U.S. patent application number 15/013633 was filed with the patent office on 2016-06-02 for n-ethyl-n-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarb- oxamide, preparation and uses thereof.
This patent application is currently assigned to Teva Pharmaceutical Industries, Ltd.. The applicant listed for this patent is Ulf Tomas Fristedt, Vladimir Ioffe, Avital Laxer, Danit Licht, Ioana Lovinger, Muhammad Safadi, Konstantin Ulanenko. Invention is credited to Ulf Tomas Fristedt, Vladimir Ioffe, Avital Laxer, Danit Licht, Ioana Lovinger, Muhammad Safadi, Konstantin Ulanenko.
Application Number | 20160151346 15/013633 |
Document ID | / |
Family ID | 48982733 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160151346 |
Kind Code |
A1 |
Ioffe; Vladimir ; et
al. |
June 2, 2016 |
N-ETHYL-N-PHENYL-1,2-DIHYDRO-4,5-DI-HYDROXY-1-METHYL-2-OXO-3-QUINOLINECARB-
OXAMIDE, PREPARATION AND USES THEREOF
Abstract
The subject invention provides a pharmaceutical composition
containing laquinimod or a pharmaceutically acceptable salt
thereof, and a compound of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinoline-
carboxamide or a salt thereof.
Inventors: |
Ioffe; Vladimir; (Kfar Saba,
IL) ; Ulanenko; Konstantin; (Netanya, IL) ;
Laxer; Avital; (Tel-Aviv, IL) ; Safadi; Muhammad;
(Nazareth, IL) ; Licht; Danit; (Givat Shmuel,
IL) ; Lovinger; Ioana; (Kfar Saba, IL) ;
Fristedt; Ulf Tomas; (Helsingborg, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ioffe; Vladimir
Ulanenko; Konstantin
Laxer; Avital
Safadi; Muhammad
Licht; Danit
Lovinger; Ioana
Fristedt; Ulf Tomas |
Kfar Saba
Netanya
Tel-Aviv
Nazareth
Givat Shmuel
Kfar Saba
Helsingborg |
|
IL
IL
IL
IL
IL
IL
SE |
|
|
Assignee: |
Teva Pharmaceutical Industries,
Ltd.
Petach-Tikva
IL
|
Family ID: |
48982733 |
Appl. No.: |
15/013633 |
Filed: |
February 2, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13768919 |
Feb 15, 2013 |
9284276 |
|
|
15013633 |
|
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|
61599680 |
Feb 16, 2012 |
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Current U.S.
Class: |
424/463 ;
206/461; 206/524.6; 215/329; 424/474; 514/312 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 37/06 20180101; B65D 1/0207 20130101; B65D 41/04 20130101;
A61P 25/00 20180101; A61P 21/00 20180101; A61P 17/00 20180101; A61P
19/02 20180101; A61P 13/12 20180101; A61P 25/28 20180101; A61K 9/20
20130101; A61K 9/2813 20130101; A61J 1/035 20130101; A61P 3/10
20180101; B65D 41/0407 20130101; A61K 9/4891 20130101; B65D 81/264
20130101; B65D 51/24 20130101; A61K 9/48 20130101; B65D 50/00
20130101; A61P 1/04 20180101; C07D 215/56 20130101; A61K 31/4704
20130101 |
International
Class: |
A61K 31/4704 20060101
A61K031/4704; B65D 50/00 20060101 B65D050/00; B65D 41/04 20060101
B65D041/04; A61J 1/03 20060101 A61J001/03; B65D 1/02 20060101
B65D001/02 |
Claims
1-28. (canceled)
29. A process for preparing a pharmaceutical composition comprising
laquinimod or a pharmaceutically acceptable salt thereof,
comprising: admixing laquinimod or a pharmaceutically acceptable
salt thereof with at least one pharmaceutically acceptable carrier
in a low-light environment to form the pharmaceutical
composition.
30. The process of claim 29 wherein the pharmaceutical composition
further comprises
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in an amount of less than 0.5% by weight relative to the
amount of laquinimod.
31. The process of claim 29 wherein the laquinimod or the
pharmaceutically acceptable salt thereof is admixed with a liquid
to form a solution.
32. The process of claim 31 wherein the liquid is water.
33. The process of claim 31 wherein the solution is combined with
at least one solid pharmaceutical excipient to form a wet
granulate.
34. The process of claim 33, further comprising drying the wet
granulate in a low-light environment.
35. The process of claim 34, further comprising compressing the
dried granulate into tablets in a low-light environment or filling
the dried granulate into capsules in a low light environment.
36. (canceled)
37. The process of claim 34, wherein the low-light environment is
an environment within non-transparent vessels or an environment in
which only yellow fluorescent light present.
38-65. (canceled)
66. A pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof prepared by the process of
claim 29, wherein the pharmaceutical composition comprises
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in an amount of less than 0.5% by weight relative to the
amount of laquinimod.
67. The pharmaceutical composition of claim 66, further comprising
a light-resistant coating wherein the coating is resistant to light
with wavelength in the range of 310-400 nm.
68. The pharmaceutical composition of claim 67, wherein the
light-resistant coating is a coating comprising titanium
dioxide.
69. The pharmaceutical composition of 66 in the form of a tablet or
a capsule.
70. The pharmaceutical composition of claim 66 in a light-resistant
packaging.
71. The pharmaceutical composition of claim 70, wherein the
light-resistant packaging is an opaque blister pack or an opaque
high density polyethylene (HPDE) container.
72. The pharmaceutical composition of claim 71, wherein the opaque
blister pack comprises: a) a blend of aluminum and aluminum-silver;
b) a blend of aluminum and poly-chloro-trifluoro-ethylene; or c) a
blend of two or more of polyvinyl chloride, polyethylene,
polycarbonate, polyvinylidene chloride and ethylene vinyl
alcohol.
73. The pharmaceutical composition of claim 71, wherein the opaque
high density polyethylene (HPDE) container is a bottle which is: a)
an opaque high density polyethylene bottle capped with
polypropylene child-resistant screw caps fitted with a silica
desiccant insert; or b) an opaque high density polyethylene bottle
capped with polypropylene child-resistant screw caps with aluminum
induction seal.
74. The pharmaceutical composition of claim 66, further comprising
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in an amount greater than about 0.02% and less than 0.50%,
by weight, relative to the amount of laquinimod, based on a
determination by an HPLC method.
75. The pharmaceutical composition of claim 74, wherein the amount
of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in the composition is greater than about 0.02% and less
than about 0.10% by weight relative to the amount of
laquinimod.
76. The pharmaceutical composition of claim 74, wherein the amount
of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is greater than about 0.05% and less than 0.50% by weight
relative to the amount of laquinimod.
77. The pharmaceutical composition of claim 66, wherein the
pharmaceutically acceptable salt of laquinimod is a sodium salt.
Description
[0001] This application claims benefit of U.S. Provisional
Application No. 61/599,680, filed Feb. 16, 2012, the entire content
of which is hereby incorporated by reference herein.
[0002] Throughout this application various publications, published
patent applications, and patents are referenced. The disclosures of
these documents in their entireties are hereby incorporated by
reference into this application in order to more fully describe the
state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] Laquinimod is a compound which has been shown to be
effective in the acute experimental autoimmune encephalomyelitis
(aEAE) model (U.S. Pat. No. 6,077,851). Its chemical name is
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-
-carboxamide, and its Chemical Registry number is 248281-84-7. The
processes of synthesis of laquinimod and the preparation of its
sodium salt are disclosed in U.S. Pat. No. 6,077,851. An additional
process of synthesis of laquinimod is disclosed in U.S. Pat. No.
6,875,869. Pharmaceutical compositions comprising laquinimod sodium
are disclosed in PCT International Application Publication No. WO
2005/074899.
[0004] Laquinimod sodium has high oral bioavailability and has been
suggested as an oral formulation for the treatment of Multiple
Sclerosis (MS). (Polman, C. et al., (2005) "Treatment with
laquinimod reduces development of active MRI lesions in relapsing
MS", Neurology. 64:987-991; Sandberg-Wollheim M, et al. (2005)
"48-week open safety study with high-dose oral laquinimod in
patients", Mult Scler. 11:S154). Studies have also shown that
laquinimod can reduce development of active MRI lesions in
relapsing MS. (Polman, C. et al., (2005) "Treatment with laquinimod
reduces development of active MRI lesions in relapsing MS",
Neurology. 64:987-991).
SUMMARY OF THE INVENTION
[0005] The subject invention provides an isolated compound having
the structure:
##STR00001## [0006] or a salt thereof.
[0007] The subject invention also provides a composition comprising
a compound having the structure:
##STR00002##
or a salt thereof, wherein the composition is free of laquinimod or
a salt thereof.
[0008] The subject invention further provides a process for
preparing
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide comprising reacting a compound having the structure:
##STR00003## [0009] wherein R.sub.1 is methyl, ethyl, halogen,
MeO--, EtO--, --CF.sub.3, pF-PhO--, MeS--, --NO.sub.2, or
--N(CH.sub.3).sub.2, [0010] with an oxidizing agent when R.sub.1 is
methyl, ethyl or --CF.sub.3; [0011] with a base when R.sub.1 is
halogen; or [0012] with a Lewis acid when R.sub.1 is MeO--, EtO--
or pF-PhO--, MeS--, --NO.sub.2, or --N(CH.sub.3).sub.2.
[0013] The subject invention yet further provides a process for
purifying
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide comprising the steps of: [0014] a) reacting
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide with an anhydride in a first solvent; [0015] b) removing
the first solvent from the reaction mixture of step a) to obtain an
residual oil; [0016] c) dissolving the residual oil in a second
solvent; [0017] d) adding a basic solution to the solution from
step c); [0018] e) obtaining the purified
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide from reaction mixture of step d).
[0019] The subject invention yet further provides a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof, and
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide or a salt thereof, wherein
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is present in the composition in an amount greater than
about 0.02% and less than about 0.50%, by weight, relative to the
amount of laquinimod, based on a determination by an HPLC
method.
[0020] The subject invention yet further provides a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof, at least one pharmaceutically acceptable carrier, and
a light-resistant coating wherein the coating is resistant to light
with wavelength in the range of 310-400 nm.
[0021] The subject invention yet further provides a process for
preparing a pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof, comprising: admixing
laquinimod or a pharmaceutically acceptable salt thereof with at
least one pharmaceutically acceptable carrier in a low-light
environment to form the pharmaceutical composition.
[0022] The subject invention yet further provides a process for
preparing a validated pharmaceutical composition comprising
laquinimod or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically acceptable carrier, comprising: [0023]
a) obtaining a batch of laquinimod or a pharmaceutically acceptable
salt thereof; [0024] b) determining the amount of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in the batch using a suitable apparatus; and [0025] c)
preparing the pharmaceutical composition from the batch only if the
batch is determined to have less than about 0.50%
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide by weight relative to the amount of laquinimod.
[0026] The subject invention yet further provides a process for
preparing a packaged pharmaceutical composition comprising
laquinimod sodium comprising: [0027] a) obtaining a pharmaceutical
composition of laquinimod or a pharmaceutically acceptable salt
thereof; [0028] b) analyzing the pharmaceutical composition for the
presence of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide; and [0029] c) packaging the pharmaceutical composition in
a light-resistant packaging only if the content of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is less than about 0.50% by weight relative to the amount
of laquinimod.
[0030] The subject invention yet further provides a process of
distributing a validated batch of a pharmaceutical composition
comprising laquinimod or a pharmaceutically acceptable salt thereof
and at least one pharmaceutically acceptable carrier, comprising:
[0031] a) obtaining a batch of the pharmaceutical composition;
[0032] b) performing stability testing with a sample of the batch;
[0033] c) determining the total amount of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-qu-
inolinecarboxamide in the sample of the batch by a suitable
apparatus after stability testing; [0034] d) validating the batch
for distribution only if the sample of the batch after stability
testing is determined to have less than about 0.50% by weight of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide relative to the amount of laquinimod; and [0035] e)
distributing the validated batch.
[0036] The subject invention yet further provides
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide or a salt thereof for use, as a reference standard to
detect trace amounts of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in a pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt of laquinimod.
[0037] The subject invention yet further provides a method for
treating Multiple Sclerosis in a patient comprising administering
to the patient an amount of the pharmaceutical composition
described herein effective to treat Multiple Sclerosis in the
patient.
[0038] The subject invention yet further provides a sealed package
containing a pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof and at least one
pharmaceutically acceptable carrier, wherein the sealed package is
light resistant packaging.
DETAILED DESCRIPTION OF THE INVENTION
[0039] Laquinimod is a small molecule having the following chemical
structure:
##STR00004##
[0040] It is an oral immunomodulator which has demonstrated
therapeutic effect in various experimental inflammatory/autoimmune
animal models, such as Experimental Autoimmune Encephalomyelitis
(EAE), an animal model for Multiple Sclerosis (MS), Dextran Sodium
Solphate (DSS) induced colitis for Inflammatory Bowel Disease,
Non-Obese Diabetic (NOD) mice for Type I Diabetes (IDDM),
Experimental Autoimmune Neuritis (EAN) for Guillain-Barre Syndrome,
Systemic Lupus Erythematosus (SLE), lupus nephritis, lupus
arthritis, Crohn's Disease and Rheumatoid arthritis. The
therapeutic activity of laquinimod in these models results from a
variety of mechanistic effects, including reduction of leukocyte
infiltration into target tissues by modulation of
chemokine-mediated T-cell adhesion, modulation of cytokine balance,
down regulation of MHC class II resulting in alteration of antigen
presentation, and effects on dendritic cells subpopulations.
[0041] A pharmaceutically acceptable salt of laquinimod includes
lithium, sodium, potassium, magnesium, calcium, manganese, copper,
zinc, aluminum and iron. Salt formulations of laquinimod and the
process for preparing the same are described, e.g., in U.S. Patent
Application Publication No. 2005/0192315 and PCT International
Application Publication No. WO 2005/074899, which are hereby
incorporated by reference into this application.
[0042] It has been found that when laquinimod or a salt thereof is
exposed to light under certain conditions, an impurity can form.
This impurity was identified to be
N-Ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide ("5-HLAQ"), having the following structure:
##STR00005##
[0043] Not to be bound by a particular theory, this impurity is
suspected to be formed via a substitution reaction in which a
chlorine group is substituted for a hydroxyl group.
[0044] The subject invention provides an isolated compound having
the structure:
##STR00006##
[0045] or a salt thereof.
[0046] The subject invention also provides a composition comprising
a compound having the structure:
##STR00007##
or a salt thereof, wherein the composition is free of laquinimod or
a salt thereof.
[0047] The subject invention further provides a process for
preparing
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide comprising reacting a compound having the structure:
##STR00008## [0048] wherein R.sub.1 is methyl, ethyl, halogen,
MeO--, EtO--, --CF.sub.3, pF-PhO--, MeS--, --NO.sub.2, or
--N(CH.sub.3).sub.2, [0049] with an oxidizing agent when R.sub.1 is
methyl, ethyl or --CF.sub.3; [0050] with a base when R.sub.1 is
halogen; or [0051] with a Lewis acid when R.sub.1 is MeO--, EtO--
or pF-PhO--, MeS--, --NO.sub.2, or --N(CH.sub.3).sub.2.
[0052] In an embodiment of the process, R.sub.1 is MeO--.
[0053] In another embodiment of the process, the Lewis acid is
AlCl.sub.3.
[0054] In yet another embodiment of the process, the solvent is an
anhydrous solvent.
[0055] The subject invention yet further provides a process for
purifying
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide comprising the steps of: [0056] a) reacting
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide with an anhydride in a first solvent; [0057] b) removing
the first solvent from the reaction mixture of step a) to obtain an
residual oil; [0058] c) dissolving the residual oil in a second
solvent; [0059] d) adding a basic solution to the solution from
step c); [0060] e) obtaining the purified
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide from reaction mixture of step d).
[0061] In an embodiment of the process the anhydride is acetic
anhydride.
[0062] In another embodiment of the process, the first solvent is
acetic anhydride.
[0063] In yet another embodiment of the process, the second solvent
is dichloromethane.
[0064] In yet another embodiment of the process, the basic solution
is NaOH solution.
[0065] The subject invention yet further provides a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof, and
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide or a salt thereof, wherein
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is present in the composition in an amount greater than
about 0.02% and less than about 0.50%, by weight, relative to the
amount of laquinimod, based on a determination by an HPLC
method.
[0066] In an embodiment of the pharmaceutical composition, the
amount of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in the composition is less than about 0.10% by weight
relative to the amount of laquinimod.
[0067] In another embodiment of the pharmaceutical composition, the
total amount of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-qu-
inolinecarboxamide is greater than about 0.05% by weight relative
to the amount of laquinimod.
[0068] In yet another embodiment of the pharmaceutical composition,
the pharmaceutical composition comprises the pharmaceutically
acceptable salt of laquinimod which is a sodium salt.
[0069] In yet another embodiment of the pharmaceutical composition,
the pharmaceutical composition comprises at least one
pharmaceutically acceptable carrier.
[0070] In yet another embodiment of the pharmaceutical composition,
the at least one pharmaceutically acceptable carrier is magnesium
stearate.
[0071] In yet another embodiment of the pharmaceutical composition,
the pharmaceutical composition is in the form of a capsule.
[0072] In yet another embodiment of the pharmaceutical composition,
the pharmaceutical composition is in the form of a tablet.
[0073] In yet another embodiment of the pharmaceutical composition,
the tablet is coated with a light-resistant coating.
[0074] In yet another embodiment of the pharmaceutical composition,
the light-resistant coating is a coating comprising titanium
dioxide.
[0075] The subject invention yet further provides a pharmaceutical
composition comprising laquinimod or a pharmaceutically acceptable
salt thereof, at least one pharmaceutically acceptable carrier, and
a light-resistant coating wherein the coating is resistant to light
with wavelength in the range of 310-400 nm.
[0076] In an embodiment of the pharmaceutical composition, the
light-resistant coating is a coating comprising titanium
dioxide.
[0077] In another embodiment of the pharmaceutical composition, the
pharmaceutical composition is in a solid form tablet.
[0078] In another embodiment of the pharmaceutical composition, the
pharmaceutical composition is in the form of a tablet.
[0079] In another embodiment of the pharmaceutical composition, the
pharmaceutical composition is in the form of a capsule.
[0080] In another embodiment, the pharmaceutical composition is in
light-resistant packaging. In another embodiment the
light-resistant packaging is an opaque blister pack or an opaque
high density polyethylene (HPDE) container.
[0081] The subject invention yet further provides a process for
preparing a pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof, comprising: admixing
laquinimod or a pharmaceutically acceptable salt thereof with at
least one pharmaceutically acceptable carrier in a low-light
environment to form the pharmaceutical composition.
[0082] In an embodiment of the process, the pharmaceutical
composition further comprises
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in an amount of less than 0.5% by weight relative to the
amount of laquinimod.
[0083] In an embodiment of the process, the laquinimod or the
pharmaceutically acceptable salt thereof is admixed with a liquid
to form a solution.
[0084] In another embodiment of the process, the liquid is
water.
[0085] In yet another embodiment of the process, the solution is
combined with at least one solid pharmaceutical excipient to form a
wet granulate.
[0086] In yet another embodiment of the process, the process
further comprises drying the wet granulate in a low-light
environment.
[0087] In yet another embodiment of the process, the process
further comprises compressing the dried granulate into tablets in a
low-light environment.
[0088] In yet another embodiment of the process, the process
further comprises filling the dried granulate into capsules in a
low-light environment.
[0089] In yet another embodiment of the process, the low-light
environment is an environment within non-transparent vessels or an
environment in which only yellow fluorescent light present.
[0090] The subject invention yet further provides a process for
preparing a validated pharmaceutical composition comprising
laquinimod or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically acceptable carrier, comprising: [0091]
a) obtaining a batch of laquinimod or a pharmaceutically acceptable
salt thereof; [0092] b) determining the amount of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in the batch using a suitable apparatus; and [0093] c)
preparing the pharmaceutical composition from the batch only if the
batch is determined to have less than about 0.50%
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide by weight relative to the amount of laquinimod.
[0094] In an embodiment of the process, in step c) the
pharmaceutical composition is prepared from the batch only if the
batch is determined to have less than about 0.10%
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide by weight relative to the amount of laquinimod.
[0095] In another embodiment of the process, in step c) the
pharmaceutical composition is prepared from the batch only if the
batch is determined to have less than about 0.05%
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide by weight relative to the amount of laquinimod.
[0096] In yet another embodiment of the process, in step c) the
pharmaceutical composition is prepared from the batch only if the
batch is determined to have less than about 0.02%
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide by weight relative to the amount of laquinimod.
[0097] The subject invention yet further provides a process for
preparing a packaged pharmaceutical composition comprising
laquinimod sodium comprising: [0098] a) obtaining a pharmaceutical
composition of laquinimod or a pharmaceutically acceptable salt
thereof; [0099] b) analyzing the pharmaceutical composition for the
presence of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide; and [0100] c) packaging the pharmaceutical composition in
a light-resistant packaging only if the content of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is less than about 0.50% by weight relative to the amount
of laquinimod.
[0101] In an embodiment of the process, in step c) packaging the
pharmaceutical composition in a light-resistant packaging only if
the content of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is less than about 0.10% by weight relative to the amount
of laquinimod.
[0102] In another embodiment of the process, in step c) packaging
the pharmaceutical composition in a light-resistant packaging only
if the content of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is less than about 0.05% by weight relative to the amount
of laquinimod.
[0103] In yet another embodiment of the process, in step c)
packaging the pharmaceutical composition in a light-resistant
packaging only if the content of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide is less than about 0.02% by weight relative to the amount
of laquinimod.
[0104] In yet another embodiment of the process, the
light-resistant packaging is a blister packaging. In one
embodiment, the blister packaging is opaque.
[0105] In yet another embodiment, the light-resistant packaging is
an opaque high density polyethylene (HPDE) container.
[0106] The subject invention yet further provides a process of
distributing a validated batch of a pharmaceutical composition
comprising laquinimod or a pharmaceutically acceptable salt thereof
and at least one pharmaceutically acceptable carrier, comprising:
[0107] a) obtaining a batch of the pharmaceutical composition;
[0108] b) performing stability testing with a sample of the batch;
[0109] c) determining the total amount of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-qu-
inolinecarboxamide in the sample of the batch by a suitable
apparatus after stability testing; [0110] d) validating the batch
for distribution only if the sample of the batch after stability
testing is determined to have less than about 0.50% by weight of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide relative to the amount of laquinimod; and [0111] e)
distributing the validated batch.
[0112] In an embodiment of the process, in step d) the batch is
validated only if the sample of the batch after stability testing
is determined to have
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinoli-
necarboxamide present in an amount of less than about 0.10% by
weight relative to the amount of laquinimod.
[0113] In another embodiment of the process, in step d) the batch
is validated only if the sample of the batch after stability
testing is determined to have
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide present in an amount of less than about 0.05% by weight
relative to the amount of laquinimod.
[0114] In yet another embodiment of the process, in step d) the
batch is validated only if the sample of the batch after stability
testing is determined to have
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide present in an amount of less than about 0.02% by weight
relative to the amount of laquinimod.
[0115] In yet another embodiment of the process, the pharmaceutical
composition comprises the pharmaceutically acceptable salt of
laquinimod which is a sodium salt.
[0116] The subject invention yet further provides
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide or a salt thereof for use, as a reference standard to
detect trace amounts of
N-ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide in a pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt of laquinimod.
[0117] The subject invention yet further provides a method for
treating Multiple Sclerosis in a patient comprising administering
to the patient an amount of the pharmaceutical composition
described herein effective to treat Multiple Sclerosis in the
patient.
[0118] The subject invention further provides the pharmaceutical
composition described herein for use in treating Multiple Sclerosis
in a patient.
[0119] The subject invention yet further provides a sealed package
containing a pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof and at least one
pharmaceutically acceptable carrier, wherein the sealed package is
light resistant packaging.
[0120] In one embodiment, the light-resistant packaging is an
opaque ampule, an opaque bag, an opaque blister pack, an opaque
bottle, an opaque can, an opaque carton, an opaque drum, an opaque
jar, an opaque pouch or an opaque tube.
[0121] In an embodiment, the light-resistant packaging is an opaque
blister pack. In another embodiment, the opaque blister pack
comprises a blend of aluminum and aluminum-silver. In another
embodiment, the opaque blister pack comprises a blend of aluminum
and poly-chloro-trifluoro-ethylene. In another embodiment, the
opaque blister pack comprises a blend of two or more of polyvinyl
chloride, polyethylene, polycarbonate, polyvinylidene chloride and
ethylene vinyl alcohol.
[0122] In an embodiment, the light-resistant packaging is an opaque
high density polyethylene (HPDE) container. In one embodiment, the
opaque high density polyethylene (HPDE) container is an opaque high
density polyethylene (HPDE) bottle. In another embodiment, the
opaque high density polyethylene (HPDE) bottle is an opaque high
density polyethylene bottle capped with polypropylene
child-resistant screw caps fitted with a silica desiccant insert.
In another embodiment, the opaque high density polyethylene (HPDE)
bottle is an opaque high density polyethylene bottle capped with
polypropylene child-resistant screw caps with aluminum induction
seal.
[0123] Any embodiment disclosed herein can be combined with any
other embodiment of the subject invention.
[0124] By any range disclosed herein, it is meant that all
hundredth, tenth and integer unit amounts within the range are
specifically disclosed as part of the invention. Thus, for example,
0.01 mg to 50 mg means that 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . .
0.9; and 1, 2 . . . 49 mg unit amounts are included as embodiments
of this invention.
[0125] A characteristic of a compound refers to any quality that a
compound exhibits, e.g., peaks or retention times, as determined by
1H nuclear magnetic spectroscopy, mass spectroscopy, infrared,
ultraviolet or fluorescence spectrophotometry, gas chromatography,
thin layer chromatography, high performance liquid chromatography
(HPLC), elemental analysis, Ames test, dissolution, stability and
any other quality that can be determined by an analytical method.
Once the characteristics of a compound are known, the information
can be used to, for example, screen or test for the presence of the
compound in a sample. Quantity or weight percentage of a compound
present in a sample can be determined by a suitable apparatus, for
example, a HPLC.
[0126] A "detection limit" for an analytical method used in
screening or testing for the presence of a compound in a sample is
a threshold under which the compound in a sample cannot be detected
by the analytical method used. For example, the detection limit of
a currently commercial HPLC method for 5-HLAQ in a sample
containing laquinimod is 0.02% by weight relative to the amount of
laquinimod.
[0127] The subject invention is also intended to include all
isotopes of atoms occurring on the compounds disclosed herein.
Isotopes include those atoms having the same atomic number but
different mass numbers. By way of general example and without
limitation, isotopes of hydrogen include tritium and deuterium.
Isotopes of carbon include C-13 and C-14.
[0128] It will be noted that any notation of a carbon in structures
throughout this application, when used without further notation,
are intended to represent all isotopes of carbon, such as .sup.12C,
.sup.13C, or .sup.14C. Furthermore, any compounds containing
.sup.13C or .sup.14C may specifically have the structure of any of
the compounds disclosed herein.
[0129] It will also be noted that any notation of a hydrogen in
structures throughout this application, when used without further
notation, are intended to represent all isotopes of hydrogen, such
as .sup.1H, .sup.2H, or .sup.3H. Furthermore, any compounds
containing .sup.2H or .sup.3H may specifically have the structure
of any of the compounds disclosed herein.
[0130] Isotopically-labeled compounds can generally be prepared by
conventional techniques known to those skilled in the art or by
processes analogous to those described in the Examples disclosed
herein using an appropriate isotopically-labeled reagents in place
of the non-labeled reagents employed.
[0131] As used herein, a "low-light environment" is an environment
substantially devoid of the presence of light having a wavelength
of 310-400 nm. One example of a low-light environment is an
environment enclosed with non-transparent vessels. Another example
of a low-light environment is an environment in which yellow
fluorescent light is used in place of standard fluorescent light.
Yellow fluorescent light bulbs have filters which substantially
limit the amount of light in the 310-400 nm wavelength range.
[0132] As used herein, a "light-resistant" packaging or coating is
packaging or coating which inhibits the penetration of light, in
particular fluorescent light, more particularly light having a
wavelength of 310-400 nm.
[0133] As used herein, a "pharmaceutically acceptable" carrier or
excipient is one that is suitable for use with humans and/or
animals without undue adverse side effects (such as toxicity,
irritation, and allergic response) commensurate with a reasonable
benefit/risk ratio.
[0134] As used herein, "drug substance" refers to the active
ingredient in a drug product, which provides pharmacological
activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease, or to affect the structure or
any function of the body of man or animals.
[0135] As used herein, "drug product" refers to the finished dosage
form containing the drug substance as well as at least one
pharmaceutically acceptable carrier.
[0136] As used herein, an "isolated" compound is a compound
isolated from the crude reaction mixture following an affirmative
act of isolation. The act of isolation necessarily involves
separating the compound from the other known components of the
crude reaction mixture, with some impurities, unknown side products
and residual amounts of the other known components of the crude
reaction mixture permitted to remain. Purification is an example of
an affirmative act of isolation.
[0137] As used herein, a composition that is "free" of a chemical
entity means that the composition contains, if at all, an amount of
the chemical entity which cannot be avoided following an
affirmative act intended to purify the composition by separating
the chemical entity from the composition. A composition which is
"free" of a laquinimod of a salt thereof, if present, as used
herein, means that the laquinimod or a salt thereof is a minority
component relative to the amount of 5-HLAQ, by weight.
[0138] As used herein, "stability testing" refers to tests
conducted at specific time intervals and various environmental
conditions (e.g., temperature and humidity) to see if and to what
extent a drug product degrades over its designated shelf life time.
The specific conditions and time of the tests are such that they
accelerate the conditions the drug product is expected to encounter
over its shelf life. For example, detailed requirements of
stability testing for finished pharmaceuticals are codified in 21
C.F.R .sctn.211.166, the entire content of which is hereby
incorporated by reference.
[0139] As used herein, "about" in the context of a measurable
numerical value means the numerical value within the standard error
of the analytical method used to measure.
[0140] A dosage unit may comprise a single compound or mixtures of
compounds thereof. A dosage unit can be prepared for oral dosage
forms, such as tablets, capsules, pills, powders, and granules.
[0141] Laquinimod and its salts can be administered in admixture
with suitable pharmaceutical diluents, extenders, excipients, or
carriers (collectively referred to herein as a pharmaceutically
acceptable carrier) suitably selected with respect to the intended
form of administration and as consistent with conventional
pharmaceutical practices. The unit is preferably in a form suitable
for oral administration. Laquinimod and its salts can be
administered alone but is generally mixed with a pharmaceutically
acceptable carrier, and co-administered in the form of a tablet or
capsule, liposome, or as an agglomerated powder. Examples of
suitable solid carriers include lactose, sucrose, gelatin and agar.
Capsule or tablets can be easily formulated and can be made easy to
swallow or chew; other solid forms include granules, and bulk
powders. Tablets may contain suitable binders, lubricants,
disintegrating agents, coloring agents, flavoring agents,
flow-inducing agents, and melting agents. For instance, for oral
administration in the dosage unit form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic,
pharmaceutically acceptable, inert carrier such as lactose,
gelatin, agar, starch, sucrose, glucose, methyl cellulose,
dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the
like. Suitable binders include starch, gelatin, natural sugars such
as glucose or beta-lactose, corn starch, natural and synthetic gums
such as acacia, tragacanth, or sodium alginate, povidone,
carboxymethylcellulose, polyethylene glycol, waxes, and the like.
Lubricants used in these dosage forms include sodium oleate, sodium
stearate, sodium benzoate, sodium acetate, sodium chloride, stearic
acid, sodium stearyl fumarate, talc and the like. Disintegrators
include, without limitation, starch, methyl cellulose, agar,
bentonite, xanthan gum, croscarmellose sodium, sodium starch
glycolate and the like.
[0142] Specific examples of the techniques, pharmaceutically
acceptable carriers and excipients that may be used to formulate
oral dosage forms of the present invention are described, e.g., in
U.S. Patent Application Publication No. 2005/0192315, PCT
International Application Publication Nos. WO 2005/074899, WO
2007/047863, and WO 2007/146248, the contents of which are
incorporated herein by reference.
[0143] General techniques and compositions for making dosage forms
useful in the present invention are described in the following
references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker &
Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets
(Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical
Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical
Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985);
Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones,
Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David
Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous
Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the
Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);
Pharmaceutical Particulate Carriers: Therapeutic Applications:
Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,
1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood
Books in the Biological Sciences. Series in Pharmaceutical
Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.);
Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40
(Gilbert S. Banker, Christopher T. Rhodes, Eds.). These references
in their entireties are hereby incorporated by reference into this
application.
[0144] This invention will be better understood by reference to the
Experimental Details which follow, but those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention as described more fully in the
claims which follow thereafter.
EXPERIMENTAL DETAILS
Example 1
Formation of 5-HLAQ in Light Exposure of Laquinimod Solution
[0145] Various forms of laquinimod were exposed to light, as
specified below. Presence of 5-HLAQ was determined using HPLC.
TABLE-US-00001 TABLE 1 Presence of 5- Light Source Laquinimod
medium HLAQ* (wt %) Light chamber 310-400 nm 1 mg/ml in 0.02M NaOH
33 (~8 hrs.) Light chamber 310-400 nm 0.05 mg/ml in 71 (~8 hrs.)
0.02M NaOH Light chamber 310-400 nm 0.05 mg/ml in 0.02M HCl 1.5 (~8
hrs.) Sunlight cabinet 0.09 mg/ml aqueous 11.8 (5 minutes) solution
Sunlight cabinet Wet granulate** 17.2 (5 minutes) 0.2 mg/ml
Sunlight cabinet Milled granulate*** 2.6 (20 minutes) *The wt % of
5-HLAQ is a weight percent relative to laquinimod amount before
applying photodegradation. **Wet granulate was prepared by 1)
mixing 90% of the total desired meglumine and mannitol in a high
shear granulating mixer for 30 seconds, 2) mixing 10% of the total
desired meglumine, a solution of laquinimod sodium, and purified
water in a mixer until dissolved, and 3) adding the solution from
2) to the contents of the high shear granulating mixer and mixed.
***Milled granulate was prepared by drying the wet granulate in a
fluid bed dryer at an inlet temperature of 50.degree. C., then
milling the dried granulate, which comprises of laquinimod sodium,
meglumine and mannitol, using a 0.8 mm screen, and blending with
sodium stearyl fumarate.
Discussion
[0146] The results in Table 1 show that exposure to light sources,
including florescent light or sunlight, can cause the
transformation of laquinimod sodium, whether in solution, in solid
powder form or granulate form, into 5-HLAQ. Solutions, both aqueous
and non-aqueous, of laquinimod sodium are more susceptible to this
transformation than solid forms.
[0147] Therefore, when preparing laquinimod compositions one or
more of the steps listed below are contemplated to avoid formation
of 5-HLAQ: [0148] 1. Combining laquinimod or salts thereof with
water or other solvents in an environment free of light or in a
low-light environment. [0149] 2. Admixing solutions of laquinimod
or salts thereof with a pharmaceutically acceptable excipient in an
environment free of light or in a low-light environment. [0150] 3.
Manufacturing of laquinimod drug product using "yellow light"
instead of standard lighting in an environment free of light or in
a low-light environment. [0151] 4. Limiting exposure of solutions
comprising laquinimod or salts thereof to fluorescent light while
manufacturing laquinimod drug product. [0152] 5. Limiting exposure
to light of laquinimod acid while being converted to a salt of
laquinimod including laquinimod sodium. [0153] 6. Coating
pharmaceutical formulations with a coating which inhibits light
penetration. Colored coatings or coating containing Titanium
Dioxide could be used as well, if they prevent penetration of
light.
Example 2
Synthesis and Purification of
N-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carb-
oxamide
##STR00009##
[0155] 5-MeO-LAQ
(N-ethyl-4-hydroxy-5-methoxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-
-3-carboxamide, Compound 1) was prepared according to Journal of
Medicinal Chemistry (2004), 47(8), 2075-2088.
[0156] Compound 1 (12.0 g, 0.034 mol) was dissolved in
dichloromethane (DCM, 240 ml) and cooled at 0-5.degree. C.
AlCl.sub.3 (12.0 g) was added and the reaction mixture was stirred
for 0.5 hr at 0-5.degree. C. followed by 7 hr at RT. The solution
was evaporated to dryness at 30.degree. C. (water bath) and water
(300 ml) was added. The obtained grey solid was filtered, washed
with 1N HCl (100 ml) and dried at 30.degree. C. in vac oven. Yield:
14.5 g of Compound 2 (crude title compound).
[0157] Compounds, which have the same chemical structures as
Compound 1 except for the substituent at position 5 of the
dihydroquinoline ring, can also be used to prepare 5-HLAQ under
suitable conditions. Such compounds can be prepared according to
Journal of Medicinal Chemistry (2004), 47(8), 2075-2088.
Acetylation of Crude Title Compound:
[0158] Acetic anhydride (40 ml) was added to a solution of the
crude title compound from the previous step (14.5 g) in Pyridine
(100 ml) and the reaction mixture was stirred for 1 hr at room
temperature. Pyridine was evaporated to dryness and the residue oil
was dissolved in DCM (300 ml). The organic solution was washed with
1N HCl (200 ml) followed by water (200 ml.times.2). Crude Compound
3
(3-(ethyl(phenyl)carbamoyl)-1-methyl-2-oxo-1,2-dihydroquinoline-4,5-diyl
diacetate) (15.5 g) was purified by flash chromatography on silica
gel using a mobile phase of 1% MeOH in DCM. Yield: 10.2 g of
Compound 3 (71% yield for two steps).
Hydrolysis of Compound 3 and Purification to Form Purified Title
Compound:
[0159] 1N NaOH solution (190 ml) was added to 5.6 g (0.013 mol) of
Compound 3 suspended in EtOH (130 ml). The reaction mixture was
stirred for 40 min and EtOH was evaporated (.about.150 ml). Residue
was acidified with 5N HCl up to pH=1-2 and the white solid was
filtered, washed with water and dried.
[0160] Yield: 4.3 g of
N-Ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecar-
boxamide, Compound 4 (98% yield, purity by HPLC >99%) as a white
solid.
[0161] Identity and purity were verified by NMR, MS and EA.
Discussion
[0162]
N-Ethyl-N-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinol-
inecarboxamide (5-HLAQ) is not stable in most of the organic
solvents as well as in aqueous acidic conditions. Therefore common
purification methods were extremely difficult. The di-acetate
derivative Compound 3 is an elegant way to purify the material
followed only by basic hydrolysis, acidic precipitation and rapid
filtration.
[0163] The synthesis enables the use of 5-HLAQ as a standard for
the quantification of 5-HLAQ in a sample comprising a 5-HLAQ and
laquinimod.
Example 3
Manufacture of Formulations Comprising Laquinimod Sodium
[0164] Capsules corresponding to 0.3 mg laquinimod acid per capsule
(0.32 mg laquinimod sodium, 151.08 mg mannitol USP, 5.0 mg
meglumine USP, 1.6 mg sodium stearyl fumarate NF) and 0.6 mg of
laquinimod acid per capsule (0.64 mg laquinimod sodium, 302.16 mg
mannitol USP, 10.0 mg meglumine USP, 3.2 mg sodium stearyl fumarate
NF) were manufactured according to procedures described below:
[0165] 1. Mixing 90% of the total desired meglumine and mannitol in
a high shear granulating mixer for 30 seconds in a room in which
the only source of light was yellow fluorescent lamp. [0166] 2. In
a room in which the only source of light was yellow fluorescent
lamp, mix 10% of the total desired meglumine, a solution of
laquinimod sodium, and purified water in a mixer until dissolved.
[0167] 3. In a room in which the only source of light was yellow
fluorescent lamp, add the solution from step 2 to the contents of
the high shear granulating mixer of step 1 to form a suitable
granulate. [0168] 4. In a room in which the only source of light
was yellow fluorescent lamp, dry the granulate in a fluid bed dryer
with the inlet and outlet air temperatures of 50.degree. C. and
40.degree. C., respectively. [0169] 5. In a room in which the only
source of light was yellow fluorescent lamp, mill the dry granulate
using a 0.8 mm screen, and blend it with sodium stearyl fumarate.
[0170] 6. In an enclosed environment with no light, fill the
mixture from step 5 into size 3 hard gelatin capsules (0.3 mL
volume) for the 0.3 mg of laquinimod acid dose and into size 1 hard
gelatin capsules (0.5 mL volume) for the 0.6 mg laquinimod acid
dose.
Discussion
[0171] Example 3 demonstrated that in a commercial-scale production
of laquinimod Drug Substances with non-detectable level of 5-HLAQ
can be prepared in a low-light environment.
Example 4
Manufacture of Laquinimod Sodium Drug Substance
[0172] Four batches of laquinimod sodium drug substance were
manufactured. The specification for impurities content for these
batches was not more than (NMT) 1.0% of total impurities and less
than (LT) 0.05% for any single impurity. During analysis,
insufficient light protection of sample solution was provided. As a
result, 5-HLAQ content of three of the four batches measured
exceeded the specification (the 5-HLAQ contents were 0.04%, 0.11%,
0.06% and 0.05%).
[0173] Twelve additional batches of laquinimod sodium drug
substance were manufactured at various manufacturing facilities.
During analysis, sufficient light protection of sample solution was
provided. The specification for 5-HLAQ content for these batches
was NMT 0.1%. All twelve batches met the specification (one batch
has 5-HLAQ content of less than 0.05, the remaining batch have
5-HLAQ content of less than 0.02, i.e., below detection limit).
Example 5
Manufacture of Laquinimod Sodium Drug Product
[0174] Twenty-six batches of laquinimod sodium drug product of
various strengths were manufactured at various manufacturing
facilities. Table 2 below shows the 5-HLAQ content for each
batch.
TABLE-US-00002 TABLE 2 5-HLAQ Content (%) Batch No. Drug Product
Specification NMT 0.5 1 Laquinimod 0.6 mg capsules <0.02* 2
Laquinimod 0.6 mg capsules <0.02* 3 Laquinimod 0.6 mg capsules
<0.02* 4 Laquinimod 0.6 mg capsules <0.02* 5 Laquinimod 0.6
mg capsules <0.02* 6 Laquinimod 0.6 mg capsules <0.02* 7
Laquinimod 0.6 mg capsules <0.02* 8 Laquinimod 0.6 mg capsules
<0.02* 9 Laquinimod 0.6 mg capsules <0.02* 10 Laquinimod 0.6
mg capsules <0.02* 11 Laquinimod 0.6 mg capsules <0.02* 12
Laquinimod 0.6 mg capsules <0.02* 13 Laquinimod 0.6 mg capsules
<0.02* 14 Laquinimod 0.6 mg capsules <0.02* 15 Laquinimod 0.6
mg capsules <0.02* 16 Laquinimod 0.6 mg capsules <0.02* 16
Laquinimod 0.3 mg capsules <0.02* 17 Laquinimod 0.3 mg capsules
<0.02* 18 Laquinimod 0.3 mg capsules <0.02* 19 Laquinimod 0.3
mg capsules <0.02* 20 Laquinimod 0.3 mg capsules 0.1* 21
Laquinimod 0.05 mg tablets <0.1** 22 Laquinimod 0.25 mg tablets
<0.1** 23 Laquinimod 0.3 mg tablets <0.03** 24 Laquinimod 0.3
mg tablets <0.030** 25 Laquinimod 0.3 mg tablets <0.030** 26
Laquinimod 0.3 mg tablets <0.030** *Specification NMT 0.5
**Specification NMT 0.1
Discussion for Examples 4 and 5
[0175] Examples 4 and 5 demonstrate that batches of laquinimod drug
substance and laquinimod drug product can be consistently produced
meeting the specification for 5-HLAQ content.
Example 6
Laquinimod 0.6 mg White Opaque Capsules, Photo-Degradation
Study
[0176] The goal of this study was to examine the photo-degradation
of laquinimod 0.6 mg white opaque capsules after exposure to
artificial sunlight in a glass plate (Petri dish) as compared to a
glass plate covered by aluminum foil.
Materials and Methods
[0177] White opaque capsule shells were filled with laquinimod
sodium 0.6 mg, and placed into photostability chamber in two Petri
dishes, one plate open and one covered by aluminum foil.
[0178] The capsules were exposed to the following conditions:
[0179] 1. Cool White Fluorescent Lamp, 11 days at 25.degree. C./60%
RH. [0180] 2. Near UV Fluorescent Lamp, 5 days at 25.degree. C./60%
RH.
Results
[0181] Exposure to artificial sunlight did not affect the
appearance of capsules' body and content. Main Degradation products
of laquinimod in the non-polar HPLC system appear at RRT 1.41 in
the open plate only.
[0182] The results of testing in Polar HPLC system is shown in
Table 3 below:
TABLE-US-00003 TABLE 3 Degradation Products detected in Polar
System, by Area % Dissolution % Assay % 5-HLAQ Total Time Zero 99
99.6 <0.03 <0.05 Aluminum Foil 98 101.0 <0.03 <0.05
Covered Plate Open Plate 74 76.0 2.1 16.0
Conclusions & Results
[0183] Based on the results shown in Table 3 it can be concluded
that laquinimod 0.6 mg white opaque capsules exposed to artificial
sunlight are sensitive to light and the protection of the drug
product provided by white opaque gelatin capsules is not
enough.
Example 7
Laquinimod 0.6 mg capsules--Influence of Blister Pack Material on
Photo-Degradation
[0184] The goal of this study is to examine the photo-degradation
of laquinimod sodium capsules, 0.6 mg, packed in blisters of
various materials.
Materials and Methods
[0185] One batch of laquinimod sodium capsules, 0.6 mg/capsule was
packed into four different types of blisters: PVC/AC/PVDC/PVLE/P058
504 142 (transparent), PVC/PE-EVOH/AC (A 300) G03 140 MM
(transparent), A-/PVC/PE-EVOH/AC-PC (opaque), and KPMAX WH
(opaque). Control was the same batch not exposed to sunlight in
HDPE 50 cc DUMA.TM. bottle.
Results
[0186] The results are shown in Table 4.
[0187] Exposure to sunlight affected the appearance of capsules of
laquinimod in clear blister packages, as well as the appearance of
granulate.
[0188] No developing degradation products were detected in the
Non-Polar HPLC system. However, they do appear in the Polar HPLC
system.
TABLE-US-00004 TABLE 4 Packaging Appearance of Appearance of
Material Blister Package Granulate Assay 5-HLAQ PVC/AC/PVDC/
Intensively Yellowish 53.0% 1.8% PVLE/P058 colored in powder 504
142 brownish-gold (transparent) PVC/PE- Colored in Intensive 38.6$
2.5% EVOH/AC (A brownish-gold yellowish 300) G03 140 powder MM
(transparent) A-/PVC/PE- Unchanged White Powder 94.7% 0.28%
EVOH/AC-PC (opaque) KPMAX WH Unchanged White Powder 99.1% 0.07%
(opaque) Control N/A White Powder 98.3%
Conclusions & Results
[0189] Laquinimod is sensitive to light. Opaque blisters, as
compared to transparent, provide better protection of laquinimod
from light against its photodegradation.
Example 8
Photostability of Laquinimod 0.6 mg Capsules in Various
Packaging
Summary
[0190] The studies summarized in this section evaluated the
stability of laquinimod 0.6 mg capsules after exposure to light
outside the immediate pack and when packed in several immediate
packaging configurations. The study results demonstrate that
laquinimod 0.6 mg capsules drug product is unstable when directly
exposed to light outside the immediate pack. By contrast, when the
laquinimod 0.6 mg capsules drug product is packed in the immediate
container closure systems being tested (three types of HDPE bottles
with child resistance caps and aluminum/aluminum blisters) it is
photostable when directly exposed to light. The photostability
study was performed and all analytical parameters for all the
tested packaging configurations were well within the rug product
specification limits. It can be concluded that the three types of
HDPE bottles with child resistance caps, and aluminum/aluminum
blisters can be considered appropriate and suitable container
closure systems for protecting laquinimod 0.6 mg capsules from
light.
Procedure
[0191] In each of the two photostability studies performed, each
tested packaging configuration was either directly exposed to
artificial sunlight or wrapped in aluminum foil as a "dark control"
to eliminate the possible effect of heating action of light. The
tested container closure systems were exposed to cool white
fluorescent light (approximately 5 KLUX) for 11 days (264 hours)
followed by exposure to near ultraviolet (UV) light for additional
5 days (120 hours). Exposure limits are shown in Table 5 below:
TABLE-US-00005 TABLE 5 Light Source Minimal Exposure Limits Time of
Exposure Cool White Fluorescent 1.2 million lux hours 11 days Lamp
New UV Fluorescent Lamp 200 watt hours/square 5 days meter
[0192] The entire photostability study was carried out at
25.degree. C. and at 60% relative humidity (RH) conditions. All
samples described above were exposed to the Cool White Fluorescent
Lamp (light capacity about 5 Klux/h) for 11 days under monitoring
of exposure by using calibrated lux meter. Then all samples
together with the quinine actinometric solution in quartz 1 cm UV
cells (two cells not wrapped with aluminum foil and two cells
wrapped with aluminum foil used as controls) placed on each shelf
of the Climated Stability chamber were exposed to the Near UV
Fluorescent Lamp for 5 days. After that, the absorbance of the
actinometric solution and its wrapped control solution on each
shelf was measured at 400 nm to ensure a change in absorbance of
not less than 0.5 between the non-wrapped actinometric solution and
its wrapped control on each shelf.
[0193] For this purpose the actinometric solutions (wrapped and not
wrapped) were removed from the stability chamber, transferred in
light resistance containers to the analytical laboratory and
submitted for UV testing. Each sample type along with its control
was tested for assay, dissolution, impurities, water content and
appearance.
Study 1
[0194] The first study tested whether the drug product is
photostable when exposed to light outside its immediate pack. The
photostability of capsules packed in transparent and opaque
blisters was also tested as follows: [0195] 1. Unpacked capsules in
a closed transparent Quartz dish. The capsules were inserted into
the Quartz dish to form one layer of capsules in a way that they do
not touch each other. [0196] 2. Transparent Aluminum/Aclar.RTM.
(KPMAX.RTM.) blister packs containing 10 capsules per card. [0197]
3. White opaque Aluminum/Aclar.RTM. (KPMAX.RTM.) blister packs
containing 10 capsules per card.
Study 2
[0198] The second photostability study tested the protection from
light of laquinimod 0.6 mg capsules packed in various immediate
container closure system: [0199] Container system 1: White 50 cc
round opaque high density polyethylene containers (DUMA.sup.T14
system) capped with white round polypropylene child-resistant screw
caps fitted with a silica desiccant insert. The bottle is filled
with 30 capsules and contains cotton wool located between the
capsules and the cap. [0200] Container system 2: White 100 cc round
opaque high density polyethylene containers (DUMA.TM. system)
capped with white round polypropylene child-resistant screw caps
fitted with a silica desiccant insert. The bottle is filled with 90
capsules and contains cotton wool located between the capsules and
the cap. [0201] Container system 3: White 60 cc round opaque high
density polyethylene containers capped with white round
polypropylene child-resistant screw caps with aluminum induction
seal. The bottle is filled with 30 capsules and also contains a
silica desiccant canister and cotton wool located between the
capsules and the cap. [0202] Container system 4:
Aluminum-silver/aluminum-soft blister packs containing 7 capsules
per card.
Conclusions & Results
[0203] The results of studies 1 and 2 are summarized in Table 6
below:
TABLE-US-00006 TABLE 6 5-HLAQ Total polar Assay Content IDD**
Specification: Specification: Specification: Configuration Interval
95.0-105.0% NMT 0.5% NMT 2.0% Unpacked capsules Time zero 96.8
<0.02 <0.05 (Quartz dish) Covered* 99.7 <0.02 0.06 Not
covered* 78.7 1.6 11.8 Transparent KPMA Time zero 99.0 <0.02
<0.05 Covered* 98.8 <0.02 <0.05 Not covered* 76.7 2.3 13.1
Opaque KPMAX Time zero 101.1 <0.02 <0.05 Covered* 98.6
<0.02 <0.05 Not covered* 98.9 <0.02 <0.05 Container
System 1 Time zero 99.0 <0.02 <0.05 Covered* 98.8 <0.02
<0.05 Not covered* 99.8 <0.02 <0.05 Container System 2
Time zero 99.9 <0.02 <0.05 Covered* 100.1 <0.02 <0.05
Not covered* 99.7 <0.02 <0.05 Container System 3 Time zero
100.0 <0.02 <0.05 Covered* 99.9 <0.02 <0.05 Not
covered* 100.2 <0.02 <0.05 Container System 4 Time zero 100.5
<0.02 <0.05 Covered* 99.0 <0.02 <0.05 Not covered*
100.1 <0.02 <0.05 *Covered or not covered with aluminum foil
and exposed to a Cool White Fluorescent Lamp for 11 days followed
by exposure to Near UV Fluorescent Lamp for 5 days.
**Impurities/Degradation Products Determination
[0204] An out of specification (OOS) assay result of 78.1 was
observed for the unpacked capsules when exposed to light. In
addition, the 5-HLAQ polar impurity levels observed were OOS and
the total polar impurities level was 11.8%. The exposure of the
transparent KPMAX blisters to light gave very similar results as
those of the unpacked capsules. By contrast, the results of the
dark control samples (Quartz dish wrapped with aluminum and
transparent KPMAX blisters wrapped with aluminum) that were not
exposed to light were acceptable and well within the speciation
results. In addition, the white opaque KPMAX blisters (both control
and samples directly exposed to light) gave satisfactory results
that are well within the drug product specifications.
[0205] The results of Study 1 demonstrate that the drug product
outside its immediate pack is not phtostable and protection from
light should be considered when choosing an appropriate container
closure system. In study 2 no significant difference in assay
dissolution, water content, appearance, impurities formation and
photostability was observed between the different packaging
configurations when exposed to light. In addition, there is no
difference in photostability results between time zero and end of
photostability intervals, and between the exposed and dark control
results for all immediate configurations tested.
* * * * *