METHOD OF OBTAINING IT

The object of the invention is a membrane made of an organic material with pore forming, anti-inflammatory and anticoagulant properties, intended in particular for the construction of medical devices and the method of obtaining it.

Materials with pore-forming properties are used to make selective membranes, that is, membranes that only allow particles of a certain size to pass through. Such materials are used, among other things, to make membranes for use in the manufacture of everyday objects such as: tents, jackets, filters, but also osmotic membranes for medical applications: in filters for renal replacement therapy and in oxygenators for blood oxygenation.

The most common, high-tech - in non-medical applications - pore-forming material (used, for example, in the manufacture of jackets), from which membranes were made is poly (tetrafluoroethylene) .

However, in medical applications, i.e. for the construction of medical devices, from the current state of technology, there are known membranes, including porous membranes used in devices having direct contact with body fluids, made of various materials.

For example, PL225257 patent description presents a membrane system for local immobilization of eukaryotic cells, having a support and at least one bilayer formed of successively one polyelectrolyte layer comprising polysaccharide hydrogels, especially sodium alginate containing in its structure incorporated fullerenol and protein A, characterized in that the first layer is applied directly to the group of isolated cells then placed on a support made of the same material in terms of composition, and, a second polymeric layer of aliphatic secondary and tertiary amines - containing ethyl or methyl groups with incorporated fullerenol. In this system, a single layer is applied directly to a group of isolated eukaryotic cells, and it allows eukaryotic cells to be isolated from the external environment, particularly microorganisms, while not restricting nutrient transport across the membrane, allowing for directed growth.

PL212620 patent description presents a specially modified polyolefin membrane (PP, PE) and a method of modifying microporous polyolefin membranes intended for the isolation of Gram (+) bacteria, consisting in that a solution of polycation, selected from the group consisting of aliphatic amino acids, especially protein amino acids, preferably polar and dissolved in NaCl solution, is then introduced into the structure of a polyolefin membrane of high porosity in a known way, preferably by soaking, and then the solution of polyanion, selected from the group consisting of polymeric secondary and tertiary amines, especially methylamine and ethylamine, preferably containing 100% methyl or ethyl groups, dissolved in the solution of NaCl.

PL165872 patent description presents a method for producing a multilayer porous membrane of poly(tetrafluoroethylene) containing at least two layers having pores of different average diameters, which includes the steps of: filling the extruder barrel with at least two different types of fine poly(tetrafluoroethylene) powders, with a liquid lubricant mixed with each.

EP0409496 patent description presents a process for preparing microporous membranes containing at least a partially crystalline aromatic polymer containing ether or thioether and ketone bonds in the chain. The process allows membranes to be made from certain aromatic polymers with high melting points, such as PEDK.

The type of materials from which the membranes known from the above solutions were made allows - for steric reasons - their use for blood oxygenation, however their significant biochemical limitations significantly limit this application. This is because these membranes did not contain additives to provide anticoagulant release, which was a significant disadvantage in such applications. Moreover, due to their structure, they are characterized by developed surface topography on the micrometer scale, which was the reason for their negative effects on living organisms. At the cellular level, these membranes cause steric damage to cell membranes, resulting in cell destabilization. Furthermore, membranes cannot inhibit thrombus formation and do not protect against bacterial biofilm formation.

So far, polypropylene (PP) and polyurethane (PU) have mainly been used as pore forming materials in medical applications. For example, in devices used in the process of oxygenation of blood, polyurethane was used as a porous material for the construction of membranes, and polypropylene was used for the construction of elements for separation of membrane layers (spacers). Despite the high efficiency of such membranes in terms of gas exchange, they have limitations mainly related to the initiation of inflammatory reaction from the low bioinertness of these materials. This affected the formation of progressively growing thrombi on the membrane surface. In this case, in order to maintain the effectiveness of blood oxygenation, it was necessary to increase the oxygen concentration, which induces oxidative stress and intensifies the clotting process, triggering an unfavorable cascade of rapidly successive adverse factors, because the oxygen concentration must be constantly increased to maintain the blood saturation level, and this intensifies oxidative stress and enhances clotting. After crossing a certain threshold, the amount of thrombi is already so high that the device is no longer suitable for further operation (does not perform its function) and the entire oxygenator system must be replaced.

Consequently, there was a need to develop membranes made of materials not known so far, especially for medical applications, that would allow for a high level of anti-inflammatory and anticoagulant properties, while also ensuring their biocompatibility and bioinertness (neutrality) when in contact with patient’s blood. The reason for using the new material for the membrane in the oxygenator is the need to reduce the risk of inducing inflammation, thereby slowing down the clotting process on the membrane and extending the life of the device.

Various compounds with anticoagulant activity are known from the state of the art. Among others, we know albumins - blood proteins produced in the liver and responsible for maintaining oncotic pressure in blood vessels, transport of substances poorly soluble in plasma (fatty acids, some hormones, calcium ions) and buffering blood. The anti-inflammatory effects of albumins include inhibition of leukotriene production by neutrophils and thrombocytes and decreased sensitivity of neutrophils to inflammatory cytokines. On the other hand, their anticoagulant effect is through activation of antithrombin III and inhibition of thrombocyte aggregation. Also known is argatroban, a synthetic analogue of hirudin, which is a small- molecule direct thrombin inhibitor (DTI) used for anticoagulant therapy in patients with heparin-induced thrombocytopenia type II who require parenteral anticoagulant therapy. The first mechanism of DTI activity involves blocking the active site of thrombin, whereas the second involves inhibition of the fibrin binding site, where the substrate is recognized and spatially correctly oriented. The activity of these inhibitors is direct and does not depend on the presence of antithrombin. Unlike indirect DTI inhibitors, they can inhibit fibrin-bound thrombin. Bivalirudin is also known - an anticoagulant from a group of direct specific thrombin inhibitors (DTI). DTIs block the active site responsible for the main thrombin activity and/or the external site where the substrate is recognized and spatially correctly oriented. The activity of these inhibitors is direct and does not depend on the presence of antithrombin. Unlike indirect DTI inhibitors, they can inhibit fibrin -bound thrombin, which prevents thrombin from splitting fibrinogen to fibrin monomers, activating factors XIII, V, VIII, and stimulating thrombocytes to aggregate. A compound with an anticoagulant effect is also fondaparinux - an organic chemical compound, an oligosaccharide. It is a synthetic pentasaccharide with a sequence identical with the pentasaccharide hydrolysis products of fondaparinux, and contains an additional methyl group at the reducing end. It is a selective inhibitor of factor Xa. Fondaparinux is used as an anticoagulant to prevent the formation of thrombi and is used as standard in patients undergoing surgery and immobilized due to disease, in venous thromboembolism, acute coronary syndromes. Heparin, an organic chemical compound, a polysaccharide composed primarily of N-sulfate and O-sulfate of glycosaminoglycan made up of D-glucosamine and L-iduronic acid radical linked into an unbranched chain, also exhibits anticoagulant activity. Heparin is a natural agent that, by inhibiting the transition of prothrombin to thrombin, causes a potent blood anticoagulant effect and, due to its effect on lipids through lipase activation, is also used as an anticoagulant used for anticoagulant coatings. When released in a controlled manner, it can also inhibit thrombocyte aggregation and adhesion (sticking to surfaces) to blood vessel walls. Heparin is trapped by the vessel walls and increases their negative charge, making it difficult for thrombocytes to adhere and preventing the formation of wall clots. Heparin is used as an anticoagulant drug to prevent thrombus formation, standard treatment for patients undergoing surgery and immobilized due to a disease, in venous thromboembolism, acute coronary syndromes.

So far, however, there are no known membranes made of materials with pore-forming, anti-inflammatory and anticoagulant properties, containing immobilized in their composition active admixtures of albumin, argatroban, bivalirudin, fondaparinux or heparin, semi- permeable to gases, intended especially for use in medical gas exchange systems, especially for blood oxygenation (oxygenators) and effective ways of obtaining such membranes, and their development has become the aim of the authors of the present invention.

In the first variation of the invention, its essence is a membrane characterized in that it is in the form of a flat foil with a thickness from 0.2 to 200 pm, preferably 30 pm, or a tube with an outer diameter from 30 to 600 pm, preferably 100 pm, and, is made of an organic material having pore-forming, anti-inflammatory and anticoagulant properties comprising:

- base in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE, Teflon) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), and

- active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin, embedded in the micro structure of the base material, in the ratio of base/active admixture from 80÷1 to 1200÷1, preferably 150÷1.

In the second variation of the invention, the essence of it is a membrane characterized in that it is in the form of a flat foil with a thickness from 0.2 to 200 pm, preferably 30 pm, or a tube with an outer diameter from 30 to 600 pm, preferably 100 pm, and, is made of an organic material having pore-forming, anti-inflammatory and anticoagulant properties comprising: - base in the form of polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP),

- 4-(diphenylamino)benzaldehyde admixture with the base/admixture ratio from 50÷1 to 5000÷1, preferably 100÷1,

- admixture of 1,3-indandione with the base/admixture ratio from 50÷1 to 5000÷1, preferably 100÷1, and

- active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin, embedded in the micro structure of the base material, in the proportion of base/active admixture from 80÷1 to 1200÷1, preferably 150÷1.

The essence of the invention also comprises a method for obtaining a membrane made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties, in the first variation, characterized in that a material in the form of a fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE, Teflon) or poly vinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) is extruded on a linear head in the form of a string, preferably with an outer diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, then the process of immobilization of active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin into the steric structure of the material thus obtained is carried out in a manner ensuring its content in the material with the base/active admixture ratio from 80÷1 to 1200÷1, preferably 150÷1, in such a way, that after initial cooling in a bath containing a supersaturated aqueous solution of the active admixture to a temperature within ±30°C from the plastic transition temperature, preferably below the plastic transition temperature, it is stretched on calenders (by known methods of forming fibers or foils) to obtain an elongation of 5-20 times, preferably 10 times, which results in the formation of micropores in which the active admixture immobilizes, whereby in the variant with an extruded string, the elongation process is carried out linearly - maintaining the string form, or in two directions - forming a flat foil from the string. The second and final step of membrane production is then carried out, which is performed in three ways depending on the form of the material obtained in step one, that is, either:

- according to variant a), wherein the material obtained in the first step in the form of a string is brought to a temperature within ±30°C from the plastic transition temperature, preferably exactly to the plastic transition temperature, after which it is stretched - by known methods - on calenders, preferably in two directions, so as to obtain a membrane in the form of a flat foil with a thickness between 0.2 and 200 pm, preferably 30 pm, or

- according to variant b), wherein the material in the form of a hollow fiber tube obtained in the first step is brought to a temperature within ±30°C from the plastic transition temperature, preferably exactly to the plastic transition temperature, and is then stretched - by known methods on calenders - preferably in two directions, to obtain a membrane in the form of a tube with an outer diameter between 30 and 600 pm, preferably 100 pm, or

- according to variant c), wherein the material obtained in the first step in the form of a foil is brought to a temperature within ±30°C from the plastic transition temperature, preferably exactly to the plastic transition temperature, after which it is stretched - by known methods - on calenders, preferably in two directions, so as to obtain a membrane in the form of a flat foil with a thickness between 0.2 and 200 pm, preferably 30 pm.

The essence of the invention also comprises a method for obtaining a membrane from an organic material with pore-forming, anti-inflammatory and anticoagulant properties, in a second variation, characterized in that in the first step a material for the membrane is produced in such a way that a polar solvent and an acid selected from the following ones are introduced into a reactor made of a non-reactive material in an inert (neutral) gas atmosphere: sulfuric acid VI, hydrochloric acid or acetic acid, in proportions from 2 ÷ 0.002 to 7 ÷ 0.002, preferably 5 ÷ 0.002, and then per 50mL of a mixture thus formed, 4-(diphenylamino)benzaldehyde in the amount from 0.2g to 0.7g and 1,3-indandione in the amount of O.Olg to 0.08g are added and stirred until a homogeneous mixture is obtained in no less than 1 minute, after which the suspension is washed with inert gas for at least 5 minutes, preferably not more than 60 minutes, heated to boiling under a reflux condenser in an inert gas atmosphere and stirred intensely at 100-1000 rpm, preferably 350-450 rpm for at least 18 hours, preferably not more than 30 hours. After the mixing process, the resulting mixture is cooled to 20 to 35°C and subjected to column chromatography in a S1O2 bed and in the mobile phase of the mixture of hexane and methylene chloride, in the amounts of hexane from 0.5 to 2 times the volume of the reaction mixture, and methylene chloride from 0.5 to 2 times the volume of the reaction mixture. The product is then vacuum-dried for at least 20 hours, preferably 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and the base is introduced as: polypropylene (PP) or polyurethane (PU) or polyethylene terephthalate (PET) or polycarbonate (PC) or polyoxymethylene (POM) or polysulfone (PSU) or silicone or fluoropolymer, preferably poly(tetrafluoroethylene) (PTFE) or polyvinylidene fluoride (PVDF) or a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP), in the ratio of base/recrystallizate from 50÷2 to 5000÷2, preferably 100÷2, and then mixed to a homogeneous mixture and dried for at least 20 hours at 80-110°C, after which the material is extruded on a linear head is extruded on a linear head in the form of a string, preferably with an outer diameter of 2 to 10 mm, or on a cross head in the form of a tube, preferably with an outer diameter of 2 to 10 mm, or on a flat head in the form of a foil preferably with a thickness of 0.1 to 3 mm, and in the next step the process of immobilization of active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin into the steric structure of the material thus obtained is carried out in a manner ensuring its content in the material with the base/active admixture ratio from 80÷1 to 1200÷1, preferably 150÷1, in such a way, that after initial cooling in a bath containing a supersaturated aqueous solution of the active admixture to a temperature ±30°C from the plastic transition temperature, preferably below the plastic transition temperature, it is stretched on calenders (by known methods of forming fibers or foils) to obtain an elongation of 5-20 times, preferably 10 times, which results in the formation of micropores in which the active admixture immobilizes, whereby in the variant with an extruded string, the elongation process is carried out linearly - maintaining the string form, or in two directions - forming a flat foil from the string. The second and final step of membrane fabrication is then performed, which is carried out in three ways depending on the form of the material obtained in step one, that is, either:

- according to variant a), wherein the material obtained in the first step in the form of a string is brought to a temperature within ±30°C from the plastic transition temperature, preferably exactly to the plastic transition temperature, after which it is stretched - by known methods - on calenders, preferably in two directions, so as to form a membrane in the form of a flat foil with a thickness between 0.2 and 200pm, preferably 30pm, or

- according to variant b), wherein the tubular material obtained in the first step is brought to a temperature within ±30°C from the plastic transition temperature, preferably exactly to the plastic transition temperature, and is then stretched - by known methods - on calenders, preferably in two directions, so as to obtain a membrane in the form of a tube with an outer diameter between 30 and 600pm, preferably 100pm, or

- according to variant c), wherein the material obtained in the first step in the form of a foil is brought to a temperature within ±30°C from the plastic transition temperature, preferably exactly to the plastic transition temperature, after which it is stretched - by known methods - on calenders, preferably in two directions, so as to obtain a membrane in the form of a flat foil with a thickness between 0.2 and 200 p , preferably 30pm. In all variants a) and b) and c) of both the first and second variation of the method according to the invention, a porous membrane is formed, since during the stretching process pores with a size of 1 nm to 150 pm are produced, the membrane contains pores of which 40 to 60% are open pores (not filled) and the remaining pores are closed pores, i.e. they are filled with the active admixture.

As the membrane is used, the active admixture is gradually released and thus consumed, and the total amount of active admixture decreases and the number of open pores increases, resulting in a larger gas exchange surface area, i.e., better oxygenation. New pores are also formed that take over the gas exchange function from open pores that may have been blocked by progressively forming thrombi or biofilm formation on the membrane surface.

Flat membranes (foils) obtained in variants a) and c) are used after cutting from them the required shape for specific applications.

On the other hand, using the method according to variant b) hollow fiber tubes are obtained, which due to the porous structure of the wall can serve as cylindrical gas exchange membranes. Preferably, the tubes obtained in variant b) are cut into pieces of an appropriate length and then knitted on textile machines to form a membrane, most preferably with a distance of about 35 pm between the individual hollow fiber tubes in the knitted fabric and in this form they can preferably be used as membranes for oxygenating blood in oxygenators.

Preferably, the first step of the method according to the invention in the second variation is carried out in a glass or ceramic or stainless steel reactor.

Preferably, the first step of the method according to the invention in the second variation is carried out in a reactor in the form of a round-bottomed three-necked flask, due to its good functional properties.

Preferably, in the method according to the invention in the second variation, argon or nitrogen or xenon is used as the inert gas.

Preferably, in the method according to the invention in the second variation, anhydrous ethanol is used as the polar solvent.

Preferably, in the method according to the first or second variation, the base material is added in the form of a crushed material or aggregate or most preferably granulate.

Preferably, in the method according to the first or second variation, during the calendering step during the immobilization of the active admixture, a cyclic decrease and increase of the stress is applied, which increases the efficiency of the immobilization of the active admixture in the pores of the material. According to the invention, a membrane is obtained having pores oriented in the direction or directions of stretching. Their characteristic feature is the absence of sharp edges and cracks around the pores. Such membrane materials, characterized by pores with irregular morphology prevent low molecular weight materials, including organic ones, from depositing in the vicinity of possible pore fractures. The membrane, thanks to its smooth surfaces and pore orientation along the flow path, reduces the risk of thrombosis due to the absence of steric obstacles that could be centers of thrombosis (no thrombi formation on the surface of the material occurs). These types of membranes are relatively fragile, with little resistance to external forces. Thus, in medical applications, for example in blood oxygenation systems, such membranes can be used in their manufactured form due to the absence of external forces that can break the continuity of the material. However, in applications where the membrane film membrane is exposed to external forces, especially outdoor membranes (such as membranes for construction of tents), it is recommended that the membrane be stabilized with a natural loose knit to improve its strength, which will improve the mechanical performance of the membrane without changing its high selectivity.

The membranes obtained by the methods according to the invention are characterized by full controllability of the size of the pores formed as well as their arrangement along the axis of flow of gases and body fluids, which results in higher gas exchange efficiency. The analyses show that such membranes have better selectivity performance than membranes with rough edges at the pore boundaries. The solution according to the invention makes it possible to obtain membranes with a very wide range of pore sizes from nano/micro scale (application especially for oxygenation, gas exchange) to macro pore size of even tenths of a millimeter (application as waterproof, breathable materials).

The membrane is characterized by low flow resistance, i.e., it enables to maintain proper, i.e., unobstructed flow despite low pressure - which is a result of the directional pore arrangement created by the directional stretching process on the calenders and the orientation of the macromolecules that results from such stretching. In the absence of this orientation of the pore system, turbulence would occur to interfere with the flow, resulting in an increase in flow resistance and consequently an increase in pressure.

In the membrane according to the invention, a decrease in gas flow pressure on one side of the membrane results in an increase in oxygen saturation while maintaining flow parameters, which results in better oxygenation of blood flowing on the other side of the membrane due to the maintenance of laminar flow continuity. An additional advantage is that the material used does not release chemicals toxic to cells and does not itself cause pathogenic reactions on cells.

A membrane constructed from the materials described above protects against biofilm formation (no bacterial plaque forms on it), due to the internal structure of the material, i.e. the arrangement of macromolecules and pores in the material, which is not a protagonist of bacterial plaque development and adhesion.

The chemical structure of macromolecules of materials for construction of membranes obtained by the method according to the invention affects their good pore-forming, anti inflammatory and anticoagulant properties and at the same time ensures their biocompatibility and bioinertness (full neutrality). When these materials are used to manufacture membranes for oxygenators, the risk of inducing inflammation in cells is reduced, and thus the process of coagulation on the membrane slows down. The method according to the invention makes it possible to obtain membranes made of materials with a pore size in the nano range so that a single molecule of oxygen and carbon dioxide is able to penetrate the pores, and at the same time so that the pores are smaller than the macromolecular packets of which body fluids are composed, which in effect makes it possible to effectively oxygenate the blood without the risk of blood molecules penetrating the pores. Additionally, the method of pore formation in the process of directional stretching causes the pores to be oriented along the longitudinal axis of the hollow fiber tube or foil which ensures laminarity of the flow (the flow is not turbulent).

Studies on the ability of releasing the active admixture in the form of albumin or argatroban or bivalirudin or fondaparinux or heparin from the membrane obtained by the method according to the invention were carried out in a known flow-through vessel using a constant volume of polar solvent in the form of 18.2 MW ultrapure water. The membrane was immersed in the solvent for 30 minutes. The solvent was then extracted and injected into the flow-through vessel and changes in the frequency of disc vibrations in the form of a quartz resonator with an applied electrode were observed, in accordance with Sauerbrey's relation, i.e. the relation linking the change in vibration to the change in mass. The disc was positioned so that possible sedimentation of the analyte from the solvent would not falsify the result by gravitational settling on the disc. Positioning of the disc ensured that only the mass of the absorbed analyte was measured. Based on the observed changes in the frequency of disc vibrations (decrease of vibrations), the presence of an active admixture in the solvent was found to be deposited on the electrode. This indicates that when the membrane was immersed in the solvent, the active admixture was released from the membrane into the solvent. The experiment was repeated ten times on the same sample and the measurement results were similar each time (within the measurement error). The constancy of the changes over time indicates a controlled process of releasing the active admixture from the membrane.

The use of an immobilized active admixture allows its concentration on the part contact surface to remain constant throughout the application of the materials (planned product life). The possibility of excessive leaching of the active admixture is minimized, and because of the diffusion-controlled release of the active admixture, its contact concentration on the product surface is constant.

Introduction of the active admixture into the material of the membrane according to the invention also gives the material the desired anticoagulant and anti-inflammatory properties. The active admixture as noted above has potent blood anticoagulant activity and due to its effect on lipids through lipase activation it is also used as an anticoagulant agent used for anticoagulant coatings. The active admixture is embedded both in the pores of the material and in microcracks formed as equilibrium defects during the material formation step. This significantly improves the surface continuity of the material structure and thus prevents organic material from depositing in pores and microcracks and significantly reduces coagulation.

Introduction of 4-(diphenylamino)benzaldehyde and 1,3-indandione admixtures in the invention according to the second variation results in a reduction of the internal stresses of the material which results in a better orientation of the macromolecules during processing and pore formation, which is ultimately observed as a smooth outer structure so that there are no mechanical steric centers for thrombus formation due to the uniformity of the material as well as the absence of sharp edges around the pores and cracks.

A method for preparing a membrane made of an organic material with pore-forming, anti-inflammatory and anticoagulant properties according to the invention will be further explained by means of the following examples.

Example 1

PTFE granules are introduced into a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PTFE and hollow fiber tubes with an outer diameter of 2 mm are extruded on a cross head, and in the next step the process of immobilization of albumin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PTFE-albumin ratio of 1200÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature of 180°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 10 times, which results in the formation of micropores in which albumin is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 600pm.

As a result, a membrane with albumin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of albumin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The hollow fiber tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 2

PTFE granules are introduced into a twin-screw ten-zone extruder with counter-rotating screws arrangement and geometry specified for PTFE and a foil of thickness 3 mm is extruded on a flat head and in the next step the process of immobilization of albumin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PTFE/albumin ratio of 80÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of albumin to 300°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension, so as to obtain an elongation of 5 times, which results in the formation of micropores in which albumin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a flat foil is brought to a temperature of 295°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 200 pm thick flat foil.

As a result, a membrane with albumin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of albumin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

These membranes can be used as gas-exchanging surfaces in flat membrane oxygenators or as osmotic membranes. Example 3

PVDF aggregate is introduced into a twin-screw ten-zone extruder with counter-rotating screws arrangement and geometry specified for PVDF and a string with an outer diameter of 10 mm is extruded on a linear head and in the next step the process of immobilization of argatroban into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PVDF/argatroban ratio of 150÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to 185°C, i.e. below the plastic transition temperature, it is stretched on calenders in two directions to form a flat foil, by cyclically decreasing and increasing the tension so as to obtain an elongation of 20 times, which results in the formation of micropores in which argatroban is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 180°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 0,2pm thick foil.

As a result, a membrane with argatroban introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of argatroban, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

These membranes can be used as gas-exchanging surfaces in flat membrane oxygenators or as osmotic membranes.

Example 4

Milled FEP is introduced into a twin-screw ten-zone extruder with counter-rotating screws arrangement and geometry specified for FEP and hollow fiber tubes with an outer diameter of 10 mm are extruded on a cross head and in the next step the process of immobilization of argatroban into the steric structure of the material obtained in such a way that its content in the material in the FEP/argatroban ratio of 150÷1 is carried out in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature of 245°C, i.e. below the plastic transition temperature, it is stretched on calenders by cyclically decreasing and increasing the tension so as to obtain an elongation of 10 times, which results in the formation of micropores in which argatroban is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 240°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 30mih.

As a result, a membrane with argatroban introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of argatroban, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The hollow fiber tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

These membranes can be used as gas-exchanging surfaces in flat membrane oxygenators or as osmotic membranes.

Example 5

PVDF granulate is introduced into a twin-screw ten-zone extruder with counter-rotating screws arrangement and geometry specified for PVDF and a string with an outer diameter of 2 mm is extruded on a linear head and in the next step the process of immobilization of bivalirudin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material with the PVDF/bivalirudin ratio of 150÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of bivalirudin to 185°C, i.e. below the plastic transition temperature, it is linearly stretched on calenders, so as to obtain an elongation of 20 times, which results in the formation of micropores in which bivalirudin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a string is brought to a temperature of 180°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of 0.2pm thick foil.

As a result, a membrane with bivalirudin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of bivalirudin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

These membranes can be used as gas-exchanging surfaces in flat membrane oxygenators or as osmotic membranes.

The method according to the invention makes it possible to obtain membranes made of materials with anti-inflammatory and anticoagulant properties, especially for the construction of medical equipment, in particular for components which are in direct contact with blood. Such membranes may, among other things, be used in oxygenators for blood oxygenation and as other gas- selective membranes.

Example 6

PTFE granules are introduced into a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PTFE and hollow fiber tubes with an outer diameter of 2 mm are extruded on a cross head and in the next step the process of immobilization of fondaparinux into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PTFE/fondaparinux ratio of 1200÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature of 180°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 10 times, which results in the formation of micropores in which fondaparinux is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 600p

As a result, a membrane with fondaparinux introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of fondaparinux, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 7

PTFE granules are introduced into a twin-screw ten-zone extruder with counter-rotating screws arrangement and geometry specified for PTFE and a foil of thickness 3 mm is extruded on a flat head and in the next step the process of immobilization of heparin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PTFE/heparin ratio of 80÷1, in such a way in that after initial cooling in a bath containing a supersaturated aqueous solution of heparin to 300°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension, so as to obtain an elongation of 5 times, which results in the formation of micropores in which heparin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a flat foil is brought to a temperature of 295°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 200 pm thick flat foil.

As a result, a membrane with heparin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of heparin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

These membranes can be used as gas-exchanging surfaces in flat membrane oxygenators or as osmotic membranes.

Example 8

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 5÷0.002 is introduced into a dried round bottom three-neck glass flask in an argon atmosphere and 0.3 g of 4- (diphenylamino)benzaldehyde and 0.06 g of 1,3-indandione are added. The mixture is homogenized by stirring for 5 minutes and purged with argon for 30 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 400 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 300 g of polycarbonate (PC) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 90°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PC - hollow fiber tubes with an outer diameter of 2 mm are extruded on a cross head, and in the next step the process of immobilization of albumin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PC/albumin ratio of 150÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature of 180°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 8 times, which results in the formation of micropores in which albumin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a flat hollow fiber tube with an outer diameter of 30pm

As a result, a membrane with albumin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of albumin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 9

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 5 ÷ 0.002 is introduced into a dried stainless steel reactor in a xenon atmosphere and 0.5 g of 4- (diphenylamino)benzaldehyde and 0.02 g of 1,3-indandione are added. The mixture is homogenized by stirring for 1 minute and purged with xenon for 10 minutes. It is then heated up to boiling under a reflux condenser in a xenon atmosphere and stirred intensely at 350 rpm for 20 hours. After obtaining a homogeneous mixture, the solution is cooled down to 35°C and subjected to column chromatography in a SiC bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 25g polyurethane (PU) aggregate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 20 hours at 105°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for polyurethane - a hollow fiber tube with an outer diameter of 8 mm is extruded from the material on a cross head, and in the next step the process of immobilization of albumin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PU/albumin ratio of 80÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of albumin to a temperature of 180°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 5 times, which results in the formation of micropores in which albumin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 600pm.

As a result, a membrane with albumin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of albumin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 30 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 10

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 5÷0.002 is introduced into a dried round bottom three-neck glass flask in an argon atmosphere and 0.7 g of 4- (diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 3 minutes and purged with argon for 45 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 450 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 350 g of milled polypropylene (PP) are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for polypropylene - a hollow fiber tube with an outer diameter of 10 mm is extruded from the material on a cross head, and in the next step the process of immobilization of argatroban into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PP/argatroban ratio of 80÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature of 150°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 20 times, which results in the formation of micropores in which argatroban is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 145°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 100 pm.

As a result, a membrane with argatroban introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of argatroban, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 11

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 5 ÷ 0.002 is introduced into a dried ceramic reactor in an argon atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 2 minutes and purged with argon for 45 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 450 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recrystallizate) is placed in a homogenizer and 350 g of poly(ethylene terephthalate) (PET) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PET - a 1 mm thick foil is extruded from the material on a flat head, and in the next step the process of immobilization of argatroban into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PET/argatroban ratio of 700÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature of 230°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 15 times, which results in the formation of micropores in which argatroban is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 225°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 1 Opm thick flat foil.

As a result, a membrane with argatroban introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of argatroban, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

Example 12

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 6 ÷ 0.002 is introduced into a dried round bottom three-neck glass flask in a nitrogen atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 1 minute and purged with nitrogen for 35 minutes. It is then heated up to boiling under a reflux condenser in a nitrogen atmosphere and stirred intensely at 600 rpm for 30 hours. After obtaining a homogeneous mixture, the solution is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 0.5 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 71 g of poly(tetrafluoroethylene) (PTFE) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 100°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for poly(tetrafluoroethylene) - a 0.5 mm thick foil is extruded from the material on a flat head, and in the next step the process of immobilization of argatroban into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PTFE/argatroban ratio of 450÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of argatroban to a temperature of 300°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 12 times, which results in the formation of micropores in which argatroban is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 295°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 5 pm thick flat foil.

As a result, a membrane with argatroban introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of argatroban, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

Example 13

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 3 ÷ 0.002 is introduced into a dried round bottom three-neck glass flask in a nitrogen atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 2 minutes and purged with nitrogen for 60 minutes. It is then heated up to boiling under a reflux condenser in a nitrogen atmosphere and stirred intensely at 500 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 140 g of poly oxy methylene (POM) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 20 hours at 110°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for POM - an 8 mm thick string is extruded from the material on a linear head, and in the next step the process of immobilization of bivalirudin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the POM/bivalirudin ratio of 100÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of bivalirudin to a temperature of 180°C, i.e. below the plastic transition temperature, it is linearly stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 14 times, which results in the formation of micropores in which bivalirudin is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a string is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 35 pm thick flat foil.

As a result, a membrane with bivalirudin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of bivalirudin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

Example 14

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 3 ÷ 0.002 is introduced into a dried round bottom three-neck glass flask in a nitrogen atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 2 minutes and purged with nitrogen for 60 minutes. It is then heated up to boiling under a reflux condenser in nitrogen atmosphere and stirred intensely at 900 rpm for 20 hours. After obtaining a homogeneous mixture, the solution is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 310 g of polysulfone (PSU) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 30 hours at 90°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for polysulfone - a 3 mm thick foil is extruded from the material on a flat head, and in the next step the process of immobilization of bivalirudin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PSU/bivalirudin ratio of 1200÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of bivalirudin to a temperature of 190°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 8 times, which results in the formation of micropores in which bivalimdin is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 185°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 200pm thick flat foil.

As a result, a membrane with bivalimdin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of bivalimdin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

Example 15

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 5 ÷ 0.002 is introduced into a dried round bottom three-neck glass flask in an argon atmosphere and 0.3 g of 4-(diphenylamino)benzaldehyde and 0.06 g of 1,3-indandione are added. The mixture is homogenized by stirring for 4 minutes and purged with argon for 30 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 500 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 0.5 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 150 g of polyvinylidene fluoride (PVDF) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 90°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PVDF - a 2.5 mm thick foil is extruded from the material on a flat head, and in the next step the process of immobilization of bivalirudin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PVDF/bivalirudin ratio of 150÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of bivalirudin to a temperature of 185°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 10 times, which results in the formation of micropores in which bivalirudin is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 180°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 1 p thick flat foil.

As a result, a membrane with bivalirudin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of bivalirudin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

Example 16

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 2÷0.002 is introduced into a dried round-bottomed triple-necked glass flask in a nitrogen atmosphere and 0.5 g of 4- (diphenylamino)benzaldehyde and 0.02 g of 1,3-indandione are added. The mixture is homogenized by stirring for 1 minute and purged with nitrogen for 10 minutes. It is then heated up to boiling under a reflux condenser in a nitrogen atmosphere and stirred intensely at 400 rpm for 30 hours. After obtaining a homogeneous mixture, the solution is cooled down to 25°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 2 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 50 g of a copolymer of tetrafluoroethylene and hexafluoropropylene (FEP) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 30 hours at 95°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for FEP - a string with an outer diameter of 2 mm is extruded from the material on a linear head, and in the next step the process of immobilization of fondaparinux into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the FEP/fondaparinux ratio of 120÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature of 245°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 8 times, which results in the formation of micropores in which fondaparinux is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 240°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 30pm thick flat foil.

As a result, a membrane with fondaparinux introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of fondaparinux, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

Example 17

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and sulfuric acid (VI) in proportions of 5 ÷ 0.002 is introduced into a dried round bottom three-neck glass flask in an argon atmosphere and 0.3 g of 4-(diphenylamino)benzaldehyde and 0.06 g of 1,3-indandione are added. The mixture is homogenized by stirring for 5 minutes and purged with argon for 30 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 400 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a SiC bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 300 g of polycarbonate (PC) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 90°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PC - hollow fiber tubes with an outer diameter of 2 mm are extruded from the material on a cross head, and in the next step the process of immobilization of fondaparinux into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PC/fondaparinux ratio of 150÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of fondaparinux to a temperature of 180°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 8 times, which results in the formation of micropores in which fondaparinux is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a flat hollow fiber tube with an outer diameter of 30pm.

As a result, a membrane with fondaparinux introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of fondaparinux, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 18

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and hydrochloric acid in proportions of 5 ÷ 0.002 is introduced into a dried stainless steel reactor in a xenon atmosphere and 0.5 g of 4- (diphenylamino)benzaldehyde and 0.02 g of 1,3-indandione are added. The mixture is homogenized by stirring for 1 minute and purged with xenon for 10 minutes. It is then heated up to boiling under a reflux condenser in a xenon atmosphere and stirred intensely at 350 rpm for 20 hours. After obtaining a homogeneous mixture, the solution is cooled down to 35°C and subjected to column chromatography in a SiC bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 2 times the volume of the reaction mixture, and of methylene chloride equal to 1 times the volume of the reaction mixture. The product is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 25g polyurethane (PU) aggregate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 20 hours at 105°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for polyurethane - a hollow fiber tube with an outer diameter of 8 mm is extruded from the material on a cross head, and in the next step the process of immobilization of heparin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PU/heparin ratio of 80÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of heparin to a temperature of 180°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 5 times, which results in the formation of micropores in which heparin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 175°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 600pm.

As a result, a membrane with heparin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of heparin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 30 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 19

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 5 ÷ 0.002 is introduced into a dried round-bottomed triple-necked glass flask in an argon atmosphere and 0.7 g of 4- (diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 3 minutes and purged with argon for 45 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 450 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. It is then vacuum-dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recry stallizate) is placed in a homogenizer and 350g of milled polypropylene (PP) are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. Then - using a twin-screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for polypropylene - a hollow fiber tube with an outer diameter of 10 mm is extruded from the material on a cross head, and in the next step the process of immobilization of heparin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PP/heparin ratio of 80÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of heparin to a temperature of 150°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 20 times, which results in the formation of micropores in which heparin is immobilized.

Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a hollow fiber tube is brought to a temperature of 145°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a hollow fiber tube with an outer diameter of 100 pm.

As a result, a membrane with heparin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of heparin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange. The tubes thus obtained can be spun on textile machines into knitted fabrics so that in the knitted fabric the distance between individual hollow fiber tubes is 35 pm and in this form they can be used as membranes for blood oxygenation in oxygenators.

Example 20

In the first step, the material for membrane construction is produced in such a way that 50 mL of a mixture of anhydrous ethanol and acetic acid in proportions of 5 ÷ 0.002 is introduced into a dried ceramic reactor in an argon atmosphere and 0.7 g of 4-(diphenylamino)benzaldehyde and 0.08 g of 1,3-indandione are added. The mixture is homogenized by stirring for 2 minutes and purged with argon for 45 minutes. It is then heated up to boiling under a reflux condenser in an argon atmosphere and stirred intensely at 450 rpm for 24 hours. After obtaining a homogeneous mixture, the solution is cooled down to 30°C and subjected to column chromatography in a S1O2 bed and in a mobile phase of the mixture of hexane and methylene chloride, with the amount of hexane equal to 1 times the volume of the reaction mixture, and of methylene chloride equal to 0.5 times the volume of the reaction mixture. It is then vacuum- dried for at least 24 hours to constant weight, after which it is recrystallized from chloroform. The product after recrystallization from chloroform (recrystallizate) is placed in a homogenizer and 350 g of poly(ethylene terephthalate) (PET) granulate are added. The solution is mixed until a homogeneous mixture is obtained and dried for 24 hours at 110°C. Then - using a twin- screw ten-zone extruder with a counter-rotating screws arrangement and geometry specified for PET - a 1 mm thick foil is extruded from the material on a flat head, and in the next step the process of immobilization of heparin into the steric structure of the material thus obtained is carried out in such a way as to ensure its content in the material in the PET/heparin ratio of 700÷1, in such a way that after initial cooling in a bath containing a supersaturated aqueous solution of heparin to a temperature of 230°C, i.e. below the plastic transition temperature, it is stretched on calenders, by cyclically decreasing and increasing the tension so as to obtain an elongation of 15 times, which results in the formation of micropores in which heparin is immobilized. Then, the second, final step of membrane production is carried out in such a way that the material obtained in the first step in the form of a foil is brought to a temperature of 225°C, after which it is stretched on calenders, in two directions, so as to obtain a membrane in the form of a 1 Opm thick flat foil.

As a result, a membrane with heparin introduced into its pores is obtained, which can be used, for example, in blood oxygenation systems, because due to its structure and the possibility of controlled release of heparin, it prevents thrombus formation while maintaining very high osmotic gas-selective exchange.

The method according to the invention makes it possible to obtain membranes made of materials with pore-forming, anti-inflammatory and anticoagulant properties, especially intended for the construction of medical equipment, in particular for construction of components which are in direct contact with blood. Such membranes may, among other things, be used in oxygenators for blood oxygenation and as other gas-selective membranes.