U.S. patent application number 12/308878 was filed with the patent office on 2010-03-18 for combination of hmg-coa reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary disease.
This patent application is currently assigned to Nycomed GmbH. Invention is credited to Stefan-Lutz Wollin.
Application Number | 20100069392 12/308878 |
Document ID | / |
Family ID | 37311957 |
Filed Date | 2010-03-18 |
United States Patent
Application |
20100069392 |
Kind Code |
A1 |
Wollin; Stefan-Lutz |
March 18, 2010 |
Combination of HMG-COA Reductase Inhibitors with Phosphodiesterase
4 Inhibitors for the Treatment of Inflammatory Pulmonary
Disease
Abstract
The invention relates to the combined use of a PDE4 inhibitor
with a HMG-CoA reductase inhibitor for the preventive and curative
treatment of an inflammatory pulmonary disease.
Inventors: |
Wollin; Stefan-Lutz; (Bad
Waldse, DE) |
Correspondence
Address: |
NATH & ASSOCIATES PLLC
112 South West Street
Alexandria
VA
22314
US
|
Assignee: |
Nycomed GmbH
Konstanz
DE
|
Family ID: |
37311957 |
Appl. No.: |
12/308878 |
Filed: |
July 3, 2007 |
PCT Filed: |
July 3, 2007 |
PCT NO: |
PCT/EP2007/056683 |
371 Date: |
December 29, 2008 |
Current U.S.
Class: |
514/248 ;
514/293; 514/339; 514/342; 514/352; 514/423; 514/460; 514/470;
514/548; 514/567 |
Current CPC
Class: |
A61K 31/40 20130101;
A61P 11/04 20180101; A61K 31/405 20130101; A61P 29/00 20180101;
A61K 31/352 20130101; A61K 31/4439 20130101; A61K 31/277 20130101;
A61P 11/06 20180101; A61K 31/343 20130101; A61K 31/405 20130101;
A61K 31/437 20130101; A61K 31/505 20130101; A61K 31/366 20130101;
A61K 31/40 20130101; A61K 31/453 20130101; A61K 31/4425 20130101;
A61K 31/453 20130101; A61K 31/44 20130101; A61K 31/437 20130101;
A61K 31/44 20130101; A61P 35/00 20180101; A61K 31/277 20130101;
A61K 31/502 20130101; A61P 11/00 20180101; A61K 31/4439 20130101;
A61K 31/502 20130101; A61K 31/352 20130101; A61K 31/366 20130101;
A61K 31/22 20130101; A61K 45/06 20130101; A61K 31/505 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/22
20130101; A61K 31/343 20130101 |
Class at
Publication: |
514/248 ;
514/293; 514/339; 514/342; 514/352; 514/423; 514/460; 514/470;
514/548; 514/567 |
International
Class: |
A61K 31/502 20060101
A61K031/502; A61K 31/437 20060101 A61K031/437; A61K 31/4439
20060101 A61K031/4439; A61K 31/44 20060101 A61K031/44; A61K 31/40
20060101 A61K031/40; A61K 31/366 20060101 A61K031/366; A61K 31/343
20060101 A61K031/343; A61K 31/215 20060101 A61K031/215; A61K 31/192
20060101 A61K031/192; A61P 11/04 20060101 A61P011/04; A61P 29/00
20060101 A61P029/00; A61P 11/00 20060101 A61P011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 5, 2006 |
EP |
06116625.2 |
Claims
1. Pharmaceutical composition comprising a pharmaceutical
formulation including a first amount of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof, a second amount of a
HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt
thereof, wherein the first amount and the second amount together
comprise an effective amount for the preventive or curative
treatment of an inflammatory pulmonary disease, and at least one
pharmaceutically acceptable auxiliary.
2. A combination product comprising the components: (A) a first
amount of a PDE4 inhibitor or a pharmaceutically acceptable salt
thereof; (B) a second amount of a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof; wherein the first and the
second amount together comprise an effective amount for the
preventive or curative treatment of an inflammatory pulmonary
disease and wherein each of the components (A) and (B) is
formulated in admixture with at least one pharmaceutically
acceptable auxiliary.
3. A kit comprising the components: (A) a pharmaceutical
formulation including a first amount of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof, in admixture with at
least one pharmaceutically acceptable auxiliary; (B) a
pharmaceutical formulation including a second amount of a HMG-CoA
reductase inhibitor or a pharmaceutically acceptable salt thereof,
in admixture with at least one pharmaceutically acceptable
auxiliary; wherein the first and the second amount together
comprise an effective amount for the preventive or curative
treatment of an inflammatory pulmonary disease.
4. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is selected from the group consisting of
ROFLUMILAST, ROFLUMILAST N-Oxide, CILOMILAST, AWD-12-281,
TOFIMILAST, TETOMILAST, LIRIMILAST, L-869298, OGLEMILAST,
2-{4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-pht-
halazin-2-yl]-piperidin-1-yl}-acetamide and a pharmaceutically
acceptable salt of these compounds.
5. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is selected from the group consisting of
ROFLUMILAST, a pharmaceutically acceptable salt of ROFLUMILAST,
ROFLUMILAST-N-oxide and a pharmaceutically acceptable salt of
ROFLUMILAST-N-oxide.
6. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is ROFLUMILAST.
7. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is ROFLUMILAST-N-oxide.
8. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is CILOMILAST or a pharmaceutically acceptable salt
thereof.
9. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is AWD-12-281 or a pharmaceutically acceptable salt
thereof.
10. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is TOFIMILAST or a pharmaceutically acceptable salt
thereof.
11. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is TETOMILAST or a pharmaceutically acceptable salt
thereof.
12. Pharmaceutical composition according to claim 1, wherein the
PDE4 inhibitor is OGLEMILAST or a pharmaceutically acceptable salt
thereof.
13. Pharmaceutical composition according to claim 1, wherein the
HMG-CoA reductase inhibitor is selected from the group consisting
of LOVASTATIN, PRAVASTATIN, SIMVASTATIN, ATORVASTATIN, FLUVASTATIN,
ROSUVASTATIN, PITAVASTATIN, BERVASTATIN, DALVASTATIN, GLENVASTATIN
and the pharmaceutically acceptable salts of these compounds.
14. Pharmaceutical composition according to claim 1, wherein the
HMG-CoA reductase inhibitor is selected from the group consisting
of ATORVASTATIN, SIMVASTATIN, PRAVASTATIN, ROSUVASTATIN and the
pharmaceutically acceptable salts of these compounds.
15. Pharmaceutical composition according to claim 1, wherein the
inflammatory pulmonary disease is selected from the group
consisting of asthma, COPD, sclerosis, alveolitis, sarcoidosis,
idiopathic pulmonary fibrosis and pulmonary hypertension.
16. (canceled)
17. (canceled)
18. A method for the preventive or curative treatment of an
inflammatory pulmonary disease comprising administering to a
patient in need thereof a pharmaceutical composition comprising a
pharmaceutical formulation including a first amount of a PDE4
inhibitor or a pharmaceutically acceptable salt thereof, a second
amount of a HMG-CoA reductase inhibitor or a pharmaceutically
acceptable salt thereof, wherein the first amount and the second
amount together comprise an effective amount for the preventive or
curative treatment of an inflammatory pulmonary disease, and at
least one pharmaceutically acceptable auxiliary.
19. A method for the preventive or curative treatment of an
inflammatory pulmonary disease comprising administering to a
patient in need thereof a combination product comprising the
components: (A) a first amount of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof; (B) a second amount of a
HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt
thereof; wherein the first and the second amount together comprise
an effective amount for the preventive or curative treatment of an
inflammatory pulmonary disease; wherein each of the components (A)
and (B) is formulated in admixture with at least one
pharmaceutically acceptable auxiliary; and wherein the components
(A) and (B) are administered simultaneously, sequentially or
separately.
20. Method according to claim 18, wherein the PDE4 inhibitor is
selected from the group consisting of ROFLUMILAST, ROFLUMILAST
N-Oxide, CILOMILAST, AWD-12-281, TOFIMILAST, TETOMILAST,
LIRIMILAST, L-869298, OGLEMILAST, 2-{4-[(4aS,
8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-y-
l]-piperidin-1-yl}-acetamide and a pharmaceutically acceptable salt
of these compounds.
21. Method according to claim 18, wherein the PDE4 inhibitor is
selected from the group consisting of ROFLUMILAST, a
pharmaceutically acceptable salt of ROFLUMILAST, ROFLUMILAST
N-oxide and a pharmaceutically acceptable salt of
ROFLUMILAST-N-oxide.
22. Method according to claim 18, wherein the PDE4 inhibitor is
ROFLUMILAST.
23. Method according to claim 18, wherein the PDE4 inhibitor is
ROFLUMILAST-N-oxide.
24. Method according to claim 18, wherein the PDE4 inhibitor is
CILOMILAST or a pharmaceutically acceptable salt thereof.
25. Method according to claim 18, wherein the PDE4 inhibitor is
AWD-12-281 or a pharmaceutically acceptable salt thereof.
26. Method according to claim 18, wherein the PDE4 inhibitor is
TOFIMILAST or a pharmaceutically acceptable salt thereof.
27. Method according to claim 18, wherein the PDE4 inhibitor is
TETOMILAST or a pharmaceutically acceptable salt thereof.
28. Method according to claim 18, wherein the PDE4 inhibitor is
OGLEMILAST or a pharmaceutically acceptable salt thereof.
29. Method according to claim 18, wherein the HMG-CoA reductase
inhibitor is selected from the group consisting of LOVASTATIN,
PRAVASTATIN, SIMVASTATIN, ATORVASTATIN, FLUVASTATIN, ROSUVASTATIN,
PITAVASTATIN, BERVASTATIN, DALVASTATIN, GLENVASTATIN and the
pharmaceutically acceptable salts of these compounds.
30. Method according to claim 18, wherein the HMG-CoA reductase
inhibitor is selected from the group consisting of ATORVASTATIN,
SIMVASTATIN, PRAVASTATIN, ROSUVASTATIN and the pharmaceutically
acceptable salts of these compounds.
31. Method according to claim 19, wherein the inflammatory
pulmonary disease is selected from the group consisting of asthma,
COPD, sclerosis, alveolitis, sarcoidosis, idiopathic pulmonary
fibrosis and pulmonary hypertension.
32. Method according to claim 19, wherein the inflammatory
pulmonary disease is COPD.
33. Process for the preparation of a pharmaceutical composition as
defined in claim 1 which comprises mixing the PDE4 inhibitor or a
pharmaceutically acceptable salt thereof with the HMG-CoA reductase
inhibitor or a pharmaceutically acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to the combination of certain
known therapeutic compounds for therapeutic purposes. The
substances used in the combinations according to the invention are
known active agents from the phosphodiesterase 4 (PDE4) inhibitor
class and active agents from the HMG-CoA-reductase inhibitor
class.
BACKGROUND ART
[0002] Statins are widely used as cholesterol lowering therapeutic
agents. They reduce cholesterol levels through competitive
inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase, the key enzyme that regulates cholesterol synthesis. The
cholesterol-lowering effect of statins is also due to an increase
in the uptake of cholesterol by cells as a result of intracellular
cholesterol depletion and enhanced expression of low-density
lipoprotein (LDL) receptors.
[0003] However, statins exhibit properties that are beyond their
lipid-lowering effects. These non-lipid-lowering properties involve
the inhibition of the isoprenoid pathway including the cholesterol
precursor mevalonate which is required as a precursor for the
prenylation of a number of proteins leading to a change in function
[Drugs of Today; 2004; 40: 975-990]. For example simvastatin
modulates chemokine and chemokine receptor expression by
geranylgeranyl isoprenoid pathway in human endothelial cells and
macrophages [Veillard N R et al; Simvastatin modulates chemokine
and chemokine receptor expression by geranylgeranyl isoprenoid
pathway in human endothelial cells and macrophages;
Atherosclerosis; 2005 Nov. 28; Epub ahead of print]. Statins also
have a potential role as antioxidants leading to downregulation of
inflammation [Drugs of Today; 2004; 40: 975-990]. Recent research
data demonstrated that statins inhibit the induction of the major
histocompatibility (MHC) class II expression by interferon-gamma
(IFN-gamma), leading to repression of MHC II-mediated T-cell
activation. Furthermore, statins inhibit the expression of specific
cell surface receptors on monocytes, adhesion molecules and also
integrin-dependent leucocyte adhesion [Timely Top Med Cardiovasc
Dis; 2005; 9: E3]. Statins exhibit additional effects on
inflammation by decreasing IL-6, IL-8, and MCP-1 synthesis in human
vascular smooth muscle cells (VSMC) in vitro [Cardiovas Res; 2003;
59: 755-66]. Simvastatin inhibits growth factor expression and
modulates profibrogenic markers in lung fibroblasts [Am J Respir
Cell Mol. Biol. 2005; 32: 290-300]. Furthermore, statins increase
bioavailability of nitric oxide. Cerivastatin increased eNOS
expression a NO release in human endothelial cells [J Physiol
Pharmacol. 2002; 53:585-95]. In vivo statins exert
anti-inflammatory effects in many models of inflammatory airway
diseases like asthma and COPD. Simvastatin was shown to inhibit
pulmonary inflammatory cell accumulation and IL-4 and IL-5 release
into the alveolar lumen after allergen challenge in mice [J
Immunol. 2004; 172: 2903-8]. Simvastatin inhibits cigarette
smoking-induced emphysema and pulmonary hypertension in rat lungs
[Am J Respir Crit. Care Med. 2005; 172: 987-93]. Overall statins
exhibit inhibitory properties on inflammation and modulation on the
immune system.
[0004] In the international patent application WO00/48626
(University of Washington) aerosol compositions of HMG-CoA
reductase inhibitors for inhibiting inflammation associated with a
pulmonary disease, such as asthma, interstitial pneumonitis,
emphysema, chronic bronchitis, adult respiratory distress syndrome
(ARDS) and cystic fibrosis, are described. In EP1275388 (Takeda)
several statins are described as useful for the treatment of
TNF.alpha. associated diseases such as inflammatory diseases
including asthma and COPD. In US20050119330 the use of HMG-CoA
reductase inhibitors is described for the treatment of lung
proliferative vascular disorders, such as for example, pulmonary
hypertension and pulmonary fibrosis.
[0005] There is pressing need to improve the treatment of
inflammatory pulmonary diseases like asthma and COPD. These
inflammatory diseases are characterized by multifactorial
pathologies. Several inflammatory mediators are involved as well as
various cell types. Therefore, in medical practice for the
treatment of e.g. asthma and COPD the targeting of a single
mediator or cell type has not lead to satisfactory results. For
both asthma and COPD at present combination therapies are used but
in many instances with limited success especially in COPD.
[0006] Cyclic nucleotide phosphodiesterase (PDE) inhibitors,
particularly inhibitors of type 4 (PDE4), are useful in the
treatment of a variety of allergic and inflammatory diseases, for
example in respiratory diseases, such as asthma and chronic
obstructive pulmonary disease.
[0007] HMG-CoA reductase inhibitors, by a route different from PDE4
inhibitors, are also useful in the treatment of inflammatory
diseases.
[0008] It would be desirable to provide combinations and methods of
treatment that can take advantage of the different therapeutic
pathways of a PDE4 inhibitor and a HMG-CoA reductase inhibitor to
more effectively treat inflammatory disorders, in particular asthma
and COPD.
DESCRIPTION OF THE INVENTION
[0009] It has now been found that the combined use of a PDE4
inhibitor and a HMG-CoA reductase inhibitor potentiates the
anti-inflammatory effect of either component alone.
[0010] Therefore, according to a first aspect of the present
invention there is provided a pharmaceutical composition comprising
a pharmaceutical formulation including an amount of a PDE4
inhibitor or a pharmaceutically acceptable salt thereof, an amount
of a HMG-CoA reductase inhibitor or a pharmaceutically acceptable
salt thereof, wherein the first amount and the second amount
together comprise an effective amount for the preventive or
curative treatment of an inflammatory pulmonary disease, and at
least one pharmaceutically acceptable auxiliary.
[0011] The above-mentioned pharmaceutical composition provides for
the administration of a PDE4 inhibitor or a pharmaceutically
acceptable salt thereof with a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof and is thus presented as a
single formulation.
[0012] Alternatively, the PDE4 inhibitor or a pharmaceutically
acceptable salt thereof and the HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof may be presented as
separate formulations, wherein at least one of those formulations
comprises a PDE4 inhibitor or a pharmaceutically acceptable salt
thereof and at least one comprises a HMG-CoA reductase inhibitor or
a pharmaceutically acceptable salt thereof.
[0013] Thus, there is further provided:
[0014] A combination product comprising the components: (A) an
amount of a PDE4 inhibitor or a pharmaceutically acceptable salt
thereof; (B) an amount of a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof; wherein the first and the
second amount together comprise an effective amount for the
preventive or curative treatment of an inflammatory pulmonary
disease and wherein each of the components (A) and (B) is
formulated in admixture with at least one pharmaceutically
acceptable auxiliary.
[0015] A kit comprising the components: (A) a pharmaceutical
formulation including an amount of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof, in admixture with at
least one pharmaceutically acceptable auxiliary; (B) a
pharmaceutical formulation including an amount of a HMG-CoA
reductase inhibitor or a pharmaceutically acceptable salt thereof,
in admixture with at least one pharmaceutically acceptable
auxiliary; wherein the first and the second amount together
comprise an effective amount for the preventive or curative
treatment of an inflammatory pulmonary disease.
[0016] The combinations according to the invention can be used for
the preventive or curative treatment of inflammatory pulmonary
diseases, such as, for example, asthma, COPD, sclerosis,
alveolitis, sarcoidosis, idiopathic pulmonary fibrosis and
pulmonary hypertension.
[0017] Therefore, further aspects of the invention are:
[0018] Combination of a PDE4 inhibitor or a pharmaceutically
acceptable salt thereof and a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof for use as a
medicament.
[0019] Combination of a PDE4 inhibitor or a pharmaceutically
acceptable salt thereof and a HMG-CoA reduc tase inhibitor or a
pharmaceutically acceptable salt thereof for the preventive or
curative treatment of an inflammatory pulmonary disease.
[0020] Pharmaceutical composition, combination product or kit, as
described in the preceding paragraphs, for use as a medicament.
[0021] Pharmaceutical composition, combination product or kit, as
described in the preceding paragraphs, for the preventive or
curative treatment of an inflammatory pulmonary disease.
[0022] The use of a PDE4 inhibitor or a pharmaceutically acceptable
salt thereof and a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof for the manufacture of a
medicament, in particular the pharmaceutical composition according
to the invention, for the preventive or curative treatment of an
inflammatory pulmonary disease.
[0023] Another aspect of the present invention is the use of a PDE4
inhibitor or a pharmaceutically acceptable salt thereof and a
HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt
thereof for the manufacture of a sequential or separate
co-administrable medicament, in particular the combination product
or kit according to the invention, for the preventive or curative
treatment of an inflammatory pulmonary disease.
[0024] Still another aspect of the present invention is a method
for the preventive or curative treatment of an inflammatory
pulmonary disease comprising administering to a patient in need
thereof a pharmaceutical composition comprising a pharmaceutical
formulation including an amount of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof, an amount of a HMG-CoA
reductase inhibitor or a pharmaceutically acceptable salt thereof,
wherein the first amount and the second amount together comprise an
effective amount for the preventive or curative treatment of an
inflammatory pulmonary disease, and at least one pharmaceutically
acceptable auxiliary.
[0025] A further aspect of the present invention is a method for
the preventive or curative treatment of an inflammatory pulmonary
disease comprising administering to a patient in need thereof a
combination product comprising the components:
(A) an amount of a PDE4 inhibitor or a pharmaceutically acceptable
salt thereof; (B) an amount of a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof; wherein the first and the
second amount together comprise an effective amount for the
preventive or curative treatment of an inflammatory pulmonary
disease; wherein each of the components (A) and (B) is formulated
in admixture with at least one pharmaceutically acceptable
auxiliary; and wherein the components (A) and (B) are administered
simultaneously, sequentially or separately.
[0026] The pharmaceutical compositions according to the invention
may be prepared by mixing the first active agent with the second
active agent.
[0027] In the above-mentioned mixing process the first active agent
and the second active agent can
a) in a first step be mixed as such, afterwards be processed with
at least one pharmaceutically acceptable auxiliary and finally, for
example, be pressed to tablets or caplets or b) in a first step
separately be processed with at least one pharmaceutically
acceptable auxiliary to give granules or pellets containing each
only one of the two active agents; the pellets or granules for
their part then can be mixed in an appropriate ratio and either
pressed--optionally with further pharmaceutically acceptable
auxiliaries--to give, for example tablets or caplets, or can be
filled in loose form in capsules.
[0028] Therefore, in a still further aspect of the present
invention there is provided a process for the preparation of a
pharmaceutical composition which comprises mixing a first active
agent, which is a PDE4 inhibitor or a pharmaceutically acceptable
salt thereof with a second active agent, which is a HMG
CoA-reductase inhibitor or a pharmaceutically acceptable salt
thereof.
[0029] Simultaneous administration of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof and a HMG-CoA reductase
inhibitor or a pharmaceutically acceptable salt thereof can be
preferably accomplished, by administering to the patient in need of
inflammatory pulmonary disease therapy the pharmaceutical
composition according to the invention in one dosage form, such as
for example in a single capsule, tablet or injection.
[0030] Components (A) and (B) of the combination product as well as
of the kit may be administered sequentially or separately over the
course of the preventive or curative treatment of an inflammatory
pulmonary disease.
[0031] Sequential or separate administration of a PDE4 inhibitor or
a pharmaceutically acceptable salt thereof and a HMG-CoA reductase
inhibitor or a pharmaceutically acceptable salt thereof can be
preferably accomplished, by administering to the patient in need of
inflammatory pulmonary disease therapy components (A) and (B) of
the combination product or the kit according to the invention in
(multiple) separate dosage forms, such as for example, in separate
capsules, tablets or injections. The components (A) and (B) of the
combination product or the kit according to the invention can also
be administered simultaneously, for example by swallowing the two
tablets containing the both active agents at the same time, or by
using an inhaler system, which contains both active agents in
separate containers, but deliver them together.
[0032] In an alternative, one of the components (A) and (B) may be
formulated as tablet or capsule and the other component may be
formulated for administration, for example, by injection or
inhalation.
[0033] Sequential administration encompasses a short time period
between the administration of components (A) and (B) of the
combination product or the kit according to the invention (for
example, the time that is needed to swallow one tablet after the
other).
[0034] Separate administration encompasses both relatively short
and relatively long time periods between the administration of
components (A) and (B) of the combination product or the kit
according to the invention. However, for the purposes of the
present invention at least one of the components is administered
while the other component is still having an effect on the patient
being treated. In a preferred embodiment of the invention the
effect on the patient being treated is a synergistic effect.
[0035] The combined administration of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof and a HMG-CoA reductase
inhibitor or a pharmaceutically acceptable salt thereof, either in
form of the pharmaceutical composition, combination product or kit
according to the invention, lead to an effective preventive or
curative treatment of the inflammatory pulmonary disease, and in a
preferred embodiment is superior to the use of either active
compound alone. Moreover, in a particularly preferred embodiment,
the combined administration of a PDE4 inhibitor or a
pharmaceutically acceptable thereof and a HMG-CoA reductase
inhibitor or a pharmaceutically acceptable salt thereof shows a
synergistic efficacy for treating an inflammatory pulmonary
disease.
[0036] As used herein, the term "synergistic" refers to the
combination of a PDE4 inhibitor or a Pharmaceutically acceptable
salt thereof with a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof either in form of the
pharmaceutical composition, combination product or kit according to
the invention having an efficacy for the preventive or curative
treatment of an inflammatory pulmonary disease that is greater than
would be expected from the sum of their individuals effects. The
synergistic effects of the embodiments of the present invention
encompass additional unexpected advantages for the preventive or
curative treatment of inflammatory pulmonary diseases. Such
additional advantages may include, but are not limited to, lowering
the required dose of one or more of the active compounds of the
combination, reducing the side effects of one or more of the active
compounds of the combination or rendering one or more of the active
compounds more tolerable to the patient in need of an inflammatory
pulmonary disease therapy. The combined administration of a PDE4
inhibitor or a pharmaceutically acceptable salt thereof and a
HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt
thereof may also be useful for decreasing the required number of
separate dosages, thus, potentially improving compliance of the
patient in need of inflammatory pulmonary disease therapy.
[0037] The therapeutic effect of the combinations according to the
invention may be also observed with regard to the fast decline in
lung function that is a hallmark of COPD, and effects may be
observed regarding the systemic inflammation that is also a
characteristic of COPD. The long-term effect of the combinations
according to the invention will be the conservation of lung
function and putatively less co-morbidity (based on effects on the
systemic inflammation).
[0038] The term "active compound" as used herein refers to a
compound useful in the preventive or curative treatment of a
disease.
[0039] The term "effective amount" as used herein refers to a
therapeutically effective amount for treating an inflammatory
pulmonary disease. In case of a combination therapy the term
"effective amount" refers to the sum of the amounts of the
combination partners, which is therapeutically effective for the
preventive or curative treatment of an inflammatory pulmonary
disease.
[0040] The term "patient" includes both humans and other mammals.
In a preferred embodiment of the invention the term "patient"
stands for humans.
[0041] The term "PDE4 inhibitor" as used herein refers to an active
compound that is capable of reducing the physiological effect of
the PDE4 isoenzyme of phosphodiesterase preferentially over other
isoenzyme of phosphodiesterase.
[0042] Non-limiting examples of PDE4 inhibitors, which may be
usefully employed in the pharmaceutical compositions, combination
products and kits according to the invention are listed in Table
1.
[0043] In one embodiment of the present invention the PDE4
inhibitor is selected from the group consisting of ROFLUMILAST
(CAS-No. 162401-32-3), ROFLUMILAST-N-Oxide (CAS-No. 292135-78-5),
CILOMILAST (CAS-No. 153259-65-5), AWD-12-281 (CAS-No. 257892-33-4),
TOFIMILAST (CAS-No. 185954-27-2), TETOMILAST (CAS-No. 145739-56-6),
LIRIMILAST (CAS-No. 329306-27-6), L-869298 (CAS-No. 362718-73-8),
OGLEMILAST (CAS-No. 778576-62-8),
2-{4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4-a,5,8,8a-tetrahydro-1H-ph-
thalazin-2-yl]-piperidin-1-yl}-acetamide (hereinafter referred to
as COMPOUND A; CAS-No. 449760-58-1) and the pharmaceutically
acceptable salts of these compounds.
[0044] In another embodiment of the present invention the PDE4
inhibitor is selected from the group consisting of ROFLUMILAST, a
pharmaceutically acceptable salt of ROFLUMILAST,
ROFLUMILAST-N-oxide and a pharmaceutically acceptable salt of
ROFLUMILAST-N-oxide.
[0045] In another embodiment of the present invention the PDE4
inhibitor is ROFLUMILAST.
[0046] In another embodiment of the present invention the PDE4
inhibitor is ROFLUMILAST-N-oxide.
[0047] In another embodiment of the present invention the PDE4
inhibitor is CILOMILAST or a pharmaceutically acceptable salt
thereof.
[0048] In another embodiment of the present invention preferred
pharmaceutically acceptable salts of CILOMILAST are the lithium,
sodium, ethylene diamine and tromethamine salt of CILOMILAST. A
particularly preferred pharmaceutically acceptable salt of
CILOMILAST is the sodium salt of CILOMILAST. Another particularly
preferred pharmaceutically acceptable salt of CILOMILAST is the
lithium salt of CILOMILAST. As an example for a hydrate of
CILOMILAST may be mentioned the monohydrate of the lithium salt of
CILOMILAST.
[0049] In another embodiment of the present invention the PDE4
inhibitor is AWD-12-281 or a pharmaceutically acceptable salt
thereof.
[0050] In another embodiment of the present invention a preferred
pharmaceutically acceptable salt of AWD-12-281 is the sodium salt
of AWD-12-281.
[0051] In another embodiment of the present invention the PDE4
inhibitor is TOFIMILAST or a pharmaceutically acceptable salt
thereof.
[0052] In another embodiment of the present invention the PDE4
inhibitor is TETOMILAST or a pharmaceutically acceptable salt
thereof.
[0053] In another embodiment of the present invention the PDE4
inhibitor is LIRIMILAST or a pharmaceutically acceptable salt
thereof.
[0054] In another embodiment of the present invention the PDE4
inhibitor is L-869298 or a pharmaceutically acceptable salt
thereof.
[0055] In another embodiment of the present invention the PDE4
inhibitor is OGLEMILAST or a pharmaceutically acceptable salt
thereof.
[0056] In another embodiment of the present invention preferred
pharmaceutically acceptable salts of OGLEMILAST are the mono-sodium
and the di-sodium salt of OGLEMILAST.
[0057] In another embodiment of the present invention the PDE4
inhibitor is COMPOUND A or a pharmaceutically acceptable salt
thereof.
TABLE-US-00001 TABLE 1 INN or Research Code Structure/Chemical Name
ROFLUMILAST ##STR00001##
3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-
(difluoromethoxy)benzamide N-oxide of ROFLUMI- Last = ROFLUMI-
LAST-N-oxide ##STR00002##
3-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-4-
(difluoromethoxy)benzamide CILOMILAST ##STR00003##
cis-4-cyano-4-[3-(cyclopentyloxy)-4-
methoxyphenyl]cyclohexanecarboxylic acid AWD-12-281 ##STR00004##
N-(3,5-dichloropyridin-4-yl
)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]- 2-oxoacetamide
TOFIMILAST ##STR00005##
9-cyclopentyl-7-ethyl-3-(2-thienyl)-6,9-dihydro-5H-pyrazolo[3,4-
c][1,2,4]triazolo[4,3-a]pyridine TETOMILAST ##STR00006##
6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic
acid LIRIMILAST ##STR00007##
3-[(aminocarbonyl)amino]-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl
methanesulfonate L-869298 ##STR00008##
2-{5-[(1S)-1-[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]-2-(1-
oxidopyridin-3-yl)ethyl]-1,3-thiazol-2-yl}-1,1,1,3,3,3-hexafluoropropan-2-
-ol OGLEMILAST ##STR00009##
N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8-
[(methylsulfonyl)amino]dibenzo[b,d]furan-1-carboxamide Compound A
##STR00010##
2-{4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-
phthalazin-2-yl]-piperidin-1-yl}-acetamide
Additional information with regard to the preparation, suitable
dosage forms and dose ranges of the PDE4 inhibitors ROFLUMILAST,
ROFLUMILAST-N-oxide and the pharmaceutically acceptable salts
thereof can be found in the following patents/patent applications:
WO9501338, WO03070279 and WO2006032676.
[0058] Additional information with regard to the preparation,
suitable dosage forms and dose ranges of the PDE4 inhibitors
CILOMILAST, AWD-12-281, TOFIMILAST, TETOMILAST, LIRIMILAST,
L-869298, OGLEMILAST, COMPOUND A and the pharmaceutically
acceptable salts thereof can be found in the following
patents/patent applications: WO9319749, WO9809946, WO9955696,
WO9639408, WO9209586, EP0731099, WO0170738, WO04089940 and
WO02064584.
[0059] The term "HMG-CoA reductase inhibitor" as used herein refers
to competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase, which catalyzes an early, rate-limiting step
in cholesterol biosynthesis, thereby lowering levels of cholesterol
and triglyceride in hyperlipidemic patients.
[0060] Non-limiting examples of HMG-CoA reductase inhibitors, which
may be usefully employed in the pharmaceutical compositions,
combination products and kits according to the invention are listed
in Table 2.
[0061] In one embodiment of the present invention the HMG-CoA
reductase inhibitor is selected from the group consisting of
LOVASTATIN (CAS-No. 75330-75-5), PRAVASTATIN (CAS-No. 081093-37-0),
SIMVASTATIN (CAS-No. 079902-63-9), ATORVASTATIN (CAS-No.
134523-00-5), FLUVASTATIN (093957-54-1), ROSUVASTATIN (CAS-No.
287714-41-4), PITAVASTATIN (CAS-No. 147511-69-1), BERVASTATIN
(CAS-No. 132017-01-7), DALVASTATIN (CAS-No. 132100-55-1),
GLENVASTATIN (CAS-No. 122254-45-9) and the pharmaceutically
acceptable salts of these compounds.
[0062] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is LOVASTATIN or a pharmaceutically acceptable
salt thereof.
[0063] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is PRAVASTATIN or a pharmaceutically acceptable
salt thereof.
[0064] In another embodiment of the present invention preferred
pharmaceutically acceptable salts of PRAVASTATIN are the potassium,
lithium, sodium and hemi-calcium salt of PRAVASTATIN. A
particularly preferred pharmaceutically acceptable salt of
PRAVASTATIN is the sodium salt of PRAVASTATIN.
[0065] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is SIMVASTATIN or a pharmaceutically acceptable
salt thereof.
[0066] In another embodiment of the present invention the
pharmaceutically acceptable salt of SIMVASTATIN is the sodium salt
of SIMVASTATIN.
[0067] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is ATORVASTATIN or a pharmaceutically
acceptable salt thereof.
[0068] In another embodiment of the present invention preferred
pharmaceutically acceptable salts of ATORVASTATIN are the
potassium, sodium and the hemi-calcium salt of ATORVASTATIN. A
particularly preferred pharmaceutically acceptable salt of
ATORVASTATIN is the hemi-calcium salt of ATORVASTATIN. As an
example for a hydrate of ATORVASTATIN may be mentioned the
trihydrate and the sesqui-hydrate of the hemi-calcium salt of
ATORVASTATIN.
[0069] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is FLUVASTATIN or a pharmaceutically acceptable
salt thereof.
[0070] In another embodiment of the present invention the
pharmaceutically acceptable salt of FLUVASTATIN is the sodium salt
of FLUVASTATIN.
[0071] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is ROSUVASTATIN or a pharmaceutically
acceptable salt thereof.
[0072] In another embodiment of the present invention preferred
pharmaceutically acceptable salts of ROSUVASTATIN are the
potassium, lithium, sodium, hemi-magnesium and the hemi-calcium
salt of ROSUVASTATIN. A particularly preferred pharmaceutically
acceptable salt of ROSUVASTATIN is the hemi-calcium salt of
ROSUVASTATIN. Another particularly preferred pharmaceutically
acceptable salt of ROSUVASTATIN is the sodium salt of
ROSUVASTATIN.
[0073] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is PITAVASTATIN or a pharmaceutically
acceptable salt thereof.
[0074] In another embodiment of the present invention preferred
pharmaceutically acceptable salts of PITAVASTATIN are the
potassium, sodium and the hemi-calcium salt of PITAVASTATIN. A
particularly preferred pharmaceutically acceptable salt of
PITAVASTATIN is the hemi-calcium salt of PITAVASTATIN.
[0075] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is BERVASTATIN or a pharmaceutically acceptable
salt thereof.
[0076] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is DALVASTATIN or a pharmaceutically acceptable
salt thereof.
[0077] In another embodiment of the present invention the HMG-CoA
reductase inhibitor is GLENVASTATIN or a pharmaceutically
acceptable salt thereof.
TABLE-US-00002 TABLE 2 INN or Research Code Structure/Chemical Name
LOVASTATIN ##STR00011##
(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-
yl]ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl
(2S)-2- methylbutanoate PRAVASTATIN ##STR00012##
(3S,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-{[(2S)-
2-methylbutanoyl]oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]heptanoic
acid SIMVASTATIN ##STR00013##
(1R,3S,7R,8R,8aS)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-
yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-
dimethylbutanoate ATORVASTATIN ##STR00014##
(3S,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-
- pyrrol-1-yl]-3,5-dihydroxyheptanoic acid FLUVASTATIN ##STR00015##
(3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-
dihydroxyhept-6-enoic acid ROSUVASTATIN ##STR00016##
(3R,5R)-7-{4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3,5-dihydroxyheptanoic
acid PITAVASTATIN ##STR00017##
(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-
dihydroxyhept-6-enoic acid BERVASTATIN ##STR00018## Ethyl
(3S,5S,6E)-7-[4-(4-fluorophenyl)spiro[chromene-2,1'-cyclopentan]-3-
yl]-3,5-dihydroxyhept-6-enoate DALVASTATIN ##STR00019##
(4R,6S)-6-{(E)-2-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-
- 1-en-1-yl]vinyl}-4-hydroxytetrahydro-2H-pyran-2-one GLENVASTATIN
##STR00020##
(4R,6S)-6-{(E)-2-[4-(4-fluorophenyl)-2-isopropyl-6-phenylpyridin-3-
yl]vinyl}-4-hydroxytetrahydro-2H-pyran-2-one
The HMG-CoA reductase inhibitors LOVASTATIN, PRAVASTATIN,
SIMVASTATIN, ATORVASTATIN, FLUVASTATIN, ROSUVASTATIN and
PITAVASTATIN listed in Table 2 are commercially available. The
person skilled in the art is familiar with suitable formulations
and dose ranges of these compounds. Additional information with
regard to the preparation, suitable dosage forms and dose ranges of
these HMG-CoA reductase inhibitors and the pharmaceutically
acceptable salts thereof can be found in the following
patents/patent applications: EP022478, DE3122499, EP033538,
EP0247633, EP0114027, EP0521471 and EP0304063.
[0078] Additional information with regard to the preparation,
suitable dosage forms and dose ranges of the HMG-CoA reductase
inhibitors BERVASTATIN, DALVASTATIN, GLENVASTATIN and the
pharmaceutically acceptable salts thereof can be found in the
following patents/patent applications: EP0380392, WO8905639 and
EP0307342.
[0079] Salts encompassed within the term "pharmaceutically
acceptable salts" are not restricted to the specific examples given
above. The term refers to non-toxic salts of the PDE4 inhibitors or
the HMG-CoA reductase inhibitors, which are generally prepared by
reacting a free base with a suitable organic or inorganic acid
(acid addition salt) or by reacting the free acid with a suitable
organic or inorganic base. Acid addition salts include, but are not
limited to, hydrochlorides, hydrobromides, phosphates, nitrates,
sulfates, acetates, citrates, D-gluconates, benzoates,
2-(4-hydroxybenzoyl)benzoates, butyrates, sulfosalicylates,
maleates, laurates, malates, fumarates, succinates, oxalates,
tartarates, stearates, toluenesulfonates, methanesulfonates,
3-hydroxy-2-naphthoates and trifluoroacetates. Examples of salts
with bases include, but are not limited to, lithium, sodium,
potassium, calcium, aluminum, magnesium, titanium, ammonium,
meglumine and guanidinium salts.
[0080] It is understood that the PDE4 inhibitors, the HMG-CoA
reductase inhibitors as well as their pharmaceutically acceptable
salts can also be present in the form of their pharmaceutically
acceptable solvates and in particular in the form of their
pharmaceutically acceptable hydrates.
[0081] The combinations according to the invention may be
administered by any suitable route, for example, by the oral,
sublingual, buccal, intravenous, intraarterial, intramuscular,
subcutaneous, intracutaneous, topical, transdermal, intranasal,
intraperitoneal, rectal or vaginal route, by inhalation or by
insufflation.
[0082] Tablets, coated tablets (dragees), pills, cachets, capsules
(caplets), granules, solutions, emulsions and suspensions are e.g.
suitable for oral administration. In particular, said formulations
can be adapted so as to represent, for example, an enteric form, an
immediate release form, a delayed release form, a repeated dose
release form, a prolonged release form or a sustained release form.
Said forms can be obtained, for example, by coating tablets, by
dividing tablets into several compartments separated by layers
disintegrating under different conditions (e.g. pH conditions) or
by coupling the active compound to a biodegradable polymer.
[0083] Administration by inhalation is preferably made by using an
aerosol. The aerosol is a liquid-gaseous dispersion, a
solid-gaseous dispersion or a mixed liquid/solid-gaseous
dispersion.
[0084] The aerosol may be generated by means of aerosol-producing
devices such as dry powder inhalers (DPIs), pressurized metered
dose inhalers (PMDIs) and nebulizers. Depending on the kind of the
active compound to be administered, the aerosol-producing device
can contain the active compound in form of a powder, a solution or
a dispersion. The powder may contain, for example, one or more of
the following auxiliaries: carriers, stabilizers and fillers. The
solution may contain in addition to the solvent, for example, one
or more of the following auxiliaries: propellants, solubilizers
(co-solvents), surfactants, stabilizers, buffers, tonicity
adjusting agents, preservatives and flavorings. The dispersion may
contain in addition to the dispersant, for example, one or more of
the following auxiliaries: propellants, surfactants, stabilizers,
buffers, preservatives and flavorings. Examples of carriers
include, but are not limited to, saccharides, e.g. lactose and
glucose. Examples of propellants include, but are not limited to,
fluorohydrocarbons, e.g. 1,1,1,2-tetrafluoroethane and
1,1,1,2,3,3,3-heptafluoropropane.
[0085] The particle size of the aerosol particles (solid, liquid or
solid/liquid particles) is preferably less than 100 .mu.m, more
preferably it is in the range of from 0.5 to 10 .mu.m, in
particular in the range of from 2 to 6 .mu.m (D50 value, measured
by laser diffraction).
[0086] For parenteral modes of administration such as, for example,
intravenous, intraarterial, intramuscular, subcutaneous,
intracutaneous and intraperitoneal administration, preferably
solutions (e.g. sterile solutions, isotonic solutions) are used.
They are preferably administered by injection or infusion
techniques.
[0087] The pharmaceutical compositions (formulations) comprising
the PDE4 inhibitor or a pharmaceutically acceptable salt thereof
and/or the HMG CoA reductase inhibitor or a pharmaceutically
acceptable salt thereof and at least one pharmaceutically
acceptable auxiliary can be manufactured in a manner known to a
person skilled in the art, e.g. by dissolving, mixing, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping
or lyophilizing processes. As pharmaceutically acceptable
auxiliaries, any auxiliaries known to be suitable for preparing
pharmaceutical compositions (formulations) can be used. Examples
thereof include, but are not limited to, solvents, excipients,
dispersants, emulsifiers, solubilizers, gel formers, ointment
bases, antioxidants, preservatives, stabilizers, carriers, fillers,
binders, thickeners, complexing agents, disintegrating agents,
buffers, permeation promoters, polymers, lubricants, coating
agents, propellants, tonicity adjusting agents, surfactants,
colorants, flavorings, sweeteners and dyes. In particular,
auxiliaries of a type appropriate to the desired formulation and
the desired mode of administration are used.
[0088] The most preferred mode of administration of Roflumilast,
Roflumilast-N-oxide or a pharmaceutically acceptable salt of either
is oral. In another preferred embodiment Roflumilast,
Roflumilast-N-oxide or a pharmaceutically acceptable salt of either
is administered by intravenous infusion or injection. In a further
embodiment Roflumilast, Roflumilast-N-oxide or a pharmaceutically
acceptable salt of either is administered by intramuscular or
subcutaneous injection. Other routes of administration are also
contemplated, including for example intranasal and transdermal
routes, and by inhalation.
[0089] The preferred mode of administration of the PDE4 inhibitors
CILOMILAST, TETOMILAST, LIRIMILAST, L-869298, OGLEMILAST and
COMPOUND A is oral, while the preferred mode of administration of
the PDE4 inhibitors AWD-12-281 and TOFIMILAST is administration by
inhalation.
[0090] The preferred mode of administration of the HMG CoA
reductase inhibitors LOVASTATIN, PRAVASTATIN; SIMVASTATIN;
ATORVASTATIN, FLUVASTATIN, ROSUVASTATIN, PITAVASTATIN, BERVASTATIN,
DALVASTATIN and GLENVASTATIN is oral.
[0091] The exact dosage and regimen for administering a PDE4
inhibitor or a pharmaceutically acceptable salt thereof in
combination with a HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof will necessarily depend on
the potency and duration of action of the active compounds used,
the nature and severity of the inflammatory pulmonary disease to be
treated, as well as the sex, age, weight, general health and
individual responsiveness of the patient to be treated, and other
relevant circumstances.
[0092] As part of the combination therapy according to the
invention the PDE4 inhibitor or a pharmaceutically acceptable salt
thereof and the HMG-CoA reductase inhibitor or a pharmaceutically
acceptable salt thereof are dosed in an order of magnitude
customary for the mono-therapy, it more likely being possible, on
account of the individual actions, which are mutually positively
influencing and reinforcing, to reduce the respective doses on the
combined administration of the PDE4 inhibitor or a pharmaceutically
acceptable salt thereof and the HMG-CoA reductase inhibitor or a
pharmaceutically acceptable salt thereof with the norm.
[0093] Without intended to be limiting, the orally administered
daily dosage (for an adult patient) of the PDE4 inhibitors or the
pharmaceutically acceptable salts thereof will generally range from
about 0.05 mg to about 200 mg; without intended to be limiting, the
daily dosage (for an adult patient) of a PDE4 inhibitor or a
pharmaceutically acceptable salt thereof for administration by
inhalation will generally range from 0.05 mg to about 100 mg.
[0094] In the case of oral administration of
3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamid-
e (ROFLUMILAST) the daily dose (for an adult patient) for the
mono-therapy is in the range from 50 to 1000 .mu.g per day,
preferably in the range of 50 to 500 .mu.g per day, preferably by
once daily administration. In the case of intravenous
administration of
3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamid-
e (ROFLUMILAST) the daily dose (for an adult patient) for the
mono-therapy is in the range from 50 to 500 .mu.g per day,
preferably 150 to 300 .mu.g per day.
[0095] In the case of oral administration of CILOMILAST the daily
dose (for an adult patient) for the monotherapy is likely to be in
the range from 10 to 40 mg per day, preferably from 20 to 30 mg per
day, preferably by twice daily administration.
[0096] In the case of administration by inhalation of AWD-12-281
the daily dosage (for an adult patient) for the mono-therapy is
likely to be in the range of 500 to 2000 .mu.g per day.
[0097] In the case of oral administration of LIRIMILAST the daily
dosage (for an adult patient) for the monotherapy is likely to be
in a range of 1 to 10 mg per day.
[0098] In the case of oral administration of OGLEMILAST the daily
dosage (for an adult patient) for the monotherapy is likely to be
in the range of 1 to 10 mg per day.
[0099] In the case of oral administration of COMPOUND A the daily
dosage (for an adult patient) for the monotherapy is likely to be
in a range of 0.1 to 10 mg once daily, preferably 0.1 to 2 mg once
daily.
[0100] The orally administered daily dosage (for an adult patient)
of the HMG-CoA reductase inhibitors or the pharmaceutically
acceptable salts thereof will generally range from about 0.01 mg to
about 200 mg, preferably from 10 to 80 mg, more preferably from 5
to 40 mg; for administration by inhalation a dosage range of 0.001
mg to about 25 mg is preferred, even more preferable is a dosage
from 0.1 to 25 mg.
TABLE-US-00003 TABLE 3 Preferred Combinations Example Number
Combination 1 ROFLUMILAST LOVASTATIN 2 ROFLUMILAST-N-Oxide
LOVASTATIN 3 ROFLUMILAST PRAVASTATIN 4 ROFLUMILAST-N-Oxide
PRAVASTATIN 5 ROFLUMILAST PRAVASTATIN sodium 6 ROFLUMILAST-N-Oxide
PRAVASTATIN sodium 7 ROFLUMILAST SIMVASTATIN 8 ROFLUMILAST-N-Oxide
SIMVASTATIN 9 ROFLUMILAST ATORVASTATIN 10 ROFLUMILAST-N-Oxide
ATORVASTATIN 11 ROFLUMILAST ATORVASTATIN hemi-calcium
sesqui-hydrate 12 ROFLUMILAST-N-Oxide ATORVASTATIN hemi-calcium
sesqui-hydrate 13 ROFLUMILAST FLUVASTATIN 14 ROFLUMILAST-N-Oxide
FLUVASTATIN 15 ROFLUMILAST FLUVASTATIN sodium 16
ROFLUMILAST-N-Oxide FLUVASTATIN sodium 17 ROFLUMILAST ROSUVASTATIN
18 ROFLUMILAST-N-Oxide ROSUVASTATIN 19 ROFLUMILAST ROSUVASTATIN
hemi-calcium 20 ROFLUMILAST-N-Oxide ROSUVASTATIN hemi-calcium 21
ROFLUMILAST ROSUVASTATIN sodium 22 ROFLUMILAST-N-Oxide ROSUVASTATIN
sodium 23 ROFLUMILAST PITAVASTATIN 24 ROFLUMILAST-N-Oxide
PITAVASTATIN 25 ROFLUMILAST PITAVASTATIN hemi-calcium 26
ROFLUMILAST-N-Oxide PITAVASTATIN hemi-calcium 27 ROFLUMILAST
BERVASTATIN 28 ROFLUMILAST-N-Oxide BERVASTATIN 29 ROFLUMILAST
DALVASTATIN 30 ROFLUMILAST-N-Oxide DALVASTATIN 31 ROFLUMILAST
GLENVASTATIN 32 ROFLUMILAST-N-Oxide GLENVASTATIN 33 CILOMILAST
LOVASTATIN 34 CILOMILAST PRAVASTATIN 35 CILOMILAST PRAVASTATIN
sodium 36 CILOMILAST SIMVASTATIN 37 CILOMILAST ATORVASTATIN 38
CILOMILAST ATORVASTATIN hemi-calcium sesqui-hydrate 39 CILOMILAST
FLUVASTATIN 40 CILOMILAST FLUVASTATIN sodium 41 CILOMILAST
ROSUVASTATIN 42 CILOMILAST ROSUVASTATIN hemi-calcium 43 CILOMILAST
ROSUVASTATIN sodium 44 CILOMILAST PITAVASTATIN 45 CILOMILAST
PITAVASTATIN hemi-calcium 46 CILOMILAST BERVASTATIN 47 CILOMILAST
DALVASTATIN 48 CILOMILAST GLENVASTATIN 49 AWD-12-281 LOVASTATIN 50
AWD-12-281 PRAVASTATIN 51 AWD-12-281 PRAVASTATIN sodium 52
AWD-12-281 SIMVASTATIN 53 AWD-12-281 ATORVASTATIN 54 AWD-12-281
ATORVASTATIN hemi-calcium sesqui-hydrate 55 AWD-12-281 FLUVASTATIN
56 AWD-12-281 FLUVASTATIN sodium 57 AWD-12-281 ROSUVASTATIN 58
AWD-12-281 ROSUVASTATIN hemi-calcium 59 AWD-12-281 ROSUVASTATIN
sodium 60 AWD-12-281 PITAVASTATIN 61 AWD-12-281 PITAVASTATIN
hemi-calcium 62 AWD-12-281 BERVASTATIN 63 AWD-12-281 DALVASTATIN 64
AWD-12-281 GLENVASTATIN 65 TOFIMILAST LOVASTATIN 66 TOFIMILAST
PRAVASTATIN 67 TOFIMILAST PRAVASTATIN sodium 68 TOFIMILAST
SIMVASTATIN 69 TOFIMILAST ATORVASTATIN 70 TOFIMILAST ATORVASTATIN
hemi-calcium sesqui-hydrate 71 TOFIMILAST FLUVASTATIN 72 TOFIMILAST
FLUVASTATIN sodium 74 TOFIMILAST ROSUVASTATIN 75 TOFIMILAST
ROSUVASTATIN hemi-calcium 76 TOFIMILAST ROSUVASTATIN sodium 77
TOFIMILAST PITAVASTATIN 78 TOFIMILAST PITAVASTATIN hemi-calcium 79
TOFIMILAST BERVASTATIN 80 TOFIMILAST DALVASTATIN 81 TOFIMILAST
GLENVASTATIN 82 TETOMILAST LOVASTATIN 83 TETOMILAST PRAVASTATIN 84
TETOMILAST PRAVASTATIN sodium 85 TETOMILAST SIMVASTATIN 86
TETOMILAST ATORVASTATIN 87 TETOMILAST ATORVASTATIN hemi-calcium
sesqui-hydrate 88 TETOMILAST FLUVASTATIN 89 TETOMILAST FLUVASTATIN
sodium 90 TETOMILAST ROSUVASTATIN 91 TETOMILAST ROSUVASTATIN
hemi-calcium 92 TETOMILAST ROSUVASTATIN sodium 93 TETOMILAST
PITAVASTATIN 94 TETOMILAST PITAVASTATIN hemi-calcium 95 TETOMILAST
BERVASTATIN 96 TETOMILAST DALVASTATIN 97 TETOMILAST GLENVASTATIN 98
OGLEMILAST LOVASTATIN 99 OGLEMILAST PRAVASTATIN 100 OGLEMILAST
PRAVASTATIN sodium 101 OGLEMILAST SIMVASTATIN 102 OGLEMILAST
ATORVASTATIN 103 OGLEMILAST ATORVASTATIN hemi-calcium sesqui-hydate
104 OGLEMILAST FLUVASTATIN 105 OGLEMILAST FLUVASTATIN sodium 106
OGLEMILAST ROSUVASTATIN 107 OGLEMILAST ROSUVASTATIN hemi-calcium
108 OGLEMILAST ROSUVASTATIN sodium 109 OGLEMILAST PITAVASTATIN 110
OGLEMILAST PITAVASTATIN hemi-calcium 111 OGLEMILAST BERVASTATIN 112
OGLEMILAST DALVASTATIN 113 OGLEMILAST GLENVASTATIN 114 COMPOUND A
LOVASTATIN 115 COMPOUND A PRAVASTATIN 116 COMPOUND A PRAVASTATIN
sodium 117 COMPOUND A SIMVASTATIN 118 COMPOUND A ATORVASTATIN 119
COMPOUND A ATORVASTATIN hemi-calcium sesqui-hydate 120 COMPOUND A
FLUVASTATIN 121 COMPOUND A FLUVASTATIN sodium 122 COMPOUND A
ROSUVASTATIN 123 COMPOUND A ROSUVASTATIN hemi-calcium 124 COMPOUND
A ROSUVASTATIN sodium 125 COMPOUND A PITAVASTATIN 126 COMPOUND A
PITAVASTATIN hemi-calcium 127 COMPOUND A BERVASTATIN 128 COMPOUND A
DALVASTATIN 129 COMPOUND A GLENVASTATIN
Pharmacology:
[0101] Synergistic Inhibition of LPS-Induced Systemic TNF.alpha.
Release in Rats by a Combination of ATORVASTATIN Hemi-Calcium
Sesqui-Hydrate and
2-{4-[(4aS,8aR)-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-pht-
halazin-2-yl]-piperidin-1-yl}-acetamide (COMPOUND A)
[0102] Animals: male Sprague Dawley rats 200-280 g
[0103] Drugs: ATORVASTATIN hemi-calcium sesqui-hydrate (Alexis
Pharmaceuticals, San Diego, Calif., USA) and COMPOUND A (ALTANA
Pharma, Konstanz, Germany).
[0104] Methods: Drugs were administered by gavage as a
methocel/polyethylenglycol 400 suspension 1 h before intravenous
administration of LPS (0.1 mg/kg). Euthanasia was induced 90
minutes later by injecting pentobarbital (48 mg/kg) and heparin
(1,000 U/kg). Heparinized blood was obtained by heart puncture.
Blood was centrifuged (21,000.times.g, 4.degree. C., 15 min), and
plasma samples were kept frozen at -80.degree. C. until
determination of TNF.alpha. levels by a commercially available
ELISA kit (Quantakine.RTM.M, Rat TNF.alpha. immunoassay, R&D,
MN, USA).
[0105] Statistics: All data are given as mean.+-.SEM. Significances
were calculated on the primary TNF.alpha. concentrations in
comparison with the LPS-challenged control group using ANOVA with
subsequent Dunnett's Test provided by GraphPadPrism software
package. Differences with p<0.05 were considered significant.
Dose-response curves were calculated by non-linear regression
analysis within fixed limits of 0 to 100% inhibition. 50%
inhibitory dose (ED.sub.50) values were derived from dose-response
curves.
[0106] Results: LPS-induced systemic TNF.alpha. release was dose
dependently inhibited by COMPOUND A and ATORVASTATIN calcium with
ED.sub.50 values of 0.14 mg/kg (FIG. 1) and 23 mg/kg (FIG. 2),
respectively. COMPOUND A at a dose of 0.013 mg/kg (1% increase
versus placebo) as well as ATORVASTATIN hemi-calcium sesqui-hydrate
at a dose of 0.5 mg/kg (11% decrease versus placebo) showed no
significant effects. However combination of COMPOUND A (0.13 mg/kg)
with ATORVASTATIN hemi-calcium sesqui-hydrate (0.5 mg/kg)
unexpectedly led to a significant inhibition of >50%
(P<0.01).
[0107] Conclusion: The combination of sub-effective doses of the
PDE4 inhibitor COMPOUND A and the HMG-CoA reductase inhibitor
ATORVASTATIN hemi-calcium sesqui-hydrate unexpectedly showed a
potent (synergistic) and effective inhibition of inflammatory
processes.
DESCRIPTION OF THE FIGURES
[0108] In the figures ATORVASTATIN hemi-calcium sesqui-hydrate is
indicated simply as "ATORVASTATIN Ca"
[0109] FIG. 1: Inhibition of LPS-induced (systemic) TNF.alpha.
release in rats by COMPOUND A
[0110] FIG. 2: Inhibition of LPS-induced (systemic) TNF.alpha.
release in rats by ATORVASTATIN hemi-calcium sesqui-hydrate
[0111] FIG. 3: Inhibition of LPS-induced (systemic) TNF.alpha.
release in rats by a combination of COMPOUND A and ATORVASTATIN
hemi-calcium sesqui-hydrate
* * * * *