U.S. patent application number 10/571241 was filed with the patent office on 2007-02-01 for use of fumaric acid derivatives for treating cardiac insufficiency, and asthma.
This patent application is currently assigned to FUMAPHAM AG. Invention is credited to Rajendra K. Joshi, Hans-Peter Strebel, Michael Tamm, Christian Zaugg.
Application Number | 20070027076 10/571241 |
Document ID | / |
Family ID | 34276548 |
Filed Date | 2007-02-01 |
United States Patent
Application |
20070027076 |
Kind Code |
A1 |
Joshi; Rajendra K. ; et
al. |
February 1, 2007 |
Use of fumaric acid derivatives for treating cardiac insufficiency,
and asthma
Abstract
According to a first aspect the invention relates to the use of
fumaric acid derivatives selected from the group consisting of
dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid
monoalkyl ester salts, fumaric acid monoamides, monoamido fumaric
acid salts, fumaric acid diamides, monoalkyl monoamido fumarates,
carbocyclic and oxacarbocyclic oligomers of these compounds and
mixtures thereof for preparing a drug for the treatment or
prevention of cardiac insufficiency, in particular left ventricular
insufficiency, myocardial infarction and angina pectoris. According
to a second aspect the invention relates to the use of fumaric acid
derivatives, selected from the group consisting of dialkyl
fumarates, monoalkyl hydrogen fumarates, fumaric acid monoalkyl
ester salts, fumaric acid monoamides, monoamido fumaric acid salts,
fumaric acid diamides, monoalkyl monoamido fumarates, carbocyclic
and oxacarbocyclic oligomers of these compounds and mixtures
thereof for preparing a drug for the treatment of asthma and
chronic obstructive pulmonary diseases, especially asthma caused by
allergies, infections, analgesics, job conditions or physical
effort, mixed forms of asthma, or asthma cardiale.
Inventors: |
Joshi; Rajendra K.; (Zurich,
CH) ; Strebel; Hans-Peter; (Luzera, CH) ;
Zaugg; Christian; (Rheinfelden, CH) ; Tamm;
Michael; (Basel, CH) |
Correspondence
Address: |
Patent & Trademark Coordinator;Legal Department
14 Cambridge Center
Cambridge
MA
02142
US
|
Assignee: |
FUMAPHAM AG
|
Family ID: |
34276548 |
Appl. No.: |
10/571241 |
Filed: |
September 3, 2004 |
PCT Filed: |
September 3, 2004 |
PCT NO: |
PCT/EP04/09835 |
371 Date: |
March 9, 2006 |
Current U.S.
Class: |
514/310 ;
514/1.7; 514/16.4; 514/171; 514/563; 514/574 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 9/00 20180101; A61K 31/197 20130101; A61P 9/10 20180101; A61K
31/231 20130101; A61P 11/06 20180101; A61K 31/231 20130101; A61K
31/573 20130101; A61K 31/573 20130101; A61K 2300/00 20130101; A61K
31/225 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/012 ;
514/013; 514/014; 514/015; 514/016; 514/017; 514/018; 514/019;
514/563; 514/171; 514/574 |
International
Class: |
A61K 38/16 20070101
A61K038/16; A61K 38/10 20070101 A61K038/10; A61K 38/08 20070101
A61K038/08; A61K 38/06 20070101 A61K038/06; A61K 38/04 20070101
A61K038/04; A61K 31/573 20070101 A61K031/573; A61K 31/198 20070101
A61K031/198; A61K 31/19 20070101 A61K031/19 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 9, 2003 |
DE |
103 41 530.0 |
Dec 23, 2003 |
DE |
103 60 869.9 |
Claims
1.-26. (canceled)
27. A method for the treatment or prevention of cardiac
insufficiency, myocardial infarct and/or angina pectoris, which
method comprises administering to a patient at least one fumaric
acid derivative selected from the group consisting of dialkyl
fumarates, monoalkyl hydrogen fumarates, fumaric acid monoalkyl
ester salts, fumaric acid monoamides, monoamido fumaric acid salts,
fumaric acid diamides, monoalkyl monoamido fumarates, carbocyclic
oligomers of these compounds, oxacarbocyclic oligomers of these
compounds, and mixtures of the foregoing.
28. The method according to claim 27 comprising administering said
at least one fumaric acid derivative to treat or prevent left
ventricular insufficiency.
29. A method for the treatment of asthma and chronic obstructive
pulmonary diseases, which method comprises administering to a
patient at least one fumaric acid derivative selected from the
group consisting of dialkyl fumarates, monoalkyl hydrogen
fumarates, fumaric acid monoalkyl ester salts, fumaric acid
monoamides, monoamido fumaric acid salts, fumaric acid diamides,
monoalkyl monoamido fumarates, carbocyclic oligomers of these
compounds, oxacarbocyclic oligomers of these compounds, and
mixtures of the foregoing.
30. The method according to claim 29 comprising administering said
at least one fumaric acid derivative to treat (i) asthma caused by
allergies, infections, analgesics, job conditions or physical
effort, (ii) mixed forms of asthma, (iii) asthma cardiale, or (iv)
chronic obstructive pulmonary disease.
31. The method according to claim 29 comprising also administering
a glucocorticoid to the patient.
32. The method according to claim 31 wherein the glucocorticoid
being administered is selected from the group consisting of
dexamethasone, cortisone, hydrocortisone, prednisolone, prednisone,
methylprednisolone, fluocortolone, triamcinolone, beclomethasone,
budenoside, flunisonide, fluticasone, betamethasone, and
pharmaceutically acceptable salts and derivatives thereof.
33. The method according to any of claims 27, 29 or 31 wherein the
fumaric acid derivative is selected from one or more fumaric acid
dialkyl esters of the formula (I) ##STR6## wherein R.sub.1 and
R.sub.2 which may be the same or different independently represent
a linear, branched or cyclic, saturated or unsaturated C.sub.1-24
alkyl radical or a C.sub.5-20 aryl radical and wherein said
radicals may optionally be substituted with halogen (F, Cl, Br, I),
hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, nitro or cyano.
34. The method according to any of claims 27, 29 or 31 wherein the
fumaric acid derivative is selected from one or more fumaric acid
monoalkyl esters of the formula (II) ##STR7## wherein R.sub.1
represents a linear, branched or cyclic, saturated or unsaturated
C.sub.1-24 alkyl radical or a C.sub.5-20 aryl radical; A represents
hydrogen, an alkaline or alkaline earth metal cation or a
physiologically acceptable transition metal cation, preferably
selected from Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+
Zn.sup.2+, Fe.sup.2+, and Mn.sup.2+ and n equals 1 or 2 and
corresponds to the valence of A.
35. The method according to any of claims 27, 29, or 31 wherein the
fumaric acid derivative is selected from one or more compounds of
the formulae (I) and (II) and mixtures thereof.
36. The method according to claim 35 wherein the fumaric acid
derivative is selected from the group consisting of fumaric acid
dimethyl ester, fumaric acid diethyl ester, fumaric acid methyl
ethyl ester, methyl hydrogen fumarate, ethyl hydrogen fumarate,
calcium methyl fumarate, calcium ethyl fumarate, magnesium methyl
fumarate, magnesium ethyl fumarate, zinc methyl fumarate, zinc
ethyl fumarate, iron methyl fumarate, iron ethyl fumarate and
mixtures thereof.
37. The method according to any of claims 27, 29, or 31 wherein the
fumaric acid derivative is selected from one or more fumaric acid
amides of the general formula III ##STR8## wherein R.sub.a
represents OR.sub.3 or a D- or L-amino acid radical
--NH--CHR.sub.4--COOH bonded via an amide bond, wherein R.sub.3 is
hydrogen, a straight-chain or branched, optionally substituted
C.sub.1-24 alkyl radical, a phenyl radical or a C.sub.6-10 aralkyl
radical and R.sub.4 is a side chain of a natural or synthetic amino
acid; and R.sub.b represents a D- or L-amino acid radical
--NH--CHR.sub.5--COOH bonded via an amide bond, wherein R.sub.5 is
a side chain of a natural or synthetic amino acid which may be the
same as or different from R.sub.4 or a peptide radical with 2 to
100 amino acids bonded via an amide bond, which amino acids may be
the same or different.
38. The method according to claim 37, wherein the side chain of a
natural or synthetic amino acid is selected from the group
consisting of the side chains of Ala, Val, Leu, Ile, Trp, Phe, Met,
Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrulline, Hcy,
Hse, Hyp, Hyl, Orn, Sar, and Me-Gly.
39. The method according to claim 37, wherein the side chain of a
natural or synthetic amino acid is selected from the group
consisting of the side chains of Gly, Ala, Val, Ile, Leu, and Me
Gly.
40. The method according to claim 37 wherein R.sub.a is the radical
--OR.sub.3 and R.sub.b is an L-amino acid radical
--NH--CHR.sub.5--COOH or a peptide radical, R.sub.5 being as
defined in claim 37.
41. The method according to any of claims 27, 29, or 31 wherein the
fumaric acid derivative is a carbocyclic oligomer consisting of 2
to 10 fumaric acid moieties as repetitive moieties, wherein the
fumaric acid moieties are derived from monomers selected from the
group consisting of fumaric acid, dialkyl fumarates, monoalkyl
hydrogen fumarates, fumaric acid monoamides, fumaric acid diamides,
monoalkyl monoamido fumarates and salts and mixtures thereof.
42. The method according to any of claims 27, 28, 29, 30, 31, or 32
wherein the alkyl radicals having 1 to 24 carbon atoms are selected
from the group consisting of methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl,
hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl,
2-hydroxy ethyl, 2 or 3 hydroxy propyl, 2,3-dihydroxypropyl,
2-methoxy ethyl, methoxy methyl, 2-methoxy propyl, 3-methoxy propyl
and 2,3-dimethoxy propyl.
43. The method according to claim 42 wherein said alkyl radicals
are methyl or ethyl.
44. The method according to any of claims 27, 28, 29, 30, 31, or 32
wherein the drug is administered in a form suitable for oral,
rectal, transdermal, dermal, ophthalmological, nasal, pulmonary or
parenteral application.
45. The method according to claim 44 wherein the drug is provided
in the form of tablets, coated tablets, capsules, granulate,
solutions for drinking, liposomes, nano particles, nano-capsules,
micro-capsules, micro-tablets, pellets or powders and in the form
of granules filled in capsules or sachets, micro-tablets filled in
capsules or sachets, pellets filled in capsules or sachets,
nano-particles filled in capsules or sachets or powder filled in
capsules or sachets.
46. The method according to claim 45, wherein the drug is present
in the form of nano particles, pellets or micro-tablets which may
optionally be filled in sachets or capsules.
47. The method according to claim 45 wherein the solid oral dosage
forms are provided with an enteric coating.
48. The method according to claim 46 wherein the solid oral dosage
forms are provided with an enteric coating.
49. The method according to any of claims 27, 28, 29, 30, 31, or 32
wherein the drug contains an amount of fumaric acid derivative(s)
corresponding to 1 to 500 mg of fumaric acid.
50. A method of inhibiting PDGF induced thymidine uptake of
bronchial smooth muscle cells, which method includes the step of
cultivating the cells in the presence of an amount of a fumaric
acid derivative sufficient to inhibit said uptake, which fumaric
acid derivative is selected from the group consisting of dialkyl
fumarates, monoalkyl hydrogen fumarates, fumaric acid monoalkyl
ester salts, fumaric acid monoamides, monoamido fumaric acid salts,
fumaric acid diamides, monoalkyl monoamido fumarates, carbocyclic
oligomers of these compounds, oxacarbocyclic oligomers of these
compounds, and mixtures of the foregoing.
51. A method of inhibiting bronchial smooth muscle cell
proliferation, which method includes the step of bringing bronchial
smooth muscle cells directly or indirectly in contact with a
proliferation inhibiting amount of a fumaric acid derivative
selected from the group consisting of dialkyl fumarates, monoalkyl
hydrogen fumarates, fumaric acid monoalkyl ester salts, fumaric
acid monoamides, monoamido fumaric acid salts, fumaric acid
diamides, monoalkyl monoamido fumarates, carbocyclic oligomers of
these compounds, oxacarbocyclic oligomers of these compounds, and
mixtures of the foregoing.
52. The method of any of claims 50 or 51, wherein the fumaric acid
derivative is selected from one or more fumaric acid dialkyl esters
of the formula I ##STR9## wherein R.sub.1 and R.sub.2 which may be
the same or different independently represent a linear, branched or
cyclic, saturated or unsaturated C.sub.1-24 alkyl radical or a
C.sub.5-20 aryl radical and wherein said radicals may optionally be
substituted with halogen (F, Cl, Br, I), hydroxy, C.sub.1-4 alkoxy,
C.sub.1-4 alkyl, nitro or cyano.
53. The method of any of claims 50 or 51, wherein the fumaric acid
derivative is selected from one or more fumaric acid monoalkyl
esters of the formula II ##STR10## wherein R.sub.1 represents a
linear, branched or cyclic, saturated or unsaturated C.sub.1-24
alkyl radical or a C.sub.5-20 aryl radical; A represents hydrogen,
an alkaline or alkaline earth metal cation or a physiologically
acceptable transition metal cation, preferably selected from
Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+ Zn.sup.2+,
Fe.sup.2+, and Mn.sup.2+ and n equals 1 or 2 and corresponds to the
valence of A.
54. The method of any of claims 50 or 51, wherein the fumaric acid
derivative is a mixture of: I) one or more fumaric acid dialkyl
esters of the formula ##STR11## wherein R.sub.1 and R.sub.2 which
may be the same or different independently represent a linear,
branched or cyclic, saturated or unsaturated C.sub.1-24 alkyl
radical or a C.sub.5-20 aryl radical and wherein said radicals may
optionally be substituted with halogen (F, Cl, Br, I), hydroxy,
C.sub.1-4 alkoxy, C.sub.1-4 alkyl, nitro or cyano; and II) one or
more fumaric acid monoalkyl esters of the formula ##STR12## wherein
R.sub.1 represents a linear, branched or cyclic, saturated or
unsaturated C.sub.1-24 alkyl radical or a C.sub.5-20 aryl radical;
A represents hydrogen, an alkaline or alkaline earth metal cation
or a physiologically acceptable transition metal cation, preferably
selected from Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+
Zn.sup.2+, Fe.sup.2+, and Mn.sup.2+ and n equals 1 or 2 and
corresponds to the valence of A.
55. The method of claim 51, which is carried out in vivo, by
administering the fumaric acid derivative to a subject.
56. The method of claim 55, wherein said administration is an oral
administration.
57. The method of inhibiting bronchial smooth muscle cell
proliferation, which method comprises treating the cells with a
fumaric acid derivative selected from the group consisting of
dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid
monoalkyl ester salts, fumaric acid monoamides, monoamido fumaric
acid salts, fumaric acid diamides, monoalkyl monoamido fumarates,
carbocyclic oligomers of these compounds, oxacarbocyclic oligomers
of these compounds, and mixtures of the foregoing.
58. The method of inhibiting PDGF induced STAT1 activation, which
method comprises treating the cells with a fumaric acid derivative
selected from the group consisting of dialkyl fumarates, monoalkyl
hydrogen fumarates, fumaric acid monoalkyl ester salts, fumaric
acid monoamides, monoamido fumaric acid salts, fumaric acid
diamides, monoalkyl monoamido fumarates, carbocyclic oligomers of
these compounds, oxacarbocyclic oligomers of these compounds, and
mixtures of the foregoing.
59. A method of preparing a drug for treatment or prevention of
cardiac insufficiency, myocardial infarct and/or angina pectoris,
which method comprises formulating at least one fumaric acid
derivative selected from the group consisting of dialkyl fumarates,
monoalkyl hydrogen fumarates, fumaric acid monoalkyl ester salts,
fumaric acid monoamides, monoamido fumaric acid salts, fumaric acid
diamides, monoalkyl monoamido fumarates, carbocyclic oligomers of
these compounds, oxacarbocyclic oligomers of these compounds, and
mixtures of the foregoing into a form suitable for administration
as a drug for treating or preventing cardiac insufficiency,
myocardial infarct and/or angina pectoris.
60. The method according to claim 59 comprising formulating said at
least one fumaric acid derivative into a form for treating or
preventing left ventricular insufficiency.
61. A method of preparing a drug for treatment of asthma and
chronic obstructive pulmonary diseases, which method comprises
formulating at least one fumaric acid derivative selected from the
group consisting of dialkyl fumarates, monoalkyl hydrogen
fumarates, fumaric acid monoalkyl ester salts, fumaric acid
monoamides, monoamido fumaric acid salts, fumaric acid diamides,
monoalkyl monoamido fumarates, carbocyclic oligomers of these
compounds, oxacarbocyclic oligomers of these compounds, and
mixtures of the foregoing into a form suitable for treating asthma
and chronic obstructive pulmonary diseases.
62. The method according to claim 61 comprising formulating said at
least one fumaric acid derivative into a form for treating (i)
asthma caused by allergies, infections, analgesics, job conditions
or physical effort, (ii) mixed forms of asthma, (iii) asthma
cardiale, or (iv) chronic obstructive pulmonary disease.
63. The method according to claim 61 comprising formulating a
combination of said at least one fumaric acid derivative and a
glucocorticoid into said form.
64. The method according to claim 63 comprising formulating a
combination of said at least one fumaric acid derivative and a
glucocorticoid selected from the group consisting of dexamethasone,
cortisone, hydrocortisone, prednisolone, prednisone,
methylprednisolone, fluocortolone, triamcinolone, beclomethasone,
budenoside, flunisonide, fluticasone, betamethasone, and
pharmaceutically acceptable salts and derivatives thereof into said
form.
Description
[0001] The present invention relates to the use of fumaric acid
derivatives for preparing a drug for treating cardiac
insufficiency, and asthma.
PRIOR ART
[0002] Fumaric acid dialkyl esters and fumaric acid monoalkyl
esters and salts thereof have been successfully used for treating
psoriasis for a long time. The use has been described in a number
of patents, cf. e.g. DE 25 30 372, DE 26 21 214 or EP-B-0 312
697.
[0003] Also, the use of fumaric acid mono- and diesters for
treating autoimmune diseases such as e.g. polyarthritis or multiple
sclerosis (cf. DE 197 21 099.6 and DE 198 53 487.6), but also for
use in transplantation medicine (cf. DE 198 53 487.6 and DE 198 39
566.3) has been described. Moreover, the use of fumaric acid mono-
and diesters for treating NFkappaB-mediated diseases as well as the
treatment of mitochondrial diseases and/or as NFkappaB inhibitor is
known from DE 101 01 307.8 and DE 100 00 577.2. All mentioned
publications describe fumaric acid mono- and diesters, optionally
in the form of certain salts.
[0004] Also, the use of fumaric acid mono- and diamides for
treating said indications is known from DE 101 33 004.9. These
amides are formed with amino acids and preferably with specific
peptides. Finally, fumaric acid oligomers and their use for
treating said diseases are known from DE 102 17 314.1.
[0005] A paroxysmal, marked respiratory distress is understood by
asthma (bronchial asthma) from which approx. 4 to 5% of the
population of the industrial nations are suffering, there being an
upward tendency. This respiratory distress is based on a variable
and reversible obstruction of the respiratory tract due to a
hyperreactive bronchial system, which is triggered by exogenic
and/endogenic stimuli. These include chemical or physical
provocative factors, infections, physical effort and/or emotional
factors. After a longer duration of the disease, secondary diseases
such as a chronic bronchitis, a pulmonary emphysema,
bronchiectases, atelectases or a pulmonary heart disease or a
respiratory cardiac insufficiency usually occur.
[0006] Depending upon the cause, differentiation is made between
the following variants of asthma, namely asthma caused by
allergies, infections, analgesics, job conditions or physical
effort, mixed forms of asthma or asthma cardiale (cardiac asthma),
nasal asthma and asthma uremicum. In particular, asthma cardiale
may result in respiratory distress due to increased congestion in
the lesser circulation in the case of a left ventricular
insufficiency.
[0007] Nowadays, beta-2 sympathomimetics, corticosteroids,
parasympatholytics, theophylline, anti-inflammatory agents and
anti-allergic agents are, for instance, administered in the drug
treatment of and/or for alleviating asthma, in addition to the
still proven means of just avoiding the triggering stimulus.
[0008] On a molecular level, asthma seems to be characterized by an
increased activity of Th2 lymphocytes in the lung, which, in turn,
results in an increased release of some Th2 cytokines which,
ultimately, gives rise to the known features of asthma such as IgE
isotype switching, mucus production and recruitment and activation
of eosinophils. Moreover, Th2 cytokines seem to result in the
differentiation of further Th2 cells through the signal
transduction pathway known as JAK-STAT, from which a self-enhancing
circle results. An increased proliferation of mesenchymal cells, in
particular bronchial smooth muscle cells, was also observed.
[0009] The so-called JAK-STAT signal transduction pathway (JAnus
Kinase Signal Transducer and Activator of Transcription pathway) is
a pathway for transmitting information to be transmitted by signal
peptides such as e.g. cytokines to the interior of the cell and/or
the nucleus. Signal transduction takes place through STAT proteins
that are present in the cytoplasm and are at first inactive; 7
different STAT proteins are know in man. As a result of a receptor
ligand bonding on the cell surface, these STAT proteins are quickly
activated by means of phosphorylation, e.g. by means of the Janus
kinase. Phosphorylation results in the homo- or heterodimerization
of the STAT proteins, the dimers being rapidly transported into the
nucleus, where they bond to a target promoter and drastically
enhance the transcription rate of this promoter.
[0010] An acute or chronic inability of the heart to deliver the
output of blood required for metabolism and/or receive the venous
return under stress (stress insufficiency) or already at rest
(=rest insufficiency) are understood by cardiac insufficiency. The
insufficiency may occur as a pure left ventricular or right
ventricular insufficiency, but may as well affect both
ventricles.
[0011] The clinical picture of cardiac insufficiency can be
attributed to various causes in terms of etiology, above all to
inflammatory and degenerative changes of the myocardium and
endocardium, coronary circulatory disorders, myocardial infarction
and injuries. Subsequently, cardiac insufficiency results in
changes in the peripheral circulation, breathing disorders, in
particular cardiac asthma, renal insufficiency and disorders of the
electrolyte metabolism and edemas and a reduced functional capacity
of the skeletal muscles.
[0012] As regards to the indication, differentiation is made
between acute cardiac insufficiency, energetic cardiac
insufficiency, energetic-dynamic cardiac insufficiency and
hypodynamic cardiac insufficiency, also called HEGGLIN syndrome II,
excitomotoric cardiac insufficiency, cardiac insufficiency as a
result of cardiac arrythmics, hypoxemic, latent, primary,
compensated, relative or stress insufficiency and/or left
ventricular insufficiency.
[0013] At present, contraction-promoting substances are used for
the drug treatment of cardiac insufficiency, glycosides (above all
digoxin and digitoxin) being still used today for treating the
chronic forms. However, during the last few years, vasodilators
(nitro-compounds and dihydralazine, alpha blockers, calcium
antagonists and above all ACE inhibitors) have gained in
importance. ACE inhibitors are most important for long-term
treatment. Moreover, diuretics are used. Acute forms are treated
with catecholamines, possibly also with amrinone.
[0014] It is an object of the invention to provide a further agent
for the treatment of cardiac insufficiency and asthma. In
particular, it is an object of the invention to provide a
therapeutic agent for both cardiac asthma and left ventricular
insufficiency in the area in which they overlap with each other. It
is another object of the invention to provide a therapeutic agent
for both indications individually or in the area in which they
overlap with each other, which, due to its good tolerance, is
suited for long-term therapy.
[0015] The present object is attained by the use of fumaric acid
derivatives for preparing pharmaceuticals or pharmaceutical
preparations for treating asthma and/or cardiac insufficiency, in
particular in man.
SUMMARY OF THE INVENTION
[0016] According to a first aspect the invention relates to the use
of fumaric acid derivatives selected from the group consisting of
dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid
monoalkyl ester salts, fumaric acid monoamides, monoamido fumaric
acid salts, fumaric acid diamides, monoalkyl monoamido fumarates,
carbocyclic and oxacarbocyclic oligomers of these compounds and
mixtures thereof for preparing a pharmaceutical preparation for the
treatment or prevention of cardiac insufficiency, in particular
left ventricular insufficiency, myocardial infarction and angina
pectoris.
[0017] According to a second aspect the invention relates to the
use of fumaric acid derivatives, selected from the group consisting
of dialkyl fumarates, monoalkyl hydrogen fumarates, fumaric acid
monoalkyl ester salts, fumaric acid monoamides, monoamido fumaric
acid salts, fumaric acid diamides, monoalkyl monoamido fumarates,
carbocyclic and oxacarbocyclic oligomers of these compounds and
mixtures thereof for preparing a pharmaceutical prepration for the
treatment of asthma and chronic obstructive pulmonary diseases,
especially asthma caused by allergies, infections, analgesics, job
conditions or physical effort, mixed forms of asthma, or asthma
cardiale.
[0018] The present invention likewise concerns a method for
inhibiting .sup.3H-thymidine uptake by bronchial smooth muscle
cells, and a method of inhibiting proliferation of these cells as
described below and in the appending claims.
[0019] The present invention finally concerns the use of the above
fumaric acid derivatives for inhibiting the PDGF induced STAT1
activation;
DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a bar chart which shows the extent of infarctions
after administration of DMF, ischemia and for controls.
[0021] FIG. 2 shows the percentage inhibition of PDGF-induced
.sup.3H-thymidine incorporation in bronchial smooth muscle cells,
when DMF is added.
[0022] FIG. 3 is a bar chart showing percentage of cell
proliferation of bronchial smooth muscle cells upon PDGF
stimulation in the absence or presence of DMF and/or
dexamethasone.
[0023] FIG. 4 is a bar chart showing left ventricular enddiastolic
diameters on Dahl rats before and after 8 weeks of high salt diet
in the absence and presence of DMF.
DETAILED DESCRIPTION OF THE INVENTION
[0024] According to one aspect thereof the present invention
relates to the use of fumaric acid derivatives for preparing a
pharmaceutical preparation for treating asthma and chronic
obstructive pulmonary diseases in general. Preferably, this asthma
is caused by allergies, infections, analgesics, job conditions or
physical effort, particularly preferred asthma cardiale.
[0025] According to a second aspect thereof the invention also
relates to the use of fumaric acid derivatives for preparing a
pharmaceutical preparation for treating or preventing cardiac
insufficiency, myocardial infarction and angina pectoris. The
cardiac insufficiency concerned may be any type of cardiac
insufficiency regardless of its form and/or etiology. Examples of
cardiac insufficiency to be treated according to the invention are
acute cardiac insufficiency, energetic cardiac insufficiency,
energetic-dynamic cardiac insufficiency and hypodynamic cardiac
insufficiency, also called HEGGLIN syndrome II, excitomotor cardiac
insufficiency, cardiac insufficiency as a result of cardiac
irregularities, hypoxemic, latent, primary, compensated,
decompensated, relative or stress insufficiency and/or left
ventricular insufficiency most preferably, left ventricular
insufficiency. The compositions are also effective in preventing
these illnesses and/or myocordial infarctions, including first,
second or further infarctions.
[0026] These uses are based on the finding that fumaric acid
derivatives inhibit PDGF--(platelet derived growth factor) induced
STAT1 activation. As described above, it was assumed that, in
asthma, STAT activation results in a shifting of the cytokine
pattern and, ultimately, in a vicious circle with increased Th2
cell activity and the consequences of mucous secretion, IgE
production and recruiting of eosinophils (A. B. Pernis, P. B.
Rothman, "JAK-STAT signalling in asthma" in: The J. of Clin.
Investigation, vol. 10, No. 1, May 2002).
[0027] The shifting of the cytokine pattern from Th1 to Th2 that is
described in the literature for the substance class of fumaric acid
derivatives (cf. the aforementioned patent specifications) would
rather give rise to expecting an intensification of this vicious
circle. Accordingly, they would not be suited for treating asthma.
Surprisingly, it turned out that fumaric acid derivatives can
inhibit the proliferation of smooth muscle cells of the respiratory
tract. This seems to take place through the inhibition of the
PDGF-inducible transcription factor STAT1. It was possible to
specifically show that fumaric acid derivatives can inhibit the
PDGF-induced STAT1 activation and the PDGF-stimulated thymidine
incorporation in BSM (bronchial smooth muscle) cells. Without
wanting to be bound thereby, this proliferation-inhibiting effect
could be causal for both the effectiveness of fumaric acid
derivatives in the therapy of asthma.
[0028] The fumaric acid derivatives to be used according to the
invention may be one or several selected from the group consisting
of dialkyl fumarates (fumaric acid dialkyl esters, respectively),
monoalkyl hydrogen fumarates (fumaric acid monoalkyl esters,
respectively), monoalkyl ester fumaric acid salts (fumaric acid
monoalkyl ester salts, respectively) of physiologically acceptable
cations, in particular alkaline or alkaline earth metal cations or
transition metal cations such as Li.sup.+, Na.sup.+, K.sup.+,
NH.sub.4.sup.+, Mg.sup.2+, Ca.sup.2+, Fe.sup.2+, Mn.sup.2+, and
Zn.sup.2+, fumaric acid monoamides and fumaric acid diamides and
their salts, carbocyclic and oxacarbocyclic oligomers of these
compounds and mixtures thereof.
[0029] In a preferred embodiment the fumaric acid derivative is
selected from the group consisting of optionally substituted
fumaric acid dialkyl esters and fumaric acid monoalkyl esters in
the form of the free acid or its salts and mixtures thereof.
[0030] Particularly prefered in this case is the use of fumaric
acid dialkyl esters of the formula (I) ##STR1## as they are
described in DE 198 53 487.6, wherein R.sub.1 and R.sub.2 which may
be the same or different independently represent a C.sub.1-24 alkyl
radical or a C.sub.5-20 aryl radical and these radicals are
optionally substituted with halogen (F, Cl, Br, I), hydroxy,
C.sub.1-4 alkoxy, nitro or cyano. With special preference, the
dialkyl fumarate is dimethyl fumarate, diethyl fumarate and/or
methyl ethyl fumarate.
[0031] In general, an alkyl group is to be understood as a
saturated or unsaturated, straight-chain, branched or cyclic
hydrocarbon group having 1 to 24 carbon atoms according to the
invention, which may be optionally substituted with one or more
substituents. Preferably, the alkyl group is methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl,
cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl,
octyl, vinyl, allyl, 2-hydroxy ethyl, 2-hydroxy propyl, 3-hydroxy
propyl, 2,3-dihydroxypropyl, 2-methoxy ethyl, methoxy methyl,
2-methoxy propyl, 3-methoxy propyl or 2,3-dimethoxy propyl. Methyl
or ethyl are most preferred.
[0032] According to the invention an aryl group is to be understood
as an optionally substituted aryl, alkyl substituted aryl or
aralkyl group having 5 to 20 carbon atoms, preferably an aryl,
alkyl substituted aryl or aralkyl group having 6 to 10 carbon
atoms. Exemplary groups are phenyl, benzyl, phenethyl, methyl
phenyl, ethyl phenyl, propyl phenyl and butyl phenyl, t-butyl
phenyl, phenyl and benzyl being especially preferred.
[0033] The substituents of said groups are preferably selected from
the group consisting of halogen (F, Cl, Br, I), hydroxy, C.sub.1-4
alkoxy, C.sub.1-4 alkyl, nitro and cyano.
[0034] Fumaric acid monoalkyl esters of the formula (II) ##STR2##
as they are described in DE 197 21 099.6 can also be advantageously
used, wherein R.sub.1 is as defined above, A is hydrogen, an
alkaline or alkaline earth metal cation or a physiologically
acceptable transition metal cation, preferably selected from
Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+, Zn.sup.2+,
Fe.sup.2+, and Mn.sup.2+, and n equals 1 or 2 and corresponds to
the valence of A.
[0035] Exemplary compounds of the formulae (I) and (II) are fumaric
acid dimethyl ester, fumaric acid diethyl ester, fumaric acid
methyl ethyl ester, methyl hydrogen fumarate, ethyl hydrogen
fumarate, calcium methyl fumarate, calcium ethyl fumarate,
magnesium methyl fumarate, magnesium ethyl fumarate, zinc methyl
fumarate, zinc ethyl fumarate, iron methyl fumarate and iron ethyl
fumarate. They can be used individually or as mixtures.
[0036] Preferably, the fumaric acid amides to be used according to
the invention are those described in DE 101 33 004.9. They
correspond to the general formula (III) ##STR3##
[0037] wherein [0038] R.sub.a represents OR.sub.3 or a D- or
L-amino acid radical --NH--CHR.sub.4--COOH bonded via an amide
bond, wherein R.sub.3 is hydrogen, a straight-chain or branched,
optionally substituted C.sub.1-24 alkyl radical, a phenyl radical
or a C.sub.6-10 aryl or aralkyl radical and R.sub.4 is a side chain
of a natural or synthetic amino acid; and [0039] R.sub.b represents
a D- or L-amino acid radical --NH--CHR.sub.5--COOH bonded via an
amide bond, wherein R.sub.5 is a side chain of a natural or
synthetic amino acid, or a peptide radical with 2 to 100 amino
acids bonded via an amide bond, wherein each amino acid may be the
same or different.
[0040] The side chain of a natural or synthetic amino acid is
typically a side chain selected from the group consisting of the
side chains of Ala, Val, Leu, Ile, Trp, Phe, Met, Tyr, Thr, Cys,
Asn, Gln, Asp, Glu, Lys, Arg, His, Citrulline, Hcy, Hse, Hyp, Hyl,
Orn, Sar, and Me-Gly. The side chains of Gly, Ala, Val, Ile, Leu,
and Me-Gly are preferred. If R.sub.a is an L amino acid radical
--NH--CHR.sub.4--COOH and R.sub.b is an L-amino acid radical
--NH--CHR.sub.5--COOH, R.sub.4 and R.sub.5 may be the same or
different. More preferably, R.sub.4 and R.sub.5 are the same. Most
preferably R.sub.a and R.sub.b each are glycine.
[0041] Alternatively, R.sub.a may be the radical --OR.sub.3, and
R.sub.b may be an L-amino acid radical --NH--CHR.sub.5--COOH or a
peptide radical, R.sub.5 having the meaning indicated above. In
this case, the fumaric acid derivative is a monoalkyl monoamido
fumarate.
[0042] The peptide radical is bonded via an amide bond and has 2 to
100, preferably 2 to 30, most preferably 2 to 15 amino acids, which
may be the same or different. The peptide radical R.sub.b is most
preferably selected from the group consisting of peptide hormones,
growth factors, cytokines, neurotransmitters, neuropeptides,
antibody fragments, coagulation factors and cyclosporines and
derivatives and fragments thereof. Preferably, R.sub.a is methoxy
or ethoxy and R.sub.b is Gly, Ala, Val, He, Leu and Me-Gly.
[0043] The fumaric acid amides as defined above can be used
individually or in admixture or also in mixture with the fumaric
acid monoalkyl or dialkyl esters defined above.
[0044] Finally, carbocyclic or oxacarbocyclic fumaric acid
oligomers can also be used as they are described in DE 102 17
314.1. They contain 2 to 10, preferably 2 to 6 and most preferably
2 to 3 units derived from fumaric acid and/or its esters and/or
amides as defined above as repetitive units.
[0045] These fumaric acid oligomers are preferably obtained by
means of the (olefinic) polymerization of the C--C double bonds
(for the carbocyclic oligomers) and/or the C--C double bonds and
the carbonyl oxygens of the units (for the oxacarbocyclic
oligomers). Preferably, the units derived from the fumaric acid are
derived from monomers selected from the group consisting of fumaric
acid and the dialkyl fumarates, monoalkyl hydrogen fumarates,
fumaric acid monoamides, fumaric acid diamides, monoalkyl monoamido
fumarates and their salts and mixtures thereof, which are defined
above. More preferably, the oligomer only contains units derived
from one or two monomers. Most preferably, the oligomer exclusively
contains identical monomer units.
[0046] The carbocyclic oligomers are composed of the units derived
from the fumaric acid in such a way that the units are bonded to
the carbon atoms 2 and 3 of the fumaric acid backbone by means of
covalent C--C bonds in such a way that a carbocyclic oligomer is
formed. The oligomer backbone comprises an even number of carbon
atoms and does not contain any other monomers and/or heteroatoms.
This backbone is substituted at each carbon atom with one of the
carboxylic acid and/or carboxylic acid amide groups of the fumaric
acid monomer unit(s), from which it is built up.
[0047] The oxacarboxylic oligomers are composed of the fumaric acid
monomers in such a way that the units are bonded to each other at
the carbon atoms 1 and 3 via ether bridges. At the same time, the
ethylenic unsaturation of the atoms C.sub.2 and C.sub.3 is shifted
to C.sub.1 and C.sub.2. Thus, the ring contains polyoxypropene
units in the case of the oxacarboxyclic oligomers according to the
invention.
[0048] The term "oligomer" used herein relates to a number of at
least two fumaric acid monomer units. Customarily, the carboxyclic
fumaric acid oligomer contains 2 to 10, preferably 2 to 6 and most
preferably 2 to 3 units derived from fumaric acid. Preferably, the
carboxylic acid and/or carboxylic acid amide groups as substituents
of the cycle are all in a transposition to each other.
[0049] In a preferred embodiment, a carbocyclic fumaric acid
oligomer corresponding to the following formula (IVa) ##STR4## is
used, wherein the radicals R.sub.c and R.sub.d are the same or
different and are selected among amine radicals
(--NR.sub.1R.sub.2), amino acid radicals --NH--C(COOH)--R.sub.5,
peptide radicals having 2 to 100 amino acids, alkoxy radicals
(--OR.sub.1) and a hydroxyl radical, R.sub.1, R.sub.2 and R.sub.5
being as defined above and n being an integer from 2 to 10
inclusive, preferably 2 to 6 inclusive.
[0050] Preferably, the radicals R.sub.c and R.sub.d each are
independently an alkoxyl or hydroxyl radical, R.sub.c and R.sub.d
not meaning hydroxyl at the same time with the greatest preference.
Thus, the monomer(s) is (are) preferably one or several monoalkyl
hydrogen fumarate(s). In another embodiment both radicals R.sub.c
and R.sub.d may represent an alkoxy radical --OR.sub.1 which, still
more preferred, is identical. In this case, the monomer(s) is (are)
dialkyl fumarates.
[0051] Very preferably, the r-1,t-2,c-3,t-4-tetrakis(methoxy
carbonyl) cyclobutane or the r-1,t-2,c-3,t-4,c-5,t-6-hexa(alkoxy
carbonyl)cyclohexane, preferably the
r-1,t-2,c-3,t-4-tetrakis(methoxy carbonyl)cyclobutane and/or the
r-1,t-2,c-3,t-4c-5,t-6-hexa(methoxy carbonyl)cyclohexane is used
according to this embodiment.
[0052] Alternatively, the oxacarbocylic oligomer of the formula
(IVb): ##STR5## is used, wherein R.sub.1 and R.sub.2 are as defined
above and n is an integer from 2 to 10 inclusive, more preferably 2
to 6 inclusive.
[0053] The fumaric acid derivatives to be used according to the
invention can be prepared according to known processes as they are
e.g. described in DE 197 21 099.6, DE 101 33 004.9 or DE 102 17
314.1. The content of these publications is incorporated herein by
reference.
[0054] The pharmaceutical preparation may be present in a form
suitable for oral, rectal, transdermal, dermal, ophthalmological,
nasal, pulmonary or parenteral application. Preferably, the
pharmaceutical preparation is suited for oral administration. It
may then be present in the form of tablets, coated tablets,
capsules, granulate, solutions for drinking, liposomes,
nano-particles, nano-capsules, micro-capsules, micro-tablets,
pellets or powders and in the form of granulate filled in capsules
or sachets, micro-tablets filled in capsules or sachets, pellets
filled in capsules or sachets, nano-particles filled in capsules or
sachets or powder filled in capsules or sachets. Preferably, the
drug is present in the form of nano-particles, pellets or
micro-tablets, which may optionally be filled in sachets or
capsules.
[0055] Preferably, all solid oral dosage forms may be provided with
an enteric coating. It may e.g. be applied onto the tablets,
micro-tablets, pellets, etc., but may also be applied onto the
capsules that contain them.
[0056] The oral pharmaceutical forms according to the invention may
basically be prepared according to the classic compaction method
and also by direct compaction and as solid dispersions according to
the melting method or by means of the spray drying method. If
desired, an enteric coating can be poured or sprayed in portions
onto the tablet cores in a classic coating pan or applied by means
of a fluidized-bed apparatus according to known processes.
Subsequently, after drying has been completed, a film coat can be
applied in the same apparatus.
[0057] Preferably, the fumaric acid derivatives for preparing the
pharmaceutical preparations according to the invention are used in
such an amount that this pharmaceutical preparation contains an
amount of one or more fumaric acid derivative(s) per dosage unit
which corresponds and/or is equivalent to an amount of 1 to 500 mg;
preferably 10 to 300 mg, and mostly preferred 10 to 200 mg fumaric
acid.
[0058] In the case of an parenteral administration via an injection
(iv, im, sc, ip) the preparation is present in a form suitable for
this. All customary liquid carriers suitable for the injection can
be used.
[0059] According to a preferred embodiment the drug to be produced
according to the invention can contain the following individually
or in admixture: 10 to 500 mg dialkyl fumarate, in particular
dimethyl fumarate and/or diethyl fumarate, 10 to 500 mg calcium
alkyl fumarate, in particular calcium methyl fumarate and/or
calcium ethyl fumarate, 0 to 250 mg zinc alkyl fumarate, in
particular zinc methyl fumarate and/or zinc ethyl fumarate, 0 to
250 mg alkyl hydrogen fumarate, in particular methyl hydrogen
fumarate and/or ethyl hydrogen fumarate and 0 to 250 mg magnesium
alkyl fumarate, in particular magnesium methyl fumarate and/or
magnesium ethyl fumarate, the sum of said amounts corresponding to
an equivalent of 1 to 500 mg, preferably 10 to 300 mg and most
preferred 10 to 200 mg fumaric acid.
[0060] Preparations according to the invention that are used with
special preference contain exclusively dimethyl fumarate in an
amount of 10 to 300 mg.
[0061] According to an especially preferred embodiment the
pharmaceutical preparation is present in the form of micro-tablets
or pellets. They have preferably a size and/or a mean diameter of
.ltoreq.5000 micrometers, preferably 300 to 2500 micrometers, in
particular 300 to 1000 micrometers for pellets and 1000 to 2500
micrometers for micro-tablets. Due to the administration of the
fumaric acid derivatives in the form of micro-tablets, which is
preferred according to the invention, gastrointestinal irritations
and/or side effects which cannot be excluded in the administration
of conventional single unit dose tablets can be further reduced.
Presumably, this is based on the fact that the micro-tablets,
preferably enteric coated micro-tablets, already are already
distributed in the stomach and thus get into the intestine
boluswise, where the active substances are released in locally
smaller doses with the entire dosage being the same. Due to this,
the local irritation of the epithelial cells of the intestine can
be avoided, the better gastrointestinal tolerance of the
micro-tablets as compared with conventional tablets resulting from
this.
EXAMPLES OF PREPARATION
[0062] To explain the use according to the invention, various
examples for the preparation of preferred pharmaceutical
preparations are given below. The examples are for illustrations
purposes only, but not to restrict the invention.
Example 1
Preparation of Film Tablets with an Enteric Coating Containing
100.0 mg of Monomethyl Fumarate-Ca Salt, which Corresponds to 78 mg
of Fumaric Acid
[0063] Taking the necessary precautions (breathing mask, gloves,
protective clothing, etc.), 10 kg of monomethyl fumarate-Ca salt
are crushed, mixed intensely and homogenized by means of a sieve
800. Then an excipient mixture of the following composition is
prepared: 21 kg of starch derivative (STA-RX 1500.RTM.), 2 kg of
micro-crystalline cellulose (Avicel PH 101.RTM.), 0.6 kg of
polyvinyl pyrrolidone (PVP, Kollidon.RTM. 25), 4 kg of
Primogel.RTM., 0.3 kg of colloidal silicic acid (Aerosil.RTM.).
[0064] The active ingredient is added to the entire powder mixture,
mixed, homogenized by means of a sieve 200 and processed with a 2%
aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon.RTM. 25)
in the usual manner into binder granules, and then mixed with the
outer phase in a dry state. The latter consists of 2 kg of a
so-called FST complex containing 80% of talcum, 10% of silicic acid
and 10% of magnesium stearate.
[0065] Thereafter, the mixture is pressed into convex tablets with
a weight of 400 mg and a diameter of 10.0 mm by the usual method.
Instead of these classic compaction methods, other methods such as
direct compaction or solid dispersions according to the melting
method and the spray drying method may also be used for preparing
tablets.
Enteric Coating:
[0066] A solution of 2.250 kg of hydroxy propyl methyl cellulose
phthalate (HPMCP, Pharmacoat HP.RTM. 50) is dissolved in a solvent
mixture consisting of 2.50 l of demineralized water, 13 l of
acetone Ph. Helv. VII and 13 l of ethanol (94% by weight) and then
0.240 kg of castor oil (Ph. Eur. II) is added to the solution. The
solution is poured or sprayed in portions onto the tablet cores in
a coating pan in a conventional manner.
[0067] After a corresponding drying, the film coating is
subsequently applied. Said coating consists of a solution of
Eudragit.RTM. E 12.5% 4.8 kg, talcum Ph. Eur. II 0.34 kg,
titanium(VI) oxide Cronus RN 56.RTM. 0.52 kg, coloured lacquer
ZLT-2 blue Siegle) 0.21 kg, and polyethylene glycol 6000 Ph. Helv.
VII 0.12 kg in a solvent mixture of 8.2 kg of 2-propanol Ph. Helv.
VII, 0.06 kg of glycerine triacetate (Triacetin.RTM.) and 0.2 kg of
demineralized water. Homogenous distribution in the coating pan or
the fluidized bed, is followed by drying and polishing in the usual
manner.
Example 2
Preparation of Enteric Coated Capsules Containing 86.5 mg of
Monoethyl Fumarate-Ca Salt and 110.0 mg of Dimethyl Fumarate, which
Corresponds to a Total of 150 mg of Fumaric Acid
[0068] Taking the necessary precautions (breathing mask, gloves,
protective clothing, etc.), 8.65 kg of monoethyl fumarate-Ca salt
and 11 kg of dimethyl fumarate are intensely mixed with a mixture
consisting of 15 kg of starch, 6 kg of lactose Ph. Helv. VII, 2 kg
of micro-crystalline cellulose (Avicel.RTM.), 1 kg of polyvinyl
pyrrolidone (Kollidon.RTM. 25) and 4 kg of Primogel.RTM. and
homogenized by means of a sieve 800.
[0069] Together with a 2% aqueous solution of polyvinyl pyrrolidone
(Kollidon.RTM. 25) the entire powder mixture is processed in the
usual manner into a binder granulate and mixed with the outer phase
in the dried state. Said outer phase consists of 0.35 kg of
colloidal silicic acid (Aerosil.RTM.), 0.5 kg of magnesium stearate
and 1.5 kg of talcum Ph. Helv. VII. The homogeneous mixture is then
filled in portions of 500.0 mg into appropriate capsules which are
then provided with an enteric (gastric-acid resistant) coating
consisting of hydroxy propyl ethyl cellulose phthalate and castor
oil as softening agent in a customary fashion.
Example 3
[0070] Preparation of Enteric Micro-Tablets in Capsules Containing
87.0 mg of Monoethyl Fumarate-Ca Salt, 120 mg of Dimethyl Fumarate,
5.0 mg of Monoethyl Fumarate-Mg Salt and 3.0 mg of Monoethyl
Fumarate-Zn Salt, which Corresponds to a Total of 164 mg of Fumaric
Acid ("forte" Tablets)
[0071] Taking the necessary precautions (breathing mask, gloves,
protective clothing, etc.), 8:7 kg of monoethyl fumarate-Ca salt,
12 kg of dimethyl fumarate, 0.5 kg of monoethyl fumarate-Mg salt
and 0.3 kg of monoethyl fumarate-Zn salt are crushed, intensely
mixed and homogenized by means of an sieve 800. An excipient
mixture of the following composition is prepared: 18 kg of starch
derivative (STA-RX 1500), 0.3 kg of micro-crystalline cellulose
(Avicel PH 101), 0.75 kg of PVP (Kollidon 120), 4 kg of Primogel,
0.25 kg of colloidal silicic acid (Aerosil). The entire powder
mixture is added to the active ingredient mixture, homogenized by
means of a 200 sieve, and processed in the usual manner with a 2%
aqueous solution of polyvinyl pyrrolidone (Kollidon K25) to obtain
a binder granulate and mixed in a dry state with the outer phase
that consists of 0.5 kg of magnesium stearate and 1.5 kg of talcum.
Then the powder mixture is pressed by the conventional method into
convex micro-tablets with a gross mass of 10.0 mg and a diameter of
2.0 mm.
[0072] The enteric (gastric acid-resistant) coating is applied in a
fluidized-bed apparatus. In order to achieve resistance to gastric
acid, portions of a solution of 2.250 kg of hydroxy propyl methyl
cellulose phthalate (HPMCP, Pharmacoat HP 50) are dissolved in a
mixture of the following solvents: acetone 13 l, ethanol 94% by
weight denatured with 2% ketone 13.5 l and demineralized water 2.5
l. 0.240 kg of castor oil are added as softening agent to the
finished solution and applied in portions onto the tablet cores in
the usual manner.
[0073] Film coat: After drying is completed, a suspension of the
following composition is then applied as a film coat in the same
apparatus: talcum 0.340 kg, titanium(VI) oxide Cronus RN 56 0.4 kg,
coloured lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5% 4.8
kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent
mixture of the following composition: 2-propanol 8.17 kg,
demineralized water 0.2 kg and glycerine triacetate (Triacetin) 0.6
kg.
[0074] The gastric acid-resistant micro-tablets are analyzed with
respect to their ingredients and are then filled into hard gelatine
capsules at a corresponding net weight and sealed.
Example 4
Preparation of Enteric Micro-Tablets in Capsules Containing 120.0
mg Dimethyl Fumarate which Corresponds to 96 mg Fumaric Acid
[0075] Taking the necessary precautions (breathing mask, gloves,
protective clothing, etc.) 12 kg of dimethyl fumarate are crushed
and homogenized by means of a 800 sieve. An excipient mixture of
the following composition is prepared: 17.5 kg of starch derivative
(STA-RX.RTM. 1500), 0.30 kg of micro-crystalline cellulose
(Avicel.RTM. PH 101), 0.75 kg of PVP (Kollidon.RTM. 120), 4 kg of
Primogel.RTM., 0.25 kg of colloidal silicic acid (Aerosil.RTM.).
The entire powder mixture is added to the active ingredient
mixture, mixed, homogenized by means of a 200 sieve, processed in
the usual manner with a 2% aqueous solution of polyvinyl
pyrrolidone (Kollidon.RTM. K25) to obtain a binder granulate and
mixed in a dry state with the outer phase which consists of 0.5 kg
of Mg stearate and 1.5 kg of talcum.
[0076] Then, the powder mixture is pressed by the conventional
method into convex micro-tablets with a gross mass of 10.0 mg and a
diameter of 2.0 mm.
[0077] To achieve resistance to gastric acid, portions of a
solution of 2.25 kg hydroxy propyl methyl cellulose phthalate
(HPMCP, Pharmacoat.RTM. HP 50) are e.g. dissolved in a mixture of
the following solvents: acetone 13 l, ethanol (94% by weight
denatured with 2% ketone) 13.5 l and demineralized water 1.5 l.
Castor oil (0.24 kg) is added as softening agent to the finished
solution and applied in portions onto the tablet cores in the usual
manner.
[0078] After drying is completed, a suspension of the following
composition is then applied as a film coat in the same apparatus:
talcum 0.34 kg, titanium(VI) oxide Cronus RN 56 0.4 kg, coloured
lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5% 4.8 kg and
polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of
the following composition: 2-propanol 8.17 kg, demineralized water
0.2 kg and glycerine triacetate (Triacetin) 0.6 kg.
[0079] The gastric acid-resistant micro-tablets are analyzed with
respect to their ingredients and are then filled into hard gelatine
capsules at a corresponding net weight and sealed.
Example 5
Preparation of Enteric Micro-Tablets in Capsules Containing 120.0
mg of Diglycine Fumaric Acid Diamide, which Corresponds to 96 mg of
Fumaric Acid
[0080] 12 kg of diglycine fumaric acid diamide are crushed and
homogenized as indicated above. An excipient mixture of the
following composition is prepared: 23.2 kg of micro-crystalline
cellulose (Avicel.RTM. PH 200), 3 kg of croscarmelose sodium
(AC-Di-SOL-SD-711), 2.5 kg of talcum, 0.1 kg of anhydrous silicic
acid (Aerosil.RTM. 200) and 1 kg Mg stearate. The entire powder
mixture is added to the active ingredient mixture and homogeneously
mixed. Then, the powder mixture is pressed by the direct compaction
into convex micro-tablets with a gross mass of 10.0 mg and a
diameter of 2.0 mm.
[0081] Subsequently, a solution of 0.94 Eudragit.RTM. in
isopropanol is prepared which, additionally, contains 0.07 kg
dibutyl phthalate. This solution is sprayed onto the tablet cores.
Then, a dispersion of 17.32 kg Eudragit.RTM. L D-55 and a mixture
of 2.8 kg micro-talcum, 2 kg Macrogol 6000 and 0.07 kg Dimeticon in
water is prepared and sprayed onto the cores.
[0082] Subsequently, the enteric micro-tablets are analyzed with
respect to their ingredients and filled into hard gelatine capsules
at a corresponding net weight and sealed.
Example 6
Preparation of Enteric Micro-Tablets in Capsules Containing 60.0 mg
of r-1,t-2,c-3,t-4-tetrakis(methoxy carbonyl)cyclobutane and 30.0
mg r-1,t-2,c-3,t-4,c-5,t-6-hexa(methoxy carbonyl)cyclohexane
[0083] 60 kg of r-1,t-2,c-1,t-4-tetrakis(methoxy
carbonyl)cyclobutane and 3.0 kg of
r-1,t-2,c-3,t-4,c-5,t-6-hexa(methoxy carbonyl)cyclohexane are
crushed, intensely mixed and homogenized by means of sieve 800: An
excipient mixture of the following composition is prepared: 18 kg
of starch derivative (STA-RX 1500.RTM.), 0.30 kg of
micro-crystalline cellulose (Avicel PH 101), 0.75 kg of PVP
(Kollidon 120), 4.00 kg of Primogel, 0.25 kg of colloidal silicic
acid (Aerosil). The active ingredient is added to the entire powder
mixture and homogenized by means of a sieve 200 and processed with
a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon K25) in
the usual manner into binder granules, and then mixed with the
outer phase in a dry state. The latter consists of 0.50 kg of Mg
stearate and 1.50 kg of talcum. Thereafter, the powder mixture is
pressed into convex micro-tablets with a gross mass of 10.0 mg and
a diameter of 2.0 mm by the usual method.
[0084] The enteric (gastric acid-resistant) coating is poured onto
the tablet cores in a classic coating pan. In order to achieve
resistance to gastric acid, portions of a solution of 2.250 kg of
hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat HP 50)
are dissolved in a mixture of the following solvents: acetone 13.00
l, ethanol 94% by weight denatured with 2% ketone 13.50 l and
demineralized water 2.50 l. 0.240 kg of castor oil is added as
softening agent to the finished solution and applied in portions to
the tablet cores in the usual manner.
[0085] Film coat: After drying is completed, a suspension of the
following composition is applied as a film coat in the same
apparatus: talcum 0.340 kg, titanium(VI) oxide Cronus RN 56 0.400
kg, coloured lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5%
4.800 kg and polyethylene glycol 6000 pH 11 XI 0.120 kg in a
solvent mixture of the following composition: 2-propanol 8.170 kg,
demineralized water 0.200 kg and glycerine triacetate (Triacetin)
0.600 kg.
[0086] Subsequently, the enteric micro-tablets are analyzed with
respect to their active ingredients and filled into hard gelatine
capsules at a corresponding net weight and sealed.
Example 7
[0087] Preparation of a Suspension for Parenteral Application 60.0
mg of r-1,t-2,c-4,t-4-tetrakis(methoxy carbonyl)cyclobutane and
30.0 mg r-1,t-2,c-3,t-4,c-5,t-6-hexa(methoxy carbonyl)cyclohexane
TABLE-US-00001 Ingredients mg/ml r-1,t-2,c-3,t-4-tetrakis(methoxy
60.00 carbonyl)cyclobutane r-1,t-2,c-3,t-4,c-5,t-6-hexa(methoxy
30.00 carbonyl)cyclohexane Methyl cellulose 0.25 Sodium citrate,
dihydrate 30.00 Benzyl alcohol 9.00 Methyl p-hydroxybenzoic acid
1.80 Propyl p-hydroxybenzoic acid 1.20 Water for injection purposes
q.s.a.d. 1.00
[0088] The aforementioned ingredients are processed to a parenteral
suspension using standard techniques.
EXAMPLES OF APPLICATION
Example A
In Vivo Data on the Treatment of Cardiac Insufficiency with DMF
Using a Rat Model.
[0089] The effects of dimethyl fumarate were examined in the
present experiment using the model of acute ischemia and
reperfusion of the rat. For this purpose, healthy, male rats were
divided into three groups with 17 animals each. In the tests, an
ischemia was caused for 45 minutes through an occlusion of an
artery with the heart being exposed and, subsequently, reperfusion
was carried out for 120 minutes. Finally, a myocardial infarction
was triggered by means of a reocclusion and the risk area was
determined by means of dyeing with phthalocyanine blue.
[0090] The administration of the test substance was carried out iv
at the beginning of the first occlusion. The control group received
0.02% DMSO (0.5 ml/kg body weight), the DMF group received 10 mg
dimethyl fumarate in 0.02% DMSO (0.5 ml/kg body weight). The
animals were ischemically preconditioned in the second group (2
times 5 minutes each ischemia and reperfusion).
[0091] The results are represented in FIG. 1. Evidently, both
dimethyl fumarate (DMF) and the ischemic preconditioning (IPC)
limited the size of the infarction to a statistically significant
degree in our experiments, the risk area being similar in all 3
groups. Thus, the data proves that the used dimethyl fumarate can
significantly reduce the size of the infarction and thus prevent a
cardiac insufficiency.
Example B
Inhibition of the PDGF-Induced Incorporation of Thymidine
[0092] The successful treatment of asthma involves three different
pathways: (1) the reduced release of inflammatory mediators in
allergic responses, (2) the inhibition of T-lymphocyte invasion,
and (3) the inhibition of mesenchymal cell proliferation.
Glucocorticoids, which are the treatment of choice in asthma, have
been shown to inhibit mesenchymal dell proliferation. This test can
thus be used to screen for possible other active substances for
treatment of asthma.
[0093] BSM (bronchial smooth muscle) cells were cultivated in RPMI,
0.3% albumin and 0.1% DMSO at 37.degree. C. in the presence of 0,
1, 5, 10 and 20 ng/ml on PDGF with and without 10.sup.-5 M dimethyl
fumarate.
[0094] After a predetermined period of time, 5 .mu.Ci on
.sup.3H-thymidine was added to the culture medium and incubation
was continued for further 24 hours. The incorporation was finally
stopped by means of centrifugation, removal of the supernatant,
washing and lysis of the cells. The incorporation on
.sup.3H-thymidine was measured by determining the radioactivity in
the lysates in a liquid scintillation device in comparison to the
control. The results are shown in FIG. 2 as percentage values as
compared with the control (100%). The addition of PDGF evidently
increases the .sup.3H-thymidine incorporation and, thus, cell
proliferation, whereas this increase is significantly reduced upon
addition of dimethyl fumarate.
Example C
[0095] Bronchial smooth muscle cells were grown in 96 well plates
until they reached 60-70% confluency. The cells were then starved
for 48 h in serum free, 0.3% albumine containing RPMI medium. One
hour before stimulation of cell proliferation with 10 ng/ml PDGF,
the cells were treated with (a) 10.sup.-5 M DMF, (b) 10.sup.-8 M
dexamethasone (dexa), or (c) 10.sup.-5 M DMF and 10.sup.-8 M dexa.
As a control untreated cells (buffer only) were used. Cells were
treated for 36 h, whereafter 4 .mu.Ci of .sup.3H-thymidine was
added for further 8 hours. The cells were lysed, DNA-incorporated
.sup.3H-thymidine bound to filter membranes, and the incorporated
cpm measured in a liquid scintillation device. The results are
shown in FIG. 3 in percentage of control (100%) and compared to
PDGF induced proliferation.
[0096] When treating cells with dexa alone (10.sup.-8 M), which is
a therapeutically relevant dosage, cell proliferation was reduced
to about 116.+-.11%. A comparable reduction was seen with DMF at
10.sup.-5 M (117.+-.4%). Combined administration of DMF and dexa in
these concentrations resulted in a synergistic decrease of cell
proliferation to nearly baseline levels (95.+-.11%). These results
show that DMF may be useful in the treatment of asthma, either as
of its own, and also in combination with dexametasone or
glucocorticoids in general.
[0097] In a specifically preferred embodiment for the treatment of
asthma and chronically obstructive lung diseases such treatment is
thus in combination with a glucocorticoid. Administration can be in
the same dosage unit or in separate dosage units. Administration
can also be in parallel or sequentially. Preferably the
glucocorticoid is selected from the group consisting of
dexamethasone, cortisone, hydrocortisone, prednisolone, prednisone,
methylprednisolone, fluocortolone, triamcinolone, betamethasone,
beclomethasone, budenoside, flunisonide, fluticasone, and
pharmaceutically acceptable salts and derivatives thereof. Most
preferably the glucocorticoid is dexamethasone.
Example D
[0098] Dahl-rats, which are salt sensitive, were administered
varying dosages of DMF on a daily basis and put on a high salt
diet. After 8 weeks of treatment the left ventricular enddiastolic
diameters were measured for test and control groups by
echocardiographic analysis. Groups measured were control (0 mg DMF;
n 9); group 1 (2.times.5 mg DMF/kg/d; n=9) and group 2 (2.times.15
mg DMF/kg/d; n=11).
[0099] In the echocardiography analysis, DMF prevented the
dilatation of the left ventricle after 8 weeks of high salt diet in
dose dependent manner. Specifically, in the DMF group's the inner
diameter of the left ventricle remained in the same range as at
baseline (see FIG. 4). In contrast, animals in the control group
showed an enlarged left ventricle indicating dilatation of the left
ventricle. Importantly, dilatation of the left ventricle marks the
transition from compensated hypertrophy to decompensated heart
failure. Consequently, DMF delays the transition to heart failure,
and thus prevents myocardial infarctions.
* * * * *