U.S. patent application number 13/973542 was filed with the patent office on 2014-02-27 for oral dosage forms having a high loading of a methyl hydrogen fumarate prodrug.
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, Sami Karaborni, Sarina Grace Harris Ma, Peter A. Virsik, David J. Wustrow.
Application Number | 20140056973 13/973542 |
Document ID | / |
Family ID | 49085232 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140056973 |
Kind Code |
A1 |
Ma; Sarina Grace Harris ; et
al. |
February 27, 2014 |
Oral Dosage Forms Having a High Loading of a Methyl Hydrogen
Fumarate Prodrug
Abstract
Oral dosage forms and granulations with a high loading of a
methyl hydrogen fumarate prodrug are disclosed.
Inventors: |
Ma; Sarina Grace Harris;
(Santa Clara, CA) ; Bauer; Laura Elizabeth;
(Sunnyvale, CA) ; Karaborni; Sami; (Cupertino,
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
|
Family ID: |
49085232 |
Appl. No.: |
13/973542 |
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: |
424/451 ;
424/480; 424/489; 514/547 |
Current CPC
Class: |
A61K 31/215 20130101;
A61K 9/2866 20130101; A61P 25/28 20180101; A61P 25/16 20180101;
A61K 9/4866 20130101; A61P 17/02 20180101; A61K 9/2886 20130101;
A61P 25/14 20180101; A61P 19/02 20180101; A61K 9/2826 20130101;
Y02A 50/414 20180101; A61K 9/2095 20130101; A61P 29/00 20180101;
A61K 9/284 20130101; A61K 9/2054 20130101; A61K 31/5375 20130101;
A61K 9/1652 20130101; A61K 31/27 20130101; A61P 1/04 20180101; A61P
19/00 20180101; Y02A 50/30 20180101; A61P 21/02 20180101; A61K
9/146 20130101; A61K 31/225 20130101; A61P 17/06 20180101; A61K
9/4808 20130101; A61P 25/00 20180101 |
Class at
Publication: |
424/451 ;
514/547; 424/489; 424/480 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 31/225 20060101 A61K031/225 |
Claims
1. A solid pharmaceutical granulation comprising at least about 95
wt % (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
and one or more pharmaceutically acceptable excipients.
2. The granulation of claim 1, comprising at least about 97 wt %
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
3. The granulation of claim 1, wherein the pharmaceutically
acceptable excipient comprises a binder.
4. The granulation of claim 3, wherein the binder comprises a
polymer selected from hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, polyvinyl pyrrolidone and combinations thereof.
5. A mixture comprising the solid granulation of claim 1, and at
least one additional pharmaceutically acceptable excipient.
6. The mixture of claim 5, wherein the at least one additional
excipient is selected from fillers, diluents, binders, lubricants,
disintegrants, glidants, sustained release agents and combinations
thereof.
7. The mixture of claim 5, comprising a glidant, so as to improve
flowability of said mixture.
8. The mixture of claim 7, comprising up to about 3 wt % silicon
dioxide glidant.
9. The mixture of claim 7, comprising up to about 1 wt % silicon
dioxide glidant.
10. The mixture of claim 7, comprising about 0.1 to about 0.5 wt %
silicon dioxide glidant.
11. The mixture of claim 8, wherein the silicon dioxide glidant has
an average particle size of less than 200 nm.
12. An oral dosage form comprising the mixture of claim 5.
13. The dosage form of claim 12, wherein the dosage form comprises
a capsule containing the mixture.
14. The dosage form of claim 12, wherein the dosage form comprises
a tablet.
15. The dosage form of claim 13, comprising from about 100 mg to
about 1,200 mg (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate.
16. The dosage form of claim 13, comprising from about 200 mg to
about 800 mg (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate.
17. The tablet of claim 14, comprising a sustained release
agent.
18. The tablet of claim 17, wherein the sustained release agent
comprises hydroxypropylmethyl cellulose.
19. A pharmaceutical tablet dosage form, the tablet having a core
and one or more coatings surrounding the core, the core comprising
from about 70 wt % to about 98 wt % (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate.
20. The pharmaceutical tablet dosage form of claim 19, wherein the
core comprises from about 80 wt % to about 97 wt %
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
21. The pharmaceutical tablet dosage form of claim 19, including at
least one pharmaceutically acceptable excipient.
22. The pharmaceutical tablet dosage form of claim 21, wherein the
excipient is selected from fillers, diluents, binders, lubricants,
disintegrants, glidants, sustained release agents and combinations
thereof.
23. The pharmaceutical tablet dosage form of claim 19, comprising
about 5 wt % to about 15 wt % of hydroxypropylmethyl cellulose.
24. The pharmaceutical tablet dosage form of claim 23, wherein the
dosage form is a sustained release dosage formulation.
25. The dosage form of claim 12, wherein the dosage form has an
enteric coating.
26. The dosage form of claim 12, wherein in a sodium phosphate
dissolution medium buffered to pH 6.8, maintained at 37.degree. C.
and stirred at 100 rpm, the dosage form releases 90 wt % of the
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate within
0.5 to 24 hours.
27. A method of treating a disease in a subject comprising orally
administering to a subject in need of such treatment at least one
dosage form of claim 12.
28. The method of claim 27, wherein the disease is multiple
sclerosis.
29. The method of claim 27, wherein the disease is psoriasis.
30. The method of claim 27, 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. Nos. 61/692,179
filed Aug. 22, 2012, 61/692,168, filed Aug. 22, 2012, 61/713,897
filed Oct. 15, 2012, 61/733,234 filed Dec. 4, 2012, 61/769,513
filed Feb. 26, 2013, 61/841,513 filed Jul. 1, 2013, 61/692,174
filed Aug. 22, 2012, 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 with a
high loading of a methyl hydrogen fumarate prodrug.
BACKGROUND
[0003] The compound methyl hydrogen fumarate (MHF), which is
alternatively called monomethyl fumarate (MMF), has the following
chemical structure:
##STR00001##
[0004] 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 tradename 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
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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, at daily doses of 480 mg DMF, which translates to 435
mg of MHF assuming complete conversion of DMF to MHF in vivo.
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.
[0009] More recently, Gangakhedkar et al. U.S. Pat. No. 8,148,414
discloses the MHF prodrug (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate (1) having the following chemical
structure:
##STR00002##
[0010] Additional MHF prodrugs are disclosed in Cundy et al. U.S.
Patent Application 61/595,835 filed Feb. 7, 2012. Both Gangakhedkar
et al. and Cundy et al. disclose the use of fumaric acid ester
prodrugs for treating a number of medical conditions, including
multiple sclerosis and psoriasis. Both also disclose oral dosage
forms comprising a fumaric acid ester prodrug.
[0011] Pharmaceutical tablets comprising a high drug loading of
other compounds are disclosed in U.S. Patent Publication Nos.
2010/0226981 and 2010/0099907.
SUMMARY
[0012] One issue with prodrugs is that the weight of the active
metabolite portion of the prodrug molecule comprises only a portion
of the total weight of the prodrug. In the case of
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate, the
promoiety portion comprises about 47 wt % of the total weight of
the prodrug while the MHF portion comprises about 53 wt % of the
total weight of the prodrug. This means that almost one-half of the
prodrug loading in a dosage form is taken up by the
non-pharmacologically active promoiety. For example, to achieve an
equivalent daily dose of 435 mg of MHF as Biogen's BG12 product, it
would be necessary to administer daily 821 mg of
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate,
assuming complete breakdown of compound (1) to MHF in vivo.
Conventional pharmaceutical tablet formulations typically contain
high loadings of tableting excipients such as binders, fillers,
flow promoters, lubricants, etc. In cases where the drug is not
exceptionally potent, and therefore the tablets contain only a very
small amount of the drug, these excipients typically comprise at
least 30 to 50 wt % of the total weight of the tablet. In the case
of prodrugs such as (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate, the use of such conventional tablet
formulations would result in either very large tablet or capsule
sizes, or the need for a patient to take multiple tablets or
capsules for each dosing of prodrug, neither of which is
desirable.
[0013] Thus, oral dosage forms comprising a high loading of
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate and
that are amenable to high throughput commercial tableting
manufacture are disclosed.
[0014] Oral dosage forms prepared from granulations having a high
loading of (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate are disclosed.
[0015] In one aspect, oral tablet dosage forms are disclosed
comprising about 70 wt % to about 98 wt %
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate. In
certain embodiments, the oral tablet dosage forms comprise about 80
wt % to about 97 wt % (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate.
[0016] In another aspect, solid granulations comprising greater
than about 95 wt % (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate are disclosed. In certain embodiments, the
solid granulations comprise greater than about 97 wt %
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.
[0017] In yet another aspect, mixtures comprising the
above-described solid granulations and one or more pharmaceutically
acceptable excipients are disclosed.
[0018] In another aspect, mixtures comprising a small amount of
glidant markedly improve the flowability of the mixture including
high loading granules. In certain embodiments, the mixtures may
contain up to 3 wt % of a glidant, e.g., silicon dioxide as a flow
aid. In other embodiments, the mixtures contain up to 1 wt %, e.g.,
silicon dioxide.
[0019] In yet other aspects, methods of treating a disease in a
subject are disclosed comprising orally administering to a subject
in need of such treatment at least one oral dosage form provided by
the present disclosure. In certain embodiments, the dosage forms
can be used to treat multiple sclerosis and/or psoriasis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Those skilled in the art will understand that the drawings,
described herein, are for illustration purposes only. The drawings
are not intended to limit the scope of the present disclosure.
[0021] FIG. 1 is a graph showing the particle size distribution of
blends and granulations made in Example 3;
[0022] FIG. 2 is a graph showing the particle size distribution of
blends and granulations made in Example 4;
[0023] FIG. 3 is a graph showing the particle size distribution of
blends and granulations made in Example 5;
[0024] FIG. 4 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the tablets of
Example 7;
[0025] FIG. 5 is a plot illustrating flow characterization of dry
powder blends and granulations of Example 9;
[0026] FIG. 6 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the tablets of
Example 10, tested in accordance with Example 13;
[0027] FIG. 7 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the tablets of
Example 11, tested in accordance with Example 13;
[0028] FIG. 8 is a graph showing the in vitro MHF prodrug release
profile (percent MHF prodrug released over time) for the tablets of
Example 12, tested in accordance with Example 13;
[0029] FIG. 9 is a graph showing the concentration of MHF in the
blood of fasted monkeys following administration of the tablets of
Examples 10 and 11;
[0030] FIG. 10 is a graph showing the concentration of MHF in the
blood of fed monkeys following administration of the tablets of
Examples 10 and 11;
[0031] 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 15, tested in accordance with Example 17; and
[0032] 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 16, tested in accordance with Example 17.
DEFINITIONS
[0033] "Compound (1)" means the MHF prodrug (1),
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate,
alternatively named 1-[2-(diethylamino)-2-oxoethyl]4-methyl
(2E)but-2-ene-1,4-dioate, pharmaceutically acceptable solvates
thereof, and crystalline forms of any of the foregoing.
##STR00003##
[0034] 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 (Chem Innovation 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 include, for example, optical isomers, 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, the configuration of the
illustrated double bond is only in the E configuration (i.e., trans
configuration).
[0035] Compound (1) also includes isotopically labeled compounds
where one or more atoms have an atomic mass different from the
atomic mass conventionally found in nature. Examples of isotopes
that may be incorporated into the compounds disclosed herein
include, but are not limited to, .sup.2H, .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, etc. Compound (1)
may exist in unsolvated forms as well as solvated forms, including
hydrated forms and as N-oxides. In general, compound (1) may be the
free acid, hydrated, solvated, N-oxides, or combinations of any of
the foregoing. Compound (1) may exist in multiple crystalline,
co-crystalline, or amorphous forms. Compound (1) includes
pharmaceutically acceptable solvates thereof, as well as
crystalline forms of any of the foregoing. Compound (1) also
includes solvates. A solvate refers to a molecular complex of a
compound with one or more solvent molecules in a stoichiometric or
non-stoichiometric amount. Such solvent molecules are those
commonly used in the pharmaceutical art, which are known to be
innocuous to a subject, e.g., water, ethanol, and the like. A
molecular complex of a compound or moiety of a compound and a
solvent can be stabilized by non-covalent intra-molecular forces
such as, for example, electrostatic forces, van der Waals forces,
or hydrogen bonds. The term "hydrate" refers to a solvate in which
the one or more solvent molecules is water.
[0036] "Controlled-release" refers to release of a drug from a
dosage form in which the drug release is controlled or modified
over a period of time. Controlled can mean, for example, sustained,
delayed, or pulsed-release at a particular time. Controlled can
also 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.
[0037] 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 some 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 other 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.
[0038] "Dosage form" refers to a form of a formulation that
contains an amount of active agent or prodrug of an active agent,
i.e., MHF prodrug compound (1), which can be administered to a
subject to achieve a therapeutic effect. An oral dosage form is
intended to be administered to a subject via the mouth and
swallowed. A dose of a drug may include one or more dosage forms
administered simultaneously or over a period of time.
[0039] "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.
[0040] "Subject" includes mammals, such as for example, humans.
[0041] "Pharmaceutically acceptable" refers to approved or
approvable by a regulatory agency of a federal or a state
government, listed in a U.S. Pharmacopeia, or listed in other
generally recognized pharmacopeia for use in mammals, including
humans.
[0042] "Pharmaceutically acceptable salt" refers to a salt that is
pharmaceutically acceptable and that possesses the desired
pharmacological activity of the parent compound. Such salts
include: (1) 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 (2) salts formed when an acidic
proton present in the parent compound either is replaced by a metal
ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an
aluminum ion; or coordinates with an organic base such as
ethanolamine, diethanolamine, triethanolamine, N-methylglucamine,
and the like.
[0043] "Pharmaceutically acceptable vehicle" or "pharmaceutically
acceptable excipient" refers to a pharmaceutically acceptable
diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically
acceptable excipient, a pharmaceutically acceptable carrier, or a
combination of any of the foregoing with which a compound such as
the MHF prodrug, (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate, compound (1), may be administered to a
subject, which does not substantially compromise the
pharmacological activity thereof, and which is nontoxic when
administered in doses sufficient to provide a therapeutically
effective amount of the MHF prodrug or MHF metabolite.
[0044] "Prodrug" refers to a derivative of an active compound
(drug) that undergoes a transformation under the conditions of use,
such as within the body, to release an active drug. Prodrugs are
frequently, but not necessarily, pharmacologically inactive until
converted into the active drug. Prodrugs may be obtained by bonding
a promoiety (defined herein), typically via a functional group, to
a drug. For example, MHF prodrug compound (1) is metabolized within
a subject's body to form the parent drug MHF.
[0045] "Promoiety" refers to a group bonded to a drug, typically to
a functional group of the drug, via a bond(s) that is cleavable
under specified conditions of use. The bond(s) between the drug and
promoiety may be cleaved by enzymatic or non-enzymatic means. Under
the conditions of use, for example following administration to a
subject, the bond(s) between the drug and promoiety may be cleaved
to release the parent drug. The cleavage of the promoiety may
proceed spontaneously, such as via a hydrolysis reaction, or it may
be catalyzed or induced by another agent, such as by an enzyme, by
light, by acid, or by a change of or exposure to a physical or
environmental parameter, such as a change of temperature, pH, etc.
The agent may be endogenous to the conditions of use, such as an
enzyme present in the systemic circulation of a subject to which
the prodrug is administered or the pH conditions of the
gastrointestinal tract or the agent may be supplied exogenously.
For example, for MHF prodrug compound (1), the drug is MHF and the
promoiety has the structure:
##STR00004##
[0046] Consistent with "Dissolution Testing of Immediate Release
Solid Oral Dosage Forms--Guidance for Industry", FDA-CDER, August
1997, dissolution profiles may be considered similar based on a
difference factor (f.sub.1) and a similarity factor (f.sub.2). For
dissolution profiles to be considered similar, f.sub.1 values
should be close to 0, and f.sub.2 values should be close to 100.
Generally, f.sub.1 values up to 15 (0-15) and f.sub.2 values
greater than 50 (50-100) ensure sameness or equivalence of two
dissolution profiles. Procedures for calculating f.sub.1 and
f.sub.2 are set forth in the foregoing reference.
[0047] "Sustained release" refers to release of a compound from a
dosage form at a rate effective to achieve a therapeutic amount of
a compound, e.g., MHF in the systemic blood circulation over a
prolonged period of time relative to that achieved by oral
administration of an immediate release formulation, e.g., of MHF.
In some embodiments, in vivo release of MHF, from a high prodrug
load tablet disclosed herein, occurs 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.
[0048] "Therapeutically effective amount" refers to the amount of
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate that,
when administered to a subject for treating a disease, is
sufficient to reduce the severity of, eliminate, or prevent the
disease, or a symptom of the disease, in the subject. The
therapeutically effective amount may vary depending, for example,
on the form of the compound (1), the cause of disease, the severity
of the disease, the age, weight, and/or health of the subject to be
treated, and the judgment of the prescribing physician. A
therapeutically effective amount may be ascertained by those
skilled in the art and/or capable of determination by routine
experimentation.
[0049] "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.
DETAILED DESCRIPTION
[0050] Reference is now made in detail to certain embodiments of
dosage forms 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.
[0051] (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate,
has the following chemical structure:
##STR00005##
[0052] Compound (1) may be prepared using the methods described in
Gangakhedkar et al. U.S. Pat. No. 8,148,414, which is herein
incorporated by reference.
[0053] Oral dosage forms disclosed herein comprise a tablet or
capsule containing (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate and one or more pharmaceutically
acceptable excipients. In certain aspects, the oral dosage forms
comprise granules having a high loading of
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate.
High Drug Loading Granulations and Mixture Blends
[0054] In certain embodiments, high drug loading solid granulations
comprise at least about 95 wt % compound (1), and in certain
embodiments, at least about 97% compound (1).
[0055] The high drug loading granulations may also comprise one or
more pharmaceutically acceptable excipients. In an embodiment, the
pharmaceutically acceptable excipient may comprise a
pharmaceutically acceptable binder. In certain embodiments,
granulations, or granules as used interchangeably herein, may
comprise from about 0.5 wt % to about 5.0 wt %, and in certain
embodiments about 1 wt % to about 3.0 wt % of a pharmaceutically
acceptable binding agent. Binding agents may be included in
granules to facilitate adhesion of the constituents. Examples of
binding agents useful in tablet dosage forms provided by the
present disclosure include polyvinyl acetate phthalate, molasses,
starch, methylcellulose, hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, and
other polymers including vinyl pyrrolidone as a sub-unit, and
combinations thereof. In certain embodiments provided by the
present disclosure, a binder may be a polymer selected from
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl
pyrrolidone and combinations thereof. In a particular embodiment,
the binder may be hydroxypropyl cellulse (Klucel EXF, Ashland).
[0056] Granules having a high loading of compound (1) may be
prepared using high shear wet granulation. At least in part, the
amount of binder and other pharmaceutically acceptable excipients
are chosen to provide a wide processing window for the amount of
water used during granulation. For manufacturing, it is generally
desirable to be able to vary process parameters without
significantly negatively impacting the properties of the granules
and to produce granules having optimal physical and mechanical
properties to facilitate subsequent processes for manufacture of
oral dosage forms.
[0057] In certain embodiments, a mixture comprising the high drug
load granules of compound (1) may be formed. The mixture may
comprise a blend of one or more pharmaceutically acceptable
excipients and high drug load granules. If desired, the mixture may
be used in preparation of oral dosage forms, as described herein.
In certain embodiments it was unexpectedly found that the
additional of a small amount of glidant markedly improved the
flowability of the mixture including high loading granules, as
described in further detail herein. Glidants may be included in
blends provided by the present disclosure 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, the blends may contain up to 3
wt % of a glidant as a flow aid. In other embodiments, the mixtures
may contain up to 1 wt % glidant as a flow aid. In other
embodiments, the mixtures may contain 0.1 to about 0.5 wt % glidant
as a flow aid. In certain embodiments, a glidant is colloidal
silicon dioxide.
Oral Dosage Forms
[0058] The high drug loading granulations and mixtures of the
disclosure may be used to prepare any suitable pharmaceutical
formulations, including oral dosage forms. In certain embodiments,
the oral dosage forms may provide immediate release, sustained
release, delayed release or any combination thereof.
[0059] In certain embodiments, an oral dosage form comprising a
high drug load granulation may be compressed into a tablet dosage
form. In certain embodiments, a mixture comprising a high drug load
granulation may be inserted into and contained in a capsule dosage
form. In certain embodiments, an oral dosage form comprising a high
drug load granulation may be a liquid oral dosage from such as an
emulsion or suspension.
[0060] In certain embodiments, the amount of compound (1) in a
dosage form provided by the present disclosure is from about 50 mg
to about 2,000 mg, in certain embodiments, from about 100 mg to
about 1,200 mg, and in certain embodiments is about 200 mg to about
800 mg. For dosage forms comprising a pharmaceutically acceptable
solvate of compound (1), the amount of compound (1) in a dosage
form refers to the mass equivalent weight of compound (1)
comprising the solvate. For reference, one (1) mg compound (1)
corresponds to 0.53 mg-equivalents of MHF.
[0061] In certain embodiments, dosage forms may be in the form of
tablets comprising compound (1). Tablet dosage forms may be of any
shape suitable for oral administration of a drug such as
spheroidal, cube-shaped, oval, or ellipsoidal. In certain
embodiments, tablet dosage forms, e.g., an oral dosage form in the
form of a tablet, provided by the present disclosure are matrix
systems in which the compound (1) is dispersed in a matrix
comprising at least one release-rate modifying compound. Matrix
systems are well-known in the art as described, for example, in
"Handbook of Pharmaceutical Controlled Release Technology," ed.
Wise, Marcel Dekker, Inc. (2000) and "Treatise on Controlled Drug
Delivery, Fundamentals, Optimization, and Applications," ed.
Kydonieus, Marcel Dekker, Inc. (1992).
[0062] Oral dosage forms may comprise a tablet core with greater
than about 70 wt % compound (1), greater than about 80 wt %
compound (1), greater than about 85 wt % compound (1), greater than
about 90 wt % compound (1), greater than about 95 wt % compound
(1), greater than about 97 wt % compound (1), where wt % is based
on the weight of an uncoated tablet core of a dosage form. In
certain embodiments, the oral dosage form may comprise at least one
additional pharmaceutically acceptable excipient where the
pharmaceutical excipient is selected from fillers, diluents,
binders, lubricants, disintegrants, glidants, sustained release
agents, surfactants, plasticizers, anti-adherents, buffers, dyes,
wetting agents, emulsifying agents, pH buffering agents, thickening
agents, coloring agents, enteric agents, and combinations
thereof.
[0063] Diluents, or fillers, may be added to increase the bulk to
make dosage forms a practical size for compression. 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, a
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.
[0064] 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, coatings may comprise an amount
of lubricant ranging from about 0.5 wt % to about 3 wt %, from
about 1 wt % to about 3 wt %, and in certain embodiments is about 1
to about 2 wt %, based on the total solids weight of the
coating.
[0065] 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.
[0066] Examples of surfactants useful in tablet dosage forms
provided by the present disclosure include pharmaceutically
acceptable anionic surfactants, cationic surfactants, zwitterionic,
amphoteric (amphiphatic/amphiphilic) surfactants, non-ionic
surfactants, polyethyleneglycol esters or ethers, and combinations
of any of the foregoing. Examples of useful pharmaceutically
acceptable anionic surfactants include monovalent alkyl
carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl
sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty
acid-polypeptide condensates, sulfuric acid esters, alkyl sulfates
such as sodium lauryl sulfate and sodium dodecyl sulfate,
ethoxylated alkyl sulfates, ester linked sulfonates such as
docusate sodium and dioctyl sodium succinate, alpha olefin
sulfonates, or phosphated ethoxylated alcohols. Examples of useful
pharmaceutically acceptable cationic surfactants include monoalkyl
quaternary ammonium salts, dialkyl quaternary ammonium compounds,
amidoamines, and aminimides. Examples of useful pharmaceutically
acceptable amphoteric surfactants include N-substituted alkyl
amides, N-alkyl betaines, sulfobetaines, and
N-alkyl-6-aminopropionates. Examples of useful pharmaceutically
acceptable nonioinic surfactants include diblock and triblock
copolymers of polyethylene oxide, polypropylene oxide,
polyoxyethylene (20) sorbitan monooleate, and polyethyleneglycol
esters or ethers such as polyethoxylated castor oil,
polyethoxylated hydrogenated castor oil, and hydrogenated castor
oil. In certain embodiments, a surfactant is chosen from sodium
lauryl sulfate and sodium dodecyl sulfate.
[0067] Tablet dosage forms provided by the present disclosure may
further comprise one or more coatings, which may partially or fully
cover the tablets. While certain coatings may be applied to modify
or affect the release of compound (1) from a tablet dosage form in
the gastrointestinal tract, others may have no such effect. For
example, one or more additional coatings may be for physical
protection, chemical protection, aesthetics, ease in swallowing,
identification, and/or to facilitate further processing of the
tablets. Coatings may be impermeable to moisture or may be moisture
permeable. Moisture impermeable exterior tablet coatings may be
useful for maintaining low moisture content in a dosage form that
is packaged in the presence of a desiccant and may thereby enhance,
for example, the storage stability of a tablet dosage form.
Examples of materials useful in coatings for physical protection
include permeable or soluble materials such as hydroxypropyl
methylcellulose, hydroxypropyl cellulose, lactose, hydroxypropyl
ethylcellulose, hydroxyethyl cellulose, and xanthan gum. Examples
of materials useful in external tablet coatings to facilitate
further processing include talc, colloidal silica, polyvinyl
alcohol, titanium dioxide, micronized silica, fumed silica,
glycerol monostearate, magnesium trisilicate, and magnesium
stearate. An external tablet coating may further include one or
more vehicles such as plasticizers, binders, fillers, lubricants,
compression aides, and combinations of any of the foregoing. The
one or more additional coatings may comprise a single material or a
combination of more than one material including any of those
disclosed herein. These additional coatings may be applied to
tablet dosage forms by methods known to those skilled in the
art.
[0068] Plasticizers may also be included in tablet dosage forms,
e.g., in coatings, provided by the present disclosure. Examples of
plasticizers useful in tablet dosage forms provided by the present
disclosure include alkyl citrates such as triethyl citrate, acetyl
triethyl citrate, tributyl citrate, acetyl triethyl citrate, and
acetyl tributyl citrate; alkyl acetates such as triethyl acetate,
acetyl triethyl acetate, tributyl acetate, acetyl triethyl acetate,
and acetyl tributyl acetate; sucrose fatty acid esters; glycerin
mono-, di- and tri-fatty acid esters such as triacetin, glycerin
mono-fatty acid esters, glycerin monostearate and acetylated
monoglyceride; polyglycerin fatty acid esters; polyethylene glycols
such as macrogol 400, macrogol 600, macrogol 1500, macrogol 4000,
macrogol 6000, macrogol 20,000, and macrogol 35,000; dibutyl
sebacate; tributyl sebacate; vinyl pyrrolidone; propylene glycol;
sesame oil; castor oil; glycerin; silicone resins; D-sorbitol;
phytosterol; alkyl phthalates such as diethyl phthalate, dibutyl
phthalate and dioctyl phthalate; adipate polyesters; isopropyl
myristate; medium chain triglyceride; butyl phthalyl butyl
glycolate; polyoxyethylene polyoxypropylene glycol; and
combinations of any of the foregoing.
[0069] In certain embodiments, the tablet core may be coated with a
compression coating to provide, e.g., a desired release profile. In
certain aspects the compression coating layers typically release no
more than 20% of compound (1) over a period of 2 hours after the
oral dosage form is placed in an aqueous solution free of compound
(1). In certain aspects, the compression coating may comprise a the
compression coating layer comprises (i) a non-ionizable polymer
that is (a) a proton-donating acidic material having a pKa of
greater than 8 or (b) a proton-accepting basic material having a
pKa of less than 2, (ii) a natural gum or polysaccharide, (iii) a
neutral polymer salt, (iv) a sugar, or (v) a lipid.
[0070] In certain embodiments, the tablet core may be coated with a
barrier layer to provide, e.g., physical or chemical protection. In
certain aspects, the barrier layer may comprise a (i) non-ionizable
polymer material that is (a) a weakly acidic (proton-donating)
material having a pKa of greater than 8 or (b) a weakly basic
(proton-accepting) material having a pKa of less than 2, (ii) a
natural gum or polysaccharide, (iii) a neutral polymer salt, (iv) a
sugar, or (v) a lipid.
[0071] Examples of suitable non-ionizable polymers include
non-ionizable cellulosic polymers, non-ionizable vinyl and
polyvinyl alcohol polymers, and/or non-ionizable polymers that are
not cellulose or vinyl-based. In various embodiments, non-ionizable
polymers are substantially free of carboxylic acid moieties.
[0072] 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, hydroxyethyl ethyl cellulose, low-substituted
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose acetate, hydroxypropyl
methylcellulose propionate, hydroxypropyl methylcellulose butyrate,
and corresponding salts and esters.
[0073] Exemplary vinyl-based polymers include polyvinyl alcohol,
polyvinvyl acetate, polyvinylpyrrolidone, and crospovidone
(polymers of N-vinyl-2-pyrrolidone). Exemplary vinyl-containing
polymers further include vinyl polymers and copolymers having
hydroxyl-containing repeat units, alkylacyloxy-containing repeat
units, or cyclicamido-containing repeat units. 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 can having (1) substantially carboxy-free
hydroxyl-containing repeat units and (2) hydrophobic repeat
units.
[0074] In certain embodiments, the non-ionizable polyvinyl
materials show no degradation as an excipient. Non-limiting
examples of such materials include polyvinylpyrrolidone and
crospovidone.
[0075] Examples of non-cellulosic non-vinyl-based non-ionizable
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 glycol, polyethylene glycol, polypropylene glycol
copolymers, polyoxyethylene-polyoxypropylene block copolymers,
polyethylene glycol, poly(ethyl acrylate-co-methyl methacrylate)
2:1 (Eudragit NE), polyethylene glycol, polyethylene glycol
polypropylene glycol copolymers, and
polyoxyethylene-polyoxypropylene block copolymers (i.e.
poloaxamers). 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 do not
contain carboxylic acid moieties, or are substantially free of
carboxylic acid moieties.
[0076] Suitable examples of such natural gums and polysaccharides
include starch, chitin, guar gum, tara gum, locust bean gum,
carrageenan, gellan gum, alginate, and xanthan gum.
[0077] In certain embodiments, the natural gums and polysaccharides
contain carboxylic acid moieties, including salts thereof.
Non-limiting examples of such materials include gellan gum,
Alginate, and xanthan gum.
[0078] In various embodiments, natural gums or polysaccharides are
substantially free of carboxylic acid moieties. Non-limiting
examples of such materials include starch, chitin, guar gum, tara
gum, locust bean gum, carrageenan.
[0079] 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. In certain embodiments, the neutral polymer salts do not
include a carboxylate group.
[0080] 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, poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.2, and croscarmellose sodium.
[0081] In certain embodiments, certain neutral polymer salts do not
include carboxyl groups. These 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
[0082] In certain embodiments, certain neutral polymer salts
include a carboxyl group that is neutralized with a counterion.
Such compounds include crosslinked croscarmellose, 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.
[0083] In certain other embodiments, the ionizable polymers do not
contain carboxylic acid groups. Such materials include poly(butyl
methacylate-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 prontonated at
pH<5.
[0084] Examples of suitable sugars include lactose, mannitol,
sorbitol, sucrose, and trehalose.
[0085] 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.
[0086] In certain embodiments, the barrier layer may disposed
between the tablet core and an enteric coating layer. In various
aspects, the barrier layer is sufficiently thick and sufficiently
continuous to prevent direct contact between the enteric coating
and the core. Typically this can be accomplished by coating the
cores to a target weight percent range. For cores having a size
(e.g., diameter) of 2 mm or less, the barrier layer can comprise at
least 5 wt % of the coated core. For cores having a size (e.g.,
diameter) greater than 6 mm, the barrier layer comprises at least
0.5 wt % of the coated core.
[0087] Alternatively, the barrier layer can be applied to a
specified average thickness. For example, the barrier layer can
have an average thickness of at least 5 .mu.m. In other
embodiments, the barrier layer has an average thickness of at least
15 .mu.m.
[0088] Once the cores have been coated with the barrier layer, an
enteric coating may then applied. In various embodiments, the
enteric coating comprises an enteric polymer that is substantially
insoluble in aqueous solutions having a pH level below 4.5 but
which starts to become soluble at a pH between 4.5 and 7.5 and is
soluble in aqueous solutions having a pH above 7.5. The enteric
coating remains intact while the oral dosage form is in the low pH
environs of the stomach, which means that the fumarate compound
remains in the core while the dosage form is in the stomach.
[0089] Suitable enteric polymers include methacrylic acid polymers,
cellulose acetate phthalate polymers, hydroxypropylmethyl cellulose
acetate succinate polymers, hydroxypropylmethyl cellulose phthalate
polymers and polyvinyl acetate phthalate polymers. Other examples
of pH-sensitive polymers that can be used in the enteric coating
include methyl acrylate-methacrylic acid copolymers, cellulose
acetate succinate, hydroxy propyl methyl cellulose phthalate,
hydroxy propyl methyl cellulose acetate succinate (hypromellose
acetate succinate), polyvinyl acetate phthalate (PVAP), methyl
methacrylate-methacrylic acid copolymers and shellac. Specific
examples of enteric polymers include 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.
[0090] The oral dosage forms can be either immediate release,
sustained release, delayed release or combinations thereof. For
example, in order to minimize contact between the compound (1) and
the tissues lining the stomach and to prevent exposure of the
compound (1) to the low pH environs of the stomach, the dosage form
may be a delayed release dosage form, and following the delay in
prodrug release, thereafter provide either immediate release of the
compound (1) or sustained release of the compound (1). As described
herein, in certain embodiments, the oral dosage forms may be
formulated to include compression coating layers to provide, e.g.,
delayed release, and the tablet cores may be prepared as immediate
release formulations or sustained release formulations, depending
on the desired release profile. In other embodiments, the oral
dosage forms may be formulated to include a sustained release
tablet core, an enteric coating, and a protective barrier layer
intermediate the tablet core and the enteric coating.
[0091] Exemplary oral dosage forms are disclosed in co-owned
applications, filed concurrently herein, entitled "ORAL DOSAGE
FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF", under
Attorney Docket Number P234942.US.01 (X-0184 P1), and "ORAL DOSAGE
FORMS OF METHYL HYDROGEN FUMARATE AND PRODRUGS THEREOF" under
Attorney Docket Number P234941.US.01 (X-0183 P1), the contents of
which are both herein incorporated by reference.
[0092] In certain embodiments in which tablet dosage forms comprise
less than a therapeutically effective amount of compound (1),
multiple tablet dosage forms may be administered to a subject
simultaneously or over a period of time to provide a
therapeutically effective dose of compound (1). For instance, the
oral dosage form may be formulated to comprise an amount of
compound (1) suitable for twice a day administration (BID), three
times a day administration (TID), etc.
[0093] The release characteristics of dosage forms provided by the
present disclosure comprising compound (1) may be characterized, in
part, by the in vitro dissolution profile. Methods for determining
dissolution profiles of dosage forms are well known to those
skilled in the pharmaceutical arts. Standard methodologies set
forth in the U.S. Pharmacopeia may be used. For example, a
dissolution profile may be determined using either a U.S.
Pharmacopeia Type I Apparatus (baskets) or a U.S. Pharmacopeia Type
II Apparatus (paddles).
[0094] Using the latter method, dissolution, or release, profiles
of dosage forms provided by the present disclosure may be
determined by immersing the dosage forms into a dissolution vessel
(USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid
(pH 1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate
was added to the vessel resulting in a pH adjustment from 1.2 to
6.8. The dissolution medium was kept at 37.degree. C. and was
agitated at 100 rpm.
Samples are withdrawn from the dissolution medium at intervals and
the content of compound (1) in the dissolution medium determined
using reverse phase high pressure liquid chromatography (HPLC).
[0095] In certain embodiments, release of compound (1) from tablet
dosage forms provided by the present disclosure exhibits an in
vitro dissolution profile in wherein about 20% to about 45% of the
(N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate in the
dosage form is released within about 4 hours; about 40% to about
70% of the (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate is released within about 8 hours; about
60% to about 85% of the (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate is released within about 12 hours; and
about 80% to about 100% of the (N,N-Diethylcarbamoyl)methylmethyl
(2E)but-2-ene-1,4-dioate is released within about 20 hours.
[0096] In certain embodiments, a tablet exhibits a dissolution
profile that is similar to the foregoing profile as determined
using the f1 difference factor and the f2 similarity factor
according to FDA guidelines.
[0097] In certain of such embodiments, a tablet dosage form
exhibiting the foregoing release profiles comprises about 700 mg to
about 1,000 mg compound (1).
[0098] It is generally recognized that commercially acceptable
tablets have a friability of less than about 1 wt % determined
according to USP Test No. 1216. In certain embodiments, tablets
provided by the present disclosure have a friability of less than
about 1 wt %, in certain embodiments, less than about 0.5 wt %, in
certain embodiments, less than about 0.3 wt %, and in certain
embodiments, less than about 0.1 wt %.
Therapeutic Uses
[0099] 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.
[0100] 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.
[0101] 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 compound (1) 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 compound (1) 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 compound (1) 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.
[0102] MHF 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 compound (1) is
therapeutically effective.
[0103] In certain embodiments, a therapeutically effective dose of
compound (1) may provide therapeutic benefit without causing
substantial toxicity including adverse side effects. Toxicity of
compound (1) 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 compound (1) may be
within a range capable of establishing and maintaining a
therapeutically effective circulating plasma and/or blood
concentration of MHF that exhibits little or no toxicity.
[0104] 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 compound (1) 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 compound (1) 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
[0105] 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.
[0106] 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).
[0107] Efficacy of compound (1) for treating psoriasis can be
determined using animal models and in clinical trials.
Inflammatory Arthritis
[0108] Inflammatory arthritis includes diseases such as rheumatoid
arthritis, juvenile rheumatoid arthritis (juvenile idiopathic
arthritis), psoriatic arthritis, and ankylosing spondylitis, each
of which produces 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). Dimethyl fumarate has been shown to inhibit TNF and
inflammatory diseases including inflammatory arthritis, which 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).
[0109] The efficacy of compound (1) for treating inflammatory
arthritis can be determined using animal models and in clinical
trials.
Multiple Sclerosis
[0110] 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.
[0111] 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).
[0112] 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)
[0113] 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.
[0114] 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).
[0115] The efficacy of compound (1) 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
[0116] 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.
[0117] 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.
[0118] The efficacy of compound (1) for treating asthma can be
assessed using animal models and in clinical trials.
Chronic Obstructive Pulmonary Disease
[0119] 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 that can
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.
[0120] The efficacy of administering compound (1) 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
[0121] 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
[0122] 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 properly control 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).
[0123] The efficacy of compound (1) for treating Parkinson's
disease may be assessed using animal and human models of
Parkinson's disease and in clinical studies.
Alzheimer's Disease
[0124] 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.
[0125] The efficacy of compound (1) for treating Alzheimer's
disease may be assessed using animal and human models of
Alzheimer's disease and in clinical studies.
Huntington's Disease
[0126] 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.
[0127] The efficacy of compound (1) for treating Huntington's
disease may be assessed using animal and human models of
Huntington's disease and in clinical studies.
Amyotrophic Lateral Sclerosis
[0128] 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.
[0129] The efficacy compound (1) for treating ALS may be assessed
using animal and human models of ALS and in clinical studies.
Other Diseases
[0130] Other diseases and conditions for which compound (1) 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 greata, ankylosing spondylitis, antiphospholipid antibody
syndrome, autoimmune hemolytic anemia, autoimmune hepatitis,
autoimmune inner ear disease, bullous pemphigoid, Behcet's disease,
celiac disease, Chagas diseas, chronic obstructive pulmonary
disease, Crhon'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,
schizophrena, 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
[0131] 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. Compound (1) 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.
[0132] 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 compound (1) to be
administered may also depend on, among other factors, the subject
being treated, the weight of the subject, the severity of the
disease, the manner of administration, and the judgment of the
prescribing physician.
[0133] For systemic administration, a therapeutically effective
dose may be estimated initially from in vitro assays. For example,
a dose may be formulated in animal models to achieve a beneficial
circulating composition concentration range. Initial doses may also
be estimated from in vivo data, e.g., animal models, using
techniques that are known in the art. Such information may be used
to more accurately determine useful doses in humans. One having
ordinary skill in the art may optimize administration to humans
based on animal data.
[0134] 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 (1) contained within each dosage form may be the
same or different. The amount of compound (1) 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.
[0135] 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, compound (1) 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 compound (1) 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.
[0136] Since compound (1) is a prodrug of MHF, dosage forms
containing compound (1) provide MHF to a subject. The promoiety of
compound (1) may be cleaved either chemically and/or enzymatically.
One or more enzymes present in the stomach, intestinal lumen,
intestinal tissue, blood, liver, brain or any other suitable tissue
of a mammal can enzymatically cleave the promoiety of compound (1).
If the promoiety is cleaved after absorption by the
gastrointestinal tract, compound (1) can be absorbed into the
systemic circulation from the large intestine. In certain
embodiments, the promoiety is cleaved after absorption by the
gastrointestinal tract. In certain embodiments, the promoiety is
cleaved in the gastrointestinal tract and MHF is absorbed into the
systemic circulation form the large intestine. In certain
embodiments, compound (1) is absorbed into the systemic circulation
from the gastrointestinal tract, and the promoiety is cleaved in
the systemic circulation, after absorption of compound (1) from the
gastrointestinal tract.
[0137] In certain embodiments, dosage forms comprising compound (1)
may be administered concurrently with the administration of another
therapeutic agent, which may be part of the same dosage form as, or
in a different dosage form than that comprising compound (1).
Compound (1) may be administered prior or subsequent to
administration of another therapeutic agent. In certain embodiments
of combination therapy, the combination therapy may comprise
alternating between administering compound (1) and a composition
comprising another therapeutic agent, e.g., to minimize adverse
drug effects associated with a particular drug. When compound (1)
is administered concurrently with another therapeutic agent that
potentially may produce an adverse drug effect including, but not
limited to, toxicity, the other therapeutic agent may
advantageously be administered at a dose that falls below the
threshold at which the adverse drug reaction is elicited.
[0138] In certain embodiments, in the treatment of a subject
suffering from multiple sclerosis, a dosage form comprising
compound (1) may can be administered in conjunction with an agent
known or believed to be effective in treating multiple sclerosis,
including Gilenya (fingolimod), Avonex (interferon .beta.1a), Rebif
(interferon-.beta.1a), Betaseron/Extavia (interferon .beta.1b),
Copaxone (Copolymer1), Tysabri (natralizumab), Aubagio
(teriflunomide), dimethyl fumarate, laquinimod, modafinil,
azathioprine, mycophenolate mofetil, mitoxantrone, corticosteroids
such as predisolone, methylprednisolone; glatiramer, glatiramer
acetate; monoclonal antibodies that bind to the very late antigen-4
(VLA-4) integrin such as natalizumab; immunomodulatory agents such
as FTY 720 sphinogosie-1 phosphate modulator and COX-2 inhibitors
such as BW755c, piroxicam, and phenidone; and neuroprotective
treatments including inhibitors of glutamate excitotoxicity and
iNOS, free-radical scavengers, and cationic channel blockers;
memantine; AMPA antagonists such as topiramate; and glycine-site
NMDA antagonists and Lemtrada (alemtusumab).
[0139] In certain embodiments, in the treatment of a subject
suffering from psoriasis, a dosage form comprising compound (1) may
can be administered in conjunction with an agent known or believed
to be effective in treating psoriasis, including steroids such as
flurandrenolide, fluocinonide, alclometasone, amcinonide, desonide,
halcinonide, triamcinolone, clobetasol, clocortolone, mometasone,
desoximetasone, and halobetasol; anti-rheumatics such as Enbrel
(etanercept), Remicade (infliximab), and Humira (adalimumab);
immunosuppressive agents such as cyclosporine, alefacept, and
efalizumab; psoralens such as methoxsalen; and other such as
calcipotriene, methotrexate, hydrocortisone/pramoxine, Soriatane
(acitretin), betamethasone/calcipotriene, tazaraotene,
benzocaine/pyrilamine/zinc oxide, Fumaderm (dimethyl fumarate and
ethyl hydrogen fumarate), dimethyl fumarate, apremilast,
tafocitinib, LY2439821 (Eli Lilly), secukinumab, and Stelera
(ustekinumab).]
EXAMPLES
[0140] The following examples describe in detail the preparation
and properties of tablet dosage forms comprising compound (1). 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.
Synthesis of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate by General Procedure A: Nucleophilic
substitution of 1-haloacetamides or 1-halo acetic acid derivatives
with monomethyl fumarate
[0141] (2E)-3-(Methoxycarbonyl)prop-2-enoic acid (methyl hydrogen
fumarate, MHF), (2E)-3-(tert-butoxycarbonyl)prop-2-enoic acid
(tert-butyl hydrogen fumarate), or fumaric acid (FA) (1.0
equivalents) is dissolved in 5-10 mL/3.0 mmol of an inert solvent
such as N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA, DMAc), acetonitrile (MeCN),
dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene, or
mixtures thereof. To the solution, 0.8 to 1.2 equivalents of an
appropriate inorganic base such as cesium hydrogen carbonate
(CsHCO.sub.3), cesium carbonate (Cs.sub.2CO.sub.3), or potassium
carbonate (K.sub.2CO.sub.3) is added. Alternatively, 0.8 b is 1.2
equivalents of a silver salt such silver(I) oxide (Ag.sub.2O) or
silver(I) carbonate (Ag.sub.2CO.sub.3); an organic secondary or
tertiary base such as dicyclohexylamine (DCHA), triethylamine
(TEA), diisopropylethylamine (DIEA), tetrabutylammonium hydroxide
(TBAOH), amidine; or a guanidine-based base such as
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or
1,1,3,3-tetramethylguanidine (TMG), can be employed. The
corresponding alkali, silver, di-, tri- and tetraalkylammonium,
amidine, or guanide salt of monoalkyl fumarate can also be
preformed. The solution is stirred for 10-60 min at room
temperature followed by addition of 0.8-1.2 equivalents of an
appropriately functionalized 1-haloacetamide, 1-halo acetic acid
derivative, acyloxyalkyl halide, or alky- or
aryloxycarbonyloxyalkyl halide. The reaction mixture is stirred
overnight at a temperature between 40 to 100.degree. C. After
cooling to room temperature, insolubles can optionally be filtered
off and the reaction mixture diluted with one molar (1.0 M)
hydrochloric acid (HCl) and an appropriate organic solvent such as
methyl tert-butyl ether (MTBE), diethyl ether (Et.sub.2O),
ethylacetate (EtOAc), or mixtures thereof. After phase separation,
the aqueous phase is extracted several times with the same solvent.
The combined organic extracts are washed with water, brine, and
dried over anhydrous magnesium sulfate (MgSO.sub.4). After
filtration, the organic solvents are removed under reduced pressure
using a rotary evaporator. If required, the crude reaction products
are further purified by well known purification techniques such as
silica gel flash column chromatography (i.e., Biotage), mass-guided
reversed-phase preparative HPLC/lyophilization, precipitation, or
crystallization.
Example 1
Synthesis of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate (1)
##STR00006##
[0143] Following General Procedure A above, methyl hydrogen
fumarate (MHF, 9 kg) and toluene (48.3 kg) were added to a 100 L
glass-lined stainless steel conical reactor. The reactor was
agitated at 125 rpm and charged with N,N-diethylchloroacetamide
(10.4 kg). The reaction mixture was heated to 52.degree. C. and
diisopropylethylamine (9.8 kg) was added over 31 minutes, with a
final internal temperature of 57.degree. C. The reaction was then
heated to 85-90.degree. C. for 4 hours. The reaction was then
cooled to 50-55.degree. C., a sample was removed for in process
analysis and then further cooled to 30.degree. C. Water (13.5 kg)
was added to the mixture and agitated for 30 minutes. The reaction
mixture was filtered through a pressure plate with a polypropylene
cloth and a bed of diatomaceous earth (9.0 kg) into a 100 L glass
lined reactor. The filter bed was rinsed forward into the reactor
with toluene (15.6 kg). The layers were allowed to separate and the
lower aqueous layer was removed into a USP water drum. Water (6.8
kg) was charged to the reactor and agitated for 10 minutes.
Agitation was stopped and the layers were allowed to separate for
30 minutes. The lower aqueous layer was removed into a USP water
drum. Toluene (116.8 kg) was added to the upper organic phase, the
resulting solution was then passed through a previously prepared
plug of silica gel (23.4 kg). The filtrate was collected through a
1 uM in-line filter into a 100 L glass-lined stainless steel
reactor. The silica gel plug was rinsed with toluene (116.8 kg)
into a clean GMP drum. In process check for residual
Di(N,N-diethylcarbamoyl)methyl(2E)but-2-ene-1,4-dioate was taken on
both the reactor contents and the drum. The reaction solution from
the drum and reactor was concentrated under reduced pressure to an
approximate volume of 20 L, with an internal temperature of
51.degree. C. To a separate 100 L glass lined conical reactor was
added n-heptane (43.1 kg) which was cooled to 2.degree. C. The
prodrug solution in toluene at 51.degree. C. was transferred via a
transfer pump into the n-heptane containing reactor with agitation
over 19 minutes, with a final internal temperature of 4.degree. C.
The mixture was stirred at 156 rpm for 3 hours at 2-4.degree. C.
The product was collected on a filter pressure plate with a
polypropylene cloth and rinsed with n-heptane (8.6 kg). The product
was dried under nitrogen on the pressure plate for 2 hours and then
transferred to 4 drying trays and dried in a tray dryer at
43.degree. C. for 16 hours to afford 7.028 kg of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.
Example 2
Alternate Synthesis of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate (1)
##STR00007##
[0145] Following General Procedure A above, a 5-L, three-neck,
round-bottom flask was equipped with a mechanical stirrer, an
internal thermometer, a 500 mL addition funnel and a nitrogen inlet
and was charged with methyl hydrogen fumarate (MHF) (1.30 kg, 10
mol) and N,N'-diethylchloroacetamide (1.34 kg, 9 mol). The
resulting slurry was slowly heated to 50.degree. C. and
diisopropylamine (1.75 L; 1.295 kg, 10 mol) was added slowly over a
period of two hours with a final internal temperature of 75.degree.
C. The reaction mixture was heated to 70.degree. C. for three
hours. A sample was taken from the reaction mixture for in process
analysis by HPLC. The reaction mixture was then cooled to
50.degree. C. and diluted with ethyl acetate (10 L). The organic
phase was transferred into a 20 L separatory funnel and washed with
water (3.times.2 L). The organic phase was separated, dried over
sodium sulfate and then evaporated under vacuum to give the product
as a viscous oil. This crude product was dissolved in diisopropyl
ether (8 L) and warmed to 50.degree. C. The resulting warm milky
slurry was filtered through celite. The clear filtrate was slowly
cooled to room temperature and then to 0.degree. C. over a period
of four hours. During this period the compound crystallized out as
a white-solid. It was filtered and dried in a vacuum oven at
40.degree. C. for 48 hrs to afford 1.5 kg of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (68.8%
yield).
Example 3
[0146] Granulations, containing 97 wt % loading of the
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate made
in accordance with Example 2, were made having the ingredients
shown in Table 1:
TABLE-US-00002 TABLE 1 Quantity Batch Component Manufacturer Role
(% w/w) Weight (g) (N,N- XenoPort (Santa Clara, Drug substance 97.0
659.6 Diethylcarbamoyl)methyl CA) methyl (2E)but-2-ene- 1,4-dioate
(Compound (1)) Hydroxypropyl Cellulose Aqualon (Hopewell, VA)
Binder 3.0 20.4 Purified water NA Granulation NA 43.5* agent Total
100.00 680.0 g* *Water is dried off during process and does not
contribute to the final granulation weight.
[0147] The granules were prepared using a high shear wet
granulation process. The granulation batch size was 680 g. Compound
(1) 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. Compound (1) and hydroxypropyl cellulose
were combined in a Diosna P1/6 equipped with a 4 L bowl and mixed
for 2 minutes with the impeller speed of approximately 500 rpm
(.about.5.8 m/s) and chopper set to 2000 rpm. After 2 minutes of
dry mixing, the purified water (43.5 g) was added to the granulator
using a peristaltic pump at a rate of approximately 20g/min. 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. The dried
granules were passed through a 0.050'' (1270 microns) grater hole
screen using a Quadro Comil U5.
[0148] The particle size distributions of the blend before
granulation and the granules after granulation were determined
using a Sympatec QicPic particle size analyzer with a lens capable
of detecting particles from 5-1705 microns and a RODOS dry powder
dispersion system at 1.0 bar of pressure. FIG. 1 shows the particle
size distribution both before (.box-solid.-.box-solid.) and after
(o-o) granulation. FIG. 1 clearly shows the increase in particle
size due to the formation of granules.
Example 4
[0149] Granulations, containing 97 wt % loading of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate made
in Example 1 were made having the ingredients shown in Table 2:
TABLE-US-00003 TABLE 2 Quantity Batch Component Manufacturer Role
(% w/w) Weight (g) (N,N- Cambridge Major Drug substance 97.0 480.00
Diethylcarbamoyl)methyl (Germantown, WI) methyl (2E)but-2-ene-
1,4-dioate (Compound (1)) Hydroxypropyl Cellulose Aqualon
(Hopewell, VA) Binder 3.0 14.88 Purified water NA Granulation NA 55
agent Total 100.00 494.88 g* *Water is dried off during process and
does not contribute to the final granulation weight.
[0150] The granules were prepared using a high shear wet
granulation process. The granulation was performed in two batches
of 494.88 g each. Compound (1) was passed through a 1.0 mm mesh
screen. Hydroxypropyl cellulose was passed through a 600 micron
mesh screen. Compound (1) and hydroxypropyl cellulose were combined
in a 3 L bowl and mixed at 660 rpm (impeller) for 10 minutes using
the Quintech granulator. The mixture was then transferred to a 2 L
bowl and granulated with purified water (approximately 55 g) was
added to the granulator using a peristaltic pump at a rate of
approximately 5.5 g/min. 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 and 20 minutes. The dried granules were passed
through an 850 micron mesh screen.
[0151] The particle size distributions of the blend before
granulation and the granules after granulation were determined
using a Sympatec QicPic particle size analyzer with a lens capable
of detecting particles from 5-1705 microns and a RODOS dry powder
dispersion system at 1.0 bar of pressure. FIG. 2 shows the particle
size distribution both before (.tangle-solidup.-.tangle-solidup.)
and after (.box-solid.-.box-solid.) granulation. FIG. 2 clearly
shows the increase in particle size due to the formation of
granules.
Example 5
[0152] Granulations, containing 97 wt % of
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate made
in Example 2, were made having the ingredients shown in Table
3:
TABLE-US-00004 TABLE 3 Quantity Batch Component Manufacturer Role
(% w/w) Weight (g) (N,N- XenoPort (Santa Clara, Drug substance 97.0
164.9 Diethylcarbamoyl)methyl CA) methyl (2E)but-2-ene- 1,4-dioate
(Compound (1)) Hydroxypropyl Cellulose Aqualon (Hopewell, VA)
Binder 3.0 5.1 Purified water NA Granulation NA 17.2* agent Total
100.00 170.0 g* *Water is dried off during process and does not
contribute to the final granulation weight.
[0153] The granules were prepared using a high shear wet
granulation process. The granulation batch size was 170.0 g.
Compound (1) 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. Compound (1) and hydroxypropyl
cellulose were combined in a Diosna P1/6 equipped with a 1 L bowl
and mixed for 2 minutes with the impeller speed of approximately
770 rpm (.about.6.0 m/s) and chopper set to 2000 rpm. After 2
minutes of dry mixing, the purified water (17.2 g) was added to the
granulator using a peristaltic pump at a rate of approximately 4.9
g/min. 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
and 35 minutes. The dried granules were passed through a 600 micron
mesh screen.
[0154] The particle size distributions of the blend before
granulation and the granules after granulation were determined
using a Sympatec QicPic particle size analyzer with a lens capable
of detecting particles from 5-1705 microns and a RODOS dry powder
dispersion system at 1.0 bar of pressure. FIG. 3 shows the particle
size distribution both before (-) and after
(.box-solid.-.box-solid.) granulation. FIG. 3 clearly shows the
increase in particle size due to the formation of granules.
Example 6
[0155] Four different tablets (6a through 6d), containing differing
levels of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate (compound (1)) ranging from from 86 to 96
wt %, were made from the granules made in Example 3. The
compositions of the four tablets are summarized in Table 4. The
dried granules (97% (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate and 3% hydroxypropyl cellulose),
hypromellose 2208 (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 (except for
blend 6a which was not blended until addition of magnesium
stearate). Magnesium stearate was passed through a 250 micron
screen and added to the blend and blended for 1.5 minutes. Tablets
were compressed using a Carver Press with 1/4 inch (6.4 mm) round
standard concave tooling at 0.4 metric ton (MT) force. The tablets
had a final hardness of approximately 7.4 to 8.4 kp (72 to 82
Newtons).
TABLE-US-00005 TABLE 4 Example Component 6a 6b 6c 6d Compound (1)
(wt %) 95.9 90.5 87.6 85.7 Hydroxypropyl Cellulose (wt %) 3.0 2.8
2.7 2.6 Hypromellose 2208 (100000 mPa s) 0.0 5.0 8.0 10.0 (wt %)
Silicon Dioxide (wt %) 0.1 0.2 0.2 0.2 Magnesium Stearate (wt %)
1.0 1.5 1.5 1.5 Total Tablet (wt %) 100.0 100.0 100.0 100.0 Tablet
Weight (mg) 104.2 110.5 114.2 116.8 Total Blend Batch Size (g) 10.0
5.0 5.0 5.0 Tablet Hardness (kP) 7.4 7.6 8.4 8.3
Example 7
[0156] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Example 6. The two-stage dissolution test was used to better
approximate the pH conditions experienced by a dosage form after
swallowing by a patient, i.e., low pH of the stomach followed by
near neutral pH of the intestines. The dosage forms were first
placed into a dissolution vessel (USP, Type I, basket) containing
750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL
of 200 mM tribasic sodium phosphate was added to the vessel
resulting in a pH adjustment from 1.2 to 6.8. The dissolution
medium was kept at 37.degree. C. and was agitated at 100 rpm.
[0157] Samples of the dissolution medium were withdrawn after 1 and
2 hours in the low pH stage, and at 0.5, 2, 4, 7, 10 and 14 hours
following buffer addition. The released amount of compound (1) in
the samples was determined by reverse phase HPLC using a C18 column
and a 7 minute gradient method according to Table 5 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-00006 TABLE 5 Time (minutes) % Mobile Phase A Mobile Phase
B 0 85 15 5 35 65 5.5 85 15 7 85 15
[0158] FIG. 4 shows that the rate at which
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate is
released from the tablets slows with increasing percentage of
hydroxypropylmethyl cellulose (hypromellose 2208 (100000 mPas
viscosity)) in the tablets. Tablet 6a (0% HPMC K100M, - symbols in
FIG. 4) is an immediate release tablet. Tablets 6b (5% HPMC K100M,
.diamond-solid.-.diamond-solid. symbols in FIG. 4), 6c (8% HPMC
K100M, .tangle-solidup.-.tangle-solidup. symbols in FIG. 4), and 6d
(10% HPMC K100M, .box-solid.-.box-solid. symbols in FIG. 4) are
sustained release tablets with the amount of released drug reaching
90% at approximately 5, 7, and 9 hours, respectively.
Example 8
Flow Characterization of Dry Powders
[0159] The flow of dry powders was characterized using a FLODEX.TM.
Powder Flowability Index Test Instrument (Hanson Research
Corporation, Chatsworth, Calif.). The instrument was equipped with
a cylindrical metal reservoir, which holds the test powder prior to
flow testing. The cylindrical reservoir has an inside diameter of
5.7 cm and a length of 7.4 mm. The bottom end of the reservoir can
be closed with removable metal discs. Each disc has a round orifice
centered in the disc. Orifice diameters range from 4 mm to 10 mm in
1 mm increments, and from 10 mm to 34 mm in 2 mm increments. Prior
to flow testing, the orifice is blocked. Powder is then placed over
the blocked orifice. When the orifice is unblocked, powder can flow
through the orifice under the force of gravity if the orifice
diameter is sufficiently large. Powder that flows through small
orifices is considered to have flow properties useful for
tableting. For example, a Flodex measurement (Flodex) of less than
about 24 mm is typically used for high-speed tableting operations
at commercial scale. A Flodex less than about 20 mm is useful for
high-speed tableting operations. A Flodex of 18 mm or less is
considered especially useful for high speed tableting
operations.
[0160] The Flodex is determined by first gently filling the
reservoir with approximately 70 cc of test powder while the orifice
at the bottom is blocked, while avoiding severe piling, and without
vibrating or tapping the powder bed. Next, the orifice is
unblocked. This can be accomplished by opening a shutter that is
supplied with the instrument. Alternatively, if a shutter is not
used, the powder-filled reservoir fitted with a disc can be set on
a dry, flat surface to block the orifice. Then, slowly and evenly,
the reservoir is lifted to allow the powders to flow. In either
procedure, if the powder flows through the orifice, a clear channel
is left within the powder bed. If the powder does not flow through
the orifice, an arch-shaped cavity within the powder bed is formed
above the orifice and is referred to as an arch. The flow test is
conducted with various orifice sizes until the minimum orifice size
for good flow is identified, which is referred to as the Flodex.
The Flodex is the minimum orifice diameter at which the powder
flows through the orifice more times than it does not in at least
three measurement trials.
Example 9
[0161] Granulation blends of (N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate containing varying amounts of colloidal
silicon dioxide were prepared in order to assess the impact of
silicon dioxide on flow. The granules of Example 5 containing no
silicon dioxide (blend 9a) were used as a control. To prepare
blends 9b through 9f (at 30 g scale), (N,N-Diethylcarbamoyl)methyl
methyl (2E)but-2-ene-1,4-dioate granules (from Example 3),
hypromellose 2208, lactose, and the silicon dioxide were combined
in a glass jar and blended on the Turbula mixer for 2 min, passed
through a 600 micron mesh screen, and then blended for another 2
min. Blend 9g was prepared at 1099.2 g scale. The hypromellose 2208
(100000 mPas viscosity) and the silicon dioxide were combined,
passed through a 600 micron mesh screen, and added to the dry
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate
granules in a 5 L cube blender and blended for 10 minutes.
Magnesium stearate was passed through a 600 micron screen and added
to the blend before blending an additional 4 minutes.
[0162] Blend flow was assessed by the Flodex method described in
Example 8. The measured Flodex for each blend is listed in Table 6.
Blend 9a (the granules from Example 5) without any silicon dioxide
had a Flodex value of 34 mm. The Flodex improves to 24 mm when
granules are blended with other excipients (i.e., lactose and
hypromellose 2208 in Blend 9b); however, these Flodex values are
considered to be high for high speed tableting operations. The
Flodex values for blends 9c through 9g show significantly improved
Flowdex measurements corresponding to increased levels of colloidal
silicon dioxide from 0.1 to 0.5 wt % (blends 9c through 9f are also
shown in FIG. 5). This is especially important for high drug
loading dosage forms that do not use filler excipients as in blend
9g.
TABLE-US-00007 TABLE 6 Blend Blend Blend Blend Blend Blend Blend
Component 9a 9b 9c 9d 9e 9f 9g Example 3 0.0 69.4 69.5 69.46 69.4
66.04 0.0 granules (wt %) Example 4 0.0 0.0 0.0 0.0 0.0 0.0 90.1
granules (wt %) Example 5 100.0 0.0 0.0 0.0 0.0 0.0 0.0 granules
(wt %) Lactose 0.0 15.3 15.2 15.17 15.15 15.23 0.0 Monohydrate (wt
%) Hypromellose 0.0 15.3 15.2 15.17 15.15 15.23 7.9 2208 (wt %)
Silicon 0.0 0.0 0.1 0.2 0.30 0.5 0.5 Dioxide (wt %) Magnesium 0.0
0.0 0.0 0.0 0.0 0.0 1.5 Stearate (wt %) Total (wt %) 100.0 100.0
100.0 100.0 100.0 100.0 100.0 Flodex (mm) 34 24 12 9 7 <5 12
Example 10
[0163] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 7:
TABLE-US-00008 TABLE 7 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
[0164] The tablets were made according to the following steps. The
core tablets were prepared from the high drug load granules (97%
N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3%
hydroxypropyl cellulose) described in Example 3. The core blend
batch size was 5 g. The dried granules,
hydroxypropylmethylcellulose (i.e., hypromellose 2208 having 100000
mPas viscosity), and the silicon dioxide were then passed through a
600 micron mesh screen, combined in a glass jar and blended 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 total weight; 87.6%
wt/wt N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate)
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).
[0165] 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 11
[0166] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 8:
TABLE-US-00009 TABLE 8 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
[0167] The tablets were made according to the following steps. The
core tablets were prepared from the high drug load granules (97%
N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3%
hydroxypropyl cellulose) described in Example 3. 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 total weight; 95.3% N,N-Diethylcarbamoyl)methyl methyl
(2E)but-2-ene-1,4-dioate) 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).
[0168] The mantle blend was prepared using a direct compression
process and a batch size of 100 g. The hydroxypropylmethylcellulose
(i.e., hypromellose 2208 having 100000 MPas viscosity) and lactose
hydrate were passed through a 600 micron mesh screen, combined in a
1 quart (0.95 I) 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 12
[0169] Compression coated tablets containing
(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate were
made having the ingredients shown in Table 9:
TABLE-US-00010 TABLE 9 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
[0170] The tablets were made according to the following steps. The
core tablets were prepared from the high drug load granules (97%
N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and 3%
hydroxypropyl cellulose) described in Example 4. The core blend
batch size was 1099.2 g. The hydroxypropylmethylcellulose (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 total weight; 87.3%
wt/wt N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate)
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).
[0171] 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 13
[0172] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Examples 10, 11 and 12 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.
[0173] For the Example 10 dosage forms, samples of the dissolution
medium were withdrawn at 1 and 2 hours following the start of the
low pH stage, and at 0.5, 2, 4, 7, 10 and 14 hours following the
start of the neutral pH/buffered stage. For the Example 11 dosage
forms, samples were withdrawn at 1 and 2 hours following the start
of the low pH stage, and at 0.5, 2, 4, 7, 10, 16 and 22 hours
following the start of the neutral pH/buffered stage. For the
Example 12 dosage forms, samples were withdrawn at 1 and 2 hours
following the start of the low pH stage, and at 0.5, 2, 4, 7, 10,
14 and 20 hours following the start of the neutral pH/buffered
stage. 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 10 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-00011 TABLE 10 Time (minute) % Mobile Phase A % Mobile
Phase B 0 85 15 5 35 65 5.5 85 15 7 85 15
[0174] As shown in FIG. 6, for dosage forms prepared according to
Example 10, drug release is delayed for approximately 2 hours, and
thereafter the drug is released gradually, reaching more than 90%
released at 16 hours.
[0175] As shown in FIG. 7, for dosage forms prepared according to
Example 11, drug release is delayed for approximately 2 hours,
followed by near zero order release, reaching more than 90%
released at 24 hours.
[0176] As shown in FIG. 8, 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 14
[0177] The concentration .+-.1 SD of monomethyl fumarate (MMF) in
the blood of Cynomologous monkeys following oral dosing of delayed
release enteric coated tablets prepared according to Examples 10
and 11 is shown in FIGS. 9 and 10. In these Figures, the MMF
concentrations following dosing with the Example 10 tablets are
shown with .smallcircle.-.smallcircle. symbols and the MMF
concentrations following dosing with the Example 11 tablets are
shown with - symbols. The data in FIG. 9 is from animals dosed in a
fasted state and the data in FIG. 10 is from animals dosed in a fed
state.
Administration Protocol
[0178] Tablets prepared according to Examples 10 and 11 (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
[0179] 300 .mu.L of acetonitrile was added to 1.5 mL Eppendorf
tubes for the preparation of samples and standards.
[0180] 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.
[0181] 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).
[0182] 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
[0183] 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 15
[0184] Delayed release tablets containing compound (1) were made
having the ingredients shown in Table 11:
TABLE-US-00012 TABLE 11 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Drug substance
200.00 78.38 Diethylcarbamoyl)methyl Clara, CA) methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose Ashland
(Hopewell, Binder 6.19 2.42 VA) Lactose Monohydrate Foremost
(Rothschild, Filler 38.28 15.00 WI) Croscarmellose Sodium FMC
BioPolymer Disintegrant 7.66 3.00 (Philadelphia, PA) Silicon
Dioxide Cabot (Tuscola, IL) Glidant 0.51 0.20 Magnesium Stearate
Mallinckrodt (St. Lubricant 2.55 1.00 Louis, MO) Total Core 255.19
100.00 Opadry 03O19184 Colorcon (West Point, Barrier coat 6.80 2.66
PA) Total Barrier 6.80 2.66 Coating Methacrylic Acid Co- Evonik
Industries Enteric polymer 21.10 8.27 polymer Dispersion (Essen,
Germany) Triethyl Citrate Vertellus Plasticizer 1.10 0.43
(Greensboro, NC) PlasACRYL .TM. T20 Emerson Resources Anti-tacking
2.10 0.82 (Norristown, PA) agent Total Enteric 24.30 9.52 Coating
Total Tablet 286.29 112.19
[0185] The tablets were made according to the following steps. The
core tablets were prepared using a high drug load wet granulation
process. The granulation was performed in two batches at 463.9 g
per batch. Compound (1) and hydroxypropyl cellulose were first
passed through a conical mill with a 610 micron round holed screen.
The granulation was then performed by combining 97% of compound (1)
and 3% of hydroxypropyl cellulose in a Key KG-5 granulator bowl
followed by mixing with water addition for approximately 9 minutes.
The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at
40.degree. C. The two portions of dried granules were combined and
blended with the silicon dioxide in an 8 quart (7.6 liter)
V-blender for 5 minutes and then sized by passing through a conical
mill with an approximately 1300 micron grater type screen. The
milled granules were blended with the croscarmellose sodium and
lactose monohydrate for 10 minutes in an 8 quart (7.6 I) V-blender.
The magnesium stearate was passed through a 600 micron mesh screen
and blended with the additional core materials in the V-blender for
5 minutes. Core tablets (254.87 mg) were compressed using a
GlobePharma Minipress II rotary tablet press with 11/32 inch (8.7
mm) round concave tooling. The core tablets had a final mean
hardness of approximately 15.5 kp. An aqueous suspension was
prepared by mixing with an impeller 68.85 g Opadry 03O19184 with
792.0 g of purified water. The water contained in the suspension is
removed during the film coating process and therefore not included
in the final formulation in Table 1. The tablets were coated with
the aqueous suspension in an O'Hara Technologies Labcoat M coater
with a 12'' (30.5 cm) diameter perforated pan until the desired
weight gain of barrier coat was achieved. The coating process
occurred at an inlet temperature of approximately 52.degree. C. and
an outlet temperature of 37.degree. C. After coating, the tablets
were dried for 2 hours at 40.degree. C. An aqueous suspension was
prepared by mixing with an impeller 578.7 g methacrylic acid
copolymer dispersion, 9.0 g triethyl citrate, 86.5 g PlasACRYL.TM.
T20 with 325.8 g water. The water contained in (i) the methacrylic
acid copolymer dispersion and (ii) the PIasACRYL.TM. T20 is removed
during the film coating process and therefore not included in the
final formulation in Table 1. The tablets were coated with the
aqueous suspension in an O'Hara Technologies Labcoat M coater with
a 12'' (30.5 cm) diameter perforated pan until the desired weight
gain of enteric film was achieved. The coating process occurred at
an inlet temperature of approximately 40.degree. C. and an outlet
temperature of 30.degree. C. After coating, the tablets were dried
for 2 hours at 40.degree. C.
Example 16
[0186] Delayed sustained release tablets containing compound (1)
were made having the ingredients shown in Table 12:
TABLE-US-00013 TABLE 12 Quantity Quantity Component Manufacturer
Role (mg/tablet) (% w/w) (N,N- XenoPort (Santa Drug substance
200.00 66.74 Diethylcarbamoyl)methyl Clara, CA) methyl
(2E)but-2-ene- 1,4-dioate Hydroxypropyl Cellulose Ashland
(Hopewell, Binder 6.19 2.06 VA) Lactose Monohydrate Foremost
(Rothschild, Filler 44.95 15.00 WI) Hypromellose 2208 Dow Chemical
Sustained 44.95 15.00 (Midland, MI) release agent Silicon Dioxide
Cabot (Tuscola, IL) Glidant 0.60 0.20 Magnesium Stearate
Mallinckrodt (St. Lubricant 3.00 1.00 Louis, MO) Total Core 299.69
100.00 Opadry 03O19184 Colorcon (West Point, Barrier coat 7.13 2.38
PA) Total Barrier 7.13 2.38 Coating Methacrylic Acid Co- Evonik
Industries Enteric polymer 24.20 8.08 polymer Dispersion (Essen,
Germany) Triethyl Citrate Vertellus Plasticizer 1.25 0.42
(Greensboro, NC) PlasACRYL .TM. T20 Emerson Resources Anti-tacking
2.41 0.80 (Norristown, PA) agent Total Enteric 27.87 9.30 Coating
Total Tablet 334.69 111.68
[0187] The tablets were made according to the following steps. The
core tablets were prepared using a high drug load wet granulation
process. The granulation was performed in two batches at 456 g per
bath. Compound (1) and hydroxypropyl cellulose were first passed
through a conical mill with a 610 micron round holed screen. The
granulation was then performed by combining 97% of compound (1) and
3% of hydroxypropyl cellulose in a Key KG-5 granulator bowl
followed by mixing with water addition for approximately 7 minutes.
The wet granules were dried in a Glatt GPCG-1 fluid bed dryer at
40.degree. C. The two portions of dried granules were sized by
passing through a conical mill with an approximately 1300 micron
grater type screen. The milled granules were blended with the
hypromellose 2208, silicon dioxide, and lactose monohydrate for 10
minutes in an 8 quart (7.6 I) V-blender. This blend was passed
through an 850 micron mesh screen. The magnesium stearate was
passed through a 600 micron mesh screen and blended with the
additional core materials in the V-blender for 5 minutes. Core
tablets (299.69 mg) were compressed using a GlobePharma Minipress
II rotary tablet press with 8.6 mm round concave tooling. The core
tablets had a final mean hardness of approximately 12 kp. An
aqueous suspension was prepared by mixing with an impeller 63.8 g
Opadry 03O19184 with 770.7 g of purified water. The water contained
in the suspension is removed during the film coating process and
therefore not included in the final formulation in Table 2. The
tablets were coated with the aqueous suspension in an O'Hara
Technologies Labcoat M coater with a 12'' (30.5 cm) diameter
perforated pan until the desired weight gain of barrier coat was
achieved. The coating process occurred at an inlet temperature of
approximately 52.degree. C. and an outlet temperature of 36.degree.
C. After coating, the tablets were dried for 2 hours at 40.degree.
C. An aqueous suspension was prepared by mixing with an impeller
405.1 g methacrylic acid copolymer dispersion, 6.3 g triethyl
citrate, 60.6 g PIasACRYL.TM. T20 with 228.1 g water. The water
contained in the methacrylic acid copolymer dispersion and the
PlasACRYL.TM. T20 is removed during the film coating process and
therefore not included in the final formulation in Table 1. The
tablets were coated with the aqueous suspension in the O'Hara
Technologies Labcoat M coater until the desired weight gain of
enteric film was achieved. The coating process occurred at an inlet
temperature of approximately 40.degree. C. and an outlet
temperature of 30.degree. C. After coating, the tablets were dried
for 2 hours at 40.degree. C.
Example 17
[0188] A two-stage dissolution method was used to determine the in
vitro dissolution profile of dosage forms prepared according to
Examples 15 and 16. The 2-stage dissolution test was used to better
approximate the pH conditions experienced by a dosage form after
swallowing by a patient, i.e., low pH of the stomach followed by
near neutral pH of the intestines. The dosage forms were first
placed into a dissolution vessel (USP, Type I, basket) containing
750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours, 250 mL
of 200 mM tribasic sodium phosphate was added to the vessel
resulting in a pH adjustment from 1.2 to 6.8. The dissolution
medium was kept at 37.degree. C. and was agitated at 100 rpm.
[0189] For the Example 15 dosage forms, samples of the dissolution
medium were withdrawn after 1 and 2 hours in the low pH stage, and
at 0.25, 0.5, 0.75, and 1 hours following buffer addition. For the
Example 16 dosage forms, samples of the dissolution medium were
withdrawn after 1 and 2 hours in the low pH stage, and at 0.5, 2,
4, 7, 10, and 14 hours following buffer addition. The released
amount of compound (1) in the samples was determined by reverse
phase HPLC using a C18 column and a 7 minute gradient method
according to Table 3 where Mobile Phase A is water/0.1%
H.sub.3PO.sub.4 and Mobile Phase B is
water/acetonitrile/H.sub.3PO.sub.4 (10/90/0.1 by volume) with UV
detection at 210 nm.
TABLE-US-00014 TABLE 13 Time (minute) % Mobile Phase A % Mobile
Phase B 0 85 15 5 35 65 5.5 85 15 7 85 15
[0190] As shown in FIG. 11, for dosage forms prepared according to
Example 15, drug release is delayed for approximately 2 hours,
followed with near immediate release with >90% released between
2 and 3 hours. As shown in FIG. 12, for dosage forms prepared
according to Example 16, drug release is delayed for approximately
2 hours, followed by sustained release reaching >90% at 12
hours.
[0191] Finally, it should be noted that there are alternative ways
of implementing the embodiments disclosed herein. Accordingly, the
present embodiments are to be considered as illustrative and not
restrictive. Furthermore, the claims are not to be limited to the
details given herein, and are entitled their full scope and
equivalents thereof.
* * * * *