WO2004098596A1

WO2004098596A1 - Composition comprising roflumilast and il-1 trap

Info

Publication number: WO2004098596A1
Application number: PCT/EP2004/050743
Authority: WO
Inventors: Johannes Barsig
Original assignee: Altana Pharma Ag
Priority date: 2003-05-12
Filing date: 2004-05-10
Publication date: 2004-11-18

Abstract

The invention relates to the combined administration of roflumilast and IL-1 Trap for the treatment of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental.

Description

COMPOSITION COMPRISING ROFLUMILAST AND IL-1 TRAP

Field of application of the invention

The invention relates to the combination of certain known active compounds for therapeutic purposes. The substances used in the combination according to the invention are known active compounds from the PDE4 inhibitor class and known active compounds from the interleukin-1 (IL-1) antagonist class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.

Prior art

In the international patent application WO95/01338 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5- dichloropyrid-4-yl)benzamide (INN: ROFLUMILAST), its N-Oxide and the use of these compounds as selective PDE4 inhibitors is described. In the International patent application WO03/39552 the combination of Roflumilast with several disease modifying anti-rheumatic drugs (DMARDs) is disclosed. In the Journal of Pharmacology and Experimental Therapeutics Vol. 297, 2001 pp. 267-279 and 280-290 the anti-inflammatory and immunomodulatory potential of Roflumilast in vitro, and its in vivo efficacy in airway disease models is described. In Emerging Drugs Vol. 5, 2000 pp. 309-319 the use of PDE4 inhibitors in the treatment of chronic obstructive pulmonary disease is reviewed. In the U.S. Patents Nos. 5,844,099 and 6,472,179 methods of making and using the Interleukin-1 (IL-1) Trap of Regen- eron Pharmaceuticals Inc are disclosed. In Current Opinion in Investigational Drugs Vol. 4 2003, pp. 593-597 a summary of available information concerning IL-1 Trap of Regeneron is given. In Nature Medicine Vol. 9, 2003, pp. 47-52 information about cytokine traps is given.

Summary of the invention

The invention relates to pharmaceutical compositions and methods for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental.

In particular it relates to compositions and methods for treating a disease mediated by phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity by administering a PDE4 inhibitor in combination with an IL-1 antagonist. In this connection, it is the object of the present invention to make available a certain anti-inflammatory therapeutic, which fulfills the following conditions:

Pronounced antiinflammatory action

Minor side effects

Good suitability for long-term therapy

It has now been found that the combined use of the PDE4 inhibitor roflumilast and the IL-1 antagonist IL-1 Trap outstandingly fulfills the abovementioned conditions.

Accordingly, the invention relates in a first aspect to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental by administering to a patient in need thereof simultaneously an effective amount of (1) roflumilast and (2) IL-1 Trap.

In a second aspect the invention relates to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is detrimental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1) roflumilast and (2) IL-1 Trap.

The invention also relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, comprising as a fixed combination an effective amount of

(a) roflumilast and

(b) IL-1 Trap and optionally

(c) a pharmaceutically acceptable carrier.

The invention further relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, comprising as a free combination an effective amount of

(a) roflumilast and optionally a pharmaceutically acceptable carrier and (b) IL-1 Trap and optionally a pharmaceutically acceptable carrier.

The invention additionally relates to a method for preparing a pharmaceutical composition which is effective for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, which method comprises mixing an effective amount of roflumilast and IL-1 Trap with a pharmaceutically acceptable carrier.

The invention furthermore relates to the use of a combination of roflumilast and IL-1 Trap for the preparation of a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is detrimental.

Detailed description of the invention

The combination therapy, which is the subject matter of this invention comprises administering roflumilast with IL-1 Trap to prevent onset of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental or to treat such an existing condition.

The invention thus relates to the combined use of roflumilast and IL-1 Trap in preventing the symptoms of, or treating a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental.

In the sense of the invention, the term "roflumilast" is understood to include the pharmaceutically acceptable salts and the N-oxide of ROFLUMILAST, which can likewise be used according to the invention.

ROFLUMILAST is the international non proprietary name (INN) for 3-cyclopropylmethoxy-4-difluoro- methoxy-N-(3,5-dichloropyrid-4-yl)benzamide [structure of formula (1.1)]. The preparation of 3-cyclo- propylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide, its pharmaceutically acceptable salts and its N-oxide [3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1 -oxypyrid-4-yl)- benzamide; structure of formula (1.2)] as well as the use of these compounds as phosphodiesterase (PDE) 4 inhibitors is described in WO95/01338.

Suitable pharmaceutically acceptable salts of ROFLUMILAST are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methaπesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.

It is understood that the active compounds and their pharmaceutically acceptable salts mentioned can also be present, for example, in the form of their pharmaceutically acceptable solvates, in particular in the form of their hydrates.

In the sense of the invention, the term "IL-1 Trap" is understood to represent the IL-1 Trap of Regen- eron Pharmaceuticals Inc. The IL-1 Trap is an Fc fusion protein consisting of both the IL-1 Type I Receptor and the IL-1 Receptor Accessory Protein. In the U.S. Patents Nos. 5,844,099 and 6,472,179 methods of making and using the Interleukin-1 (IL-1) Trap of Regeneron Pharmaceuticals Inc are disclosed.

"Diseases in which phosphodiesterase 4 (PDE4) and/or interleukins-1 (IL-1) activity is detrimental" which may be mentioned are in particular acute and chronic (in particular inflammatory and allergen- induced) airway disorders of varying origin (bronchitis, allergic bronchitis, chronic bronchitis, bronchial asthma, severe bronchial asthma, emphysema, COPD, pulmonary sarcoidosis, pulmonary fibrosis, silicio- sis); dermatoses (especially of proliferative, inflammatory and allergic type) such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders; disorders which are based on an excessive release of TNF and leukot- rienes, for example disorders of the arthritis type (rheumatoid arthritis, psoriatric arthritis, juvenile rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions), spondy- larthropathies (ankylosing spondylitis), Wegener's granulomatosis, adult Still's disease, Behcet's disease, polymyositis, myelodysplastic syndrome, scleroderma, dermatomyositis, Sjogren's syndrome, disorders of the immune system (AIDS), autoimmune diseases (e.g., Multiple Sclerosis, allergy, autoimmune uveitis and nephritic syndrome), transplant rejection, including rejections of allografts and xenografts, graft versus host disease, types of shock [septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)] and also generalized inflammations in the gastrointestinal region (Inflammatory bowel disease, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reactions in the region of the upper airways (pharynx, nose) and the adjacent regions (paranasal sinuses, eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitis and also nasal polyps; but also disorders of the heart which can be treated by PDE and/or TNFα inhibitors, such as cardiac insufficiency, ischemia of the heart and congestive heart failure, or disorders which can be treated on account of the tissue-relaxant action of the PDE inhibitors, such as colics of the kidneys and of the ureters in connection with kidney stones. The pharmaceutical compositions according to the invention can furthermore be used in the treatment of conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease or multiinfarct dementia; in the treatment of malignancies to inhibit tumor growth, or metastasis, and/or to alleviate cachexia secondary to malignancy; in the treatment of infectious diseases like bacterial meningitis, cachexia or cerebral malaria; and in the treatment of diseases like inflammatory bone disease, bone resorption disease, hepatitis, viral hepatitis, reperfusion injury, scar tissue formation, pyrexia, periodontal disease and radiation toxicity. The pharmaceutical compositions according to the invention can as well be used in the treatment of chronic fever syndromes, metabolic syndrome and sequalae, e.g. type 2 diabetes.

The phrase "combined use" (or "combination") embraces the administration of roflumilast and IL-1 Trap as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually, minutes, hours, days or weeks depending upon the combination selected). "Combined use" generally is not intended to encompass the administration of two of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.

"Combined use" or "combination" within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament - fixed combination) or more or less simultaneously, respectively in succession (from separate pack units -free combination; directly in succession or else alternatively at a relatively large time interval). As an example, one therapeutic agent could be taken in the morning and one later in the day. Or in another scenario, one therapeutic agent could be taken once daily and the other once weekly or only once in a 2 weeks time interval. Simultaneous administration preferably is accomplished by administering to the subject in need thereof, for example, a single intravenous injection having a fixed ratio of each therapeutic agent. More or less simultaneous administration or administration in succession of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and by infusion techniques. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous or subcutaneous injection while the other therapeutic agent of the combination may be administered orally. The sequence in which the therapeutic agents are administered is not narrowly critical.

The therapeutic agent(s) according to the invention may be administered in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., inject- able and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes or suppositories. The preferred form depends on the intended mode of administration and therapeutic application.

The most preferred mode of administration of roflumilast is oral. In another preferred e bodiment roflumilast is administered by intravenous infusion or injection. In a further embodiment roflumilast is administered by intramuscular or subcutaneous injection. Other routes of administration are also contemplated, including intranasal and transdermal routes, and by inhalation.

Typically pharmaceutical compositions for use according to the invention include the IL-1 Trap in a pharmacologically acceptable liquid, solid or semi-solid carrier, linked to a carrier or targeting molecule (e.g., antibody, hormone, growth factor, etc.) and/or incorporated into liposomes, microcapsules, and controlled release preparation (including antagonist expressing cells) prior to administration in vivo. For example, the pharmaceutical composition comprise the IL-1 Trap in an aqueous solution, such as sterile water, saline, phosphate buffer or dextrose solution. Alternatively, IL-1 Trap may be comprised in a solid (e.g. wax) or semi-solid (e.g. gelatinous) formulation that may be implanted into a patient in need of such treatment. The administration route may be any mode of administration known in the art, including but not limited to intravenously, intrathecally, subcutaneously, by injection into involved tissue, intraarterially, intranasally, orally, or via an implanted device.

Typically, the therapeutic agent(s) according to the invention will be administered in the form of a composition comprising the therapeutic agent in conjunction with pharmaceutically acceptable carriers. In this connection "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial, and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, giycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example sug- ars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life and the effectiveness of the therapeutic agent(s).

Therapeutic compositions typically must be sterile and stable under the condition of manufacture and storage. The composition can be formulated, for example, as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.

Sterile injectable solutions can be prepared by incorporating the therapeutic agent(s) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic agent(s) into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the therapeutic agent(s) plus any additional desired ingredient from the previously sterile filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, mono- stearate salts and gelatin.

The therapeutic agent(s) of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route of administration for a fixed combination of roflumilast and the IL-1 Trap according to the invention is intravenous injection or infusion.

In certain embodiments, the therapeutic agent(s) may be prepared with a carrier that will protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhyd rides, polyglycolic acid, collagen, polyorthoesters, and poylactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art.

In certain embodiments, the therapeutic agent(s) of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier. The therapeutic agent(s) may also be enclosed in a hard or soft shell gelatine capsule or compressed into tablets. For oral therapeutic admin- stration the therapeutic agent(s) may be incorporated with excipients and used in the form of ingesta- ble tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer the therapeutic agent(s) according to the invention it may be necessary to coat the therapeutic agent(s) with, or co-administer with the therapeutic agent(s) with, a material to prevent its inac- tivation.

The therapeutic agent(s) are dosed in an order of magnitude customary for the individual dose, 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 therapeutic agent(s) with the norm.

In case of oral administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)- benzamide (ROFLUMILAST), the adult daily dose is in the range from 50 - 1000μg, preferably in the range from 250 - 500μg, preferably by once daily administration.

In case of subcutaneous administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro- pyrid-4-yl)benzamide (ROFLUMILAST), the adult daily dose is in the range from 50 - 1000μg, preferably in the range from 250 - 500μg.

In case of intravenous administration of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid- 4-yl)benzamide (ROFLUMILAST), the adult daily dose is in the range from 50 - 600μg, preferably in the range from 150 - 300μg.

An exemplary, non-limiting range for the IL-1 Trap is 50-800 μg/kg body weight of the subject to be treated by a once weekly administration.

In one embodiment of the present invention the adult dose of the IL-1 Trap is 25-100 mg administered by a once weekly subcutaneous injection.

Claims

Patent claims

1. Combined use of roflumilast and IL-1 Trap for preventing or reducing the onset of symptoms of, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, in a patient in need thereof.

2. Pharmaceutical composition suited for the combined use according to claim 1 , comprising as a fixed combination an effective amount of

(a) roflumilast and

(b) IL-1 Trap and optionally

(c) a pharmaceutically acceptable carrier.

3. Pharmaceutical composition according to claim 2, which is a fixed injectable combination.

4. Pharmaceutical composition suited for the combined use according to claim 1 , comprising as a free combination an effective amount of

(a) roflumilast and optionally a pharmaceutically acceptable carrier and

(b) IL-1 Trap and optionally a pharmaceutically acceptable carrier.

5. Method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental by administering to a patient in need thereof simultaneously an effective amount of (1) roflumilast and (2) IL-1 Trap.

6. Method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1) roflumilast and (2) IL-1 Trap.

7. Use of a combination of roflumilast and IL-1 Trap for the preparation of a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental.

8. Pharmaceutical composition, use or method according to any of claims 1 to 7, wherein roflumilast represents 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide.

9. Pharmaceutical composition, use or method according to any of claims 1 to 7, wherein roflumilast represents 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1 -oxy-pyrid-4-yl)benzamide.

10. Pharmaceutical composition, use or method according to any of claims 1 to 9, wherein the disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental is selected from rheumatoid arthritis, psoriasis, psoriatric arthritis, juvenile arthritis, inflammatory bowel disease, spondylarthropathies (ankylosing spondylitis), adult-onset Still's disease, Behcet's disease, polymyositis, sarcoidosis, Wegener granulomatosis, myelodysplastic syndrome, inflammatory myositis, Sjόgren syndrome, severe chronic asthma, septic shock, uveitis and graft versus host disease.

11. Pharmaceutical composition, use or method according to any of claims 1 to 9, wherein the disease in which phosphodiesterase 4 (PDE4) and/or interleukin-1 (IL-1) activity is detrimental is selected from rheumatoid arthritis, psoriasis, psoriatric arthritis, juvenile arthritis, inflammatory bowel disease and spondylarthropathies (ankylosing spondylitis).