DE102005047616A1 - combination - Google Patents

Abstract

The present invention relates to a combination comprising at least one NSAID (non-steriodial anti-inflammatory medication) and at least one proton pump inhibitor, for the prevention and / or treatment of tumor diseases, medicaments containing them and their production.

Description

The The present invention relates to a combination comprising at least an NSAID (non-steroidal anti-inflammatory drugs) and at least one proton pump inhibitor for prevention and / or Treatment of tumor diseases, medicines containing them and their production.

The Treatment of tumor diseases, despite great progress, that have been made in recent years, an unresolved medical one Problem dar. Beside the therapy of manifest tumors the scientific aims Interest increasingly in the therapy of precancerous changes. This is the goal pursues to delay the development of malignant neoplasia or to prevent.

The Adenomatosis coli (Syn .: familial adenomatous Polyposis = FAP) is a neoplastic syndrome with numerous forms Colon polyps. The disease occurs familial and is autosomal inherited dominant. In symptomatic patients with FAP, the carcinoma rate is 50 to 100%, for diseases detected by check-ups 10 to 15%. While the proportion of FAP patients represents about 1% of the total number of colon carcinoma cases (Rustgi AK, Hereditary Gastrointestinal Polyposis and Nonpolyposis syndromes. N Engl J Med 1994, 331, 1694-1702), become adenomatous polyps in about 33% of the total population at the age of about 50 years and at about 50% at the age of 70 years found (Williams AR, Balasooriva BA, Day DW, Polyps and cancer of the large bowel: a necropsy study in Liverpool. Well. 1982, 23, 835-842). Histologically, neoplasms are adenomas. Become frequent also participations of the small intestine and neoplasms in the duodenum and papilla. Diagnosis is already presymptomatic possible by genetic test. Because of the carcinomer maintenance is usually after diagnosis therapeutically performed proctomucoseectomy and colectomy.

In Studies have shown that non-steroidal anti-inflammatory Medication (NSAID) for the treatment of FAP and adenomatous polyps are suitable and thus significantly reduce the risk of colon cancer (Jänne 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 been shown to work Prophylactic against the development of colon cancer, 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 tumorigenesis in A / J mice by acetylsalicylic and and NS-398. Cancer Research 1998, 58, 5354-5360). However, high dosages or long-term use of NSAIDs can undesirable Cause side effects, for example in the gastrointestinal area (Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal Toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999; 340: 1888-1899 (Erratum, N Engl J med 1999; 341: 548).).

The Avoidance of medication-related gastrointestinal side effects in the gastrointestinal track when taking NSAIDs by using a combination from the proton pump inhibitor pantoprazole and a NSAID described in WO 2005/074930.

Recently became demonstrated that the long-term use of o-acetylsalicylic acid for Prophylaxis of diseases of the cardiovascular system or stroke even in patients with increased Risk of gastrointestinal bleeding, for example, in existing Gastrointestinal ulcers carried out can be without the feared Bleeding as side effects occur when using o-acetylsalicylic acid Esomeprazole is combined (Chan FKL, Ching JYL, Hung LCT, Wong VWS, Leung VKS et al. Clopidogel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005, 352, 238-244).

task The present invention is to provide a combination for prevention and / or treatment of tumor diseases comprising an NSAID, wherein NSAID related unwanted Side effects are reduced.

It it has now been found that the combination according to the invention unexpected beneficial effects and properties related to prevention and / or treatment of tumor diseases.

object The present invention is a combination comprising at least an NSAID as component A and at least one proton pump inhibitor as component B for prevention and / or treatment of tumor diseases.

NSAID (non-steroidal antiinflammatory drugs) is within the scope of the invention in general for all substance classes listed under this term in the prior art. For example, NSAID stands for Aceclofenac, acetaminophen, o-acetylsalicylic acid, alclofenac, alminprofen, Amfenac, Ampiroxicam, Amtolmetinguacil, Anirolac, Antrafenin, Azapropazone, Benorilate, Bermoprofen, Bindarit, Bromfenac, Bucloxin, Bucolom, Bufexamac, Bumadizone, Butibufen, Butixirat, Carbasalate Calcium, Carprofen, Cinmetacin, cinnoxicam, clidanac, clobuzarite, deboxamet, dexibuprofen, Dexketoprofen, diclofenac, diflunisal, eltenac, enfenamic acid, egg salad, Etodolac, etofenamate, feclobuzone, felbinac, fentiazac, fepradinol, Flobufen, floctafenine, flufenamic acid, Fluoxaprofen, Flurbiprofen, Flurbiprofen Axetil, Furpfenac, Furprofen, Glucametacin, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin Franesil, Indoprofen, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac, Lornoxicam, loxoprofen, mefenamic acid, Meloxicam, mesalazine, mofezolac, nabumetone, naproxen, niflumic, Olsalazine, Oxaprozin, Pelubiprofen, Phenylbutazone, Pimeprofen, Pirazolac, Piroxicam, pirprofen, pranoprofen, prifelone, prinomide, proglumetacin, Proquazone, protic acid, Romazaritol, salicylamide, salicylic acid, Salmistein, Salnacedin, Salsalat, Sulindac, Suprofen, Talniflumate, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofen acid, Tiaramid, Tilnoprofen arbamel, timegadine, tinoridine, tolfenamic acid, tolmetin, Ufenamate, Ximoprofen, Zaltoprofen and Zoliprofen.

Prefers NSAIDs are acetaminophen, o-acetylsalicylic acid, clidanac, diclofenac, Flurbiprofen, ibuprofen, ketoprofen and sulindac. Especially preferred as NSAID is o-acetylsalicylic acid.

Proton pump inhibitor is in the context of the invention in general for all in the prior art under listed in this term Classes. Proton pump inhibitor is, for example, ranitidine, famotidine, Pantoprazole, lansoprazole, esomeprazole, omeprazole and rabeprazole. Preferred proton pump inhibitors are pantoprazole, rabeprazole, Lansoprazole, esomeprazole and omeprazole. Especially preferred as a proton pump inhibitor are lansoprazole, esomeprazole and omeprazole.

The in the combination according to the invention contained compounds also used in the form of their salts, solvates and solvates of the salts as far as they are not already salts, solvates and solvates salts.

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

Provided in the combination according to the invention contained compounds in tautomeric forms may include the present invention all tautomeric forms.

When Salts are physiologically acceptable in the context of the present invention Salts of the compounds of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for insulation or cleaning the compounds of the invention can be used.

physiological Safe salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, trifluoroacetic, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

physiological acceptable salts of the compounds of the invention also include Salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, Prokain, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

When In the context of the invention, solvates are those forms of the compounds according to the invention, which in solid or liquid Condition by coordination with solvent molecules a complex form. Hydrates are a special form of solvates in which the coordination with water takes place.

The Invention combination can for prevention and / or treatment of tumor diseases.

tumor diseases are in the context of the invention cancerous diseases of the organs warmblooded Organisms and their precursors, especially tumors, in those by inhibition of Cox-1 and / or Cox-2 therapeutic effects can be achieved. These are carcinomas of the gastrointestinal tract and its appendages such as the liver, pancreas, especially the small intestine, the colon, the rectum and their precursors. Under preliminary stages are understood as changes, which do not yet constitute cancer, prefers intestinal polyps, for example adenomatous Intestinal polyps. Other tumor diseases within the scope of the invention are Lung carcinomas, tumors of the skin, in particular melanomas, prostate cancers, breast cancers, Tumors of the skeleton, lymphatic tumors, tumors of the ovaries, tumors of the endocrine system and tumors of the central nervous system.

Prefers can the combination according to the invention for prevention and / or treatment of lung carcinomas, breast cancers, tumors the ovaries and carcinomas of the gastrointestinal tract such as of the small intestine, of the colon and rectum.

Of further, the combination of the invention for prevention and / or treatment of the family adenomatous Polyposis (FAP), the familial heaping Tumor disease without polyposis (Hereditary Non-Polyposis Colorectal Carcinoma - HNPCC), as well as the primary or secondary chemoprevention and therapy of colorectal cancer.

Under prevention becomes a primary one as well as secondary prevention Understood. Under primary prevention In this context, the protection of patients is understood a first disease that causes organ damage. Under secondary prevention In this context, we understand the protection of patients who already an organ damage suffered as a result of a tumor disease, before a renewed Tumor disease.

at Use of the combination according to the invention the effect becomes an unexpected synergistic effect observed. With that you can the amounts of the active ingredients used in the combination in comparison be reduced to monotherapy. Likewise, when using a equivalent to monotherapy equivalent Amount of active ingredient observed an unexpected better effect become.

Of the synergistic effect of the combination according to the invention is preferably observed when the combination according to the invention 0.1 to 20 mg / kg, in particular from 0.5 to 15 mg / kg of active ingredient of component A and 0.01 to 15 mg / kg, in particular 0.05 to 10 mg / kg of active ingredient of the component B in each case based on kg body weight of the patient when administered orally.

Of Further, the synergistic effect of the combination according to the invention preferably observed when the combination according to the invention as NSAID o-acetylsalicylic acid in a Dosage of 25 to 1500 mg, preferably in a dosage of 75 to 750 mg, and as a proton pump inhibitor omeprazole in one Dosage of 5 to 100 mg, preferably in a dosage of 15 to 50 mg, more preferably in a dosage of 20 to 40 mg, pantoprazole in a dosage of 5 to 100 mg, preferably in a dosage of 15 to 50 mg, more preferably in one Dosage of 20 to 40 mg, lansoprazole 5 to 100 mg, preferably in a dosage of 10 to 50 mg, more preferably in one Dosage of 15 to 30 mg, or esomeprazole in one dose from 5 to 100 mg, preferably at a dosage of 15 to 50 mg, more preferably in a dosage of 20 to 40 mg.

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

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

Under "ratio" in the context of the invention will be the weight ratio the individual components unless otherwise stated.

Optionally, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of application route, the individual behavior towards the drugs, the nature of their formulation and the time or interval at which the administration takes place. So it may be sufficient in some cases, with less than the aforementioned minimum amount, while in other cases the above upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

Possibly it may be appropriate the combination according to the invention supplement by adding one or more other components. When Examples include vitamin C, vitamin E and folic acid. These others Components can individually or jointly added.

The inventive combination is also characterized by a surprisingly good compatibility out.

The inventive combination is preferably used in human medicine, but is suitable also for veterinary medicine, especially for the treatment of mammals.

The Administration of the combinations according to the invention can be parenteral, topical or oral, preferably topical or oral, particularly preferably be made orally.

One Another object of the present invention is the use the combination according to the invention for the preparation of dosage forms for the prevention and / or treatment of tumor diseases.

Under "combinations" within the meaning of the invention not just dosage forms containing all components (so-called fixed combinations), and combination packs containing the components contained separately, understood, but also at the same time or staggered applied components, as long as they are for treatment or prophylaxis of the same disease. The single ones Components can then present in different dosage forms (e.g. different tablets and / or capsules), then at the same time or temporally offset for the treatment or prophylaxis thereof Illness are used.

The Active ingredients of components A and B can in known manner in Form of medicines or dosage forms in the usual Formulations are transferred, which is liquid or solid formulations. Examples are tablets, Dragees, pills, capsules, granules, aerosols, syrups, emulsions, Suspensions, juices, Ointments, creams, powders and solutions. About that can out with the combination according to the invention impregnated Plasters or bandages be used. Regulations for the preparation of these dosage forms containing the combination according to the invention are known in the art.

The Topical treatment is carried out by applying the combination according to the invention in appropriate formulations on the affected skin (skin lesion) or in the vicinity the skin lesions to be treated.

There the combinations according to the invention well tolerated and partially already in low dosages are effective to realize the most diverse formulation variants. So exists on the one hand the possibility to formulate the individual components separately. In this case, the Individual components A and B are not necessarily taken at the same time rather, a staggered intake can be achieved optimal effects be beneficial. In such a separate Presentation it is appropriate to the formulations of the individual components, for example, tablets or capsules, simultaneously next to each other in a suitable primary packaging to combine. In the primary packaging the components are each in separate containers, at which are e.g. around tubes, phial or blister packs. Such a separate packaging The components in a common primary packaging is also called a kit designated.

When additional formulation variant for the combinations according to the invention are preferably also fixed combinations. Under "fixed combination" are here such Dosage forms are understood in which the components are common in a fixed quantity ratio available. Such fixed combinations may be in the already mentioned liquid or solid formulations, for example as solutions, capsules or tablets will be realized.

The combinations according to the invention be up to 3 times a day metered, preferred are those combinations which are 1 to 2 times daily Allow application.

The Active ingredients of components A and B are particularly suitable in one Fixed combination in the form of a solid peroral dosage form to be formulated. It is well known that the intake reliability (Compliance) in patients to a significant degree by the number factors the dosage forms per administration and size and weight the (solid peroral) dosage form is dependent. Therefore, both should the number of different medicines to be taken separately as low as possible be (advantage of a fixed combination), as well as the size and the Weight of a solid peroral dosage form to be as small as possible at full therapeutic potency, in order to intake for the patient like that pleasant as possible to design. This allows fixed combinations in the form of fixed peroral drug formulations with minimal size and weight. The fixed combinations according to the invention therefore offer the highest possible patients Compliance, thereby improving safety and reliability a therapy crucial.

By Combination of components A and B and modification of the composition or the functionality let yourself control drug release. For example, can be delayed by Drug release (retardation) of a component the above temporal Decoupling of the entry into action can also be realized in fixed combinations.

The listed here solid peroral dosage forms are produced according to the general standard procedure. Ingredients are those that are pharmaceutical 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 phosphates), binders (e.g., polyvinylpyrrolidone, Gelatin, starch and cellulose derivatives), as well as all other adjuvants which are used for Production of pharmaceutical formulations of the desired properties are required, e.g. Lubricant (magnesium stearate), e.g. Disintegrants (e.g., cross-linked Polyvinylpyrrolidone, sodium carboxymethylcellulose), e.g. wetting agent (e.g., sodium lauryl sulfate), e.g. Retarding agents (e.g., cellulose derivatives, Polyacrylic acid derivatives), e.g. Stabilizers, e.g. Flavors, e.g. Color pigments.

Liquid formulations are also used by standard method with pharmaceutically acceptable Prepared excipients and contain the active ingredients either dissolved or suspended. Typical application volumes of these pharmaceutical preparations are 1 to 10 ml. Examples of Excipients in these liquid Formulations are: solvent (e.g., water, alcohol, natural and synthetic oils, e.g. Medium chain triglcerides), solubilizers (e.g., glycerol, Glycol derivatives), wetting agents (e.g., polysorbate, sodium lauryl sulfate), as well as other auxiliaries used for the preparation of pharmaceutical formulations the desired Properties needed, e.g. viscosity increasing agents, e.g. pH corrigents, e.g. Sweeteners and flavors, e.g. antioxidants e.g. Stabilizers, e.g. Preservative.

Main components the covers of capsule formulations are, for example, gelatin or hydroxypropylmethylcellulose.

pharmaceutical Adjuvants, as known to the expert, are, for example also described in the following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, P.J. American Pharmaceutical Association, Washington, 2nd edition 1994.

EXAMPLES

Example 1:

80 mg o-acetylsalicylic acid and 20 mg omeprazole are used to prepare a tablet if necessary used with the addition of other auxiliaries.

Example 2:

600 mg o-acetylsalicylic acid and 15 mg lansoprazole are used to prepare a tablet if necessary used with the addition of other auxiliaries.

Example 3:

80 mg o-acetylsalicylic acid and omeprazole 40 mg if necessary for the preparation of a tablet used with the addition of other auxiliaries.

Example 4:

600 mg o-acetylsalicylic acid and lansoprazole 30 mg if necessary for the preparation of a tablet used with the addition of other auxiliaries.

Example 5:

100 mg o-acetylsalicylic acid and 20 mg omeprazole are used to prepare a tablet if necessary used with the addition of other auxiliaries.

Example 6:

500 mg o-acetylsalicylic acid and 15 mg lansoprazole are used to prepare a tablet if necessary used with the addition of other auxiliaries.

Example 7:

100 mg o-acetylsalicylic acid and omeprazole 40 mg if necessary for the preparation of a tablet used with the addition of other auxiliaries.

Example 8:

500 mg o-acetylsalicylic acid and lansoprazole 30 mg if necessary for the preparation of a tablet used with the addition of other auxiliaries.

Example 9:

500 mg o-acetylsalicylic acid and omeprazole 40 mg if necessary for the preparation of a tablet used with the addition of other auxiliaries.

Example 10:

100 mg o-acetylsalicylic acid and 15 mg lansoprazole are used to prepare a tablet if necessary used with the addition of other auxiliaries.

Example 11:

500 mg o-acetylsalicylic acid and 20 mg omeprazole are used to prepare a tablet if necessary used with the addition of other auxiliaries.

Example 12:

100 mg o-acetylsalicylic acid and lansoprazole 30 mg if necessary for the preparation of a tablet used with the addition of other auxiliaries.

Colony Formation assay

used are: 96Well plates, previously: cell culture-treated (351172 BD Biosciences), DMEM / F12 Powder Medium (42400-010 Invitrogen), or RPMI Powder Medium (51800-019 Invitrogen), Sea Plaque Agarose (50100 Cambrex) (USA: Biowhittaker BMA 50100, 125grams), Cell titre Blue (Best. # G8080, 20 ml / G8081, 100 ml / G8082, 10 x 100 ml, Promega), cells: A549 (ATCC # CCL 185); HCT116 (ATCC # CCL 247).

First, a bottom layer with doubly concentrated agar is heated to 44 ° C (Eppendorf Thermo-Mixer). Then 50 .mu.l of bottom agar / well are plated and about 30 min. incubated at room temperature. This is followed by the application of the top layer with the tumor cells (HCT 116). For this, the cell suspension is mixed with Bottom Agar (44 ° C) 1: 1 quickly and thoroughly in 50 ml Falcon. 50 μl of the mixture of top agar / cells are plated without touching the bottom agar and for approx. 30 min. incubated at room temperature. Finally, 80 μl of DMEM / F12 (standard medium) is added as a final layer per well, without touching the soft agar. The substance is added 24 hours after sowing. The substances are dissolved in DMSO in the concentrations given below and 10 .mu.l / well added. The incubation takes place for 2 weeks in the presence of 10 mM Hepes buffer. The evaluation is carried out by means of the CTB assay according to the manufacturer's instructions (Promega), the calculation of the IC ₅₀ using the program GraphPad Prism.

Table 1: Activity of o-acetylsalicylic acid, lansoprazole or omeprazole or the respective combinations on tumor cells (HCT 116 colon carcinoma cells) in the Soft Agar Colony Formation Assay. (PPI: Proton Pump Inhibitor - Specification in Table Column) Softagar Assay IC50 Calculation with Prism: Sigmoidal dose-response (variable slope), Bottom = 0 HCT116

Table 2: Activity of o-acetylsalicylic acid and lansoprazole or combinations on human lung carcinoma cells (A549) in the Soft Agar Colony Formation Assay.

The growth of tumor cell colonies is markedly more inhibited by the combination of o-acetylsalicylic acid with the proton pump inhibitors lansoprazole or omeprazole than by o-acetylsalicyl acid alone.

Migration Assay:

• * Angegeben ist die Prozentzahl der in die untere Kammer migrierten Zellen relativ zur unbehandelten Kontrolle in [%].

The miration assay is performed with DLD 1 cells (ATCC # CCL 221). The cells are grown in RPMI 1640 / Glutamine 1% / Glutamax 1% / (FCS 10%) and used at a confluence of approximately 80% for the assay. First, in each case, 750 μl of medium + 10% FCS, 10 nM IL-8 and 20 nM SDF-1 are placed in the 24-well companion plate. The plate is heated to 37 ° C. The cells are then trypsinized from culture flasks, quenched with medium + 10% FCS, centrifuged, washed once with medium without FCS, resuspended and counted in a Neubauer chamber. Thereafter, 8 μM individual inserts (without fluoroblock) are set and charged with 500 μl cells (corresponding to 5 × 10 ⁵ cells / well). Substances are prepared in DMSO at the concentrations below and then added to the Companion Plate medium (3.75 μl) and to the cells in the inserts (2.5 μl). After 48 hours migration time, the medium is removed from the inserts and washed in fresh Companion-plate with 500 .mu.l preheated D-PBS (Gibco). The inserts are then placed in a new companion plate, each with 200 ul preheated Accutase and incubated for 10 minutes at 37 ° C without shaking and another 5 minutes at 600 rpm in the Eppendorf Thermomixer. The inserts are then removed and from the companion-plate (bottom cells) are added in each case 150 .mu.l in white 96-well MTP and processed with CellTiter-Glo (Promega # G7571) according to the manufacturer's instructions. The measurement takes place in a Lumibox at 0.5% sensitivity. The evaluation is performed with Excel and GraphPad Prism. Table 3: Influence of a combination of o-acetylsalicylic acid and the proton pump inhibitor lansoprazole on the migration behavior of DLD-1 colon carcinoma cells.

• * The percentage of cells migrated into the lower chamber is given relative to the untreated control in [%].

It is an inhibitory effect on the migration behavior of Tumor cells detected. The combination is clear less DLD-1 cells in the bottom chamber than with o-acetylsalicylic acid alone.

Claims (15)

Use of a combination comprising at least an NSAID as component A and at least one proton pump inhibitor as component B for the preparation of dosage forms for the prevention and / or Treatment of tumor diseases. Use according to claim 1, wherein component A is acetaminophen, o-acetylsalicylic acid, clidanac, diclofenac, Flurbiprofen, ibuprofen, ketoprofen or sulindac Use according to one the claims 1 to 2, wherein component B is pantoprazole, rabeprazole, lansoprazole, Esomeprazole or omeprazole is. Use according to one the claims 1 to 3, wherein component A is o-acetylsalicylic acid and component B is lansoprazole or omeprazole. Use according to one the claims 1 to 4, wherein the weight ratio between component A and component B is 2: 1 to 100: 1. Use according to one the claims 1 to 4, wherein the dosage for o-acetylsalicylic acid 25 to 1500 mg, for Omeprazole 5 to 100 mg, for Pantoprazole 5 to 100 mg, for Lansoprazole 5 to 100 mg and for esomeprazole 5 to 100 mg. Use according to one the claims 1 to 6 for prevention and / or treatment of tumor diseases in which by inhibition Cox-1 and / or Cox-2 therapeutic effects can be achieved. Use according to one the claims 1 to 6 for prevention and / or treatment of carcinomas of the gastrointestinal tract, the liver, the pancreas, the small intestine, of the large intestine, the rectum and their precursors. Use according to one the claims 1 to 6 for prevention and / or treatment of intestinal polyps, adenomatous intestinal polyps, familial adenomatous polyposis (FAP) or the familial heaping Tumor disease without polyposis (Hereditary Non-Polyposis Colorectal Carcinoma - HNPCC). Use according to one the claims 1 to 6 for prevention and / or treatment of lung carcinomas, tumors of the skin, melanomas, Prostate cancer, breast cancer, skeletal tumors, lymphoid Tumors, tumors of the ovaries, tumors of the endocrine system or Tumors of the central nervous system. Use according to one the claims 1 to 6 to the primary or secondary prevention and / or treatment of colorectal carcinoma. Use according to one the claims 1 to 11 for making a kit. Use according to one the claims 1 to 12, wherein administration forms applied at different times become. Use according to one the claims 1 to 13, the administration being topical. Use according to one the claims 1 to 13, the administration being oral.