CA2624513A1 - Combination - Google Patents

Abstract

The invention relates to a combination which comprises at least one NSAID (non-steroidal anti-inflammatory medicament) and at least one proton pump inhibitor for the prevention and/or treatment of tumour illnesses. The invention also relates to medicaments containing said combination and to the production thereof.

Description

BHC 05 1 108-Foreign Countries A1/wa/XP

Combination The present invention relates to a combination comprising at least one NSAID
(non-steroidal antiinflammatory drug) and at least one proton pump inhibitor for the prevention and/or treatment of tumours, to medicaments containing them and to their production.

The treatment of tumours, in spite of great advances which have been made in the last few years, is a still unsolved medical problem. In addition to the treatment of manifest tumours, scientific interest is also being aimed increasingly at the therapy of precancerous changes. The aim is being pursued here of delaying or of preventing the development of malignant neoplasias.

Adenomatosis coli (syn.: familial adenomatous polyposis = FAP) is a neoplastic syndrome with formation of numerous large intestinal polyps. The disease occurs to an increased extent familially and is inherited autosomally dominantly. In symptomatic patients with FAP, the carcinoma rate is 50 to 100%, in diseases detected by preventive medical checkups 10 to 15%.
While the proportion of FAP patients makes up about 1% of the total number in the colonic carcinoma family (Rustgi AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J
Med 1994, 331, 1694-1702), adenomatous polyps are found in about 33% of the total population at the age of approximately 50 years and in about 50% at the age of 70 years (Williams AR, Balasooriva BA, Day DW. Polyps and cancer of the large bowel: a necropsy study in Liverpool.
Gut. 1982, 23, 835-842). Histologically, the neoplasias are adenomas. Often, involvements of the small intestine and neoplasms in the duodenum and papillae are also found. Diagnosis is already possible presymptomatically by means of a gene test. Because of the expectation of carcinoma, proctomucosectoiny and colectomy are generally carried out therapeutically after diagnosis.

It was proved in studies that non-steroidal antiinflammatory drugs (NSAID) are suitable for the treatment of FAP and of adenomatous polyps and thus markedly reduce the risk of bowel cancer (Janne PA, Mayer RJ. Chemoprevention of colorectal cancer N Engl J Med 2000, 342, 1960-1968; Steinbach G, Lynch PM, Phillips RKS, Wallace MH, Hawk E et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000, 342, 1946-1952). O-Acetylsalicylic acid has a demonstrably prophylactic action against the formation of cancer of the large intestine, breast cancer and in experimental models against lung cancer (Harris R E, Kasbari S, Farrar WB. Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer. Oncology Reports 1998, 6, 71-73; Rioux N., Castonguay A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer research 1998, 58, 5354-5360). High doses or long-term administration of NSAIDs, however, can cause undesired side effects, for example in the gastrointestinal region (Wolfe MM, Lichtenstein DR, Singh G.
Gastrointestinal Toxicity of nonsteroidal antiinflammatory drugs. N Eng] J Med 1999; 340:1888-BHC 05 1 108-Foreign Countries 1899 (Erratuin, N Engl J med 1999;341:548).).

The avoidance of medicament-related gastrointestinal side effects in the gastrointestinal tract by use of a combination consisting of the proton pump inhibitor pantoprazole and an NSAID when taking NSAIDs is described in WO 2005/074930.

Briefly, it was shown that the permanent administration of o-acetylsalicylic acid for the prophylaxis of diseases of the cardiovascular system or stroke can be carried out even in patients with an increased risk of gastrointestinal bleeding, for example in the case of existing gastrointestinal ulcers, without the feared bleeding occurring as side effects, if o-acetylsalicylic acid is combined with esomeprazole (Chan FKL, Ching JYL, Hung LCT, Wong VWS, Leung VKS et al. Clopidogel versus Aspirin and Esomeprazole to prevent recurrent ulcer bleeding. N
Eng] J Med 2005, 352, 238-244).

The object of the present invention is the provision of a combination comprising an NSAID for the prevention and/or treatment of tumours, where NS AID-related adverse side effects are reduced.

It has now been found that the combination according to the invention has unexpected advantageous effects and properties with respect to prevention and/or treatment of tumours.

The present invention relates to a combination comprising at least one NSAID
as component A
and at least one proton pump inhibitor as component B for the prevention and/or treatment of tumours.

NSAID (non-steroidal antiinflammatory drugs) in the context of the invention in general represent all classes of substance mentioned under this term in the prior art. NSAID
represents, for example, aceclofenac, acetaminophen, o-acetylsalicylic acid, alclofenac, alminprofen, amfenac, ampiroxicam, amtolmetinguacil, anirolac, antrafenine, azapropazone, benorilate, bermoprofen, bindarit, bromfenac, bucloxic acid, bucolom, bufexamac, bumadizon, butibufen, butixirate, carbasalate calcium, carprofen, cinmetacin, cinnoxicam, clidanac, clobuzarit, deboxamet, dexibuprofen, dexketoprofen, diclofenac, diflunisal, eltenac, enfenamic acid, etersalate, etodolac, etofenamate, feclobuzon, felbinac, fentiazac, fepradinol, flobufen, floctafenine, flufenamic acid, flunoxaprofen, flurbiprofen, flurbiprofen axetil, furpfenac, furprofen, glucametacin, ibufenac, ibuprofen, indobufen, indometacin, indometazin franesil, indoprofen, ketoprofen, ketorolac, lobenzarit, lonazolac, lornoxicam, loxoprofen, mefenamic acid, meloxicam, mesalazine, mofezolac, nabumetone, naproxen, niflumic, olsalazine, oxaprozine, pelubiprofen, phenylbutazone, pimeprofen, pirazolac, piroxicam, pirprofen, pranoprofen, prifelone, prinomide, proglumetacin, proquazone, protizinic acid, romazarit, salicylamide, salicylic acid, salmistein, BHC 05 1 108-Foreign Countries salnacedin, salsalate, sulindac, suprofen, talniflumate, tenidap, tenosal, tenoxicam, tepoxalin, tiaprofenic acid, tiaramide, tilnoprofen arbamel, timegadine, tinoridine, tolfenamic acid, tolmetin, ufenamate, ximoprofen, zaltoprofen and zoliprofen.

Preferred NSAIDs mentioned are acetaminophen, o-acetylsalicylic acid, clidanac, diclofenac, flurbiprofen, ibuprofen, ketoprofen and sulindac. A particularly preferred NSAID is o-acetyl-salicylic acid.

Proton pump inhibitors in the context of the invention in general represent all classes of substance mentioned under this term in the prior art. Proton pump inhibitors represent, for example, ranitidine, famotidine, pantoprazole, lanzoprazole, esomeprazole, omeprazole and rabeprazole.
Preferred proton pump inhibitors mentioned are pantoprazole, rabeprazole, lanzoprazole, esomeprazole and omeprazole. Particularly preferred proton pump inhibitors are lanzoprazole, esomeprazole and omeprazole.

The compounds contained in the combination according to the invention can also be employed in the form of their salts, solvates and solvates of the salts, if they are not already salts, solvates and solvates of the salts.

The compounds contained in the combination according to the invention, depending on their structure, can also exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore comprises the enantiomers or diastereomers and their respective mixtures.

If the compounds contained in the combination according to the invention can occur in tautomeric forms, the present invention comprises all tautomeric forms.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also comprised, however, are salts which themselves are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention comprise acid addition salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluor-oacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also comprise salts of BHC 05 1 108-Foreign Countries customary bases, such as, by way of example and preferably, alkali metals salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
Solvates in the context of the invention are designated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of the solvates, in which the coordination takes place with water.

The combination according to the invention can be used for the prevention and/or treatment of tumours.

Tumours in the context of the invention are cancerous diseases of the organs of warm-blooded organisms and their precursors, in particular tumours, in which therapeutic effects can be achieved by inhibition of Cox-I and/or Cox-2. These are carcinomas of the gastrointestinal tract and its appended organs such as the liver, pancreas, in particular of the small intestine, of the large intestine, of the rectum, and of their precursors. Precursors are understood as meaning changes which are still not cancer, preferably intestinal polyps, for example adenomatous intestinal polyps.
Other tumours in the context of the invention are carcinomas of the lungs, tumours of the skin, in particular melanoma, carcinoma of the prostate, carcinoma of the breast, skeletal tumours, lymphatic tumours, tumours of the ovaries, tumours of the endocrine system and tumours of the central nervous system.

Preferably, the combination according to the invention can be used for the prevention and/or treatment of carcinomas of the lungs, carcinomas of the breast, tumours of the ovaries and carcinomas of the gastrointestinal tract such as, for example, of the small intestine, of the large intestine and of the rectum.

In addition, the combination according to the invention can be used for the prevention and/or treatment of familial adenomatous polyposis (FAP), familially cumulative tumours without polyposis (Hereditary Non-Polyposis Colorectal Carcinoma - HNPCC), and primary or secondary chemoprevention and therapy of colorectal carcinoma.

Prevention is understood as meaning both primary and secondary prevention.
Primary prevention is understood in this connection as meaning the protection of patients from a first disease which BHC 05 1 108-Foreign Countries results in organ damage. Secondary prevention is understood in this connection as meaning the protection of patients, who are already suffering from organ damage as a result of a tumour, from a fresh tumour.

When using the combination according to the invention, a synergistic effect which is not to be expected is observed in the action. Thus the amounts of the active substances employed in the combination can be reduced in comparison to monotherapy. Likewise, when using an amount of active substance equivalent in comparison to monotherapy, a better action which is not to be expected can be observed.

The synergistic effect of the combination according to the invention is preferably observed if the combination according to the invention comprises 0.1 to 20 mg/kg, in particular 0.5 to 15 mg/kg, of active substance of the component A and 0.01 to 15 mg/kg, in particular 0.05 to 10 mg/kg of active substance of the component B, in each case based on kg of body weight of the patient on oral administration.

In addition, the synergistic effect of the combination according to the invention is preferably observed if the combination according to the invention comprises as the NSAID
o-acetylsalicylic acid in a dose of 25 to 1500 mg, preferably in a dose of 75 to 750 mg, and as the proton pump inhibitor omeprazole in a dose of 5 to 100 mg, preferably in a dose of 15 to 50 mg, particularly preferably in a dose of 20 to 40 mg, pantoprazole in a dose of 5 to 100 mg, preferably in a dose of 15 to 50 mg, particularly preferably in a dose of 20 to 40 mg, lansoprazole in a dose of 5 to 100 mg, preferably in a dose of 10 to 50 mg, particularly preferably in a dose of 15 to 30 mg, or esomeprazole in a dose of 5 to 100 mg, preferably in a dose of 15 to 50 mg, particularly preferably in a dose of 20 to 40 mg.

A combination comprising as component A o-acetylsalicylic acid and as component B
pantoprazole, lansoprazole, esomeprazole or omeprazole is preferred. A
combination comprising as component A o-acetylsalicylic acid and as component B lansoprazole or omeprazole is particularly preferred.

The synergistic effect of the combinations according to the invention is preferably observed if the components A and B of the combination according to the invention are present in a ratio of 2:1 to 100:1, preferably 2:1 to 40:1, based on A and B.

"Ratio" within the meaning of the invention is understood as meaning the weight ratio of the individual components, if not stated otherwise.

If appropriate, it may be necessary to depart from the amounts mentioned, namely depending on BHC 05 1 108-Foreign Countries the body weight or the type of administration route, on individual behaviour towards the medicaments, the manner of their formulation and the time or interval in which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned above has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into a number of individual doses over the course of the day.

If appropriate, it may be expedient to supplement the combination according to the invention by addition of one or more further components. Examples which may be mentioned are vitamin C, vitamin E and folic acid. These other components can be added individually or alternatively together.

The combination according to the invention is furthermore distinguished by a surprisingly good tolerability.

The combination according to the invention is preferably employed in human medicine, but is also suitable for veterinary medicine, in particular for the treatment of mammals.

The combinations according to the invention can be administered parenterally, topically or orally, preferably topically or orally, particularly preferably orally.

The present invention further relates to the use of the combination according to the invention for producing administration forms for the prevention and/or treatment of tumours.

"Combinations" within the meaning of the invention are not only understood as meaning administration forms which contain all components (fixed combinations), and combination packs which contain the components separately from one another, but also components which are administered simultaneously or staggered in terms of time, provided they are employed for the treatment or prophylaxis of the same disease. The individual components can then be present in different administration forms (e.g. in different tablets and/or capsules), which are then employed siinultaneously or staggered in terms of time for the treatment or prophylaxis of the same disease.
The active substances of components A and B can be converted into the customary formulations in the form of medicaments or administration forms in a known manner, where these can be liquid or solid formulations. Examples are tablets, sugar-coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices, ointments, creams, powders and solutions. Moreover, impregnated plasters or dressings can be used with the combination according to the invention.
Procedures for the production of these administration forms comprising the combination according to the invention are known to the person skilled in the art.

BHC 05 1 108-Foreign Countries Since the combinations according to the invention are highly tolerable and in some cases efficacious even in low doses, very different formulation variants can be realized. Thus, on the one hand, the possibility of formulating the individual components separately exists. In this case, the individual components A and B do not definitely have to be taken at the same time, but on the other hand taking staggered in terms of time can be advantageous for the achievement of optimum effects. In the case of a separate administration of this type, it is obvious to combine the formulations of the individual components, for example tablets or capsules, together at the same time in a suitable primary pack. In the primary pack, the components are in each case situated in separate containers, which can be, for example, tubes, vials or blister packs.
A separate packaging of this type of the components in a common primary pack is also designated as a kit.

Further suitable formulation variants for the combinations according to the invention are preferably also fixed combinations. "Fixed combination" is understood here as meaning those administration forms in which the components are present together in a fixed quantitative ratio.
Fixed combinations of this type can be realized in the already mentioned liquid or solid formulations, for example as solutions, capsules or tablets.

The combinations according to the invention are dosed up to 3 times daily;
those combinations are preferred which allow administration I to 2 times daily.

The active substances of the components A and B are particularly suitable for formulation in a fixed combination in the form of a solid peroral administration form. It is generally known that the compliance in patients is dependent to a crucial extent on the factors number of administration forms per taking time and size and weight of the (solid peroral) pharmaceutical form. Therefore both the number of the various medicaments to be taken separately should be kept as low as possible (advantage of a fixed combination), and the size and the weight of a fixed peroral administration form should be as small as possible with full therapeutic potency, in order to make taking as pleasant as possible for the patient. Fixed combinations in the form of solid peroral pharmaceutical formulations having minimum size and minimum weight can thus be realized. The fixed combinations according to the invention accordingly offer a patient compliance which is as high as possible and thereby improve the safety and reliability of a treatment decisively.

By combination of the components A and B and modification of the composition or of the functionality, the release of active substance can be controlled. For example by means of delayed release of active substance (retardation) of a component, the abovementioned decoupling of the onset of action in terms of time can also be realized in fixed combinations.

The solid peroral administration forms mentioned here are produced by the general standard BHC 05 1 108-Foreign Countries processes. Ingredients are those which are pharmaceutically accepted and physiologically harmless, for example: as fillers, cellulose derivatives (e.g.
microcrystalline cellulose), sugars (e.g.
lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g.
calcium phosphate), binding agents (e.g. polyvinylpyrrolidone, gelatin, starch and cellulose derivatives), and all further excipients which are needed for the production of pharmaceutical formulations with the desired properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g.
crosslinked polyvinyl pyrrol idone, sodium carboxymethylcellulose), e.g. wetting agents (e.g. sodium laurylsulphate), e.g. retarding agents (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g.
stabilizers, e.g. flavourings, e.g. colour pigments.

Liquid formulations are likewise produced according to standard methods using pharmaceutically customary excipients and contain the active substances in either dissolved or suspended form.
Typical administration volumes of these pharmaceutical preparations are I to 10 ml. Examples of excipients in these liquid formulations are: solvents (e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglycerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium laurylsulphate), and further excipients which are needed for the production of pharmaceutical formulations with the desired properties, e.g.
viscosity-enhancing agents, e.g. pH corrigents, e.g. sweeteners and flavourings, e.g.
antioxidants, e.g. stabilizers, e.g.
preservatives.

The main constituents of the shells of capsule formulations are, for example, gelatin or hydroxy-propylmethylcellulose.

Pharmaceutical excipients, as are familiar to the person skilled in the art, are also described, for example, in the following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. &
Weller, P.J., American Pharmaceutical Association, Washington, 2nd edition 1994.

For the use of the two components A and B according to the invention for the treatment of the disease states mentioned, the oral administration route is preferred. The present invention further relates to medicaments which contain the components A and B, customarily together with one or more inert, non-toxic, pharmaceutically suitable excipients.

For oral administration, administration forms functioning according to the prior art, releasing the components A and B according to the invention rapidly and/or in modified form, which contain the two components in crystalline (ground or micronized) and/or amorphous and/or dissolved form are suitable. Influence can be brought to bear on the absorption from the gastrointestinal tract, for example, by means of the rate of solution and thus the particle size of the components A and B
employed. Among these suitable administration forms are (enteric-)coated or uncoated tablets, BHC 05 1 108-Foreign Countries hard capsules made of gelatin, HPMC, pullulan or other materials, soft gelatin capsules, powders, granules and pellets. Depending on the half-life, the stability of the components A and B, of the site of absorption and/or of a desired decoupling of the onset of action in terms of time, further controlled-release formulations are suitable. These include, for example, structured tablets, erosion matrix tablets, tablets or mini-tablets having a diffusion-controlling coating, capsules containing pellets, granules or tablets having a diffusion-controlling coating, capsules containing eroding pellets, granules or tablets and osmotic-release tablets. A more accurate description of selected systems of the rapid-release and of the controlled-release formulations and their production is given below.

The components A and B used according to the invention can be converted to the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.

For the processing of the component A in combination with component B to give a joint oral administration form (fixed combination), all abovementioned administration forms are suitable. In the case of mutual impairment of the stability, the two components can be separated spatially in the pharmaceutical form. For this, separate granules or pellets, for example, are filled into capsules or two granulates are compressed to give a 1-layer/2-layer or a jacket-core tablet. In addition, it is also possible to coat at least one of the two components or a powder, granules or a pellet preparation which contains at least one of the two components with polymer and subsequently to process it further to give a tablet or capsule.

On account of the pH-dependent instability of component B, coating of the formulation stage containing this component (e.g. active substance crystals, granules, pellets or mini-tablets; see later) or of the entire formulation with an enteric coating is preferred.
Coatings within the meaning of this invention are in particular film coatings. The process of lacquering generally follows standard processes and makes the addition of further excipients necessary. For the enteric film coating, film-forming agents (e.g. cellulose acetate phthalate, polymethacrylic acid derivatives [=
EUDRAGITS L and S] or hydroxypropylmethylcellulose phthalate), plasticizers (e.g.
polyethylene glycols, triacetin, glycerol, dibutyl phthalate), colourants/pigments (e.g. titanium dioxide, iron oxide) and release agents (e.g. talc, highly disperse silica, silica gel, magnesium stearate, glycerol monostearate) are distinguished. The coating is carried out by spraying on a suspension, preferably based on water. Replacement of the water by a suitable organic solvent is possible. Appropriate lacquering can be carried out in a different position in the production process. If only the formulation stage discussed above is enteric-coated, further lacquering, for example in the form of a sugar or film coating, can moreover take place at the end of the = BHC 05 1 108-Foreign Countries production process. The preferred film-forming agents in this position are, for example, modified celluloses, polymethacrylates and polyvinylpyrrolidone.

In certain cases of the combinations mentioned, a delayed controlled release of the components A
and/or B can be particularly advantageous. This can lead to an improved pharmacological effect, reduce the occurrence of undesired side effects or contribute to simplification of treatment for the patient. The invention therefore also relates to formulations which contain both components and release both components or one of the two components in controlled form. Here, both component A and component B, only component A or only component B can be released in controlled form, while in the latter two cases the other component is rapidly released.

A) Rapid-release formulations The fixed combination according to the invention is, inter alia, a formulation rapidly releasing the components A and/or B. "Rapid-release formulation" is understood as meaning a formulation of the type (e.g. tablet, capsule, sachet) which releases > 80% of its contained active substance doses within 30 minutes (blade stirrer apparatus according to USP; UV detection;
release medium 900 ml of 0.1 N hydrochloric acid or acetate buffer pH 4.5 surfactant; speed of rotation 75 rpm).
Consequently, the fixed combination within the meaning of this invention can be administered up to three times daily; a combination which allows administration I to 2 times daily is preferred.
Various systems are suitable for the achievement of a rapid active substance release. For example powders and/or granules and/or pellets which are subsequently filled into capsules or sachets, 1-layer/2-layer or jacket-core tablets, film tablets, sugar-coated tablets or soft gelatin capsules are distinguished.

For example, the production of an administration form comprising the fixed combination according to the invention of the components A and B can be carried out by filling a mixture of both components directly into a capsule with addition of suitable excipients and/or formulating to give a tablet. Suitable excipient additives are, inter alia, fillers, disintegrating agents and glidants.
Examples for the excipient groups mentioned can be - as fillers: cellulose derivatives (e.g.
microcrystalline cellulose) and starches (native or modified, e.g. potato starch), sugars (e.g.
lactose) and sugar alcohols (e.g. mannitol, sorbitol) and inorganic fillers (e.g. calcium phosphate, magnesium oxide) and buffer substances; as disintegrants: starch derivatives (e.g. crosslinked sodium carboxymethylstarch, sodium starch glycolate), cellulose derivatives (e.g. crosslinked sodium carboxymethylcellulose) or crosslinked polyvinylpyrrolidone; as glidants (understood here as the generic term for flow-regulating agents/lubricants/mould-release agents): magnesium stearate, calcium stearate, stearic acid, talc and highly disperse silica. In order to make possible a BHC 05 1 108-Foreign Countries -ll-uniform distribution of the two substances in the mixture, the two components A and B, for example, can be mixed with one another first and the excipients can be added thereto in stages.
The present invention also relates to further processing of the active substance/excipient mixture already described to give granules. For granulation, according to the invention the known conventional processes in the form of fluidized bed agglomeration, rotor granulation and wet extrusion are suitable as wet granulation processes and roll compaction is suitable as a dry granulation process. A preferred wet granulation process is fluidized bed agglomeration. In wet granulation, water or a suitable organic solvent, for example ethanol, acetone or isopropanol, or a mixture of water with a suitable organic solvent can generally be employed as solvent. The addition of hydrophilizing agents in the form of surfactants (e.g. sodium laurylsulphate, polysorbates) is possible. Additionally to the already mentioned excipient groups, the use of binding agents, for example sugars, sugar alcohols, starches, cellulose derivatives, alginates, pectins, polyethylene glycols and polyvinylpyrrolidones can take place. The addition of antistatics, in particular in the case of finer active substance batches, is also possible.
Here, polyethylene glycols, sodium laurylsulphate, highly disperse silica/alumina or dicalcium phosphate, for example, suggest themselves. The granules produced can be filled directly (sachet/capsule) or formulated further to give tablets.

Independently of the chosen production pathway (direct mixing or granulation), the resulting pharmaceutical form, that is a capsule, tablet or alternatively even the granules (in the case of sachet filling), can be provided with an enteric coating for stability reasons.

Moreover, the preparation of the fixed combination can also be carried out by the production of two mixtures/granulates independent of one another, which are combined in an additional process step and filled thereafter (capsule/sachet) and/or formulated to give a tablet. Each individual production step can be characterized by the addition of suitable excipients.
The preferred granulation process both for component A and component B is a dry granulation process.
Processing to give the final pharmaceutical form is carried out after combination of the two granulates.

The utilization of this production pathway allows both the separate enteric lacquering of one or both granulates of components A and B before their combination/further processing and an enteric lacquering of the pharmaceutical form resulting at the end (combined granules, capsule or tablet).

The production of a rapid-release administration form, comprising the fixed combination according to the invention of the components A and B, can also be carried out by absorbing both components on neutral pellets. For the production of rapid-release pellets using the above-BHC 05 1 108-Foreign Countries mentioned components A and/or B, neutral pellets of sucrose or microcrystalline cellulose, for example, can be coated with a mixture of the active substances, customary binding agents and further customary excipients. If, per component, one batch of pellets is produced, the pellet batches comprising the components A and B are subsequently combined to give one stage.
These pellets can be filled into capsules and/or sachets or processed further to give tablets.

If this production path is taken, there are again the options to enterically lacquer one or both pellet batches separately of one another, to coat the pellets after combination to give one batch or to enterically lacquer the pharmaceutical form (capsule/tablet) resulting after further processing of the pellet batches.

The present invention likewise relates to the production of a fixed combination in the form of a 2-layer or jacket-core tablet. This is in particular of advantage if an incompatibility is expected between the two components to be processed. Moreover, this process offers the possibility of employing various excipients or stabilizers (e.g. antioxidants or buffer substances) in the respective layer or in the core or the shell, depending on the component. For the production of a 2-layer tablet, a press having two filling and press stations is suitable in particular. Each component is fed to one of the filling stations in each case as a direct mixture with suitable excipients or in the form of granules. In the case of the production of a jacket-core tablet, after pressing of the cores a feed and centring unit for a 2-layer press is additionally needed, which guarantees the correct introduction of the cores into the jacket.

According to the preceding comments, the separate enteric lacquering of only one or both granulates of the components A and B or an enteric lacquering of the resulting 2-layer tablet, an enteric lacquering of only the core or an enteric lacquering of the resulting jacket-core tablet is possible.

The present invention also relates to the production of a fixed combination using melt extrusion, a process which likewise follows standard processes. Here, component A, for example, can be employed in the form of one of the already described active substance/excipient mixtures or granulates, while component B is first processed to give a melt extrudate. For the process of melt extrusion, the use of one/a number of polymer(s), plasticizers and carriers is necessary. Suitable polymers can be, for example, hydroxypropylcellulose or polyvinylpyrrolidone.
Possible plasticizers are, inter alia, triethyl citrate, benzoic acid and succinic acid. The term vehicles is understood here as meaning excipients such as, for example, sugar alcohols, in particular mannitol, microcrystalline cellulose and crosslinked sodium carboxymethylcellulose. The melt extrudate obtained is either rounded to give pellets or comminuted after its production, preferably to a particle size < 0.3 15 [mm], and can subsequently be processed further with the powder/granulate BHC 05 1 108-Foreign Countries mixture comprising the component A. Here, direct filling as granules (sachet/capsule) or compaction to give tablets (1-layer or 2-layer tablets) can take place.
Addition of lubricants is advisable under these conditions.

Moreover, the production of the fixed combination can also be carried out by the production of two melt extrudates independent of one another, which are combined in an additional process step and filled therein and/or formulated to give a tablet (1-layer or 2-layer tablets). Each individual production step can be characterized by the addition of suitable excipients.
After melt extrusion has taken place, either rounding to give pellets or comminution of the melt extrudate follows, preferably to a particle size < 0315 mm. The pellets/granules thus obtained are mixed. The mixed extrusion pellets can be packed directly (sachet/capsule) or the mixed granules can be compressed to give tablets.

Moreover, this invention also relates to the production of a fixed combination by the joint melt extrusion of both active substances in an active substance-excipient mixture.
After melt extrusion has taken place, either rounding to give pellets or comminution of the melt extrudate follows, preferably to a particle size < 0.315 mm. The pellets thus obtained can be packed directly (sachet/capsule) or the granules can be compressed to give tablets.

Independently of the preferred production procedure, there are various options for the enteric lacquering which is to be carried out: the extrudates obtained (granules or pellets) can be coated separately of one another or alternatively lacquered after mixing them or the resulting pharmaceutical forms (capsule/tablet) can be coated.

B) Formulations having controlled active substance release Corresponding to the rapid-release tablets, the controlled active substance release is likewise defined by means of the release rate of the components A and/or B from the formulation. For the determination of the average release rate according to the definition of the invention, the pharmaceutical formulations of the present invention are tested in the "Apparatus 2" of the USP
(test medium 900 ml of phosphate buffer pH 6.8 surfactant; speed of rotation 75 rpm; UV
detection). A formulation shows controlled active substance release if, for the delayed release component(s), a release rate of 80% in more than 45 minutes, preferably between 80% in 2 hours to 80% in 16 hours, results.

Various systems are suitable for the achievement of controlled active substance release. These can be subdivided into, for example, enveloping forms, diffusion-controlled pellets, which are filled into capsules or sachets or can be compressed to give tablets, into matrix tablets, into 2- or 1-layer tablets or into osmotic release systems. Depending on the desired release profile (dependent on the BHC 05 1 108-Foreign Countries properties of the active substances, in particular the stability, the half-life and the indication), both components or alternatively only one can be processed in the controlled-release form.

For the formulation of the components A and B in controlled-release form, single crystals of the active substances, active substance-containing granule particles or pellets can be provided with a coating and subsequently filled into capsules or processed to give tablets.
Tablets themselves can also be enveloped. Excipients used are fats, waxes and various polymers.
Should the coating consist of digestible or non-digestible fats or fat-like substances, the digestible substances employed can be, for example, glycerol monostearate, glycerol monopalmitate, stearic acid, diglycol stearate or glycerol trioleate and the non-digestible substances employed can be, for example, carnauba wax, beeswax and cetystearyl alcohol. The formation of pores can be controlled by addition of water-soluble excipients and the release rate can be controlled by means of their size. Possible pore-forming agents for controlling the pore size are, inter alia, soluble polymers, such as, for example, polyethylene glycols, polyvinylpyrrolidones, hydroxypropylmethylcelluloses, carboxymethylcelluloses or their salts, methylcelluloses, dextrins, maltodextrins, cyclodextrins, dextrans or other soluble compounds, such as, for example, salts (sodium chloride, potassium chloride, ammonium chloride etc.), urea, sugar (glucose, sucrose, fructose, lactose etc.), sugar alcohols (mannitol, sorbitol, lactitol etc.).

If necessary, enteric lacquering of the resulting pharmaceutical form follows.

For the formulation of the components A and B in controlled-release form for subsequent filling into a capsule/a sachet or for subsequent tabletting, diffusion-controlling pellets are in particular suitable. For the production of the diffusion-controlling pellets containing one of the above-mentioned active substances, neutral pellets of sucrose or microcrystalline cellulose, for example, are coated with a mixture of the active substance, customary binding agents and further customary excipients and subsequently coated with a diffusion lacquer, which can contain a plasticizer. The binding agents used are preferably hydroxypropylmethylcellulose or polyvinylpyrrolidone.
Likewise, other natural, synthetic or semisynthetic polymers such as, for example, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyacrylic acids, polyvinyl alcohols or gelatin can be employed. A suitable diffusion lacquer is particularly ethylcellulose. However, other materials such as poly[(methacrylic acid)(ethyl acrylate)] (1:1) or other acrylates, cellulose acetate or cellulose acetate butyrate can also be used. Suitable plasticizers are, inter alia, phthalic acid derivatives (e.g. dimethyl phthalate, diethyl phthalate, dibutyl phthalate), citric acid derivatives (e.g. triethyl citrate, tributyl citrate, acetyltriethyl citrate), other esters (e.g. diethyl sebacate, triacetin), fatty acids and derivatives (glycerol monostearate, acetylated fatty acid glycerides, castor oil and other native oils, miglyol), or polyols (glycerol, 1,2-propanediol, polyethylene glycol BHC 05 1 108-Foreign Countries of differing chain length). In addition, the type and amount of the plasticizer are adjusted such that the above-defined release according to the invention and the necessary stability of the pellets are achieved. The adjustment of the above-defined release is further carried out by control of the pore size of the diffusion lacquer and/or its thickness. The proportion of the pore-forming agent in the amount of lacquer here is 0 to 50% by weight. The adherence of a certain weight ratio of active substance-coated pellets to diffusion membrane and of a certain ratio of the diffusion lacquer to amount of plasticizer is crucial here for pellet production. Some of the plasticizer employed can evaporate during the lacquering and subsequent malleablizing. On changing the peripheral conditions, a change in the amount of coating to diffusion lacquer is necessary. Thus a higher amount of coating is necessary, for example, if the desired release rate is reduced, the amount of the pore-forming agent is increased or in the case of certain plasticizers the proportion of plasticizer is reduced. A lower amount of coating is necessary if the desired release rate is increased, the amount of the pore-forming agent is reduced or in the case of certain plasticizers the proportion of plasticizer is increased. The diffusion pellets can be produced, inter alia, by suspending or dissolving the components A and B in water and thickening with a concentrated hydroxypropylmethylcellulose solution. The suspension or solution thus obtained is absorbed on neutral pellets in a spray process in a fluidized bed unit. The coating of the pellets with a diffusion membrane follows, preferably in a fluidized bed unit by spraying on, for example, an aqueous ethylcellulose dispersion or organic ethylcellulose solution, which contains a suitable, physiologically tolerable plasticizer. The pellets are subsequently malleablized at temperatures of 50 to 125 C, preferably 60 to 110 C. Here, higher malleablizing temperatures lead to the fact that, for the achievement of the release according to the invention, rather lower lacquer application amounts are sufficient and the resulting pellets are physically more stable on storage. The thickness of the diffusion membrane, plasticizer type, amount of plasticizer and pellet size are chosen such that the above-described release rate is achieved. The quantity of pellets of both components corresponding to the daily dose is filled into a hard gelatin capsule or a sachet or further processed to give tablets. In addition to the described coating of neutral pellets, other methods of pellet production are also possible, such as wet extrusion with subsequent rounding, rotor granulation, fluidized bed agglomeration or melt extrusion with subsequent rounding.
Alternatively, mini-tablets having a diameter of 1- 4 mm can also be produced.
Subsequently, the active substance-containing pellets or mini-tablets are coated with a diffusion membrane as described.

If necessary, an enteric lacquer is added.

For the formulation of both components in a fixed combination and controlled-release form, tablets are likewise suitable which contain the components A and B in a matrix of a water-swellable BHC 05 1 108-Foreign Countries polymer. The size of these tablets can be dimensioned such that one or more tablets find room in the interior of a capsule or of a sachet. The tablets can be filled into the capsule in uncoated form or coated with a lacquer beforehand, for example a lacquer insoluble in gastric juice.

Tablets which contain both components in a matrix of a water-swellable polymer can be produced as follows. These "matrix formulations" expediently contain 0.1 to 70% by weight, preferably 0.2 to 60% by weight of the active substances. The proportion of the matrix of the water-swellable polymer is expediently 10 to 95% by weight, preferably 20 to 60% by weight.
Pharmaceutical preparations according to the invention in the form of erosion tablets are particularly preferred.
These tablets are characterized in that, in addition to customary excipients and vehicles and tabletting excipients, they contain a certain amount of water-swellable, hydrogel-forming polymers, where these polymers must have a viscosity of at least 15, preferably at least 50, cps (measured as a 2% strength aqueous solution at 20 C). Customary excipients and vehicles are, for example, lactose, microcrystalline cellulose, mannitol or calcium phosphate.
Customary tabletting excipients are, for example, magnesium stearate, talc or highly disperse silica. In the case of magnesium stearate, these are expediently present in an amount of 0.5 to 3% by weight, in the case of highly disperse silica expediently in an amount of 0.1 to 1% by weight. The water-soluble, hydrogel-forming polymers employed are preferably hydroxy-propylcelluloses, hydroxypropylmethylcelluloses, methylcelluloses, carboxymethylcellulose, alginates, galactomannans, polyacrylic acids, polymethacrylic acids or copolymers of inethacrylic acid and methyl methacrylate, guar, agar, pectin, tragacanth, gum arabic, xanthan or mixtures of these substances. The use of hydroxypropylmethylcelluloses is particularly preferred. Here, the erosion tablets according to the invention should contain at least 10% by weight of a hydroxypropylmethylcellulose type based on the mass of a tablet, whose viscosity (measured as a 2% strength aqueous solution at 20 C) is at least 15, preferably at least 50, cps. The pharmaceutical formulation which comprises the active substance in a matrix of a water-swellable polymer is produced by mixing the active substance, the polymer and suitable excipients and vehicles and customary tabletting excipients and directly tabletting. A prior dry granulation in the form of roll compaction is just as possible as the carrying out of a wet granulation, in which the active substance, the water-swellable polymer and suitable vehicles are granulated in the fluidized bed. When using rotor granulation, if appropriate the utilization of ethanol-water mixtures is necessary. In the case of matrix tablets, the amount and viscosity of the water-swellable polymer are chosen such that tablets with the above-described average release rates result for both components. The dry granules are screened, mixed with a lubricant, such as, for example, magnesium stearate, and tabletted. The tablet is optionally subsequently lacquered, if necessary with an enteric coating. For the subsequent filling of a capsule, erosion tablets with a diameter of 3 mm to 7 mm are preferred; an optionally enteric lacquering is also possible in this position.

BHC 05 1 108-Foreign Countries The present invention likewise relates to a pharmaceutical formulation in which the components A
and B are present in a 2-layer tablet. This consists either of two controlled-release layers or of one controlled-release and one rapid-release layer. The formulation of the in each case controlled-release layer is geared to the principles which were presented above for the matrix formulation.
For the formulation of the in each case rapid-release layer cf. section A) of the present invention.
For tabletting, in particular a 2-layer press provided with 2 filling and press stations is in particular suitable. The tablet is optionally subsequently lacquered; if necessary this lacquering can be carried out using an enteric coating. In order to prevent an initial release rate of one of the two components which is too high, the two-layer tablet can also be provided with a third, active substance-free layer.

Moreover, the components A and B can also be processed to give a 1-layer tablet. A suitable controlled-release formulation for subsequent incorporation into a 1-layer tablet is in particular the diffusion-controlling pellets already described. Either two types of diffusion-controlling pellets or one type of diffusion-controlling pellets are mixed with the active substance to be combined in rapid-release form and further excipients, vehicles and tabletting excipients and compressed to give a l-layer tablet. Granulation of the rapid-release active substance and the subsequent lacquering of the tablet are also possible.

If necessary, an enteric lacquer is to be added.

A further embodiment of the present invention is the "osmotic pharmaceutical release system".
Osmotic pharmaceutical release systems of this type are known in principle in the prior art and are treated in detail, for example, in R. W. Baker, Osmotic Drug Delivery: A
Review of the Patent Literature, Journal of Controlled Release 1995, 35: 1-21 or in R.K. Verma et al., Osmotic Pumps in Drug Delivery, Critical Reviews in Therapeutic Drug Carrier Systems 2004, 21: 477-520. The pharmaceutical formulation as an osmotic pharmaceutical release system preferably consists of a) a core which contains the components A and B, optionally a hydrophilic polymeric swelling agent and optionally a water-soluble substance for the induction of osmosis, and b) a shell which is permeable for water and impermeable for the components A
and B of the active substance-containing core, and c) an opening through the shell b) for the transport of the constituents contained in the core into the surrounding body fluid.

This special osmotic pharmaceutical release system is described in principle in the prior art, for example in DE 2 328 409 or US 3,485,770. With respect to the materials for the shell, reference BHC 05 1 108-Foreign Countries may be made to EP 0 277 092 and US 3,916,899 and US 3,977,404 mentioned there.

With respect to suitable hydrophilic polymeric swelling agents reference may be made to the polymeric swelling agents mentioned in EP 0 277 092 and WO 96/40080. For example, ethylene oxide homopolymers (polyethylene glycol) with various degrees of polymerization with molecular weights between 100 000 to 8 000 000 and vinylpyrrolidone/vinyl acetate copolymers and further water-swellable polymers mentioned in US 3,865,108, US 4,002,173 and US
4,207,893 can be used. Water-soluble substances for the induction of osmosis are in principle all water-soluble substances whose use in pharmacy is harmless, which are mentioned as water-soluble excipients, for example, in the pharmacopoeias or in "Hager's Handbuch der Pharmazeutischen Praxis"
[Hager's Handbook of Pharmaceutical Practice], 1990-1995, Springer Verlag and Remington's Pharmaceutical Sciences. Special water-soluble substances are salts of inorganic or organic acids or non-ionic organic substances with high water solubility such as, for example, carbohydrates such as sugars etc. The production of an opening in the shell of the tablet is known per se in the prior art and described, for example, in the US patent specifications US
3,485,770 and US
3,916,899. The release rate is adjusted by the type and amount of the semipermeable material forming the shell, by the type and amount of the hydrophilic polymeric swelling agent optionally contained and of the optionally present water-soluble substance for the induction of osmosis. The components A and B of the present invention can be introduced into an osmotic pharmaceutical release system in different ways. For the controlled release of both components, these are mixed with the excipients and compressed to give a joint active substance layer. If only one component is to be released in controlled form, the components not to be released in controlled form can either be incorporated separately into the lacquer shell of the tablet, or it is compressed to give a separate active substance layer, which is first pumped free from the pharinaceutical release system before the control led-re lease component.

If necessary, an enteric coating is additionally to be applied.

BHC 05 1 108-Foreign Countries Working examples:

Example 1:

80 mg of o-acetylsalicylic acid and 20 mg of omeprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 2:

600 mg of o-acetylsalicylic acid and 15 mg of lanzoprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 3:

80 mg of o-acetylsalicylic acid and 40 mg of omeprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 4:

600 mg of o-acetylsalicylic acid and 30 mg of lanzoprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 5:

100 mg of o-acetylsalicylic acid and 20 mg of omeprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 6:

500 mg of o-acetylsalicylic acid and 15 mg of lanzoprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 7:

100 mg of o-acetylsalicylic acid and 40 mg of omeprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 8:

500 mg of o-acetylsalicylic acid and 30 mg of lanzoprazole are used for the production of a tablet, if necessary with addition of further excipients.

BHC 05 1 108-Foreign Countries Example 9:

500 mg of o-acetylsalicylic acid and 40 mg of omeprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 10:

100 mg of o-acetylsalicylic acid and 15 mg of lanzoprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 11:

500 mg of o-acetylsalicylic acid and 20 mg of omeprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 12:

100 mg of o-acetylsalicylic acid and 30 mg of lanzoprazole are used for the production of a tablet, if necessary with addition of further excipients.

Example 13:

Rapid-release dry-compacted fixed formulation 400.0 g of o-acetylsalicylic acid are homogeneously mixed with 150.0 g of lanzoprazole, 162.5 g of Avicel PH 101 V, 100.0 g of maize starch, 100.0 g of sucrose and 75.0 g of AcDiSol and compacted. The resulting briquettes are screened in 2 stages and subsequently mixed with 12.5 g of magnesium stearate. The finished mixture is compressed in a rotary press to give 200.0 mg of heavy tablets in the format 9 mm WR 15 and these are subsequently provided with an enteric coating consisting of 28.0 g of Eudragit L30D , 20.0 g of talc and 2.0 g of triethyl citrate, dissolved or suspended in 200.0 g of water. The 200 mg heavy tablet cores contain 80 mg of o-acetylsalicylic acid and 30 mg of lansoprazole.

Example 14:
2-Layer tablet 640.0 g of o-acetylsalicylic acid are homogeneously mixed with 56.0 g of Avicel PH 101, 56.0 g of maize starch and 48.0 g of ascorbic acid and compacted. The resulting briquettes are screened in 2 stages.

60.0 g of omeprazole are homogeneously mixed with 28.0 g of sucrose, 80.5 g of Avicel PH 101 , BHC 05 1 108-Foreign Countries 20.0 g of AcDiSol and 12.0 g of magnesium carbonate and compacted. The resulting briquettes are screened in 2 stages. The granules obtained are dissolved or suspended with a mixture of 22.5 g of Eudragit L30D , 20.0 g of talc and 2.5 g of glycerol monostearate, in 180.0 g of water, enteric lacquered in the fluidized bed and subsequently mixed with 2.0 g of magnesium stearate.

625.0 mg of the o-acetylsalicylic acid-containing and 165.0 mg of the omeprazole-containing granules are compressed in a 2-layer press to give 790.0 mg of heavy tablets in the format 19x9 mm WR 5.7. These tablet cores contain 500 mg of o-acetylsalicylic acid and 40 mg of omeprazole. Subsequently, they are dissolved or suspended in 154.2 g of water with a mixture of 7.5 g of hydroxypropylmethylcellulose 15 cp, 2.5 g of PEG 3350 and 2.5 g of titanium dioxide, and lacquered.

Example 15:

Capsule in combination with dry compaction and melt extrusion 400.0 g of o-acetylsalicylic acid are homogeneously mixed with 40.0 g of Avicel PH 101 and 40.0 g of maize starch and compacted. The resulting briquettes are screened in 2 stages.

40.0 g of pantoprazole are homogeneously mixed and extruded with 40.0 g of mannitol and 440.0 g of HPC-SL. The resulting strand is cut to give cylinders and these are rounded off.

In each case 97.2 mg of the roll granulate comprising o-acetylsalicylic acid are filled into capsules together with 130,0 mg of pellets comprising pantoprazole. Each capsule contains 81 mg of o-acetylsalicylic acid and 10 mg of pantoprazole. The capsules are dissolved or suspended in 166.0 g of water with a mixture of 20.0 g of Eudragit L30D , 19.5 g of talc and 2.0 g of triethyl citrate, and lacquered (enteric coating).

Colony formation assay The following are used: 96 well plates, previously: cell culture-treated (351172 BD Biosciences), DMEM/F12 powder medium (42400-010 Invitrogen), or RPMI powder medium (51800-Invitrogen), Sea Plaque agarose (50100 Cambrex) (USA: Biowhittaker BMA 50100, 125 grams), Cell-Titer Blue (Ord. # G8080, 20m] / G8081, 100 ml / G8082, 1Ox100m1, Promega), cells: A549 (ATCC# CCL 185); HCT 116 (ATCC# CCL 247).

First, a bottom layer is temperature controlled at 44 C with double-concentrated agar (Eppendorf Thermo-Mixer). Then, 50 1 of bottom agar/well are plated out and incubated at room temperature for about 30 min. The application of the top layer containing the tumour cells (HCT 116) then takes place. For this, the cell suspension is rapidly and thoroughly mixed 1:1 with bottom agar BHC 05 1 108-Foreign Countries (44 C) in a 50m1 Falcon. 50 l of the mixture of top agar/cells are plated out without contacting the bottom agar in this process and incubated at room temperature for about 30 min. Finally, 80 1 of DMEM/F12 (standard medium) per well are added as the final layer, without contacting the soft agar in this process. Addition of substance is carried out 24h after inoculation. The substances are dissolved in DMSO here in the concentrations indicated below and 10 p1/well are added.
Incubation is carried out for 2 weeks in the presence of IOmM Hepes buffer.
Evaluation is carried out by means of the CTB assay according to the instructions of the manufacturer (Promega) and the calculation of the IC50 is carried out with the aid of the program GraphPad Prism.

Table 1: Activity of o-acetylsalicylic acid, lanzoprazole or omeprazole or the respective combinations on tumour cells (HCT I 16 colonic carcinoma cells) in the soft agar colony formation assay. (PPI: proton pump inhibitor - specification in the table column) Soft agar assay IC50 calculation with Prism: Sigmoidal dose-response (variable slope), bottom=O

Omeprazole Lansoprazole o- ceysaicyicact o ceysaicylcaci Combination with IC50 [mM] IC50 [mM]
Component B see above 62.5 M 0.55 0.30 Component B see above 31.3 M 0.96 0.49 Component B see above 15.6 M 0.77 1.65 1.26 1.93 meprazo e ansoprazo e Combination with IC50 [ M] IC50 [ M]
o-Acetylsalicylic acid 1.25 mM 68 84 o-Acetylsalicylic acid 0.625 mM 116 67 o-Acetylsalicylic acid 0.313 mM 99 91 o-Acetylsalicylic acid 0.156mM 126 108 Table 2: Activity of o-acetylsalicylic acid and lanzoprazole or combinations on human lung carcinoma cells (A549) in the soft agar colony formation assay.

BHC 05 1 108-Foreign Countries Combination with o-Acetylsalicylic acid IC50 [mM]
Lanzoprazole 125 M 1.04 Lanzoprazole 62.5 M 1.67 Lanzoprazole 31.3 M 2.09 Lanzoprazole 15.6 M 2.00 3.11 Lanzoprazole Combination with IC50 [[tM]
o-Acetylsalicylic acid 2.5 mM 44 o-Acetylsalicylic acid 1.25 mM 88 o-Acetylsalicylic acid 0.625 mM 117 o-Acetylsalicylic acid 0.313 mM 128 o-Acetylsalicylic acid 0.156 mM 141 The growth of tumour cell colonies is markedly more strongly inhibited by the combination of o-acetylsalicylic acid with the proton pump inhibitors lanzoprazole or omeprazole than by o-acetylsalicylic acid on its own.

Migration assay:

The migration assay is carried out with DLD I cells (ATCC# CCL 221). The cells are cultured in RPMI 1640/glutamine 1 /o/Glutamax 1% /(FCS 10%) and used for the assay at a confluence of about 80%. First, 750 l each of medium + 10% FCS, l OnM IL-8 and 20nM SDF-1 are introduced into a 24-well Companion Plate. The plate is temperature controlled at 37 C.
The cells are then trypsinized from culture bottles, stopped with medium + 10% FCS, centrifuged, washed once with medium without FCS, resuspended and counted in a Neubauer chamber. 8 M
individual batches are then employed (without Fluoroblock) and coated with 500 l each of cells (corresponds to 5x105 cells/well). Substances are prepared in DMSO in the concentrations indicated below and then added to the medium of the Companion Plate (3.75 1) and to the cells in the batches (2.5 1).
After a migration period of 48h, the medium is removed from the batches and these are washed in a fresh Companion Plate with 500 l each of prewarmed D-PBS (Gibco).
Subsequently, the batches are placed in a new Companion Plate with 200 l each of prewarmed Accutase and incubated for 10 minutes at 37 C without shaking and a further 5 minutes at 600 rpm in an BHC 05 1 108-Foreign Countries Eppendorf Thermomixer. The batches are then removed and in each case 150 1 from the Companion Plate (bottom cells) are added to white 96 well MTP and processed with CellTiter-Glo (Promega #G7571) according to the instructions of the manufacturer.
Measurement is carried out in a Lumibox at 0.5% sensitivity. The evaluation is carried out with Excel and GraphPad Prism.

Table 3: Influence of a combination of o-acetylsalicylic acid and the proton pump inhibitor lanzoprazole on the migration behaviour of DLD-1: colon carcinoma cells.

Conc. [mM] of o-acetylsalicylic o-Acetylsalicylic o-Acetylsalicylic acid acid/lanzoprazole acid* Lanzoprazole* + lanzoprazole*
0.313 / 0.031 79 41 24 0.625 / 0.031 82 41 23 1.25 / 0.031 35 41 10 *The percentage of the migrated cells in the lower chamber relative to the untreated control is indicated in [%].

An inhibitory effect on the migration behaviour of tumour cells is found. As a result of the combination, markedly fewer DLD-1 cells reach the bottom chamber than with o-acetylsaticylic acid on its own.

Claims (32)

1. Use of a combination comprising at least one NSAID as component A and at least one proton pump inhibitor as component B for the production of administration forms for the prevention and/or treatment of tumours.

2. Use according to Claim 1, where component A is acetaminophen, o-acetylsalicylic acid, clidanac, diclofenac, flurbiprofen, ibuprofen, ketoprofen or sulindac.

3. Use according to one of Claims 1 to 2, where component B is pantoprazole, rabeprazole, lanzoprazole, esomeprazole or omeprazole.

4. Use according to one of Claims 1 to 3, where component A is o-acetylsalicylic acid and component B is lanzoprazole or omeprazole.

5. Use according to one of Claims 1 to 4, where the dose for o-acetylsalicylic acid is 25 to 1500 mg, for omeprazole 5 to 100 mg, for pantoprazole 5 to 100 mg, for lanzoprazole 5 to 100 mg and for esomeprazole 5 to 100 mg.

6. Use according to one of Claims 1 to 5 for the prevention and/or treatment of tumours, in which therapeutic effects can be achieved by inhibition of Cox-1 and/or Cox-2.

7. Use according to one of Claims 1 to 5 for the prevention and/or treatment of carcinomas of the gastrointestinal tract, of the liver, of the pancreas, of the small intestine, of the large intestine, of the rectum, and their precursors.

8. Use according to one of Claims 1 to 5 for the prevention and/or treatment of intestinal polyps, adenomatous intestinal polyps, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal carcinoma (HNPCC).

9. Use according to one of Claims 1 to 5 for the prevention and/or treatment of carcinomas of the lung, tumours of the skin, melanomas, prostate carcinomas, breast carcinomas, tumours of the skeleton, lymphatic carcinomas, tumours of the ovaries, tumours of the endocrine system or tumours of the central nervous system.

10. Use according to one of Claims 1 to 5 for the primary or secondary prevention and/or treatment of colorectal carcinoma.

11. Use according to one of Claims 1 to 10 for the production of a kit.

12. Use according to one of Claims 1 to 11, where administration forms are administered at different times.

13. Use according to one of Claims 1 to 12, where administration takes place orally.

14. Medicament consisting of a fixed combination comprising an NSAID as component A and at least one proton pump inhibitor as component B and one or more further suitable inert excipients.

15. Medicament according to Claim 14 as an oral administration formed comprising the components A and/or B in a rapid-release administration form.

16. Medicament according to Claim 14, characterized in that the components A
and B are mixed and directly filled or tabletted.

17. Medicament according to Claim 14, characterized in that the components A
and B are dry-or wet-granulated and subsequently directly filled or tabletted.

18. Medicament according to Claim 14, characterized in that the components A
and/or B are mixed or granulated independently of one another to be brought together in an additional process step and directly filled or tabletted.

19. Medicament according to Claim 14, characterized in that the components A
and/or B are absorbed separately on neutral pellets and directly filled or tabletted.

20. Medicament according to Claim 14, characterized in that the components A
and B are processed in the form of a 2-layer or jacket-core tablet, where A and B are contained in separate layers or one component is contained in the core and the other component is contained in the jacket.

21. Medicament according to Claim 14, characterized in that the component A
and/or B enter the final pharmaceutical form in the form of a powder mixture, of granules and/or as melt extrusion granules.

22. Medicament according to Claim 14, characterized in that the components A
and B are jointly melt-extruded and subsequently filled in the form of extrusion granules or compressed to give tablets.

23. Medicament according to Claim 14, characterized in that a formulation stage comprising component A or B or the final product is coated with an enteric lacquer.

24. Medicament according to Claim 14 as an oral administration form comprising the components A and/or B in a controlled-release administration form.

25. Medicament according to Claim 14, characterized in that component A and/or B is contained in the form of pellets, granules or tablets, which are coated with a diffusion-controlling membrane.

26. Medicament according to Claim 14, characterized in that component A and/or B are contained in a matrix having controlled release of active compound.

27. Medicament according to Claim 14 in the form of a two-layer tablet, in which one layer contains component A in the form of a controlled-release matrix formulation and/or another layer contains component B in the form of a controlled-release matrix formulation.

28. Medicament according to Claim 14 in the form of an osmotic pharmaceutical release system.

29. Medicament according to Claim 14, characterized in that a formulation stage comprising component A and/or B, or the final product, is enteric-coated.

30. Medicament according to one of Claims 14 to 28, characterized in that the pharmaceutical form has an outer sugar coating or film coating.

31. Use according to one of Claims 1 to 13 for the production of a medicament as defined in one of Claims 14 to 30.

32. Production of a medicament as defined in one of Claims 14 to 30, by processing component A and component B together to give a fixed combination.