Title:
Combination of HMG-COA Reductase Inhibitors with Phosphodiesterase 4 Inhibitors for the Treatment of Inflammatory Pulmonary Disease
Kind Code:
A1


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)
Application Number:
12/308878
Publication Date:
03/18/2010
Filing Date:
07/03/2007
Assignee:
Nycomed GmbH (Konstanz, DE)
Primary Class:
Other Classes:
514/293, 514/339, 514/342, 514/352, 514/423, 514/460, 514/470, 514/548, 514/567
International Classes:
A61K31/502; A61K31/192; A61K31/215; A61K31/343; A61K31/366; A61K31/40; A61K31/437; A61K31/44; A61K31/4439; A61P11/00; A61P11/04; A61P29/00
View Patent Images:



Foreign References:
WO2002064584A12002-08-22
Other References:
Ascer et al. in Atherosclerosis 177 (2004) 161 - 166
Primary Examiner:
HEYER, DENNIS
Attorney, Agent or Firm:
NATH & ASSOCIATES PLLC (112 South West Street, Alexandria, VA, 22314, US)
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-phthalazin-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-yl]-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

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

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.

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.

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 TNFα 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.

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.

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.

HMG-CoA reductase inhibitors, by a route different from PDE4 inhibitors, are also useful in the treatment of inflammatory diseases.

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

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.

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.

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.

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.

Thus, there is further provided:

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.

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.

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.

Therefore, further aspects of the invention are:

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.

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.

Pharmaceutical composition, combination product or kit, as described in the preceding paragraphs, for use as a medicament.

Pharmaceutical composition, combination product or kit, as described in the preceding paragraphs, for the preventive or curative treatment of an inflammatory pulmonary disease.

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.

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.

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.

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.

The pharmaceutical compositions according to the invention may be prepared by mixing the first active agent with the second active agent.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

The term “active compound” as used herein refers to a compound useful in the preventive or curative treatment of a disease.

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.

The term “patient” includes both humans and other mammals. In a preferred embodiment of the invention the term “patient” stands for humans.

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.

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.

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-phthalazin-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.

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.

In another embodiment of the present invention the PDE4 inhibitor is ROFLUMILAST.

In another embodiment of the present invention the PDE4 inhibitor is ROFLUMILAST-N-oxide.

In another embodiment of the present invention the PDE4 inhibitor is CILOMILAST or a pharmaceutically acceptable salt thereof.

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.

In another embodiment of the present invention the PDE4 inhibitor is AWD-12-281 or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention a preferred pharmaceutically acceptable salt of AWD-12-281 is the sodium salt of AWD-12-281.

In another embodiment of the present invention the PDE4 inhibitor is TOFIMILAST or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the PDE4 inhibitor is TETOMILAST or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the PDE4 inhibitor is LIRIMILAST or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the PDE4 inhibitor is L-869298 or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the PDE4 inhibitor is OGLEMILAST or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention preferred pharmaceutically acceptable salts of OGLEMILAST are the mono-sodium and the di-sodium salt of OGLEMILAST.

In another embodiment of the present invention the PDE4 inhibitor is COMPOUND A or a pharmaceutically acceptable salt thereof.

TABLE 1
INN or Research CodeStructure/Chemical Name
ROFLUMILAST 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4- (difluoromethoxy)benzamide
N-oxide of ROFLUMI- Last = ROFLUMI- LAST-N-oxide 3-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-4- (difluoromethoxy)benzamide
CILOMILAST cis-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexanecarboxylic acid
AWD-12-281 N-(3,5-dichloropyridin-4-yl )-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]- 2-oxoacetamide
TOFIMILAST 9-cyclopentyl-7-ethyl-3-(2-thienyl)-6,9-dihydro-5H-pyrazolo[3,4- c][1,2,4]triazolo[4,3-a]pyridine
TETOMILAST 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid
LIRIMILAST 3-[(aminocarbonyl)amino]-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl methanesulfonate
L-869298 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 N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8- [(methylsulfonyl)amino]dibenzo[b,d]furan-1-carboxamide
Compound A 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.

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.

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.

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.

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.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is LOVASTATIN or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is PRAVASTATIN or a pharmaceutically acceptable salt thereof.

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.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is SIMVASTATIN or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the pharmaceutically acceptable salt of SIMVASTATIN is the sodium salt of SIMVASTATIN.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is ATORVASTATIN or a pharmaceutically acceptable salt thereof.

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.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is FLUVASTATIN or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the pharmaceutically acceptable salt of FLUVASTATIN is the sodium salt of FLUVASTATIN.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is ROSUVASTATIN or a pharmaceutically acceptable salt thereof.

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.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is PITAVASTATIN or a pharmaceutically acceptable salt thereof.

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.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is BERVASTATIN or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is DALVASTATIN or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention the HMG-CoA reductase inhibitor is GLENVASTATIN or a pharmaceutically acceptable salt thereof.

TABLE 2
INN or Research CodeStructure/Chemical Name
LOVASTATIN (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 (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 (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 (3S,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H- pyrrol-1-yl]-3,5-dihydroxyheptanoic acid
FLUVASTATIN (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5- dihydroxyhept-6-enoic acid
ROSUVASTATIN (3R,5R)-7-{4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl}-3,5-dihydroxyheptanoic acid
PITAVASTATIN (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5- dihydroxyhept-6-enoic acid
BERVASTATIN Ethyl (3S,5S,6E)-7-[4-(4-fluorophenyl)spiro[chromene-2,1′-cyclopentan]-3- yl]-3,5-dihydroxyhept-6-enoate
DALVASTATIN (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 (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.

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.

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.

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.

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.

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.

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.

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.

The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably it is in the range of from 0.5 to 10 μm, in particular in the range of from 2 to 6 μm (D50 value, measured by laser diffraction).

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.

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.

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.

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.

The preferred mode of administration of the HMG CoA reductase inhibitors LOVASTATIN, PRAVASTATIN; SIMVASTATIN; ATORVASTATIN, FLUVASTATIN, ROSUVASTATIN, PITAVASTATIN, BERVASTATIN, DALVASTATIN and GLENVASTATIN is oral.

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.

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.

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.

In the case of oral administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide (ROFLUMILAST) the daily dose (for an adult patient) for the mono-therapy is in the range from 50 to 1000 μg per day, preferably in the range of 50 to 500 μg per day, preferably by once daily administration. In the case of intravenous administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide (ROFLUMILAST) the daily dose (for an adult patient) for the mono-therapy is in the range from 50 to 500 μg per day, preferably 150 to 300 μg per day.

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.

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 μg per day.

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.

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.

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.

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 3
Preferred Combinations
Example
NumberCombination
1ROFLUMILASTLOVASTATIN
2ROFLUMILAST-N-OxideLOVASTATIN
3ROFLUMILASTPRAVASTATIN
4ROFLUMILAST-N-OxidePRAVASTATIN
5ROFLUMILASTPRAVASTATIN sodium
6ROFLUMILAST-N-OxidePRAVASTATIN sodium
7ROFLUMILASTSIMVASTATIN
8ROFLUMILAST-N-OxideSIMVASTATIN
9ROFLUMILASTATORVASTATIN
10ROFLUMILAST-N-OxideATORVASTATIN
11ROFLUMILASTATORVASTATIN
hemi-calcium
sesqui-hydrate
12ROFLUMILAST-N-OxideATORVASTATIN
hemi-calcium
sesqui-hydrate
13ROFLUMILASTFLUVASTATIN
14ROFLUMILAST-N-OxideFLUVASTATIN
15ROFLUMILASTFLUVASTATIN sodium
16ROFLUMILAST-N-OxideFLUVASTATIN sodium
17ROFLUMILASTROSUVASTATIN
18ROFLUMILAST-N-OxideROSUVASTATIN
19ROFLUMILASTROSUVASTATIN
hemi-calcium
20ROFLUMILAST-N-OxideROSUVASTATIN
hemi-calcium
21ROFLUMILASTROSUVASTATIN sodium
22ROFLUMILAST-N-OxideROSUVASTATIN sodium
23ROFLUMILASTPITAVASTATIN
24ROFLUMILAST-N-OxidePITAVASTATIN
25ROFLUMILASTPITAVASTATIN
hemi-calcium
26ROFLUMILAST-N-OxidePITAVASTATIN
hemi-calcium
27ROFLUMILASTBERVASTATIN
28ROFLUMILAST-N-OxideBERVASTATIN
29ROFLUMILASTDALVASTATIN
30ROFLUMILAST-N-OxideDALVASTATIN
31ROFLUMILASTGLENVASTATIN
32ROFLUMILAST-N-OxideGLENVASTATIN
33CILOMILASTLOVASTATIN
34CILOMILASTPRAVASTATIN
35CILOMILASTPRAVASTATIN sodium
36CILOMILASTSIMVASTATIN
37CILOMILASTATORVASTATIN
38CILOMILASTATORVASTATIN
hemi-calcium
sesqui-hydrate
39CILOMILASTFLUVASTATIN
40CILOMILASTFLUVASTATIN sodium
41CILOMILASTROSUVASTATIN
42CILOMILASTROSUVASTATIN
hemi-calcium
43CILOMILASTROSUVASTATIN sodium
44CILOMILASTPITAVASTATIN
45CILOMILASTPITAVASTATIN
hemi-calcium
46CILOMILASTBERVASTATIN
47CILOMILASTDALVASTATIN
48CILOMILASTGLENVASTATIN
49AWD-12-281LOVASTATIN
50AWD-12-281PRAVASTATIN
51AWD-12-281PRAVASTATIN sodium
52AWD-12-281SIMVASTATIN
53AWD-12-281ATORVASTATIN
54AWD-12-281ATORVASTATIN
hemi-calcium
sesqui-hydrate
55AWD-12-281FLUVASTATIN
56AWD-12-281FLUVASTATIN sodium
57AWD-12-281ROSUVASTATIN
58AWD-12-281ROSUVASTATIN
hemi-calcium
59AWD-12-281ROSUVASTATIN sodium
60AWD-12-281PITAVASTATIN
61AWD-12-281PITAVASTATIN
hemi-calcium
62AWD-12-281BERVASTATIN
63AWD-12-281DALVASTATIN
64AWD-12-281GLENVASTATIN
65TOFIMILASTLOVASTATIN
66TOFIMILASTPRAVASTATIN
67TOFIMILASTPRAVASTATIN sodium
68TOFIMILASTSIMVASTATIN
69TOFIMILASTATORVASTATIN
70TOFIMILASTATORVASTATIN
hemi-calcium
sesqui-hydrate
71TOFIMILASTFLUVASTATIN
72TOFIMILASTFLUVASTATIN sodium
74TOFIMILASTROSUVASTATIN
75TOFIMILASTROSUVASTATIN
hemi-calcium
76TOFIMILASTROSUVASTATIN sodium
77TOFIMILASTPITAVASTATIN
78TOFIMILASTPITAVASTATIN
hemi-calcium
79TOFIMILASTBERVASTATIN
80TOFIMILASTDALVASTATIN
81TOFIMILASTGLENVASTATIN
82TETOMILASTLOVASTATIN
83TETOMILASTPRAVASTATIN
84TETOMILASTPRAVASTATIN sodium
85TETOMILASTSIMVASTATIN
86TETOMILASTATORVASTATIN
87TETOMILASTATORVASTATIN
hemi-calcium
sesqui-hydrate
88TETOMILASTFLUVASTATIN
89TETOMILASTFLUVASTATIN sodium
90TETOMILASTROSUVASTATIN
91TETOMILASTROSUVASTATIN
hemi-calcium
92TETOMILASTROSUVASTATIN sodium
93TETOMILASTPITAVASTATIN
94TETOMILASTPITAVASTATIN
hemi-calcium
95TETOMILASTBERVASTATIN
96TETOMILASTDALVASTATIN
97TETOMILASTGLENVASTATIN
98OGLEMILASTLOVASTATIN
99OGLEMILASTPRAVASTATIN
100OGLEMILASTPRAVASTATIN sodium
101OGLEMILASTSIMVASTATIN
102OGLEMILASTATORVASTATIN
103OGLEMILASTATORVASTATIN
hemi-calcium
sesqui-hydate
104OGLEMILASTFLUVASTATIN
105OGLEMILASTFLUVASTATIN sodium
106OGLEMILASTROSUVASTATIN
107OGLEMILASTROSUVASTATIN
hemi-calcium
108OGLEMILASTROSUVASTATIN sodium
109OGLEMILASTPITAVASTATIN
110OGLEMILASTPITAVASTATIN
hemi-calcium
111OGLEMILASTBERVASTATIN
112OGLEMILASTDALVASTATIN
113OGLEMILASTGLENVASTATIN
114COMPOUND ALOVASTATIN
115COMPOUND APRAVASTATIN
116COMPOUND APRAVASTATIN sodium
117COMPOUND ASIMVASTATIN
118COMPOUND AATORVASTATIN
119COMPOUND AATORVASTATIN
hemi-calcium
sesqui-hydate
120COMPOUND AFLUVASTATIN
121COMPOUND AFLUVASTATIN sodium
122COMPOUND AROSUVASTATIN
123COMPOUND AROSUVASTATIN
hemi-calcium
124COMPOUND AROSUVASTATIN sodium
125COMPOUND APITAVASTATIN
126COMPOUND APITAVASTATIN
hemi-calcium
127COMPOUND ABERVASTATIN
128COMPOUND ADALVASTATIN
129COMPOUND AGLENVASTATIN

Pharmacology:

Synergistic Inhibition of LPS-Induced Systemic TNFα 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-phthalazin-2-yl]-piperidin-1-yl}-acetamide (COMPOUND A)

Animals: male Sprague Dawley rats 200-280 g

Drugs: ATORVASTATIN hemi-calcium sesqui-hydrate (Alexis Pharmaceuticals, San Diego, Calif., USA) and COMPOUND A (ALTANA Pharma, Konstanz, Germany).

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×g, 4° C., 15 min), and plasma samples were kept frozen at −80° C. until determination of TNFα levels by a commercially available ELISA kit (Quantakine®M, Rat TNFα immunoassay, R&D, MN, USA).

Statistics: All data are given as mean±SEM. Significances were calculated on the primary TNFα 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 (ED50) values were derived from dose-response curves.

Results: LPS-induced systemic TNFα release was dose dependently inhibited by COMPOUND A and ATORVASTATIN calcium with ED50 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).

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

In the figures ATORVASTATIN hemi-calcium sesqui-hydrate is indicated simply as “ATORVASTATIN Ca”

FIG. 1: Inhibition of LPS-induced (systemic) TNFα release in rats by COMPOUND A

FIG. 2: Inhibition of LPS-induced (systemic) TNFα release in rats by ATORVASTATIN hemi-calcium sesqui-hydrate

FIG. 3: Inhibition of LPS-induced (systemic) TNFα release in rats by a combination of COMPOUND A and ATORVASTATIN hemi-calcium sesqui-hydrate