm. The axial mantle thickness was then calculated
by taking half of the difference between the axial measurements of
the compression coated tablet and the compressed core. The same was
done for the radial mantle thickness calculation. The axial and
radial mantle thicknesses were calculated to be 0.71 mm and 0.64
mm, respectively.
Example 19
[0246] Compression coated tablets containing dimethyl fumarate were
made having the ingredients shown in Table 18:
TABLE-US-00019 TABLE 18 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) Dimethyl Fumarate TCI (Portland, OR) Drug
substance 240.00 47.17 Hydroxypropyl Cellulose Ashland (Wilmington,
Binder 7.26 1.43 DE) Hypromellose 2208 Dow Chemical Sustained 18.81
3.70 (100000 mPa s) (Midland, MI) Release Polymer Silicon Dioxide
Degussa (Parsippany, Glidant 1.34 0.26 NJ) Magnesium Stearate
Mallinckrodt (St. Lubricant 1.34 0.26 Louis, MO) Total Core 268.76
52.83 Lactose Hydrate Foremost (Rothschild, Filler 141.60 27.83 WI)
Hypromellose 2208 Dow Chemical Sustained 96.00 18.87 (100 mPa s)
(Midland, MI) Release Polymer Magnesium Stearate Mallinckrodt (St.
Lubricant 2.40 0.47 Louis, MO) Total Mantle 240.00 47.17 Total
Tablet 508.76 100.00
[0247] The tablets were made according to the following steps. The
core tablets were prepared using the same equipment and procedures
as those described in Example 15, but with the following
differences. Core tablets (268.8 mg) were compressed using a Carver
Press with 5/16 inch (7.94 mm) round standard concave tooling at
1.0 metric ton (MT) force.
[0248] The mantle blend was prepared using the same equipment and
procedures as those described in Example 17, but with the following
differences. The mantle blend was applied to the core tablets using
the Carver Press with 13/32 inch (10.32 mm) round standard concave
tooling. Half the mantle blend (120.0 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 (120.0 mg) was then added on
top of the core tablet and the mantle was compressed using 2.0 MT
force. The final compression coated tablets had a total weight of
508.8 mg with a dimethyl fumarate loading of 240 mg (47.17%). The
(axial.times.radial) dimensions of the compression coated tablet
were 5.58.times.10.33 mm. The mantle layer was removed from the
compression coated tablet exposing the compressed core. The
(axial.times.radial) dimensions of the compressed core were
4.09.times.8.71 mm. The axial mantle thickness was then calculated
by taking half of the difference between the axial measurements of
the compression coated tablet and the compressed core. The same was
done for the radial mantle thickness calculation. The axial and
radial mantle thicknesses were calculated to be 0.75 mm and 0.81
mm, respectively.
Example 20
[0249] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 19:
TABLE-US-00020 TABLE 19 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Drug substance
400.00 45.26 Diethylcarbamoyl)methyl Clara, CA) methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose Hercules
(Wilmington, Binder 12.37 1.40 DE) Hypromellose 2208 Dow Chemical
Sustained 31.72 3.59 (100000 mPa s) (Midland, MI) Release Polymer
Silicon Dioxide Cabot (Tuscola, IL) Glidant 2.27 0.26 Magnesium
Stearate Mallinckrodt (St. Lubricant 6.80 0.77 Louis, MO) Total
Core 453.16 51.31 Lactose Hydrate Foremost (Rothschild, Filler
253.70 28.73 WI) Hypromellose 2208 Dow Chemical Sustained 172.00
19.48 (100 mPa s) (Midland, MI) Release Polymer Magnesium Stearate
Mallinckrodt (St. Lubricant 4.30 0.49 Louis, MO) Total Mantle
430.00 48.69 Total Tablet 883.16 100.00
[0250] 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 and hydroxypropyl cellulose were
granulated with purified water using a Diosna P1/6 equipped with a
1 L bowl. The wet granules were passed through the Quadro Comil U5
with a 2769 micron screen at 3000 rpm and dried in a Glatt Fluid
Bed Drier at 40.degree. C. for 29 minutes. The dried granules and
half of the silicon dioxide were combined in a 1 quart (0.95 L)
V-blender and blended for 5 minutes, then passed through the Quadro
Comil U5 with a 1270 micron screen at 3000 rpm. The milled blend
was then blended for an additional 10 minutes.
[0251] The core blend batch size was 54.8 g. The second half of the
silicon dioxide and hypromellose 2208 (100000 MPas viscosity) were
then passed through a 600 micron mesh screen, combined with the
blend in a glass jar and blended on a Turbula mixer for 5 minutes.
Magnesium stearate was passed through a 600 micron screen and added
to the blend before blending an additional 1.5 minutes. Core
tablets (453.16 mg) were compressed using a Carver Press with 13/32
inch (10.32 mm) round standard concave tooling at 0.8 metric ton
(MT) force.
[0252] The mantle blend was prepared using the same equipment and
procedures as those described in Example 17, but with the following
differences. The mantle blend was applied to the core tablets using
the Carver Press with 1/2 inch (12.70 mm) round standard flat
tooling. 190.0 mg of the mantle blend 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 remaining portion of the mantle blend (240.0 mg) was then added
on top of the core tablet and the mantle was compressed using 1.6
MT force. The final compression coated tablets had a total weight
of 883.16 mg with a (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate loading of 400 mg (45.26%). The
(axial.times.radial) dimensions of the compression coated tablet
were 5.61.times.12.74 mm. The mantle layer was removed from the
compression coated tablet exposing the compressed core. The
(axial.times.radial) dimensions of the compressed core were
4.09.times.11.26 mm. The axial mantle thickness was then calculated
by taking half of the difference between the axial measurements of
the compression coated tablet and the compressed core. The same was
done for the radial mantle thickness calculation. The axial and
radial mantle thicknesses were calculated to be 0.76 mm and 0.74
mm, respectively.
Example 21
[0253] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Examples 15, 16, 17, and 18 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.
[0254] For the tested dosage forms, samples of the dissolution
medium were withdrawn at the indicated time points shown in FIG.
16. The amount of dimethyl fumarate in the dissolution medium
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-00021 TABLE 20 Time (minute) % Mobile Phase A % Mobile
Phase B 0 85 15 5 35 65 5.5 85 15 7 85 15
[0255] As shown in FIG. 16, for dosage forms prepared according to
Example 15 ( symbols), drug release is delayed for approximately 2
hours, and thereafter the drug is released gradually, reaching more
than 90% released at 20 hours. For dosage forms prepared according
to Example 16 ( symbols), drug release is delayed for approximately
1 hour, and thereafter the drug is released gradually, reaching
more than 90% released at 17 hours. For dosage forms prepared
according to Example 17 ( symbols), drug release is delayed for
approximately 4 hours, and thereafter the drug is released
gradually, reaching more than 90% released at 21 hours. For dosage
forms prepared according to Example 18 ( symbols), drug release is
delayed for approximately 2 hours, and thereafter the drug is
released gradually, reaching more than 90% released at 19
hours.
Example 22
[0256] The dissolution profile from the compression coated tablets
of Example 19 was tested according to the method described in
Example 21. As shown in FIG. 17, for dosage forms prepared
according to Example 19, drug release is delayed for approximately
2 hours, and thereafter the drug is released gradually, reaching
more than 90% released at 24 hours.
Example 23
[0257] The dissolution profile from the compression coated tablets
of Example 20 was tested according to the method described in
Example 21, but for (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate. As shown in FIG. 18, for dosage forms
prepared according to Example 20, drug release is delayed for
approximately 2 hours, and thereafter the drug is released
gradually, reaching more than 90% released at 23 hours.
Example 24
[0258] On the surface of the punches of a tablet press of the type
described in Manufacturing Example 1 of Ozeki et al., U.S. Pat. No.
7,811,488, the punches having a double structure with an inside
diameter of 8.5 mm and an outside diameter of 10.0 mm and with a
pressurizable flat edge, a small amount of magnesium stearate is
added and as the lower central punch is kept in the lowered
position, in the space above the lower central punch, enclosed by
the lower outer punch, 15 mg of a 40:60 by weight mixture of
lactose and hydroxypropylmethyl cellulose (HPMC) is added. Then the
upper central punch and the lower central punch are moved towards
each other and compression is applied manually causing the surface
to become flat. Next, as the lower central punch is kept in the
lowered position, in the space above the temporary moldings of
lactose and HPMC, enclosed by the lower outer layer, 300 mg of a
90:10 by weight mixture of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate and HPMC is added. Then the upper central
punch and the lower central punch are moved towards each other and
temporary compression is applied manually so as to maintain the
molding shape. Next, as the bottom layer is kept in the lowered
position, in the space in the die above and around the molding,
made of lactose, HPMC and (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate, the remaining 60 mg of 40:60 by weight
mixture of lactose and HPMC is added and the temporary
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
moldings are completely enclosed in lactose and HPMC. Then the
upper central punch and the lower central punch are moved towards
each other and, using a hydraulic hand press, the tablet is made
with a compression force of about 1.4 ton. Each tablet weighs 375
mg, has a thickness of 3.40 mm, and contains 270 mg of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate. The
thickness, in the radial direction, of the outer lactose and HPMC
mantle layer is 0.75 mm.
Example 25
[0259] Tablets similar to those described in Example 24 are made
using the same equipment and procedures, but with the following
difference. For the tablet core, 300 mg of a 90:10 by weight
mixture of dimethyl fumarate and HPMC is used. Each tablet weighs
375 mg, has a thickness of 3.40 mm, and contains 270 mg of dimethyl
fumarate. The thickness of the outer lactose and HPMC mantle layer
is 0.75 mm.
Example 26
[0260] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 21:
TABLE-US-00022 TABLE 21 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort Drug 400.00 51.72
Diethylcarbamoyl)methyl (Santa Clara, CA) substance methyl
(2E)but-2-ene-1,4- dioate Hydroxypropyl Cellulose Hercules Binder
12.37 1.60 (Wilmington, DE) Hypromellose 2208 Dow Chemical
Sustained 26.60 3.44 (100000 mPa s) (Midland, MI) Release Polymer
Silicon Dioxide Cabot (Tuscola, IL) Glidant 2.22 0.29 Magnesium
Stearate Mallinckrodt Lubricant 2.22 0.29 (St. Louis, MO) Total
Core 443.41 57.33 Lactose Hydrate Foremost Filler 194.70 25.17
(Rothschild, WI) Hypromellose 2208 Dow Chemical Sustained 132.00
17.07 (100 mPa s) (Midland, MI) Release Polymer Magnesium Stearate
Mallinckrodt Lubricant 3.30 0.43 (St. Louis, MO) Total 330.00 42.67
Mantle Total 773.41 100.00 Tablet
[0261] 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 and hydroxypropyl cellulose were
granulated with purified water using a Diosna P1/6 equipped with a
1 L bowl. The wet granules were passed through the Quadro Comil U5
with a 2769 micron screen at 3000 rpm and dried in a Glatt Fluid
Bed Drier at 40.degree. C. for 29 minutes. The dried granules and
half of the silicon dioxide were combined in a 1 quart (0.95 L)
V-blender and blended for 5 minutes, then passed through the Quadro
Comil U5 with a 1270 micron screen at 3000 rpm. The milled blend
was then blended for an additional 10 minutes.
[0262] The core blend batch size was 53.5 g. The second half of the
silicon dioxide was then passed through a 850 micron mesh screen,
combined with the blend in a glass jar and blended on a Turbula
mixer for 3 minutes. Hypromellose 2208 (100000 MPas viscosity) was
then passed through a 600 micron screen and blended for 5 minutes.
Magnesium stearate was passed through a 600 micron screen and added
to the blend before blending an additional 1.5 minutes. Core
tablets (443.4 mg) were compressed using a Carver Press with
0.2746.times.0.5930 inch (6.97.times.15.06 mm) modified oval
standard concave tooling at 0.7 metric ton (MT) force.
[0263] The mantle blend was prepared using a direct blending
process and a batch size of 60 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 on a Turbula mixer
for 5 minutes. Magnesium stearate was passed through a 600 micron
screen and added to the blend and blended an additional 1.5
minutes. The mantle blend was applied to the core tablets using the
Carver Press with 0.3531.times.0.6717 inch (8.97.times.17.06 mm)
modified oval standard concave tooling. Half the mantle blend
(165.0 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 (165.0 mg) was then added on top of the core tablet
and the mantle was compressed using 1.6 MT force. The final
compression coated tablets had a total weight of 773.4 mg with a
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
loading of 400 mg (51.72%). The (axial.times.minor.times.major)
dimensions of the compression coated tablet were
6.47.times.9.00.times.17.11 mm. The mantle layer was removed from
the compression coated tablet exposing the compressed core. The
(axial.times.minor.times.major) dimensions of the compressed core
were 4.85.times.7.35.times.15.03 mm. The axial mantle thickness was
then calculated by taking half of the difference between the axial
measurements of the compression coated tablet and the compressed
core. The same was done for the minor and major mantle thickness
calculations. The axial, minor, and major mantle thicknesses were
calculated to be 0.81 mm, 0.83 mm, and 0.79 mm, respectively.
Example 27
[0264] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 22:
TABLE-US-00023 TABLE 22 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort Drug 400.00 53.81
Diethylcarbamoyl)methyl (Santa Clara, substance methyl
(2E)but-2-ene-1,4- CA) dioate Hydroxypropyl Cellulose Hercules
Binder 12.37 1.66 (Wilmington, DE) Hypromellose 2208 Dow Chemical
Sustained 26.60 3.58 (100000 mPa s) (Midland, MI) Release Polymer
Silicon Dioxide Cabot (Tuscola, IL) Glidant 2.22 0.30 Magnesium
Stearate Mallinckrodt Lubricant 2.22 0.30 (St. Louis, MO) Total
Core 443.41 59.65 Lactose Hydrate Foremost Filler 177.00 23.81
(Rothschild, WI) Hypromellose 2208 Dow Chemical Sustained 120.00
16.14 (100 mPa s) (Midland, MI) Release Polymer Magnesium Stearate
Mallinckrodt Lubricant 3.00 0.40 (St. Louis, MO) Total 300.00 40.35
Mantle Total 743.41 100.00 Tablet
[0265] The tablets were made according to the following steps. The
core tablets were prepared using the same equipment and procedures
as those described in Example 26, but with the following
differences.
[0266] Core tablets (443.4 mg) were compressed using a Carver Press
with 0.2854.times.0.5709 inch (7.25.times.14.50 mm) oval standard
concave tooling at 0.7 metric ton (MT) force.
[0267] The mantle blend was prepared using the same equipment and
procedures as those described in Example 26, but with the following
differences. The mantle blend was applied to the core tablets using
the Carver Press with 0.3642.times.0.6496 inch (9.25.times.16.50
mm) oval standard concave tooling. Half the mantle blend (150.0 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
(150.0 mg) was then added on top of the core tablet and the mantle
was compressed using 1.6 MT force. The final compression coated
tablets had a total weight of 743.4 mg with a
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
loading of 400 mg (53.81%). The (axial.times.minor.times.major)
dimensions of the compression coated tablet were
6.26.times.9.27.times.16.54 mm. The mantle layer was removed from
the compression coated tablet exposing the compressed core. The
(axial.times.minor.times.major) dimensions of the compressed core
were 4.76.times.7.87.times.15.22 mm. The axial mantle thickness was
then calculated by taking half of the difference between the axial
measurements of the compression coated tablet and the compressed
core. The same was done for the minor and major mantle thickness
calculations. The axial, minor, and major mantle thicknesses were
calculated to be 0.75 mm, 0.70 mm, and 0.66 mm, respectively.
Example 28
[0268] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Example 26 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. 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 23 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-00024 TABLE 23 Time (minute) % Mobile Phase A % Mobile
Phase B 0 85 15 5 35 65 5.5 85 15 7 85 15
[0269] As shown in FIG. 19, for dosage forms prepared according to
Example 26, drug release is delayed for approximately 1 hour, and
thereafter the drug is released gradually, reaching more than 90%
released at 16 hours.
Example 29
[0270] The dissolution profile from the compression coated tablets
of Example 27 was tested according to the method described in
Example 28. As shown in FIG. 20, for dosage forms prepared
according to Example 27, drug release is delayed for approximately
1 hour, and thereafter the drug is released gradually, reaching
more than 90% released at 16 hours.
[0271] Finally, it should be noted that there are alternative ways
of implementing the embodiments provided by the present disclosure.
Accordingly, the present embodiments are to be considered as
illustrative and not restrictive, and the present disclosure is not
to be limited to the details given herein, but may be modified
within the scope and equivalents of the claim(s) issuing from a
patent claiming priority hereto.
* * * * *