ES2229902A1 - Production of medicines for e.g. high fibrinogen levels treatment involves human blood control via sulphonic derivatives - Google Patents

Abstract

Production of medicines for e.g. high fibrinogen levels treatment comprising 2,5-dihydroxy benzene sulphonic compounds for medicines reducing fibrinogen concentrations in human blood, is claimed.

Description

Use of compounds 2,5-dihydroxybenzenesulfonic for manufacturing of a medicine.

The present invention relates to the use of 2,5-dihydroxybenzenesulfonic compounds for manufacture of a drug for the reduction of fibrinogen in human blood, as well as for the prophylaxis and treatment of diseases caused by high levels of fibrinogen.

The prior art is known, by ex. of "Atherosclerosis and Coronary Artery Disease", by Valentín Fuster, Russell Ross and Eric J. Topol (Editors), Volume One, for example. P. 31, 346, 1996, Lippincott-Raven Publishers, Philadelphia, New York, which elevated levels of Fibrinogen in blood contribute to the genesis and / or progression of various diseases, particularly coronary diseases.

In addition, it is known, for example. from "Treatment of blood hyperviscosity with calcium dobesilate in patients with diabetic retinophathy", Salama et al ., Ophthalmic res. 17, 131-138 (1985) that the administration of calcium dobesilate, a 2,5-dihydroxybenzenesulfonic compound, at a daily dose of 1500 mg results in a reduction in the level of fibrinogen in the blood of human patients.

However, the administration of a medication containing such a large dose of one or more compounds 2,5-dihydroxybenzenesulfonic is critical by several  reasons. Although rare, side effects are known Adverse effects of these compounds, such as intestinal overload, skin reactions, fever, arthralgia or changes in the blood count

In addition, many patients have serious problems. when faced with the need to take such amount of medicine. Thus, the daily dose of this medication is usually split into several smaller doses that are administered to the patient  Several times during the day.

However, this requires that the patient or the health personnel who take care of it follow a strict scheme of Medication administration, which often leads to a degree of insufficient compliance.

Therefore, it was an object of the present invention provide a fibrinogen reduction medication in human blood that avoided the known disadvantages in the state of the prior art.

Surprisingly, it has been observed that one dose daily total of ≤ 500 mg of one or more of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I Shown below is sufficient to reduce the levels of fibrinogen in human blood and therefore are also useful for the prophylaxis and treatment of diseases related to high levels of fibrinogen.

Thus, one aspect of the present invention is the use of at least one of the compounds 2,5-dihydroxybenzenesulfonic as follows general formula I,

one

in the which

R represents H or SO3;

B represents at least one cation;

n represents 1 or 2;

m represents 1 or 2,

optionally in the form of a solvate pharmaceutically acceptable, for the manufacture of a medicine for the reduction of fibrinogen in human blood, in which the medication is given at a total daily dose of said 2,5-dihydroxybenzenesulfonic equivalent compound to ≤ 500 mg.

The medicine obtained according to the present invention is usually suitable for administration to humans of all age groups, in which the use of at minus one of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I for the manufacture of a medicament for administration to humans Adults.

Media experts understand that there is a normal range of the level of fibrinogen in the blood of healthy humans that can vary depending on various factors, such as the person's type or sex. These experts know methods to determine the normal range of blood fibrinogen level in a control group.
determined.

If the level of fibrinogen in the blood of Fibrinogen is elevated with respect to the normal values of control group, there is an increased risk of health problems. So therefore, it is desirable to reduce the level of fibrinogen, preferably to a value that corresponds to the normal range of the control group respective. For example, blood fibrinogen levels of 200 to 450 mg / 100 ml of plasma are considered normal in men healthy.

The cation B of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I it can be any physiologically acceptable cation known for media experts in the field, for example, P. Heinrich Stahl, Camille G. Wermuth (Editors), "Handbook of Pharmaceutical Salts - Properties, Selections and Use ", Editorial Helvetica Chimica Minutes, Zurich, Switzerland, Wiley-VCH, Weinheim, Germany, 2002, which is incorporated here as a reference and is part of the revelation. Media experts understand that the cation B must be chosen so that the overall burden of 2,5-dihydroxybenzenesulfonic compounds of formula General I be neutral.

The present invention encompasses the use of a mixture of at least two of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I above mentioned as well as mixed salts of these compounds, that is, compounds with different B and / or different cations 2,5-dihydroxybenzenesulfonic residues.

Preferably, the cation (s) B of 2,5-dihydroxybenzenesulfonic compounds of general formula I is selected (n) from the group consisting of Ca 2+, Mg 2+, Na +, K + and [NH 4 R x] +, in which s 0, 1, 2, 3 or 4 y, R, it has a branched C 1-4 alkyl radical or unbranched If x is greater than 1, that is, if there are two or more alkyl radicals in the cation [NH 4 R x] +, can be identical or different, preferring to be alkyl radicals identical

Preferably, the medication can integrate one or more compounds selected from the group consisting of Calcium 2,5-dihydroxybenzenesulfonate (dobesilate calcic), diethylamin-2,5-dihydroxybenzenesulfonate (etamsylate) and bis (diethylamin) -2,5-dihydroxybenzene-1,4-disulfonate (persilate) More preferably, for the manufacture of medicament according to the present invention, the Calcium 2,5-dihydroxybenzenesulfonate (dobesilate calcic).

The compounds 2,5-dihydroxybenzenesulfonic acids of general formula I which are used in the invention may also be in the form of solvates, particularly in the form of hydrates. The manufacture of 2,5-dihydroxybenzenesulfonic compounds of general formula I, as well as its solvates, can be achieved by using reagents and methods known to experts means in the matter.

The manufacture of Calcium 2,5-dihydroxybenzenesulfonate (dobesilate calcium) and of diethylamin-2,5-dihydroxybenzenesulfonate (etamsylate) follows, for example, from "The Merck Index "-13th Edition, Merck & Co, R. Rahway, N.J. USA 2001. The aforementioned bibliography is incorporated in this way by reference and part of the revelation. The manufacture of bis (diethylamin) -2,5-dihydroxybenzene-1,4-disulfonate  (persilate) follows, for example, from the French patent FR 73/17709 (Publication No. 2,201,888). The corresponding description is incorporated here by reference and is part of the revelation.

It has been found that the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I reduce fibrinogen levels in human blood, preferably  in adults, when administered at a total daily dose of ≤ 500 mg

The compounds 2,5-dihydroxybenzenesulfonic acids of formula I can also be administered to the patient, preferably human adult, at a daily dose of 50 to 500 mg, preferably at a total daily dose of 100 to 450 mg, and more preferably even at a Total daily dose of 150 to 400 mg.

The patients related to the present invention they are human, preferably adult human, with symptoms of disease caused by elevated fibrinogen levels, as well as humans, preferably adult humans, at greater risk for their health due to high levels of fibrinogen in the blood, that is, humans who require prophylaxis. The patients also include humans, preferably adult humans, with a disorder or others known risk factors that produce high levels of fibrinogen

Managing the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I at a total daily dose of ≤ 500 mg, both the frequency and The extent of adverse side reactions may be even smaller. The frequency of administration of medication can be reduced to twice a day, preferably to once a day, thus leading to a greater degree of compliance by part of the patient.

Since the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I reduce fibrinogen levels in human blood, are suitable for the preparation of a medication for prophylaxis and / or treatment of diseases caused by elevated levels of fibrinogen

Preferably, the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I  mentioned above can be used to manufacture a medicine for prophylaxis and / or treatment of diseases coronary, more preferably even for prophylaxis and / or treatment of atherosclerotic lesions, such as fibrotic plaques and / or thrombotic occlusions.

A group of patients with particular risk of suffer from diseases caused by high levels of fibrinogen in blood is the group of diabetics, preferably diabetics Adults. Thus, also preferably, the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I mentioned above can be used to manufacture a medication for prophylaxis and / or treatment, preferably prophylaxis of diseases caused by elevated levels of Fibrinogen in diabetics.

Medication for reducing levels of blood fibrinogen according to the present invention should be administered to patients who require this prophylaxis and / or treatment continuously, that is, for periods of time prolonged, preferably for life.

Depending on the specific embodiment, the medicament of the present invention may also contain, as additional constituents, conventional auxiliary substances known by the average experts in the field.

Medications according to the present invention can be manufactured following standard procedures known to those skilled in the art, for example, to from the indices of "Pharmaceutics: the Science of Dosage Forms ", Second Edition, Aulton, M.E. (Ed.) Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology ", Second Edition, Swarbrick, J. And Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics ", Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New York 2002, and "The Theory and Practice of Industrial Pharmacy ", Lachman L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The corresponding descriptions are incorporated by reference and They are part of the revelation.

In a preferable embodiment of the present invention, the medicament is suitable to be administered via oral.

If the medication is suitable for oral administration, may preferably be in the form of tablet, capsule or suspension.

The medicament of the present invention also it can be in the form of multiparticles, preferably in pellets or granules, optionally tablets in a tablet, filled in a capsule or suspended in a suitable liquid. Liquids Suitable are known to those skilled in the art.

In a preferable embodiment of the present invention, the medicament incorporates at least one of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I,  optionally in solvate form, at least partially in form of sustained release.

By incorporating one or more of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula 1, optionally in the form of a solvate, at least partial or completely in the form of sustained release, it is possible to expand the duration of its effect, enabling beneficial effects of this type of sustained release, for example, maintenance of constant therapeutic concentrations in blood.

The forms of sustained liberation, as well as the materials and methods of their preparation are known by the media experts in the field, for example, from Indexes of "Modified-Release Drug Delivery Technology ", Rathbone, M.J. Hadgraft, J. And Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology ", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, '2000); "Controlled Drug Delivery ", Vol. I, Basic Concepts, Bruck, S.D. (Ed.), CRC Press Inc., Boca Raton (1983) and de Takada, K. And Yoshikawa, H., "Oral Drug Delivery ", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New.York (1999), Vol. 2, 728-742; Fix J., "Oral drug delivery, small intestine and colon ", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The corresponding descriptions are incorporated by reference and They are part of the revelation.

If the medicament according to the present invention comprises at least one of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I, at least partially in the form of sustained release, said sustained release can preferably be achieved by the application of at least one coating or matrix provision that comprise at least one sustained release material.

Sustained release material is based preferably in a natural, semi-synthetic or synthetic polymer, non-water soluble, optionally modified, or in a wax, or grease, or fatty alcohol, or natural, semi-synthetic or synthetic fatty acid, or in a mixture of at least two of the compounds above mentioned.

The non-water soluble polymers used to manufacture the sustained release material are based preferably in an acrylic resin, which is selected preferably from the group of poly (meth) acrylates, more preferably of the (C 1-4) polyalkyl (meth) acrylates, polydialkylamino (C 1-4) alkyl (C 1-4) (meth) acrylates and / or copolymers or mixtures thereof, and, more preferably still, of the copolymers of ethylacrylate and the methyl methacrylate with a 2: 1 monomeric molar ratio (Eudragit NE30D®), copolymers of ethylacrylate, methyl methacrylate and chloride  trimethylammonium ethyl methacrylate with a monomeric molar ratio 1: 2: 0.1 (Eudragit RS®), copolymers of ethylacrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride with a 1: 2: 0.2 monomeric molar ratio (Eudragit RL®), or a mixture of at least two of the aforementioned copolymers. These coating materials are commercially available as 30% aqueous latex dispersions p., ie, as Eudragit RS30D®, Eudragit NE30D® or Eudragit RL30D®, and can also be used as such for coating purposes.

In another embodiment, the release material Sustained is based on non-water soluble cellulose derivatives, preferably alkylcellulose, with particular preference being given to ethyl cellulose or cellulose esters, for example, acetate cellulose The dispersions of aqueous ethylcellulose are commercially available, for example, with the Aquacoat® brands or Surelease®.

As waxes, fats or natural fatty alcohols, semi-synthetic or synthetic, sustained release material It can be based on carnauba wax, beeswax, glycerolmonwestarate, glycerolmonobehenate, glycerolditripalmitoestearato, microcrystalline wax, alcohol cetyl, cetyl stearyl alcohol or a mixture of at least two of these components.

Polymers of sustained release material above mentioned can also incorporate a plasticizer conventional, physiologically acceptable in known amounts by the average experts in the field.

Examples of suitable plasticizers are lipophilic diesters of an aliphatic dicarboxylic acid or aromatic with 6 to 40 carbon atoms and an aliphatic alcohol with 1 at 8 carbon atoms, such as dibutylphthalate, diethylphthalate, dibutyl sebacate or diethyl sebacate, esters hydrophobic or lipophilic citric acid, for example, triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyltriethyl citrate, polyethylene glycols, propylene glycols, esters of glycerol, for example, triacetin, Myvacet® (mono and acetylated diglycerides, C 23 H 44 O 5 a C 25 H 47 O 7), medium chain triglycerides (Miglyol®), oleic acid or mixtures of at least two of those mentioned plasticizers The aqueous dispersions of Eudragit RS® and optionally Eudragit RL® contain mainly triethyl citrate. The sustained release material may incorporate one or more plasticizers in the amount of, for example, 5 to 50% p. function of the amount of polymer (s) used.

Sustained release material can also contain other conventional auxiliary substances known for media experts, for example, lubricants, colored pigments or surfactants.

The medicament of the present invention also it can have at least one enteric coating that dissolves in pH function Thanks to this coating, the medicine can go through the stomach without dissolving and the compounds of formula General I are only released in the intestinal tract. Coating Enteric preferably dissolves at a pH between 5 and 7.5.

The enteric coating can be based on any enteric material known to the average experts in the matter, for example, in acid copolymers methacrylic / methyl methacrylate with a 1: 1 monomeric molar ratio (Eudragit L®), methacrylic acid / methyl methacrylate copolymers with a monomeric molar ratio of 1: 2 (Eudragit S®), copolymers of methacrylic acid / ethyl acrylate with a molar ratio 1: 1 monomer (Eudragit L30D-55®), copolymers of methacrylic acid / methyl acrylate / methyl methacrylate with a 7: 3: 1 monomeric molar ratio (Eudragit FS®), shellac, hydroxypropyl methylcellulose acetatosuccinates, acetate cellulose phthalates or a mixture of at least two of these components, which can also be used optionally in combination with non-water-soluble poly (meth) acrylates above mentioned, preferably in combination with Eudragit NE309D® and / or Eudragit RL® and / or Eudragit RS®.

The drug coatings of the present invention can be applied through conventional processes known to those skilled in the art, for example, from Johnson, J.L., "Pharmaceutical tablet coating", Coatings Technology Handbook (Second Edition), Satas, D. And Tracton, A.A. (Eds.), Marcel Dekker, Inc. New York (2001), 863-866; Castensen, T., "Coating Tablets in Advanced Pharmaceutical Solids ", Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001), 455-468; Leopold, C.S., "Coated dosage forms for colon-specific drug  delivery ", Pharmaceutical Science & Technology Today, 2 (5), 197-204 (1999), Rhodes, C.T. and Porter, S.C., Coatings, in Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 1, 299-311. The corresponding descriptions are incorporated by reference and are part of the revelation.

In another embodiment, the medication of the The present invention contains one or more of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I not only in the form of sustained release, but also in the form not delayed By combination with the release form immediate, you get a high initial dose for rapid establishment of the beneficial effect. The slow release of the form sustained release then prevents the effect beneficial decrease. Such medication is particularly useful. for the treatment of acute health problems, particularly coronary heart disease due to its high levels of blood fibrinogen

This can be achieved, for example, by a medicine that has at least one release coating Immediately understand at least one of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I to provide a rapid establishment of the beneficial effect after of its administration to the patient.

Pharmacological method

The level of fibrinogen in the blood is evaluated preferably in blood plasma. The appropriate methods are known by experts in the field.

Preferably, the level of fibrinogen in Human plasma is determined in an ACL 3000 device (Instrumentation Laboratory, USA) using 0.1 ml samples of citrated plasma maintained at a temperature of 15-25 ° C for less than 4 hours after blood draw Thrombin is used as reagent and control purified bovine and control plasma (both of Instrumentation Laboratory, USA), respectively.

Said device measures the content of plasma fibrinogen measuring the clotting time of a standard sample to which excess thrombin has been added. Since coagulation occurs because fibrinogen is transforms into fibrin, the clotting time is inversely proportional to the concentration of fibrinogen in plasma. This linearity is in the range of 60 to 600 mg / dl.

Also preferably, the levels of Fibrinogen in human plasma can be determined by coagulometry by a conventional reagent kit for determination of fibrinogen supplied by Roche.

The present invention is illustrated below. by examples. These illustrations are only given as a example and do not limit the general spirit of the present invention.

Examples Example 1 Hard gelatin capsule containing calcium dobesilate

Dobesilate calcic 0.500 g Cellulose 0.023 g Magnesium stearate 0.007 g Colloidal Silicone Dioxide 0.005 g Total weight 0.435 g

The mentioned amounts of calcium dobesilate, Cellulose, magnesium stearate and colloidal silicone dioxide se. mix well in a conventional stirrer and then They fill in a conventional hard gelatin capsule.

Example 2 Tablet containing calcium dobesilate

Dobesilate calcic 0.5000 g Starch corn 0.0650 g Lactose 0.0520 g Povidone K-30 0.0175 g Citric acid monohydrate 0.0125 g Magnesium stearate 0.0020 g Sodium bisulfite 0.0010 g Total weight 0.6500 g

The mentioned amounts of calcium dobesilate, corn starch, lactose, povidone K-30, monohydrate of citric acid, magnesium stearate and sodium bisulfite are mix well in a conventional stirrer and then compress in a conventional compression press to form a compressed.

Pharmacological data

one)

In a one-year study, male rats genetically diabetic (BB / wor rats, Mölegaard Breeding and Research, Svensved, Denmark) were continuously treated with a total oral daily dose of 500 mg / kg / day of calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate). A control group of this type of rats received the respective placebo.

Blood fibrinogen levels in rats It was evaluated after 1, 3, 6 and 12 months, as described previously.

After 3 months of treatment, the rats of the group treated with calcium dobesilate showed levels of significantly reduced fibrinogen in blood compared with the respective control group. This effect was maintained throughout  The study period of one year.

2)

Two month old transgenic mice (RIP / IFN-?) Were treated with streptozocin (20 mg / kg / day) for five days to induce diabetes.

After 15 days, the animals developed hyperglycemia of 250-300 mg / dl, values that they reached 400-600 mg / dl after two months.

15 days after administration of Streptozocin, the group of diabetic mice was divided into three groups of 40 mice each. Group I was treated with a total oral daily dose of 50 mg of calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate) per kg and day, group two was treated with a total daily dose 500 mg oral calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate) per kg and day, and group III (control group) was treated with the respective amount of placebo that only contained the substances auxiliary

Said treatment was carried out continuously. for three months, before sacrificing the mice and determine blood fibrinogen levels in samples of 250 µ blood by coagulometry using the reagent kit of Roche fibrinogen.

After 3 months of treatment, the mice the groups treated with calcium dobesilate showed levels of significantly reduced fibrinogen in blood compared with the respective control group.

Surprisingly, you get a reduction of plasma fibrinogen levels when administering a dose Total daily calcium dobesilate of only 50 mg / kg.

Claims (23)

1. Use of at least one of the compounds 2,5-dihydroxybenzenesulfonic acids of general formula I, 2 in the which R represents H or SO3; B represents at least one cation; n represents 1 or 2; m represents 1 or 2, optionally in the form of a solvate pharmaceutically acceptable for the manufacture of a medicine for the reduction of fibrinogen in human blood, in which the medication is given at a total daily dose of said 2,5-dihydroxybenzenesulfonic equivalent compound to ≤ 500 mg. 2. Use according to claim 1, characterized in that the cation (s) B is selected from the group consisting of Ca 2+, Mg 2+, Na +, K + and [NH 4 R X] +, in which x is 0, 1, 2, 3 or 4 and R represents a C 1-4 alkyl radical branched or not branched that can be the same or different for x> 1. 3. Use according to claims 1 or 2, characterized in that the compound of general formula I is 2.5 calcium dihydroxybenzenesulfonate (calcium dobesilate). 4. Use according to claims 1 or 2, characterized in that the compound of general formula I is diethylamin-2,5-dihydroxybenzenesulfonate (ethamsylate). 5. Use according to claims 1 or 2, characterized in that the compound of general formula I is bis (diethylamin) -2,5-dihydroxybenzene-1,4-disulfonate (persylate). 6. Use according to any of claims 1-5, characterized in that the medicament is administered at a daily dose of the components of the general formula I of 50 to 500 mg, preferably 100 to 450 mg and, more preferably still, at doses of 150 to 400 mg 7. Use according to any of the claims 1-6 for prophylaxis and / or treatment, preferably prophylaxis, of diseases associated with levels high fibrinogen. 8. Use according to claim 7 for the coronary heart disease prophylaxis. 9. Use according to claim 8 for atherosclerotic lesion prophylaxis. 10. Use according to claim 9 for the fibrotic plaque prophylaxis. 11. Use according to claim 9 for prophylaxis of thrombotic occlusions. 12. Use according to any of claims 1-11, characterized in that the medicament is suitable for oral administration. 13. Use according to claim 12, characterized in that the medicament is in the form of a tablet, capsule or suspension. 14. Use according to claim 12, characterized in that the medicament is in the form of multiparticles, preferably in pellets or granules, optionally compressed in a tablet, filled in a capsule or suspended in a suitable liquid. 15. Use according to any of claims 1-14, characterized in that the medicament comprises at least one of the compounds of general formula I at least partially in the form of sustained release. 16. Use according to claim 15, characterized in that the medicament has at least one coating or a matrix comprising at least one sustained release material. 17. Use according to claim 16, characterized in that the sustained-release material is based on a natural, semi-synthetic or synthetic, non-water soluble, optionally modified polymer, or on a wax, or fat, or natural fatty alcohol, or semi-synthetic fatty acid or synthetic, or in a mixture of at least two of the above-mentioned compounds. 18. Use according to claim 17, characterized in that the non-water-soluble polymer is based on an acrylic resin that is preferably selected from the group of poly (meth) acrylates, polydialkylamino (C 1-4) alkyl (C 1-1) alkyl 4}) (meth) acrylates and / or copolymers, or a mixture of at least two of the above-mentioned polymers. 19. Use according to claim 17, characterized in that the non-water soluble polymers are cellulose derivatives, preferably alkyl cellulose, and even more preferably, ethyl cellulose or cellulose esters. 20. Use according to claim 17, characterized in that the wax is carnauba wax, beeswax, glycerol monostearate, glycerolmonobehenate, glycerolditripalmithostearate, microcrystalline wax, or a mixture of at least two of these components. 21. Use according to claims 17 to 20, characterized in that the polymers have been used in combination with one or more plasticizers. 22. Use according to any of claims 12 to 21, characterized in that the medicament incorporates an enteric coating. 23. Use according to any of claims 1 to 22, characterized in that the medicament incorporates at least one immediate release coating comprising at least one of the compounds of general formula I.