Field of the Invention

[0001] The present invention relates to a pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]gly- oxylic acid amide.

Background of the Invention

[0002] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl)]glyoxylic acid amide is a 7-azaindole and an inhibitor of phosphodiesterase 4 (cf. EP 1 330 455). Accordingly, diseases can be treated with this active agent, in the case of which inhibition of PDE-4 is favorable and in particular COPO.

[0003] Activation of cell membrane receptors by transmitters leads to activation of the second messenger system. Adenylate cyclase synthesizes the active cyclic AMP (cAMP) and cyclic GMP (cGMP) respectively from AMP and GMP. cAMP and cGMP lead for example in smooth muscle cells to relaxation, and in inflammatory cells to inhibition of mediator release and synthesis. The second messengers cAMP and cOMP are degraded by phosphodiesterases (POE). To date, 1 1 families of POE enzymes (POEI -1 1 ) are known and differ through their substrate specificity (cAMP, cGMP or both) and the dependence on other substrates (e.g. calmodulin). These isoenzymes have different functions in the body and are expressed differently in individual cell types (Beavo, J. A. , Conti, M. and Heaslip, R. J., Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46:399-405; Hall, I. P., Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. din. Pharmacol. 1993, 35: 1 -7). Inhibition of the various POE isoenzyme types results in accumulation of cAMP or cGMP in cells, which can be utilized therapeutically (Torphy, T. J., Livi, G. P., Christensen, S. B. Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Orug News and Perspectives 1993, 6:203-214).

[0004] The predominant PDE-isoenzyme in cells important for allergic inflammations (lymphocytes, mast cells, eosinophilic granulocytes, macrophages) is that of type 4 (Torphy, J. T. and Undem, B. J., Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991 , 46:512-523). Inhibition of PDE 4 by suitable inhibitors is therefore regarded as an important approach to the therapy of a large number of allergically induced disorders (Schudt, Ch., Dent, C, Rabe, K, Phosphodiesterase Inhibitors, Academic Press London 1996).

[0005] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl)]glyoxylic acid amide is extremely water insoluble. Therefore, the compound cannot be solved in water. The low water-solubility coincides with a very low bioavailability. When administering the compound as suspension in water or in micronized form, a bioavailability of less than 5% was detected.

[0006] Attempts to enhance water solubility and, as a result thereof, bioavailability with formulation aids known for that purpose from other active agents such as cyclodextrin embedding or use of various surfactants did not result in a considerable improvement of bioavailability either.

[0007] Therefore, it was an object of the present invention to provide N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in a formulation providing high bioavailability.This object is achieved by the pharmaceutical composition of the present invention.

Summary of the Invention

[0008] The present invention relates to a pharmaceutical composition comprising

(i) N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide

(ii) a binder material, and

(iii) a carrier material.

[0009] The invention also relates to the pharmaceutical composition for use in the treatment and/or prophylaxis of diseases specified below.

[0010] Further, the invention relates to a process for the preparation of the pharmaceutical composition, comprising

(a) providing a carrier material (iii), and

(b) granulating said carrier material with active agent (i) and a binder material (ii).

Detailed Description of the Invention

[0011] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl)]glyoxylic acid amide has the structural formula

[0012] and is also named ELB353 or Ronomilast.

[0013] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-y)]glyoxylic acid amide has a very low solubility. Therefore, a therapeutical utility, in particular, with oral administration of N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide is difficult to achive. Since the solubility in water is just about 0.1 mg/l, only a very low bioavailability can be obtained.

[0014] Several tests using a series of formulations revealed that, in particular, standard formulations for increasing bioavailability of other drugs do not or only very little increase bioavailability of N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide.

[0015] The inventors have now found that by the composition according to the invention the active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoro- benzyl)-7-azaindol-3-yl)]glyoxylic acid amide can be provided in a manner particularly available to the body.

[0016] ELB353 is an extremely poorly soluble drug substance with a very low intrinsic bioavailability. Pharmaceutical formulation approaches which are commonly used for improvement of bioavailability of poorly soluble drugs - like cyclodextrin embedding, use of different surfactants or formation of solid dispersions and/or solution etc. - were not successful for ELB353 (see Examples 01 to 06) respectively, a very moderate bioavailability was observed only. By the present invention, it was found that the bioavailability of ELB353 is significantly improved. By this way, it became possible to administer ELB353 as an oral solid dosage form like capsules or tablets in a wide range ofstrengths (see Examples 07, 09 and 10).

[0017] With the composition of the present invention, in particular, a bioavailability of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide of greater than 50%, preferably greater than 60%, in particular, greater than 70%, and, in particular, greater than 80% can be achieved. [0018] By the present invention, a high bioavailability of N-(3,5-di- chloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)] glyoxylic acid amide is obtained despite its very low water solubility of only 0.1 mg/l. Further, in the the composition of the invention, the amount of N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)] glyoxylic acid amide can be relatively high. In particular, it is possible to provide dosages of e.g. up to 500 mg. The dosage of the active compound may vary depending on age and weight of the patient, nature and severity of the disorders to be treated, and similar factors. The daily dose may be given as a single dose to be administered once a day or divided into two or more daily doses. The daily dose is usually between 0.001 to 500 mg, preferably from 0.1 to 300 mg, more preferably from 1 .0 to 200 mg, and even more preferably from 10 to 100 mg.

[0019] The active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoro- benzyl)7-azaindol-3-yl)] glyoxylic acid amide is preferably used in micronized form. Preferably, air-jet milled active agent, even more preferably sand-milled active agent is used.

[0020] In a particularly preferred embodiment, the active agent is used in crystalline form II having a powder X-ray diffraction pattern at values of diffraction angle (2 Θ) as presented below:

Angle in

din A

2-Theta°

17.386 5.0965

20.947 4.2374

22.099 4.0190

25.488 3.4918

28.320 3.1488

31.560 2.8325

32.578 2.7463

36.098 2.4861

36,661 2.4492

38.522 2,3351

[0021] As a binder material, preferably a polymeric material is used, especially preferably a cellulose. Especially preferably, the binder material used is hydroxypropyl cellulose (HPC) and, even more preferably, hydroxypropyl methylcellulose (HPMC). Excellent bioavailability results were obtained, in particular, when using hydroxypropyl methylcellulose. Thus, especially preferably, hydroxypropyl methylcellulose is used as binder material. [0022] In a preferred embodiment, the composition does not contain any polyvinyl pyrrolidone. In a further preferred embodiment, the inventive formulation is free of methacrylic copolymers.

[0023] The composition, further, contains a carrier material, in particular, a sugar. Sugars suitable as carrier material e.g. are lactose, mannitol, glucose, xylitol, maltose and/or sorbitol. A particularly suitable sugar is lactose.

[0024] The composition of the invention may also contain pharmaceutically suitable additives, carriers or adjuvants. For example, the composition can contain separation agents and/or lubrication agents such as magnesium stearate. Magnesium stearate proved to be a particularly favorable lubrication agent.

[0025] In a preferred embodiment, the pharmaceutical composition contains the individual components (i) to (iii) in the following amounts:

[0026] from 0.3 wt.% to 40 wt.%, in particular, from I wt.% to 30 wt.%, and preferably from 6 wt.% to 20 wt.% of component (i) as active agent;

[0027] from 002 wt% to 5 wt.%, in particular, from 0.4 wt% to 2.5 wt.% binder material (ii), preferably a cellulose, and, in particular, hydroxypropyl

[0028] methylcellulose; and

[0029] from 50 to 99 wt.%, in particular, from 70 to 90 wt.% carrier material (iii), preferably a sugar, and, in particular, lactose.

[0030] The weight ratio of active agent to the sum of all other ingredients of the composition is preferably from 1 : 1 .5 to 1 :300, more preferably from 1 :5 to 1 :50. Surprisingly, it has been found that good bioavailability can be achieved even with a large amount of active agent and, thus, a small amount of additives.

[0031] Besides the active agent N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide the pharmaceutical composition may additionally contain one or more further active agents.

[0032] According to the invention, the pharmaceutical composition is provided by granulation. Thereby, preferably, a dispersion containing ELB353 and a binder material such as HPMC or HPC is used as granulation liquid to granulate a carrier material such as a sugar and, in particular, lactose or mannitol. In the particles obtained by said granulation, the active agent is distributed throughout the individual granules. The granules are formed from a plurality of small subparticles adhering to each other. [0033] For the manufacture of the composition of the invention, first, a solution of water and binder material, preferably a cellulose, and, in particular, hydroxypropyl methylcellulose or hydroxypropyl cellulose is provided. Then, the active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide is dispersed in said solution, thereby forming an active agent dispersion.

[0034] Said dispersion is granulated with a carrier material, preferably a sugar, and, in particular, lactose or mannitol. In a preferred embodiment, a sugar such as e.g. lactose or mannitol as carrier material is spray-granulated with the active agent/cellulose dispersion. Spray granulation preferably takes place in a fluid-bed processor. Thereby, an active agent containing granulate is obtained. The granulate comprises particles formed of a plurality of subparticles adhering to each other. The active agent is distributed throughout the particles. The obtained granules can be dried and passed through a sieve to homogenize the granules.

[0035] To the obtained granulate, a lubrication agent, preferably magnesium stearate, can be added.

[0036] The thus obtained granulates can be blended and filled into capsules, in particular, hard gelatin capsules. Alternatively, additional adjuvants can be added such as e.g. microcrystalline cellulose, crospovidone or croscaramellose and the obtained mix can be compressed into tablets.

[0037] Suitable dosage forms are solid dosage forms such as tablets or capsules.

[0038] The dosage forms are preferably suitable for oral administration.

[0039] In a preferred embodiment, the inventive formulation is in the form of capsules filled with active agent comprising granulate.

[0040] In a further preferred embodiment, the inventive formulation is in the form of tablets.

[0041] The active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoro- benzyl)7-azaindol-3-yl)]glyoxylic acid amide is an inhibitor of phosphodiesterase 4. The IC ₅₀ value for inhibition of PDE 4 with ELB353 is 0.004 pM, using [ ³ H]-cAMP as substrate. The IC ₅₀ value towards all other PDEs, in particular, PDE 2, 3 or 5, is at least by factor 250 higher. Phosphodiesterase activity can be determined, for example, according to the method described by Thompson et al. (W. J. Thompson et al., Adv. Cycl. Nucl. Res. 10 (1979), 69-92) (see also EP I 330 455).

[0042] It can therefore be used to inhibit phosphodiesterase 4. The active agent as well as pharmaceutical compositions comprising said active agent can be used for the treatment or/and prophylaxis of diseases for which an inhibition of phosphodiesterase 4 is useful.

[0043] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- -3-yl)]glyoxylic acid amide is particularly preferred for the treatment or/and prophylaxis of chronic obstructive pulmonary disease (COPD). The pathological condition of chronic obstructive pulmonary diseases (COPD) encompasses various pathological conditions of chronic bronchitis with the symptoms of coughing and expectoration, and progressive and irreversible deterioration in lung function (expiration is particularly affected). The course of the disease is episodic and often complicated by bacterial infections (Rennard, S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 1 13 (4) Suppl., 235S-241 S, 1998). There is a steady decline in lung function during the disorder, the lung becomes increasingly emphysematous, and the patients' breathing difficulty becomes obvious. This disorder markedly impairs the patients' quality of life (shortness of breath, low exercise tolerance) and significantly shortens their life expectancy.

[0044] Further preferred is use in the case of psoriasis or asthma.

[0045] The composition comprising N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide can be used, in particular, as bronchodilator and for asthma prophylaxis and/or treatment.

[0046] Further, it can be used for the treatment or prophylaxis of inflammation of the joints, including arthritis and rheumatoid arthritis, as well as other arthritic illnesses such as rheumatoid spondylitis and osteoarthritis, en- dotoxic shock, tissue rejection, AIDS and other immunological disorders.

[0047] Further possible applications are the treatment of patients who are suffering from osteoporosis, sepsis, septic shock, gram negative sepsis, toxic shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary diseases, bone resorprtion diseases or transplant rejection reactions or other autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and chronic demyelination. [0048] In addition, the active agent can also be used for the treatment of infections such as viral infections and parasite infections, for example, for the treatment of malaria, leishmaniasis, infection-induced fever, infection-induced muscle pain, AIDS, cachexia and non-allergic rhinitis.

[0049] The composition of the invention can likewise be used for the therapy of hyperprohferative disorders, in particular of cancers, for example for the therapy of melanomas, of breast cancer, lung cancer, bowel cancer, skin cancer and of leukemias.

[0050] The active agent, further, is an inhibitor of the release of tumor necrosis factor (TNFci) and can thus be used to inhibit the release of TNFcl, in particular, from inflammation cells. The composition of the invention can therefore also be used for the treatment of diseases for which an inhibition of TNFcl is useful. These diseases, for example, include, inflammations of the respiratory tract, inflammations of the joints, endotoxic shock, tissue rejections, AIDS and many other immunological disorders.

[0051] The active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoroben- zyl)7-azaindol-3-yl)]glyoxylic acid amide furthermore is an inhibitor of the accumulation of eosinophils as well as of their activity. The compound in crystalline form can therefore also be used to treat diseases in which eosinophils play a role. These diseases include, for example, inflammatory diseases of the respiratory tract such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczemas, allergic angiitis, eosinophil mediated inflammations such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pul- monal infiltration with eosinophils), urticaria, ulcerative colitis, Crohn's disease and proliferative skin diseases such as psoriasis and keratosis.

[0052] The active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoroben- zyl)7-azaindol-3-yl)]glyoxylic acid amide additionally has neuroprotective properties and can be used for the therapy of diseases in which neuroprotection is beneficial. Examples of such disorders are senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, strokes and intermittent claudication.

[0053] Further possible uses are the prophylaxis and therapy of prostate disorders such as, for example, benign prostate hyperplasia, polyuria, nocturia, and the treatment of incontinence, of colic induced by urinary calculi, and of male and female sexual dysfunctions. [0054] Finally, the composition of the invention can likewise be used to inhibit the development of drug dependence on repeated use of analgesics such as, for example, morphine, and to reduce the development of tolerance on repeated use of these analgesics.

[0055] The active agent N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoroben- zyl)7-azaindol-3-yl)]glyoxylic acid amide, further, suppresses the activity of neut- ronphilic granulocytes.

[0056] The invention is further illustrated by the Examples given below. Examples Example 01 :

[0057] Solution A: 1 .0 g of ELB353 was dissolved in 100 ml of acetone. Solution B: 6.43 g of hydroxypropyl-beta-cyclodextrine were dissolved in 100 ml of methanol. Solution C: solution A and solution B were mixed and stirred for 15 minutes at room temperature. A solid formulation of ELB353 was obtained by evaporation of solvents of solution C under reduced pressure.

Example 02:

[0058] Solution A: 1 .0 g of ELB353 was dissolved in 200 ml of acetone. Solution B: 2.29 g of gamma-cyclodextrine were dissolved in 20 ml of water. Solution C: solution A and solution B were mixed and stirred for 72 hours at room temperature. A solid formulation of ELB353 was obtained by evaporation of solvents of solution C under reduced pressure.

Example 03:

[0059] 27 g of Gelucire® 44/14 were heated in a beaker until melting is completed and added immediately to 3.0 g of ELB353 with agitation. After cooling to room temperature, a homogeneous solid formulation was obtained.

Example 04:

[0060] 27 g of Gelucire® 44/14 were heated in a beaker until melting is completed and added immediately to 0.3 g of ELB353 with agitation. After cooling to room temperature, a homogeneous solid formulation was obtained. Example 05:

[0061] 50 g of PEG 6000 and 50 g of Gelucire® 44/14 were heated in a beaker until melting is completed and a homogeneous mixture was obtained. Following this, the mixture was cooled down to room temperature. 27 g of the obtained mixture were heated until melting again and added immediately to 3.0 g of ELB353 with agitation. After cooling to room temperature, a homogeneous solid formulation was obtained.

Example 06:

[0062] 15 g of propylene glycol, 7.0 g of Chremophor® RH40, 6.0 g of Miglyol® 812, 10 g of Tween® 80, and 49 g of Gelucire® 44/14 were heated in a beaker until melting is completed and a homogeneous mixture was obtained. Following this, the mixture was cooled down to room temperature. 27 g of the obtained mixture were heated until melting again and added immediately to 3.0 g of ELB353 with agitation. After cooling to room temperature, a homogeneous solid formulation was obtained.

Example 07a-i: Granulates

[0063] ELB353 micronized by jet milling was suspended in an aqueous solution of hydroxypropyl methylcellucose (HMPC). Lactose as a carrier material was spray-granulated with this suspension in a fluid bed processor. After the process was finished, homogenous granulates of ELB353 were obtained.

Table 1 : Composition of examples of granulates

Example 07a 07b 07c 07d 07e 07f 07g 07h 07i

ELB353 53.22 g 10.2 g 51.0 g 204.0 g 67.8 g 180.1 g 170.5 g 446.6 g 236.7 g

Lactose 778 g 2989,2 g 2946.0 g 2784.0 g 422.0 g 614.2 g 651 ,9 g 540.5 g 331.2 g

HPMC 1.64 g 0.6 g 3.0 g 12.0 g 8.2 g 21.5 g 13.4 g 53.6 g 9.3 g Example 08:

Table 2: Bioavailability of examples tested in rats after oral administration

Example no Bioavailability in %

01 3

02 7

03 23

04 20

05 23

06 24

07a 82

Example 09a-c: Capsules

[0064] ELB353 micronized by jet milling was suspended in an aqueous solution of hydroxypropyl methylcellucose (HMPC). Lactose as a carrier material was spray-granulated with this suspension in a fluid bed processor. After addition of magnesium stearate, the obtained homogenous granulates of ELB353 were filled into the hard gelatin capsule.

Table 3: Composition of examples of capsules in mg/capsule

Example 10: Tablets

[0065] ELB353 is dispersed in an aqueous solution of HPMC or HPC; this ELB353 containing dispersion is used as granulation liquid to granulate lactose or mannitol; a suitable granulator is a fluid bed granulator equipped with standard spray nozzle; the obtained granules are dried and passed through a sieve to homogenize such granules. As a final step, the remaining components (microcrystalline cellulose, crospovidone or croscaramellose sodium and magnesium stearate) are admixed.

[0066] The obtained final mix is compressed to tablets according to the indicated weights. [0067] The obtained tablets can be packaged for final distribution; alternatively, a protective water-soluble film coat can be applied to such tablets by using equipment and coatings which are known per se.

Table 4: 10 mg Tablets/Composition per Tablet in mg

Table 5: 25 mg Tablets/Composition per Tablet in mg

Table 6: 60 mg Tablets/Composition per Tablet in mg

Example 10g 10h 101 10}

ELB353 60 60 60 60

Lactose 313.05 186.3 59.55 64.35

HPMC 7.2 7.2 7.2 2.4

Microcrystalline Cellulose 45.0 30.0 15 15

Croscaramellose Sodium 22.5 15 7.5 7.5

Magnesium stearate 2.25 1.5 0.75 0.75