MXPA01007280A - A film for medical use, consisting of linear block polymers of polyurethane and a method for the production of such a film - Google Patents

Abstract

The present invention concerns a film for medical use consisting of linear block polymers of polyurethane urea containing hydrolysable ester groups. These ester groups must be so spaced from each other on the carbon chain that on their hydrolysis such small fragments are formed that they can be secreted from a human body or that of a mammal. The film is characterised in that it is porous with an average pore size of up to 600&mgr;m. The invention also includes a procedure for the production of the film in which a solution of the film-forming polymers with a concentration of 5-30%is applied as a thin layer on a surface after which the solvent is evaporated and/or the layer is treated with a polymer-precipitating agent.

Description

A PELÍCLILA FOR MEDICAL USE, WHICH CONSISTS OF LINEAR POLYMERETHIC BLOCK POLYMERS AND A METHOD FOR THE PRODUCTION OF SUCH FILM TECHNICAL FIELD The present invention relates to a film for medical use, whose film consists of linear polyurethane block polymers containing groups that can be hydrolyzed. The film according to the invention is porous TS and is designed to be used as a temporary implant after operations on, or damage to, a human body or a mammal. The invention particularly includes a method for obtaining the desired porosity.

STATE OF THE BOX Healing of living tissue after an operation or damage means that complicated processes are established in motion that involve a range of different cell types. In approximate delineation, the following processes occur in the following order: first a fibrin matrix is formed, then the cells begin to divide and bridge the wound. Under the epithelial layer, the fibroblasts are already beginning to construct connecting tissue consisting of collagen and base substance. Thus gradually the connective tissue is vascularized and ST condenses to wound tissue. In other cases, for example the healing of broken bones, the formation of the matrix is followed by growth of stem cells, which are put in category as chondroblasts. These soft callus forms, which consist of cartilage, in the fracture. The fibroblasts migrate to the cartilage and form collagen zones. Then the osteoblasts enter and form good cancellous bone. The final phase in healing consists of the conversion to hard bone and restoration of the remaining structure. This may take years before it is completed.

THE TECHNICAL PROBLEM Even if the healing process in general is going well, its complicated course provides many facilities to go wrong, For example, microorganisms can affect it or a wounded area can act together with erroneous "surrounding areas" and form a joint growth . Fibroblasts are often found to grow rapidly and are a source of undesired correction tissue formation. This can prevent the reconstruction of bone tissue or other desired tissue.

THE SOLUTION Therefore, there has long been a desire to be able to help the self healing process and overcome the problems provided above. This has led, in accordance with the present invention, to a porous film that can be used for medical purposes consisting of linear polyurethane urea block polymers containing hydrolysable ester groups as a spacing in the carbon chain that during the hydrolysis of the ester groups said small fragments are formed so that they can be secreted from a human body or that of a mammal, whose film is characterized in that it is porous with an average pore size of up to 600 ura. According to the invention, the film is characterized in that the porosity can be varied through the thickness of the film .. According to the invention, the porosity through the thickness of the film can be asymmetric, TS say, a layer thin external has inferior porosity. In accordance with the invention, it is often appropriate for the film to be laminated with a mesh of biodegradable material. The invention also includes a process for the production of a porous film for medical use consisting of polyurethane linear block polymers containing hydrolyzable ester groups, which process is characterized in that a solution of the polymers with a concentration of 5-30 % is applied in a thin layer on a surface, after which the solvent evaporates and / or the layer is treated with a polymer precipitation agent. In accordance with the invention, the precipitation agent can be better selected from the group consisting of water, methanol and acetone. According to the invention, the porosity s? it adjusts by means of the concentration of the polymer, where the high concentrations provide small pores, by means of the solvent, where the highly volatile solvents provide small pores, by means of temperature, where the elevated temperatures provide small pores and / or time , where short evaporation or precipitation times, as appropriate, provide small pores. According to the invention, a mixture of two or more solvents with different volatilities can be used to effect variable porosity through the film thickness. According to the invention, the porosity d? The film can also be adjusted by conditioning an already formed film by immersing it in a solvent or a mixture of solvents and non-solvents and / or heat treatment. Porous films can help prevent the unwanted growth of cells by acting as a barrier over a wounded area. moreover, porous films can be used to repair or replenish a porosity in the case of transplants, e.g., of cartilage. Porosity allows the transport of dissolved substances, such as metabolites and / or proteins through d? the movie. If the pore size is enough certain cell types can also grow in the film. Films with very large pores can also allow vascularization. Due to these various processes, the following limitation values can be provided for the average pore sizes: <; 1 um diffusion of dissolved components and collagen growth, < 5 um without growth of fibrous tissue, < 15 um relatively little fibrous tissue growth, 40-200 um fibrous tissue growth plus vascularization, > 600 um reduced cell growth and tissue necrosis. The polymer used in films is degradable to harmless substances that are eliminated from the body by secretion or metabolism. According to the invention, the time for degradation is not too short so that it is possible to avoid locally high concentrations of degradation products. The rate of degradation is also varied in order to be appropriate for the need in various applications. The requirements for mechanical properties d? The films can be varied depending on the application. In many applications, the tear resistance is especially important, eg, when the films are to be fixed with pins or the like or sewn firmly. In cases that are very demanding, the modulus of elasticity, resistance to tearing, etc. they can be improved by laminating a mesh of biodegradable fibers. Alternatively, the mesh can be impregnated or coated with a solution or dispersion of the polymer with subsequent removal of the solvent.

DETAILED DESCRIPTION OF THE INVENTION Polymers It has become evident that porous films and sheets with the desired ST properties can be produced from polymers of the linear block polymer type of urea polyurethane. Suitable polymers are produced by use of diisocyanates, diols and carbon chain extenders according to known methods for the specific components. In order to form films the molecular weight of the polymers should be > 10,000 Daltons, preferably UOO, 000 Daltons. A convenient technique for producing the polymers is to use the so-called prepolymerization technique, that is, first produce an isocyanate-terminated pre-polymer and then elongate its carbon chain with a diamine so that the desired molecular weight is obtained. The equations for the reaction can be written as; 2 OCN-R ^ NCO + HO-R2OH = OCN-R, -NHCO-0-R2-0-CONH-R1-NCO (1) OCN-R1-NHCO-O-R2-O-CO-NH-RI-NCO + NH2-R3-NH2 t -CONH-R1-NHCO-0-R2-0-COHN-R1-NHCONH-R3-NH-] n- (2) wherein at least one of Ri, R2 and R3 must contain one or more aster groups in the carbon chain in order to fill the requirement of degradation capacity into small fragments. It is also possible to use mixtures d? several pre-polymers to achieve special effects, v gr, to introduce groups that can react after polymerization to introduce physiologically active groups to the polymers. In addition, small amounts of carbon chain thermostats can be added to limit the weight Higher molecular weight The diisocyanates that can be used are diphenylmethane-4,4'-diisocyanate or (MDI), dicyclohexylmethane-4, '-diisocyanate, c-clohexyl-1, -d-solacetoate, diisocyanate of toluylene and many more commonly available dusocyanates and species produced in a laboratory, v. gr, those based on amino acids e.g., Hisma methyl ester diisocyanate. The diolefms used may be simple aliphatics, such as ethylene glycol diethylene glycol or higher oligomers, tetraethylene oxide glycol or higher oligomers, diol esters such as oligocaprolactone diol, oligoethylglycol adipate diol, adipate d? oligodiethylene glycol, di ethyl propionic acid, dimethylol propionic acid methyl ester, tnmethylolpropane monoallyl ether and many more. The carbon chain extenders can STG simple diamines, such as ethylene diamine, 1, 3-prop? Lend? Amma or 1-2, propylendia ina, They can also contain ester groups in the carbon chain in order to allow degradation by hydrolysis . It is possible and often expedient to use mixtures of carbon chain extenders. Primary and secondary monoamines can be used as carbon chain terminators, v. G .. diethylamine, morpholine or propylamine. Here too, mixtures can be records. Reaction 1 in the reaction scheme given above can be carried out in bulk at elevated temperatures eg, 70-80 ° C for MDI or 100-110 ° C for diisocyanate d? dicyclohexylmethane. In the presence of a catalyst the reactions can be carried out at significantly lower temperatures. Nevertheless. Reaction 2, the carbon chain elongation, is carried out in solution in consideration of the high reaction rate and the gelling tendency of the formed polymer. The resulting polymer solution can be used directly or after dilution for film or sheet production. In certain solvents, e.g., acetone, the polymer thus formed is precipitated and can be separated by filtration and then dissolved again in a solvent therefor, e.g., dimethylformamide, dimethyl sulfoxide or dimethylacetamide.

The films The films are formed from solutions that are applied as thin layers on a flat surface after which the solvent evaporates and / or the film is treated with a precipitating agent. To obtain a porous film the concentration of polymer should be 5-30%, preferably 10-20%. After application the solvent can be completely or partially evaporated or eliminated by the addition of an anti-solvent. Examples of these are water, methanol and acetone. A prerequisite for porosity is that the polymer solution at some stage of solvent removal forms a gel, that is, coagulates. The polymers according to the invention have a pronounced tendency for this because of the strong interaction d? the blocks through phase separation and hydrogen bonding. Other important factors, which favor gel formation, are high polymer concentration and high molecular weight. The pore size and pore size distribution can be adjusted with the concentration and precipitation conditions associated with the addition of the anti-solvent. Alternatively, a previously produced film can be conditioned with solvent, solvent and anti-solvent mixtures and / or heat treatment. The conditioning is carried out by immersing a film previously produced in solvent that is subsequently allowed to evaporate or heat, whereby the film swells. In this way, the sizes d? pore and its distribution are adjusted to the desired values. The films according to the invention ST can produce from polymer solutions in various ways. The simplest is production of piece by piece on a surface. v.gr. a glass plate, to which a layer of polymer solution of controlled thickness is sprayed with an applicator, after which the solvent is removed by evaporation or precipitation under carefully controlled conditions. Continuous production can be carried out by applying the solution from polymer to a mobile band that takes the material to a zone for precipitation and then to one or more zones for subsequent treatment and final removal of the film from the band that is returned. The film strength can be increased by stretching. This causes the orientation of the polymer molecules and alteration of the sizes and shape of the pores. As a result, the resistance increases in the direction of stretching. With biaxial stretching the resistance in two dimensions can be increased. An alternative way to increase the resistance of the films is to combine them with a mesh d? degradable fibers, for example, of urea polyurethane in accordance with the description in the Swedish patent No. 505703. This describes that the mesh can be partially laminated with a previously prepared or impregnated film or the mesh reinforced with the polymer solution followed by evaporation of solvent and / or precipitation in accordance with the methods described above. A method for producing porous film on curved surfaces is by immersion. For this a former, for example a tube sealed at one end, is immersed in a polymer solution. The former is removed and the polymer is converted to the solid form by evaporation of solvent and / or coagulation with an anti-solvent. The process can be repeated until the desired film thickness is obtained, after which the film slides out of the former.

EXAMPLES Example 1: A pre-polymer was produced by reacting diphenylmethane diisocyanate (MDI) with diol d? polycaprolactone (molecular weight 530) in the molar ratio 2: 1 at 70-80aC for 2 hours. 32.35 g of the resulting prepolymer were dissolved in 138 g of dimethylformamide (DMF) and the chain was extended with 2.35 g of 1,3-diamidopropane and 0.08 g of dibutylamine in 59 g of DMF at 0CC. The solution was diluted with 12.5% and 1% LiCl was added to reduce the viscosity. Part of the resulting polymer solution was dispersed on a glass plate at a thickness of 300 μm with the aid of an applicator. Part of the solvent was evaporated on a smoke board at 20HC for 20 minutes. The film whitened by it, meaning phase separation. The rest of the solvent was removed by washing with water. The film thus formed was examined using a scanning electron microscope (SEM) and exhibited through-pores with an average diameter d? 2 um.

Example 2. Part d? the polymer solution of Example 1 ST applied to a glass plate and the solvent was evaporated on a smoke board at 20 ° C for 14 hours. The residual DMF was washed with water. The film thus formed had a through-pore structure with sizes d? pore between 2 and 7 u.

Example 3 Part of the polymer solution of Example 1 was applied to a glass plate and immersed in acetone for 10 minutes whereby the polymer was separated. Acetone and residual DMF were removed by washing with water. The film thus formed had a through-pore structure with pore sizes around 1 μm.

Example 4. Part of the polymer solution of Example 1 ST applied to a glass plate. Part of the solvent was evaporated by heating the glass plate in two minutes to 100BC. The remaining solvent was evaporated on a smoke board in one hour at 20BC. The film thus formed was washed with water to remove the remaining DMF. The film thus formed had a through-pore structure with pore sizes between 2 and 7 u.

Example 5. 12.3 g of the pre-polymer obtained in example 1 were dissolved in 52.5 g of dimethylformamide (DMF) and had the chain extended with 0.9 g of 1,3-diaminopropane and 0.06 g of dibutylamine in 22.5 g of DMF at 20flC. Part of the resulting polymer solution was applied to a glass plate at a thickness of 500 μm with the aid of an applicator. The solvent was evaporated on a smoke board for 14 hours at 20 gC. The residual DMF was removed by washing with water.

Example 6. A pre-polymer was produced by reacting diisocyanate of dicyclohexane methane (H? 2MDI) with polycaprolactone diol (molecular weight 530) in a molar ratio of 2: 1 at 100-110 ° C for four hours. Additionally. a pre-polymer was produced by reacting H 2 MDI with dimethylolpropionic acid in the ratio of 2: 1 in dimethyl sulfoxide (DMSO) at 75-80eC for one hour. 26 g of pre-polymer 1 and 8.7 g of the pr? -polymer 2 + DMSO were dissolved in 66 g of DMSO and the chain was extended with 2.12 g of 1,3-diamino? Opane at 20 g d? DMSO at 20 aC. Part of the solution d? The resulting polymer was applied to a glass plate at a thickness of 300 μm with the aid of an applicator. The settlement evaporated on a smoke board for 14 hours at 20HC. The residual DMF was removed by washing with water.

Example 7. A pro-polymer was produced by reacting di-phenylmethane diisocyanate (DMI) with polydiethylene glycol adipate (molecular weight 550) in the molar ratio of 2: 1 at 70-80eC for two hours. 13.2 g of the resultant polymer were dissolved in 34 g of dimethylformamide (DMF) and the ST chain extended with 0.68 g of 1,3-diaminopropane and 0.05 g of butylamine in 22 g of DMF at 202 ° C. Part of the resulting polymer solution was applied to a glass plate at a thickness of 500 μm with the aid of an applicator. The solvent was evaporated on a smoke board for 14 hours at 202 ° C. The residual DMF was removed by washing with water.

Example 8. A pro-polymer was produced by reacting diphenylmethane diisocyanate (MDI) with diol d? 3-allyloxy-l, 2-propane in the molar ratio of 2: 1 at 70-80aC for two hours. 6.12 g of the resulting pre-polymer and 17.62 g of the pre-polymer prepared in Example 7 were dissolved in 55 g of dimethyl sulfoxide (DMSO) and the chain was extended with 2.17 g of 1,2-diaminopropane plus 0.07 g of ethylamine. in 3.5 g of acetone and 30 g of DMSO at 20 ° C, the resulting polymer solution was diluted to 15% concentration by the addition of 35 g of DMSO, Part of the resulting polymer solution was applied to a glass plate a thickness of 500 um with the help of an applicator. The solvent was evaporated on a smoking board for 14 hours at 20 ° C. The residual DMSO was removed by washing with water.

The invention is not limited to the preparation examples shown, since these can be varied in various ways within the scope of the patent claims.

Claims (10)

1. - Porous film for medical use consisting of polyurethane linear block polymers containing hydrolyzable ester groups at such a spacing in the carbon chain that during the hydrolysis of the aster groups said small fragments are formed so that they can be secreted of a human body or of a mammal, characterized in that the film is porous with an average pore size of up to 600 um.

2. Porous film according to claim 1, characterized in that the porosity can be varied through the thickness of the film.

3. Porous film according to claim 2, characterized in that the porosity in the film thickness is asymmetric.

4. Porous film according to any of claims 1-3, characterized in what? The film is laminated with a mesh of biodegradable material.

5. porous film according to any of claims 1-3, characterized in that the film forms a coating on the individual threads of a biodegradable fabric or the like.

6. - The process for the production of a porous film for medical use consisting of polymers d? linear block of urea polyurethane containing hydrolyzable ester groups, characterized in that a solution d? polymers with a concentration of 5-30%, preferably 10-20%, are applied in a thin layer on a surface, after which the solvent is evaporated and / or the layer is treated with a polymer precipitation agent.

7. The process according to claim 6, characterized in that the precipitation agent ST selects from a group consisting of water, methanol and acetone.

8. The process according to any of claims 6 or 7, characterized in that the porosity is adjusted by polymer concentration, where the high concentrations provide small pores, by solvent, where the highly volatile solvents provide small pores, by temperature, where elevated temperatures provide small pores and / or time, where short evaporation or precipitation times, as appropriate, provide small pores.

9. The process according to any of claims 6-8, characterized in that a mixture of doe or more solvents with different volatilities is used to cause variable porosity through the thickness of the film, 10.- The compliance procedure with any of claims 6-9, characterized in that the size d? pore in the film can be adjusted by conditioning a previously produced film by immersion in a solvent, or mixture of solvents, and anti-solvent and / or heat treatment,