CZ2014825A3 - Composition for oral use - Google Patents

Abstract

The present invention provides an oral formulation for the prevention and healing of inflammatory changes in the gastrointestinal tract comprising a mucoadhesive biocompatible hydrophilic polymer comprising: at least one type of structural units A selected from the group consisting of acrylic and methacrylic acid and salts thereof, hydroxyalkyl acrylates and methacrylates, hydroxyalkylacrylamides and methacrylamides, N, N-dialkylaminoalkyl acrylates and methacrylates, N, N-dialkylaminoalkylacrylamides and methacrylamides, N-vinyl-2-pyrrolidone and mixtures thereof; at least one type of structural units B selected from the group consisting of hydroxy terminated polyoxyethylene acrylates, alkyloxy terminated polyoxyethylene acrylates and methacrylates, hydroxy terminated polyexyethylene acrylamides and methacrylamides, alkyloxy terminated polyoxyethylene acrylamides and methacrylamides, and mixtures thereof; and at least one type of structural units C derived from sterically hindered amines.

Description

Preparation for oral use

Field of technology

The subject of the invention is a polymeric preparation which regulates the internal environment of the gastrointestinal tract (GIT) by removing present harmful substances introduced with food or arising as a result of ongoing processes in the GIT, especially inflammatory processes, whereby the preparation favorably affects the function of the gastrointestinal mucosa. inflammatory diseases.

Prior art

The inner surfaces of the GIT mucosa are exposed to a very aggressive environment of digestive fluids, characterized by extreme pH values, enzymatic action of digestive juices and the action of components ingested with food. The inner surfaces of the stomach wall and other sections of the GIT are covered with a layer of mucus, which performs, among other things, the protective function of the mucosa. If this layer is disturbed for any reason, the inner wall of the organ is irritated upon contact with the digestive fluid, which can lead to inflammation. The most common inflammatory diseases of the gastrointestinal tract (QIT) include gastric ulcers, Crohn's disease and ulcerative colitis.

At present, there is still no reliable method for the prevention of inflammatory changes of the GIT mucosa and their possible treatment. The most common type of treatment is the administration of antibiotics and anti-inflammatory drugs, repeated use of antibiotics and steroidal anti-inflammatory drugs in patients can cause very adverse side effects, such as nausea, hypertension, diabetes, bone thinning, glaucoma. In patients who cannot receive antibiotics or steroids, treatment with immunosuppressants is used, which affect the excessive response of the immune system and thus alleviate the course of the disease. However, the effect of immunosuppressants in the treatment of Crohn's disease and ulcerative colitis in suppressing the autoimmune response is also a disadvantage, as long-term use of these substances makes the patient more susceptible to other types of disease.

An important factor in tissue damage in the first (inflammatory) phase is the massive production of reactive oxygen species, hereinafter referred to as ROS (reactive oxygen species), including for example hydroxyl, peroxyl and superoxide radicals, anion radicals, which occur due to the action of proinflammatory mediators. When the concentration of ROS exceeds a certain level, which exceeds the antioxidant capacity of the surrounding cells, the so-called oxidative stress occurs.

Oxidative stress caused by ROS can lead to further tissue damage, and thus worsen the overall course of the inflammatory response, which is reflected, among other things, in a significant prolongation of the treatment time.

The use of hindered amine stabilizers (HAS) and their oxidized derivatives of nitroxides and hydroxylamines for the healing of inflammatory diseases also appears in the patent literature. Patent CZ 293419 B6 discloses hydrophilic polymers in the form of a gel or cover film, which accelerate the healing process when applied to inflammatory skin injuries. The starting polymers contain covalently bonded sterically shielded amine or its oxidized derivative nitroxide or hydroxylamine, which function as very effective free radical scavengers. The materials and preparations according to these patents can be used when used on external wounds, where a localized effect can be achieved by the method of application of the preparation directly to the wound. For oral use in complex and diverse GIT environments, these preparations are suitable due to the need to ensure the effect of the preparation in a relatively large and variable volume of gastrointestinal fluids, changes in the composition and properties of the environment, eg different pH in different sections of the gastrointestinal tract. For oral use, it is necessary to address the accessibility of functional groups to the present noxa, to localize the effect of the preparation on the mucosa of the digestive tract and at the same time to minimize the possibility of systemic influence on the organism. These properties can be influenced by combining the antioxidant with the polymer.

JP 2012-111700 A deals with polymeric antioxidants for use in the digestive tract. The polymeric antioxidant, which according to this is documented in the form of particles or micelles, contains cyclic nitroxide derivatives in the structure. Block copolymers are described comprising chemically linked blocks of polyethylene glycol and polystyrene, the polystyrene block containing styrene units having functional groups in position 4, which are subsequently used for chemical modifications allowing the attachment of cyclic nitroxides. The disadvantage of this solution is that the functional nitroxide is bound to the polystyrene block of the polymer, which forms the hydrophobic core of the micelle or particle and is thus separated from the environment by a layer of polyethylene glycol, which forms the hydrophilic shell of the micelle. particle. The access of hydrophilic ROS to the antioxidant located in the core of the particle is thus severely limited.

Another factor in the development of the inflammatory process in the GIT is the action of extreme pH, such as in gastric juice. Compounds that chemically bind the hydrochloric acid contained in gastric fluid by chemical means may serve as an adjuvant to prevent the inflammatory condition of the gastric mucosa as well as to protect the mucosa in an ongoing inflammatory condition (gastritis, irritable stomach, heartburn, reflux, reflux oesophagitis, gastric and duodenal ulcers). These are mainly inorganic compounds based on bicarbonates, hydroxides, metal oxides (aluminum, magnesium), or their combination with the drug Omeprazole, which

-3 acts as a proton pump inhibitor. The low molecular weight active substances are generally dispersed in a polymeric carrier which swells in the gastric fluid, thereby ensuring their gradual release into the surrounding medium. However, the presence of low molecular weight substances can cause a number of undesirable side effects in sensitive patients, as these substances are absorbed into the bloodstream. Another disadvantage of the use of these metal-containing preparations is their interaction with commonly used drugs, especially with antibiotics, the absorption of which is significantly inhibited by the cations of these metals.

We have now found that the above drawbacks of the prior art can be overcome by using the composition of the present invention.

The essence of the invention

The present invention relates to a preparation for oral use intended for the prevention and healing of inflammatory changes in the gastrointestinal tract. The preparation contains a biocompatible, hydrophilic polymer with affinity for glycoproteins on the surface of the GIT mucosa, which in its structure contains functional groups capable of binding pollutants from the environment of the GIT fluid. The individual functional components are covalently incorporated into the polymer chains, which effectively prevents their release and absorption into the bloodstream and the consequent undesirable systemic effects.

Said polymer is preparable by radical polymerization of a mixture of three types of structural units having different functions in the structure of the polymer and in the function of the preparation. These structural units are:

Structural units A, characterized by the ability to change hydrophilic properties depending on the pH of the environment. These structural units ensure the solubility of the linear polymer, or good swelling of the branched and crosslinked polymeric structures in gastrointestinal fluids over a wide pH range (1.0 to 7.0) and the ability to adjust the pH of the gastric fluid. These units are selected from acrylic and methacrylic acid and their salts, hydroxyalkyl acrylates and methacrylates, N-vinyl-2-pyrrolidone, N, N-dialkylaminoalkyl acrylates and methacrylates, N, N dialkylaminoalkylacrylamides and methacrylamides.

Structural units B are selected from the group of substances characterized by affinity for glycoproteins on the surface of the gastrointestinal mucosa. The presence of these units in the polymer structure promotes the adhesion of the polymer to the mucosal wall, thereby keeping the active substance incorporated in the polymer chain in contact with the affected mucosal site. Suitable monomers for ensuring affinity for the gastrointestinal mucosa are selected from hydroxy-terminated polyoxyethylene acrylates and methacrylates, alkyloxy-terminated polyoxyethylene acrylates and methacrylates, hydroxy-terminated polyoxyethylene acrylamides and methacrylamides, alkyloxy-terminated polyoxyethylene acrylamides and methacrylamides, preferably up to 1000 _m in diameter. .

The term "alkyl" refers to C 1 -C 6 alkyls, unless otherwise indicated.

Salts herein include, in particular, alkali metal and ammonium salts.

Structural units C, containing chemical groups capable of binding or inactivating substances in the gastrointestinal tract toxic or adversely affecting inflammatory processes. Suitable hydrophilic monomers capable of binding and inactivating free radicals are selected from the group of sterically shielded amines and their oxidized derivatives of the general formula:

wherein R ¹ is -H or -OH or an oxygen radical, R ² to R ⁵ is C 1 to C ₄ alkyl, X is -CH (Y> - or f CH (Y) CH 2 - and Y is a radically polymerizable chemical group

wherein R is -H or -CH 3 and Z is -O- or -NH-, the content of structural units C in the polymer being at least 1%, preferably 3 to 30 mol.H.

Structural units C are preferably derived from N- (2,2,6,6-tetramethylazinan-4'-yl) methacrylamide or N- (2,2,6,6-tetramethylazinan-4-yl) methacrylate.

Preferably, the polymer contains molar up to 98% A units, 1 to 99% B units, and at least 1% C units.

Initiators are used to initiate the radical copolymerization. Suitable types of radical polymerization initiators are generally known to those skilled in the art, as are suitable polymerization procedures and polymerization conditions. For example, thermal radical initiators such as azo initiators, diacyl peroxides and other types of peroxy compounds, UV initiators generating radicals by UV radiation or redox initiators which generate radicals based on an oxidation-reduction reaction may be suitable. Initiation need not be limited to the types of initiators listed.

The polymers can be branched or crosslinked. For the preparation of branched or crosslinked polymers, for example, ethylene dimethacrylate, ethylene diacrylate, 1,1'-divinyl-3,3 '- (ethane

- 1,1'-diyl) bis (2-pyrrolidinone), 2,3-dihydroxybutane-1,4-diyl diacrylate or dimethacrylate, N, N '-

methylenebisacrylamide or other crosslinkers commonly used in the art.

Thus, the hydrophilic polymer is in the form of a high molecular weight linear polymer, a branched polymer or in the form of covalently crosslinked gel particles, is not absorbed by the gastrointestinal mucosa and does not enter the bloodstream or decompose into low molecular weight substances that could be absorbed by the gastrointestinal tract. The non-absorbable polymer eliminates its systemic side effects. Furthermore, the polymer is chemically neutral and does not undergo chain degradation in the gastrointestinal fluid environment.

The hydrophilic polymer is soluble in gastrointestinal fluids or exhibits high swelling in gastrointestinal fluids. The polymer gradually swells in contact with gastrointestinal fluids, exposing the effective structural units C incorporated into the polymer chains. At the same time, during the gradual disintegration of the structure, the polymer is attached to the mucosal wall of the gastrointestinal tract due to the presence of structural units B, which have an affinity for mucosal proteins. This brings the effective structural unit into direct contact with the affected site on the mucosa; at the same time, due to the adhesion of the polymer to the mucosa, the residence time of the polymer, including its active ingredient, in a given part of the digestive tract is prolonged.

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The composition of the present invention may preferably be in the form of a tablet (single or multilayer, coated or uncoated, effervescent), capsule suitable for oral use, syrup, solution, emulsion or suspension.

In addition to the polymer of the present invention, the composition may contain other pharmaceutically acceptable additives; for example, tableting aids commonly used in the art; acidic and alkaline components that provide an effervescent route of administration; disintegrants, eg microcrystalline cellulose, starches (corn, potato and modified starches). The content of disintegrants in the preparation can be up to about 20%, preferably between 2 and 10%.

Sweeteners may be used as additives to mask the bitter taste of the active ingredients or to impart sweetness to the dosage form. Sweeteners which may be used in accordance with the present invention are selected from sugars such as monosaccharides or disaccharides (D-glucose, Z) -fructose, Z) -xylose, maltose, sucrose or sorbitol), polyols (glycerol, dulcitol, mannitol, sorbitol or xylitol), artificial sweeteners (saccharin and its sodium, potassium or calcium salts, cyclamate and its sodium or calcium salt, aspartame, acesulfame or their potassium salts). The amount of sweeteners used in said preparation may range from 2 to 60%, based on the weight of the dosage form, preferably 5 to 10%.

Additives may also include flavoring agents that may be used in the present invention, and are selected without any limitation, e.g., orange, lemon, grape flavor, peppermint flavor, and the like. Flavoring agents may be used in the range of 0.01 to 5%. based on the weight of the dosage form.

The structure of the polymer is designed to give preference to the formulation in the immediate vicinity of the gastrointestinal mucosa, e.g., by utilizing the adhesion of the formulation to the mucosal surface. Adhesion to the mucosa, adjusting the local pH near the mucosa or preventing the access of pollutants to mucosal cells increases the protective effect of the product against the mucosa of the gastrointestinal tract. The composition includes chemical structures that specifically bind to harmful components of gastrointestinal fluids, e.g., structures that bind and inactivate free radicals, structures that adjust the pH of gastric fluid by binding hydrochloric acid, and the like.

The functional structures binding the pollutants are firmly embedded in the material of the preparation, which effectively prevents their release into the bloodstream and possible undesirable systemic effects. This incorporation is preferably achieved by covalent bonding.

In contrast to the solution according to JP 2012-111700 A, in the present solution the polymer preparation consists of copolymers in which different types of hydrophilic units (A, B, C) are incorporated statistically along the length of the polymer chain, thus ensuring uniform swelling of the whole polymer, which significantly increases the accessibility of bound antioxidant to ROS and allows antioxidant molecules to act in an environment that is in close contact with the mucosal surface.

Another advantage of the present invention is the method of introducing antioxidant molecules into a polymer by radical copolymerization, in which the antioxidant acts as a comonomer, which simplifies the production of the formulation on an industrial scale and thus increases the utility of the invention.

Image description

Giant. 1 Time dependence of the relative fluorescence intensity of the reaction mixture containing peroxyl radicals and polymer according to Example 4. Curve a corresponds to a blank without polymer, curves b, c, d, e of a sample with 5 mg, 10 mg, 20 mg and 40 mg of polymer.

Giant. 2 EPR spectrum of the polymer solution according to Example 5 after reaction with in situ generated peroxyl radicals.

Giant. 3 In vivo imaging of 3 mice 2 h, 5 h and 12 h after p.o. administration of a labeled polymer solution according to Example 8 (about 50 MBq / mouse).

Giant. 4 Ex vivo biodistribution of the polymer according to Example 8 in DBA / 2 mice 2 h, 6 h and 34 h after p.o. application expressed as a percentage of the total dose administered (% ID).

Giant. 5 Part of the colon of BALB / c mice before (left) and after exposure to ABC polymer suspensions (right) under UV light.

Giant. 6 Time dependence of polymer swelling according to Example No. 14 in simulated gastrointestinal fluids (gastric fluid - pH = 1.6, small intestinal fluid - pH = 6.5, large intestinal fluid - pH = 7.0).

Giant. 7 Time dependence of the relative fluorescence intensity of the reaction mixture containing hydroxyl radicals and polymer network according to Example No. 14. The continuous curve corresponds to a blank, other dependences belong to samples with a polymer concentration in the reaction mixture of 0.9 mg / ml (□), 4.5 mg / ml (A) and 9.0 mg / ml (o).

8 »> ♦ * · · *. *« · * ·· · · » ¹ · Fig. 8 Time dependence of polymer swelling according to Example No. 17 in simulated gastrointestinal fluids (gastric fluid - pH = 1.6, small intestinal fluid - pH = 6.5, large intestinal fluid - pH = 7.0).

Examples of embodiments of the invention

Example 1

A mixture of 0.2 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylate and 6 g of N- (2-pyrrolidone, 0.1 g, r-divinyl-3,3 '- (ethane -1,1'-diyl) bis (2-pyrrolidopropyl _{and 168} polyethylene glycol methylethermethacrylate (mean M _n = 500) was dissolved in 120 ml of methanol, and after adding 12 mg of 2,2'-azobis (2-methylpropionitrile), the mixture was heated in an inert manner. atmosphere at 55 ° C for 24 h The copolymer was extracted with ethanol and dried in vacuo.

Example 2

A mixture of 0.35 g of N, N-dimethylaminoethyl methacrylate, 4.68 g of polyethylene glycol methylethermethacrylate (average M _n = 300), 1.0 g of N- (2,2,6-6-tetramethylazinan-4-yl) methacrylamide and 35 mg of 2.2 '- Azobis (2-methylpropionitrip was dissolved in 20 ml of tetrahydrofuran (THF). The solution was heated at 60 ° C for 24 h. After completion of the polymerization, the viscous solution was precipitated into ether and repeatedly precipitated from THF to ether. polymer readily soluble in water.

Example 3

A mixture of 0.72 g of polyethylene glycol methylethermethacrylate (average M _n = 300), 1.8 g of N, N-diethylaminopropylmethacrylamide, 0.4 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylamide and 100 mg of 2.2 '- Azobis (2-methylpropionitrile) was dissolved in 27 mL of toluene and heated at 70 ° C for 24 h. The resulting solution was concentrated, the polymer precipitated into heptane and repeatedly reprecipitated from THF to heptane. After drying, a polymer of powdery consistency was obtained, which was well soluble in water.

Example 4 i a · · »i -« ···· «i * * * ·

A mixture of 2.00 g of 2-hydroxyethyl methacrylate, 1.84 g of polyethylene glycol methylethermethacrylate (prumem M _n = 300), 2.1 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylamide and 0.25 g of 2,2'-azobis (2-methylpropionitrile) was dissolved in 118 ml of toluene and heated at 70 ° C for

h. The polymer was filtered off and reprecipitated with methanol in ether. The resulting polymer has a powdery consistency and is readily soluble in water.

Example 5

For the linear polymer according to Example 4, the antioxidant capacity against in situ generated peroxyl radicals was determined in solution. The experiment was performed according to the following procedure. Stock solutions were prepared in polymer buffer at initial concentrations of 8 mg / ml, 16 mg / ml, 32 mg / ml and 64 mg / ml. 650 μΐ of the appropriate polymer solution, 1.3 ml of fluorescein solution (2.4 χ ΙΟ ' ⁵ M) and 1.95 ml of 2,2'-azobis (2 amidinopropane dihydrochloride solution (0.16 M)) were withdrawn into the vial. After mixing these components, a continuous decrease in fluorescence intensity was measured for 60 minutes at 37 DEG C. The measurement was repeated twice for each polymer concentration, and as shown in Figure 1, the polymer acts as an effective scavenger of reactive peroxyl radicals under the given conditions.

Example 6

The EPR spectrum of the polymer solution according to Example No. 5 was measured after reaction with peroxyl radicals (Fig. 2), proving the presence of the oxidized form of the sterically shielded amine.

Example 7

0.17 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylamide, 1.48 g of 2-hydroxyethyl methacrylate, 1.95 g of polyethylene glycol methylethermethacrylate (average M _n = 300), 36 mg of N-methacryloylated tyrosinamide (precursor for radiolabeling) and 153 mg of 2,2'-azobis (2-methylpropionitrile) were dissolved in 20 ml of dioxane. After adding 70 ml of toluene, the solution was heated at 70 ° C for 24 h. After concentrating the reaction mixture, the polymer was precipitated into ether and repeatedly reprecipitated from methanol to ether. Vacuum dried. The polymer has a powdery consistency, well soluble in water. The sample is purified on a desalting column.

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Example 8

The polymer sample of Example 7 with incorporated tyrosinamide was labeled with radioisotope ¹³ 'according to the following procedure. 6 mg of polymer was dissolved in 100 μΐ of phosphate buffer (PBS), and then 50 μΐ of Chloramine-T solution (20 mg chloramine / 1 ml PBS) was added. After 20 minutes of incubation, 260 μΐ of Na ¹³¹ solution was added! (corresponding to an activity of 420 MBq) and another 3 μΐ of Chloramine-T solution. After 90 minutes of incubation, the reaction was terminated by the addition of 20 μΐ ascorbic acid solution (50 mg / 1 ml PBS), 50 μΐ 2-amino-2-hydroxymethylpropane-1,3-diol solution (100 mg / 1 ml PBS) and 50 μΐ fresh NaBH solution. ₄ (20 mg hydride / 1 ml PBS). The high molecular weight fractions, which together show about 89% of the total radioactivity, were lyophilized.

Example 9 mg of the lyophilisate according to Example 8 with a specific activity of 20 MBq / mg was dissolved in 2.5 ml of physiological saline. For in vivo imaging of biodistribution, a labeled polymer solution was orally (p.o.) administered to three Balb / c mice at a dose of about 50 MBq / mouse. Imaging was performed on an imaging device for small laboratory animals - In vivo MS FX PRO. The experimental animals were anesthetized throughout the examination. Static scanning was performed at 2 h, 5 h and 12 h intervals after polymer application. Already 12 h after p.o. application of the solution, almost all activity was eliminated (Fig. 3). The experiment showed that the polymer is not absorbed into the bloodstream and is not specifically taken up and accumulated in any organ.

Example 10 mg of the lyophilisate according to Example 8 with a specific activity of 20 MBq / mg was dissolved in 2.5 ml of physiological saline. The ex vivo biodistribution of the polymer solution was monitored at three time intervals - 2 h, 6 h and 24 h after application. For the ex vivo biodistribution study, nine DBA / 2 mice were administered with the solution ^{, 31} I-H3 at a dose of about 1 MBq / mouse. Experimental animals were sacrificed at specified time intervals of 3 animals / interval. After sacrifice, the following organs were removed: blood, spleen, pancreas, stomach, intestines, kidneys, liver, heart, phce, muscle, bone, and thyroid. Radioactivity was then measured in the collected organs on an automatic gamma counter. The results were expressed as percent injected dose (% ϊ ί>> 4 » '» «4 ♦ *» η ·· ·. · _Χ ♦ ♦ 9 <

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ID). An ex vivo biodistribution study confirmed the complete elimination of the polymer by the gastrointestinal tract (Fig. 4).

Example 11

A mixture of 3.0 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylamide, 2.91 g of 2-hydroxyethyl methacrylate, 2.67 g of polyethylene glycol methylethermethacrylate (average M _n = 300), 45 mg of 5- { [3- (methacryloylamino) propyl] thioureidyl} fluorescein, 18 mg of N, N 'methylenebisacrylamide and 366 mg of 2,2'-azobis (2-methylpropionitrile) were dissolved in 30 ml of toluene and 3.5 ml of methanol. The polymerization was carried out at 70 ° C for 24 hours. The precipitated polymer (ABC) was filtered off, extracted with dioxane and dried to constant weight. In an analogous manner, a polymer sample (AC) was prepared, which does not contain a structural unit based on polyethylene glycol methylethermethacrylate.

Isolated parts of the colon of male BALB / c laboratory mice were exposed to suspensions of ABC and AC polymer (20 mg / 1 ml PBS; pH = 7.4) for 5 min. Under UV light, strong fluorescence of ABC polymer is observed on the inner mucosa of the exposed intestine, which persists even after repeated washing with buffer (Fig. 5). The experiment showed significantly stronger mucoadhesive properties of the ABC polymer compared to the AC polymer, which does not contain type B structural units.

Example 12

A mixture of 2.6 g of polyethylene glycol methylethermethacrylate (average M _n = 950), 0.8 g of 2-hydroxypropylmethacrylamide, 0.8 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylate and 32 mg of 2,2 '- Azobis (2-methylpropionitrile) was dissolved in 28 ml of acetone and heated at 50 ° C for 24 h. The polymer is soluble in water.

Example 13

A mixture of 2.91 g of 2-hydroxyethyl methacrylate, 2.67 g of polyethylene glycol methacrylate (average M _n 300), 3.0 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylamide, 18 mg of N, N ' - methylenebisacrylamide and 366 mg of 2,2'-azobis (2-methylpropionitrile) were dissolved in 90 ml of toluene and heated at 70 ° C for 24 hours. The polymer powder precipitated during the reaction and swelled well in water.

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Example 14

A mixture of 0.78 g of N- (2,2,6,6-tetramethylazinan-4-yl) methacrylate, 0.8 g of 2-

- hydroxypropyl methacrylamide, 0.2 g of polyethylene glycol methacrylate (average M _n = 360) and 0.15 g of 2,2-azobis (2-methylpropionitrile) were dissolved in 12 ml of toluene and heated at 70 ° C for 24 hours. The resulting polymer was precipitated from methanol into ether. After drying, the powdered polymer was readily soluble in water.

Example 15

2.54 g of dimethylaminopropylimethacrylate, 2.0 g of N- (2,2,6,6-tetramethylazinoline)

- yl) methacrylamide, l, 78 g polyethylenglykolmethylethermethakrylátu (average M "= 300), 92 mg of Λ) V-methylenebisacrylamide and 0.24 g of 2,2'-azobis (2-methyl _P ropionitril) was heated at 'in 20 ml of dioxane and 40 ml of heptane at 70 ° C for 24 h. The polymer network was filtered off, repeatedly extracted with heptane and dried in vacuo.

Example 16

The swelling of the polymer network according to Example 15 was determined at 37 ° C in simulated gastrointestinal fluids. In a centrifuge tube, 0.2 g of polymer was made up with the appropriate simulated fluid to a total weight of 10 g (including the tube). The tube was placed in a bath tempered at 37 ° C for the time shown in FIG. 6. The contents of the tube were then centrifuged, the top layer removed and the tube weighed. The extent of swelling was calculated from the relationship:

swelling (%) = 100 x (m _t - m ₀ ) / m ₀ where m _t is the mass of the swollen polymer at time there ₀ is the mass of the polymer in the dry state at the beginning of the experiment. The polymer network shows 800 - 1300% swelling in a wide pH range of gastrointestinal fluids (pH = 1.6 to 7.0; Fig. 6).

Example 17

For the polymer network according to Example 15, the antioxidant capacity against in situ generated hydroxyl radicals was determined in solution. The experiment was performed according to the following procedure. Eight Eppendorfs with the appropriate amount of polymer were placed in a thermoblock tempered at 37 ° C. 900 μΐ of buffer, 200 μΐ of Na ₂ solution of WO ₄ .2 H ₂ O in buffer (7.3 mM), 10 μΐ of fluorescein solution (2.4 χ 10 ^-5 M) were added to each tube and the polymer was allowed to swell in this mixture for 5 minutes. The generation of hydroxyl radicals was started by adding 10 μΐ of hydrogen peroxide solution. Throughout the reaction, the vials were shaken and warmed to 37 ° C. The eppendorfs were opened one after the other at certain time intervals. Their contents were filtered through a micron filter, and the fluorescence intensity of the clear solution was read. The measurement was repeated twice for each sample. As can be seen from FIG. 7, the polymer network exhibits the ability to effectively scavenge in situ generated hydroxyl radicals even at very low polymer concentrations in the reaction mixture.

Example 18

4.0 g N / N-dipropylaminoethyl methacrylate, 1.76 g N- (2,2,6,6-tetramethylazinan-4-yl) methacrylate, 0.3 g 2-hydroxyethyl acrylate, 0.28 g polyethylene glycol methylethermethacrylate (average M _n = 300 ), 15 mg of ethylene dimethacrylate and 0.22 g of 2,2'-azobis (2-methylpropionitrile) were heated in a mixture of dioxane and heptane at 70 ° C for 24 hours. The polymer network was filtered off, repeatedly extracted with heptane and dried in vacuo.

Example 19

The swelling of the polymer sewn according to Example 18 was determined according to the procedure described in Example 16. The results of this experiment are shown in FIG. 8. Polymeric swelling network in the range of 1000 to 1800% in gastrointestinal fluids (pH = 1.6 to 7.0).

Claims (9)

PATENT CLAIMS also in » A preparation for oral use intended for the prevention and healing of inflammatory changes in the gastrointestinal tract, comprising a mucoadhesive biocompatible hydrophilic polymer preparable by radical polymerization of a mixture comprising: - at least one type of structural units A selected from the group comprising units derived from acrylic and methacrylic acid and their salts, hydroxyalkyl acrylates and methacrylates, hydroxyalkyl acrylamides and methacrylamides, N, N-dialkylaminoalkyl acrylates and methacrylates, N, N-dialkylaminoalkylacrylamides and methacrylamides, N 2-pyrrolidone and mixtures thereof; wherein the term "alkyl" in said generic groups refers to C 1 -C ₆ alkyls; at least one type of structural units B selected from the group comprising units derived from hydroxy-terminated polyoxyethylene acrylates and methacrylates, alkyloxy-terminated polyoxyethylene acrylates and methacrylates, hydroxy-terminated polyoxyethylene acrylamides and methacrylamides, alkyloxy-terminated polyoxyethylene acrylamides and methacrylamides, and mixtures thereof; wherein the term "alkyl" in said generic groups refers to C 1 -C ₆ alkyls; and - at least one type of structural unit C derived from monomers of the general formula: wherein R ¹ is -H or -OH or an oxygen radical, R ² to R ⁵ is C 1 to C ₄ alkyl, X is -CH (Y) - or + 'CH (Y) CH ₂ - and Y is a radically polymerizable chemical group R Z wherein R is -H or -CH ₃ and Z is -O- or -NH-. Preparation according to Claim 1, characterized in that the polymer contains molars of up to 98% of A units, 1 to 99% of B units, and at least 1% of C units. 15 «· · Preparation according to any one of the preceding claims, characterized in that the structural units C are derived from N- (2,2,6,6-tetramethylazinan-4-yl) methacrylamide or N- (2,2,6,6-tetramethylazinan-4-yl) - tetramethylazinan-4-yl) methacrylate. Preparation according to any one of the preceding claims, characterized in that the polymer is in the form of a linear polymer. Preparation according to any one of claims 1 to 3, wherein the polymer is in the form of a branched polymer or a covalently crosslinked polymer obtainable by radical polymerization in the presence of crosslinkers, in particular selected from the group consisting of ethylene dimethacrylate, ethylene diacrylate, 1,1-divinyl-3,3- ( ethane-1,1'-diyl) bis (2-pyrrolidone), 2,3-dihydroxybutane-1,4-diyl diacrylate or dimethacrylate, N, N'-methylenebisacrylamide. Preparation according to any one of the preceding claims, characterized in that it contains further pharmaceutically acceptable additives selected from the group consisting of fillers to facilitate tableting, effervescent acidic and alkaline components, disintegrants, sweeteners and flavorings. Preparation according to any one of the preceding claims, characterized in that it is in the form of a tablet, capsule, syrup, solution, emulsion or suspension. A preparation according to any one of the preceding claims for use as a medicament. A preparation according to any one of the preceding claims for use in the manufacture of a medicament for the prevention and healing of inflammatory changes in the gastrointestinal tract.