DK152740B - PROCEDURE FOR THE PREPARATION OF A CROSS-BONDED SOLUTION-HYDROPHILIC COPOLYMER - Google Patents

Description

in DK 1527400

The present invention relates to a process for preparing novel cross-linked hydrophilic copolymers, optionally in the form of a hydrogel suitable for use as carriers for drugs and other active substances, as well as hydrophilic membranes for separation methods, as dressings for wounds, as body implants, e.g. artificial veins, such as glass, metal, wood or ceramic roof coatings and especially for use in cases where the strength and high water permeability of the polymer used are simultaneously required.

It is known to produce weakly crosslinked, water-insoluble, but hydrophilic polymers as the carrier for biologically active, least weakly water-soluble substances by copolymerizing a predominant amount of hydrophilic mono-olefinic monomers and a minor amount, between 0.01 and 15 $, based on the said mono-olefinic monomers, of a low molecular weight crosslinking agent. As mono-olefinic monomers, mono esters of acrylic or methacrylic acid with poly-functional alcohols such as ethylene glycol monoacetacrylate are used, and as crosslinking agents, in particular, diesters of said acids with said alcohols, such as ethylene glycol bis-methacrylate, and the copolymerization is carried out in the presence of of water, see U.S. Patent No. 3,220,960, or in an anhydrous system, see U.S. Patent No. 3,520,949. Both low molecular weight and macromolecular, water-soluble compounds such as polyethylene oxide mono-methacrylate, together with a small amount of the corresponding bis-methacrylate, have been used as monomers and cross-linkers according to U.S. Patent No. 3-220,960. The water-insoluble but hydrophilic copolymers and their method of preparation have been modified in various ways and adapted to special needs, e.g. for the production of soft contact lenses (U.S. Patent No. 3,200,960 and Reissue No. 27,401), and the copolymerization has been carried out in the presence of linear polyamide resin to enhance or alter the mechanical properties of articles formed from thus obtained polymer (U.S. Patent No. 3,520,949). Nevertheless, in all embodiments, low molecular weight polyolefinic crosslinking agents, especially ethylene glycol bis-methacrylate, have been used, and in very small to moderate amounts, having never exceeded $ 20 by the mono-olefinic monomer amount. Although the copolymers of the type described above

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2 has been able to be adapted to the different requirements of use, it has not been possible to adapt the mechanical properties satisfactorily to all uses, even in the swelling, i.e.. anhydrous state as in quiver, i.e. in equilibrium with water.

It is known that hydrophilic polymers, whose major constituent consists of acrylic and methacrylic acid monoesters and a bifunctional alcohol, have glass transition temperatures or softening points between 55 ° C and SO ° C. For this reason, objects of the prior art are brittle and glassy in the dry state at temperatures below 55 ° C. After achieving the equilibrium state in water, the said articles of the prior art become soft and malleable but also weak in flexural strength; moreover, they have low tear and shear strength, which makes them sensitive to bending or other loads. To avoid these undesirable adverse properties of prior art articles, they are enhanced by the insertion of stronger polymeric material or the prepolymerized mixture is filled with an insoluble material such as silica gel. These auxiliary measures, to a certain extent, reinforce the toughness (cohesive forces) because the hydrogel acts as a kit, yet the articles thus obtained in the dry state are subject to vitreous rupture and shear fracture in the constriction (spaces) of these objects.

The addition of filler material to the prepolymer also adversely affects the diffusion properties and water permeability of the articles.

It has now been found that crosslinked water-insoluble hydrophilic copolymers can be prepared with high flexibility and elasticity, both in predominantly anhydrous and in swollen state, i.e. in equilibrium with water or aqueous fluids, such as body fluids.

The process of the invention is peculiar to the reaction of 3

DK 152740 B

A) 30-90% by weight of an a) water-soluble monoolefinic monomer selected from acrylic acid and methacrylic acid, hydroxyalkyl esters and dialkylaminoalkyl esters thereof, wherein the alkyl group contains 2-4 carbon atoms, esters of acrylic acid or methacrylic acid derived from alcohols of the formula HO - C H - - O - (CH0 - CHo0) - R m 2m 2 2 n where R is hydrogen or methyl, m is 2-5 and n is 1-20, unsubstituted or substituted amides and imides of acrylic acid or methacrylic acid wherein the nitrogen substituent is hydroxyalkyl, oxaalkyl or dialkylaminoalkyl wherein the alkyl group contains 2-4 carbon atoms, hydroxyalkyl maleate or fumarates wherein the alkyl group contains 2-4 carbon atoms, hydroxyalkylvinyl ethers where the alkyl group contains 2-4 carbon atoms, and monoolefinic of heterocyclic nitrogen-containing monomers or a mixture of the above-mentioned monomers, or b) a mixture of one or more of the above-mentioned water-soluble monoolefinic monomers having 1-70% by weight single or different water-insoluble monoolefinic monomers selected from acrylonitrile, alkyl acrylates, alkyl methacrylates and alkyl maleates, wherein the alkyl group contains not more than 18 carbon atoms, vinyl esters of alkane carboxylic acids with not more than 5 carbon atoms, styrene and vinyl alkyl ethers, with the alkyl group having not more than 5 carbon atoms; 70% by weight of a hydrophobic macromer of formula t 3 2 2 3

T f 1 J J

HC = C -X-Y-R -Y-X-C = CH (B1) or

HC - CO 1 CO - CH

N - R - N (B2)

HC - CO CO - CH

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4 wherein R 1 is a polycondensate chain having a molecular weight of 200-8000 containing hydrocarbon groups bonded over ether or ester-2 3 bonds, R is hydrogen or methyl, R is hydrogen 4 or -C00R, where R is hydrogen or a alkyl group having 2 3

not more than 10 carbon atoms, with at least one of the groups R and R

5 is hydrogen, X is oxygen, -COO- or -CONR - wherein R 1 is hydrogen or an alkyl group having no more than 5 carbon atoms, and Y is a direct bond or the group is -R 2 -Z 2 -CO-NH-R - wherein R 1 is bonded to X and represents a branched or linear alkylene group of not more than 7 carbon atoms, Z 2 is S 7 and z is oxygen or -NR -, and R is a bivalent residue of an aliphatic or aromatic diisocyanate, however, when X is oxygen, Y is different from a direct bond and R and R are hydrogen in the presence of a catalyst or free radical system at a temperature in the range from 40 to 150 ° C.

These copolymers are suitable for use as hydrophilic membranes for separation methods, such as wound dressings, body implants, e.g. artificial veins, furthermore as coatings on glass, metal, wood or ceramics and as support material for biologically active compounds, e.g. drugs, herbicides, insecticides, fungicides, bactericides and fragrances.

The present cross-linked hydrophilic copolymers also have high tensile strength in the swollen state for the purposes defined above.

In the method of the invention, an insoluble polymer hydrogel suitable for scanning carriers for drugs administered orally or buccally (orally) or used in the form of subcutaneous or intramuscular implants can be obtained. The hydrogels of the invention can also be formed into body implants, such as artificial veins, devices for insertion into the urethra, vagina or intestinal outlet, or they can be used in the form of dressings for controlled delivery of drugs through the skin. Other uses of the water-swellable gels in question are reverse osmosis or semi-permeable membranes, hydrophilic membranes

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5 for separation methods, dressings for wound treatment, coverings on glass, metal, wood or ceramics and in general applications where both hydrophilia and toughness are required at the same time.

The present polymers are prepared by copolymerization in the presence or absence of solvents by copolymerization of free radicals, of a water-soluble monomer (As) suitable for forming a water-soluble or water-swellable polymer, i.e. a hydrophilic polymer (Aβ), with a diolefinic non-hydrophilic macromer (B), e.g. a long linear polycondensate chain divinyl compound such as polytetramethylene ether having a polymerizable vinyl group terminated on both sides. In this way, a three-dimensional macromolecular network is formed which is composed of two types of segments, whereby each segment contributes to the whole system with its specific physical properties. The A-segment provides water solubility, the hydrophobic B-segment forms the flexible cross-links.

By changing the corresponding proportions of each compound, the mechanical and diffusion properties can be varied over a wide range. For example, a polymer with excellent toughness, strength and extensibility is obtained, which polymer can nevertheless almost absorb its own weight of water, · this polymer can be obtained using suitable proportions of A and B. This option is not present in known hydrogels because their cross-links are short and inelastic, and these hydrogels are hard and brittle in the dry state.

In the polymers prepared by the process according to the invention, the incorporation of the bifunctional macrole molecule B in predominant proportions of the system is novel. In this way, the bifunctional macromer serves not only as a structural crosslinker, but also as an importer of unique physical properties to the gel.

The hydrophilic polymer Aβ is preferably a polymer of one or more water-soluble mono-olefinic monomers As, but it can also be a copolymer of a mono-olefinic water-soluble monomer and not more than 70 water-insoluble mono-olefinic monomer Ai. The water-soluble monomers are preferably acrylic and / or methacrylic acid (2-methyl-acrylic acid) or water-soluble derivatives thereof, such as their

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6 hydroxyalkyl esters, e.g. 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl or 2,3-dihydroxypropyl ester; also ethoxylated and polyethoxylated hydroxyalkyl esters, such as esters of alcohols of the formula

H0 - ° mH2m - 0 - (CH2-0H2 °) n 'E

wherein R is hydrogen or methyl, m is 2 to 5 * and n is 1 to 20, or esters of analogous alcohols in which a portion of the ethylene oxide units is replaced by propylene oxide units. Furthermore, suitable esters are dialkylaminoalkyl acrylates and methacrylates, such as the 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl and 3- (dimethylamino) -2-hydroxypropyl esters. Another class of suitable derivatives of such acids are their water-soluble amides such as the unsubstituted amides and with low hydroxyalkyl, low oxaalkyl or low dialkylaminoalkyl groups of substituted amides such as N- [hydroxymethyl) acrylamides and methacrylamides, N- ( 3-hydroxypropyl) acrylamide, M- (2-hydroxyethyl) methacrylamide, N- (1,1-dimethyl-3-oxabutyl) -acrylamide and N- [1,1-dimethyl-2- (hydroxymethyl) -3- oxa-butyl] -acrylamide; N- [2- (dimethylamino) ethyl] acrylamide and methacrylamide, N- [3- (dimethylamino) -2-hydroxypropyl] methacrylamide or monoolefinic derivatives of heterocyclic nitrogen containing monomers such as N-vinyl pyrrole, N -vinyl-succinimide, 1-vinyl-2-pyrrolidone, 1-vinyl-imidazole, 1-vinyl-indole, 2-vinyl-imidazole, 4 (5) -vinyl-imidazole, 2-vinyl-1-methyl-imidazole, 5-vinyl-pyrazoline, 3-methyl-5-isopropenyl-pyrazole, 5-methylene-hydantoin, 3-vinyl-2-oxazolidone, 3-methacrylyl-2-oxazolidone, 3-methacrylyl-5-methyl-2-oxazolidone, 3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinyl-pyridine, 5-vinyl-2-methyl-pyridine, 2-vinyl-pyridine-1-oxide, 3-isopropenyl-pyridine, 2- and 4-vinyl-piperidine, 2- and 4-vinyl-guinoline, 2,4-dimethyl-6-vinyl-s-triazine, 4-acrylyl-morpholine.

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Disso monomers can be used alone or in combination with each other or with other suitable vinyl monomers which may also be hydrophobic. The amount of these hydrophobic monomers should not exceed $ 60 of the total composition, preferably not above kO%.

Suitable hydrophobic monomers are e.g. water-insoluble olefinic monomers, such as alkyl acrylates or methacrylates, wherein alkyl has 1 to 1 $ C atoms, e.g. methyl and ethyl methacrylate or acrylate; of alkane carboxylic acids having 1 to 5 C atoms derived vinyl esters, e.g. vinyl acetate, acrylonitrile, styrene and vinyl alkyl ethers wherein the alkyl group in the ether chain has 1 to 5 C atoms, e.g. (methyl, ethyl, propyl, butyl or amyl) vinyl ether.

Water-soluble monomers that need a comonomer for polymerization are maleate, fumarates and vinyl ethers; the following monomer combinations may e.g. is used:

Di- (hydroxyalkyl) maleate such as di- (2-hydroxyethyl) maleate and ethoxylated hydroxyalkyl maleate, hydroxyalkyl monomaleate such as 2-hydroxyethyl monomaleate and hydroxylated hydroxyalkyl mono maleate with vinyl ethers, vinyl esters, styrene or general monomers which easily copolymerizes with maleate or fumarates; hydroxyalkyl-vinyl ethers such as 2-hydroxyethyl-vinyl ether, 4-hydroxybutyl-vinyl ether with maleate, fumarates or, in general, all monomers which readily copolymerize with vinyl ethers.

Particularly valuable as water-soluble monomers are hydroxyalkyl acrylates and methacrylates such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate, N-vinyl acrylic acid, methacrylic acid and a tertiary amino methacrylimide, e.g. trimethylamino-methacrylimide, as described in U.S. Pat.

3627. $ 02.

The most preferred monomers are 2-hydroxyethyl methacrylate and N-vinylpyrrolidone.

DK 152740B

8 In the diolefinic non-hydrophilic macromers B, the olefinic moiety is preferably an acyl residue of a lower α, β-mono-urea aliphatic monocarboxylic or dicarboxylic acid or a vinyloxy group. These groups are linked to each other by a macromolecular, non-hydrophilic chain having repetitive ester, amide or urethane groups, but especially ether groups. The molecular weight of the chain can vary from approx. 400 to approx. £ 000, but preferably between 600 and 5000, and especially between 1500 and 3000. Accordingly, component B corresponds to formulas R3 R2 R2 R3 11 1 11 HC = C-X-Y-R-Y-X-C = CH (Βχ) or

HC - GO .CO - CH

\ ·, / N-R -N (B «) / \

HC - CO NC0 - CH

is a polycondensation chain having a molecular weight of about 200 to about 8000 containing hydrocarbon groups bound over ether or ester groups, R is hydrogen or methyl, RJ is hydrogen or -COOR where R4 is hydrogen or an alkyl group having up to to 10 carbon atoms, provided that at least one of the groups R and R is hydrogen, X is oxo, -COO- or t 5 -CONR, wherein R is hydrogen or an alkyl group of up to 5 carbon atoms, and Y is a direct bond or the group -R 1 -Z 2 -CO-NH-R 2 -NH-CO-Z 2 - wherein R 2 is bonded to X and is a branched or straight chain alkylene group of up to 7 carbon atoms, 12 ' Z and Z are oxo or -NR, and R is the divalent residue of an aliphatic or aromatic diisocyanate, provided that Y when X is oxo is no direct bond and R and R are hydrogen . In the compounds of formulas B1 and B2, R "" means in particular a polypropylene oxide or a polytetramethylene oxide chain, but it may also be one of dicarboxylic acids, diols, diamines or diisocyanates derived by known polycondensation methods. The final 9

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groups represented in the compounds of formula B- correspond to the definitions of R 2 and b} and, when X means -C00- or -CONR 2, is derived from the acyl residue of acrylic or methacrylic acid or the monoacyl residue of maleic, fumaric or itaconic acid or of monoalkyl esters of these acids with straight or branched chain alkanols having 1 to 10 C atoms such as methanol, ethanol, butanol, diisobutyl alcohol or decanol, or, when X is oxygen, with the vinyloxy group in vinyl ethers. Compounds of formula B- wherein T is a direct bond are diesters of macromolecular diols wherein two hydroxy groups are attached to the polycondensate chain R1 in opposite, terminated or nearly terminated positions, with α, β unsaturated acids. Such diesters can be prepared from said macromolecular diols by known acylation methods, using reactive functional derivatives of suitable acids, e.g. acrylic or methacrylic acid chloride, or of monoalkyl esters of maleic, fumaric or itaconic acid. Compounds of formula B · with the amide group X are diamides obtained from macromolecular diamines by known acylation methods, e.g. using the above acid chlorides or anhydrides. The macromolecular diamines are prepared e.g. from the corresponding macromolecular diols with the double molar amount of alkyleneimine, e.g. propyleneimine.

The macromolecular bis-maleic acid acids are obtained according to the reaction described above using maleic anhydride as acylating agent for macromolecular diamines during heating or reaction with dewatering agents to prepare macromolecular bis-maleimido compounds of formula len In these compounds, R be one of the macromolecular polycondensate chains mentioned as constituents of the compounds of formula B

Furthermore, according to the definition of formula, you can mean a divalent group -R ^ -Z ^ -CONH-R ^ -NH-GO-Z ^. Therein, R methylene, propylene, trimethylene, tetramethylene, pentamethylene, neopentylene (2,2-dimethyltrimethylene), 2-hydroxytrimethylene, 1,1-dimethyl-2- (1-oxoethyl) -trimethylene or 1- (dimethylenaminomethyl) ethylene and especially ethylene . The divalent group R is derived from an organic diisocyanate and is an aliphatic group such as alkylene, e.g. ethylene, tetramethylene, hexamethylene, 2,2,4-trimethylhexamethylene, 2.1 +, 1 + -

DK 152740 B

10 trimethylhexamethylene, fumaroyl diethylene or 1-carboxypenta-methylene; a cycloaliphatic group e.g. 1,4-cyclohexylene or 2-methyl-1,4-cyclohexylene; an aromatic group such as m-phenylene, p-phenylene, 2-methyl-m-phenylene, 1,2-, 1,3-, 1,5-, 1,6-, 1,7-, 1,1- , 2,3- and 2,7-naphthylene, 4-chloro-1, 2- and 4-chloro-1, δ-naphthylene, 1-methyl-2,4-, 1-methyl-2,7-, 4 -methyl-1, 2-, 6-methyl-1,3 and 7-methyl-1,3-naphthylene 31, -dinitro-2,7-naphthylene, 4,4 * -diphenylene, 3.3, - dichloro-4,4f-diphenylene, 3,3, -dimethoxy-4,4f-diphenylene, 2,2f-dimethyl- and 3,3t-dimethyl-4,4, -diphenylene} 2,2f-dichloro-5,5 * -dimethoxy-4,4J-diphenylene, methylene-di-p-phenylene, methylene-bis- (3-chlorophenylene), ethylenedi-p-phenylene or hydroxy-diphenylene.

When the symbol Y in formula B1 is not a direct bond, R6 must always be associated with X.

Thus, compounds of formula B wherein Y means said divalent group are bis-vinyl ethers when X is oxygen, or bis-acrylates, bis-methacrylates, bis-maleate, bis-fumarates and bis-itaconates when X is -C00- or -CONE / *.

The more preferred divinyl macromers B consist of polytetramethylene oxide glycols having a molecular weight of from ca. 1000 to approx. 4000, end-saturated with 2,4-toluene diisocyanate and reacted with 2 moles of a 2-hydroxyalkyl acrylate or methacrylate. Particularly valuable are the macromers of polytetramethylene oxide glycol having a molecular weight of approx. 1500 to approx. 3000, end-saturated with 2,4-toluene diisocyanate and reacted with ca. 2 moles of 2-hydroxyethyl methacrylate.

The subject hydrophilic copolymers are prepared by free radical copolymerization, either in solution or in bulk, of water-soluble mono-olefinic monomers As or a mixture of at least $ 30 water-soluble monomers As having at most 70% water-insoluble monomers Ai of 10 to 70% macromers of the formula B 2 or B2, based on the total weight of the hydrogel. The polymerization is advantageously carried out with a free radical catalyst at temperatures in the range of from approx. 40 to approx. 150 ° C, preferably between ca.

50 and approx. 100 ° C. The presence of a therapeutic or otherwise, such as biologically active substance during polymerization may 11

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for the sake of heat stability of the fabric, require a restriction of the polymerization temperature.

A preferred laboratory preparation method for the hydrogel article comprises dissolving the drug in the macromer monomer solution prior to polymerization, thus selecting the desired drug concentration together with the macromer monomer ratio to give the hydrogel the desired mechanical and water absorption properties, admixing with about $ 0.02 to approx. 1 $ (% by weight) of a suitable free radical catalyst and polymerization of the mixture by e.g. SO ° C for approx. 2 hours in a closed form so that the hydrogel is obtained as a flat film containing the drug in quasi-solid solution. This film is then exposed for approx. 12 hours in a high vacuum for a temperature of approx. 100 ° C to remove residues of monomer and catalyst decomposition products.

A preferred laboratory method for preparing the hydrogel in cylindrical form is to fill a flexible polyethylene tube with the preferred mixture of macromer, monomer, drug and catalyst and allow the mixture to react for approx. 2 hours at $ 0 ° C.

The hydrogel article thus produced is released from the tube by longitudinal bursting and stripping thereof.

A further preferred method of preparing the hydrogel in the form of small spheres or beads is that the preferred mixture of macromer, monomer, drug and catalyst at about High speed 90 ° C is stirred in a viscous medium that does not act as a solvent for a component of the hydrogel mixture. Examples of suitable media for bead polymerization include silicon oils, polyfluorinated oils and the like, e.g. mineral oil distillates and saturated aqueous salt solutions.

Another preferred method of preparing the hydrogel in the form of a foamed article is to add a gas producing agent (propellant) such as sodium hydrogen carbonate to the preferred mixture which is then polymerized at ca. 80 ° C in a mold for approx. one hour. The closed cell foam obtained is particularly suitable for rapid water absorption and drug release.

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12

Compounds of formula B ± wherein I is -E6-Z1-CONHR7-NH-G0-Z2 are obtained in a two-step reaction by macromolecular diols or diamines, i.e. compounds containing two hydroxy or amino groups bonded in opposite end or near end position to the polycondensate chain r \ are first reacted with at least twice the amount of an aliphatic, cycloaliphatic or aromatic diisocyanate, wherein the diisocyanate consists of the 7 group R to two isocyanate groups are bonded, after which the macromolecular diisocyanates thus obtained are reacted in the second reaction step with a compound of the formula R3 R2 I 1 6 1 HC = C - X - R ° - ΖΧΗ (C) wherein R2, R3, X, R ^ and Z1 have the meaning given above (for B ^).

When X is oxygen, (C) is an active hydrogen vinyl ether, e.g. a hydroxyalkylvinyl ether or an aminoalkylvinyl ether; when X is

f C

-C00 or -ONR, is (C) an acrylate, methacrylate, maleate, fumarate, itaconate or the corresponding active hydrogen amide in the alkyl group. The macromolecular diol or diamine is preferably used in a slight excess, i.e. the amount ratio of isocyano groups to hydroxy or amino groups in the first reaction step of the macromolecular synthesis should be at least 1: 1, but preferably at least 1: 1.05 or lower. When the compound C used in the second reaction step of the macromer synthesis is identical to the hydrophilic monomeric Ås, a large excess of this compound can be used so that the obtained solution of the macromeric B is used to prepare the final product, the hydrophilic copolymer.

The preparation of the macromeric B is advantageously carried out at temperatures in the range of about room temperature to approx. 80 ° C. The temperature used is preferably not above 40 ° C and best in the range between 30 and 45 ° C. The conversion of the isocyanogroup is followed by infrared spectroscopy or titration.

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Another method of preparing the macromer consists in reaction, of a prepolymer having terminated hydroxyl groups, e.g. polybutylene or polypropylene oxide, with acryloyl chloride, methacryloyl chloride or maleic anhydride, using a non-urethane intermediate macromer such as a macromer of formula Bg or B- wherein T is a direct bond.

The free radical copolymerization is initiated by a catalyst capable of producing free peroxy or alkyl groups of sufficiently high concentration to effect the polymerization of the vinyl monomer used at the synthesis temperature.

Examples of suitable catalysts are diisopropyl peroxydicarbonates, tert.butyl perontoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic peroxide, methyl ethyl ketone peroxide, tert.butyl peroxyacetate and azoisobutyronitrile. When the polymerization is carried out in water, water-soluble peroxy compounds such as sodium, potassium or ammonium persulfate, redox systems which produce free radicals such as persulfate bisulfite combinations can be used. The catalyst is advantageously used in an amount of approx. Other systems that produce free radicals, such as gamma rays, electron beam bundles, and W radiation can also be used.

The reaction preferably takes place in an inactive or oxygen-free atmosphere if open molds are used. Oxygen is known to inhibit polymerization and prolong polymerization times until the end of the reaction. When working with closed molds to form the hydrogel article, the molds must consist of inert material of low oxygen permeability and non-solubility. Examples of suitable molding materials are Teflon ®, silicone rubber, polyethylene and Mylar®. Molds of glass and metal can be used when a suitable release agent from the mold is used.

The incorporation of the drug into the hydrogel article is accomplished either by dissolution or dispersion in the macromer solution, the monomer solution, or the mixture of the two prior to the addition of the free

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14 by catalyst or by diffusion of the drug into the article obtained after the polymerization. When the drug is not attacked by free radicals, it is advantageous to dissolve or disperse it before the polymerization in the macromer solution, the monomer solution or the mixture of the two. When the drug is attacked by free radicals, it should be incorporated into the finished article after polymerization by diffusion from a solution.

The hydrogel system, consisting predominantly of the hydrophobic macromeric segment B and the hydrophilic segment Aβ, can be of quite diverse composition, and consequently the degree of hydrophilia and mechanical strength can be weighed consecutively so that there is a wide variety of applications, such as administration systems. for drugs, insecticides, herbicides, etc., semi-permeable membranes for used osmosis, body implants and wound dressings.

Hydrogels with leathery toughness in the wet state and high elasticity in the wet state can be produced depending on the reaction ratios of the above-mentioned components with low to high water absorption capacity.

For applications such as body implants, wound dressings, and semi-permeable membranes, hydrophilic membranes are particularly advantageous, which combine a relatively high wet strength with equilibrium water content of 5 to 50µ. Subcutaneous and intramuscular implants for controlled drug delivery must, on the one hand, be capable of water absorption (15 to 25% by weight), but on the other hand must be strong enough in the dry and swollen state to endure the insertion and extraction process.

In addition to being suitable as drug carriers, the present hydrogels can also be used as carriers for antiseptics, flavors, colorants, foods, insecticides, herbicides, etc. In particular, the hydrogels may be swollen in a suitable solvent containing the active substance to be transferred; the solvent is evaporated leaving the active substance in the hydrogel particles. In contact with aqueous environment, the active substance is delivered in a uniform manner.

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The disclosed hydrogels are particularly suitable for use as intramuscular and subcutaneous implants in warm blooded animals due to the wide variation in water absorption, strength and elasticity properties. For the same reasons, the disclosed hydrogels can be used as a blood vessel or extracorporeal replacement material without the need for a supporting matrix, as is the case with relatively weak hydrogel materials.

The hydrogel substances in question are also suitable for use as hydrophilic and non-thrombogenic coating because they are strongly adhered to glass, metal and plastic. Because of their high strength and elasticity, they provide strong cover layers with high abrasion resistance and are therefore suitable for coating boat hulls to prevent clam growth or to produce cover layers on lenses and glass, which prevent their formation in humid environments.

A further excellent feature of the disclosed hydrogels is their flexibility in the dry state, in which they already assume the desired shape during their use. In the swollen state, a further advantage of the hydrogels in question is that they do not become brittle, but retain their strength and elasticity even when in the aqueous environment in the equilibrium state (with water). These properties are particularly valuable when using pressurized membranes, such as in reverse osmosis apparatus to which the hydrogels of the present invention are suitable.

Drug-containing hydrogels are also particularly suitable for use in the treatment of open wounds and burns thanks to their flexibility and form adaptability associated with the ability to bring drugs directly to the affected sites. In this mode of application, there is a particular advantage in the flexibility of the hydrogel in the dry state. It is unnecessary to swell the hydrogel before use to make it sufficiently soft and flexible to cover large wounded surfaces (wound portions); for this reason, the drug-containing hydrogel can be applied dry instead of swollen, which increases the storage resistance of the drug contained therein.

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In the copolymer support material in question, any active substance can be incorporated as an active substance, both locally and systemically. The term "drug" is used here in the broadest sense and includes any substance or mixture having pharmacological or biological effect. For therapeutic use, all drugs listed in US Patent No. 3 * 732 are suitable without restriction.

Other than the aforementioned drugs, having the same or different effects, may be used in the carriers of the present invention. Suitable mixtures of drugs can be administered just as well as the individual substances.

The drugs can be administered in various forms of administration, such as as pure active substances, as components of molecular complexes or as non-irritating, pharmacologically acceptable salts, e.g. such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate and salicylate. For acid-reacting drugs, metal salts, amines or organic cations (e.g., quaternary ammonium salts) can be used. Furthermore, simple derivatives of the drugs (such as ethers, esters and amides) can be used which have desired delay and release properties and which are readily hydrolyzed by the action of the body's pH, enzymes etc.

The amount of drug to be incorporated into the carrier depends to a large extent on the individual compound, the desired therapeutic effect and the length of time needed to release the drug. There is no critical upper limit on the amount of drug that can be brought into the carrier because the diversity of the carriers and their different sizes and shapes should allow the various diseases to build up a full spectrum of dosage forms and dosages. The lower limit will also depend on the effect of the drug and the degree of its release from the carrier. Therefore, there is no need to define an area for the therapeutically effective amount of drug released by the carrier.

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Preferred drugs that may be used are those intended for long-term treatment so that a multiple dose of daily dosage such as anabolics, e.g. methandrostenolone, analgesics, e.g. acetylsalicylic acid, phenylbutazone or methadone, androgens, e.g. methyl testosterone, antibiotics, e.g. rifampin, antidepressants, e.g. imipramine or maprotiline, antidiabetics, e.g. phenoformin, anticonvulsants, e.g. carbamazepine, antihistamines, e.g. tripelennamine, antihypertensive agents, e.g. hydralazine, antimicrobially active agents, e.g. trimethoprim, antiparasitic agents, e.g. nifurtimox, antiparkinson's agents, e.g. levodopa, antiflogistics, e.g. naproxen, antitussives, e.g. benzonate, appetite suppressants, e.g. mazindole, bronchodilators, e.g. phenoterol, conorardilators, e.g. phenalcomin, corticoids, e.g. dexamethasone, cytostatics, e.g. floxuridine, diuretics, e.g. hydrochlorothiazide, hypnotics, e.g. glutethimide, neuroleptics, e.g. reserpine or thioride-azin, psychoanaleptics, e.g. methylphenidate, tranquilizers, e.g. diazepam, uricosurica, e.g. sulfin pyrazone, vasodilators, e.g. isoproterenol.

In addition to drugs, fragrances or flavors such as orange oil, citral, coffee, tea, lemon oil, synthetic lemon-limon flavor, strawberry flavor, vanilla, diacetyl, anise, sour scent, pine scent, peppermint oil, orchid oil, anethole, ethyl propionate, ethyl acetate, acetaldehyde, menthol and garden mint, and pesticides including bactericides, fungicides, insecticides and nematodicides.

Other examples of the aforementioned biologically active additives are disclosed in U.S. Patent No. 3 * 660,563 (columns 3 to 7).

The hydrogels in question, especially those containing polyurethanes as macromer components, because of their superior dry and wet physical properties, are a cross between classical hydrogel and polyurethane and are particularly valuable as biomedical plastics with non-thrombogenic properties. They are therefore ideally suited for use as artificial skin in the treatment of burns, for the construction of artificial organs or as coverings for such.

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18

The composition of the hydrogels can range from JO to 90 $ monomer (A) and 10 to 70 $ macromer (B), with a corresponding swelling rate of about 10%. 10 to 250%. The preferred compositions contain about 15 to 50 $ macromer (B) and about 50 to $ 5 $ monomer (A), and their swelling rate ranges between 15 and 120 $.

Experimental part.

When the gel is finished, a piece weighing 3 g is cut, weighed and stored in a bottle of approx. 50 ml of water at room temperature. After 96 hours, remove the swollen sample, freeze with excess surface water filter paper and re-weigh to determine the degree of swelling (DS). Of the remaining hydrogel film, 6 test strips are punched, of which 3 are allowed to swell in water until the equilibrium content is reached. The tensile strength and expansion of the dry and moist sample are determined in an Instron test machine according to ASM test method D-63S using a type 17 test strip.

The release rate of a drug contained in a hydrogel is determined by sustained measurement of the characteristic UY absorption of a stirred amount of water containing a hydrogel disk of 16 mm diameter and a thickness of 0, S to 1.0 mm.

Weight of the Moist Sample - Weight of the Swelling Degree DS = -mgt of the dry sample "8 x 100 In the following examples, the term" terminated with isocyanate polytetramethylene oxide reacted "(with isocyanate end saturated polytetramethylene oxide) means a polytetramethylene oxide chain which the two ends are reacted with 2.alpha.-toluene diisocyanate These compounds are readily prepared and are also commercially available from Du Pont de Nemours Chemical Comp., Wilmington, Del., under the trade name "ADIPRENE".

The first seven examples show the influence of alternating amounts of macromeric, hydrophobic crosslinking agent on the physical properties of polyhydroxyethyl methacrylate gels as well as their preparation.

19

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A: 2-Hydroxyethyl methacrylate (HEMA) B: Finalized with isocyanate reacted with polytetramethylene oxide + HEMA.

Example 1.

20 g of an isocyanate-reacted polytetramethylene oxide reacted with a molecular weight of 1500 (ADIPRENE 167) are dissolved in 1 g of 2-hydroxyethyl methacrylate and reacted for 72 hours at room temperature. After 72 hours, the disappearance of all isocyanate is confirmed by the absence of the characteristic isocyanate infrared band at 2270 cm -1 in infrared spectrum. This mixture is then sprayed after adding 0.03 g of diisopropyl percarbonate in a mold for foils of 1 mm thickness and kept for 2 hours in a rotary oven at 60 ° C. The obtained solid, transparent film is immersed in water for 2 days and then dried in vacuo at> 0 ° C. The equilibrium water content, compressive strength and expansion are measured in a dry and humid state.

Example 2.

The procedure of Example 1 is repeated except that 2.0 g of isocyanate reacted polytetramethylene oxide having a molecular weight of 3000 (ADIPRENE L-42) is used. A cool, transparent film is obtained which after 2 days immersion in water and subsequent drying in vacuo at $ 0 ° C is tested as described in Example 1.

Example 3 »

The procedure of Example 1 is carried out with 5.0 g of ADIPRENE 167 (molecular weight 1500) and 15.0 g of 2-hydroxyethyl methacrylate. The product obtained is a cool, transparent film treated as described in Example 1.

Example 4

The procedure of Example 1 is repeated, however, the composition of the reaction mixture is changed to 10.0 g ADIPRENE 167 (molecular weight 1500) and 10.0 g

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2-hydroxyethyl methacrylate. A cool, transparent film is obtained which is treated as in Example 1.

Example 5

The procedure of Example 2 is repeated with altered composition of the reaction mixture, reacting 5.0 g of ADIPRENE L-42 (molecular weight 3000) and 15.0 g of 2-hydroxyethyl methacrylate. A cool, transparent film is obtained which is treated as in Example 1.

Example 6

The procedure of Example 2 is repeated with a mixture of 10.0 g of ADIPRENE L-42 (molecular weight 3000) and 10.0 g of 2-hydroxyethyl methacrylate. A cool, transparent film is obtained which is treated and tested as in Example 1.

Comparative Example 1.

For control, a conventional poly (2-hydroxyethyl) methacrylate gel is prepared from 1.2 $ ethyl engly coldimethacrylate as a crosslinking agent, otherwise the same procedure is used as for the gels previously described. A hard, brittle, transparent sheet is obtained that is treated and tested in the same manner as described above. Table 1 shows a decreasing swelling rate with increasing amounts of the hydrophobic macromer B. The dry state tensile strength of the products of Examples 1 to 6 is higher than that of the usual poly-HEMA prepared above. The tensile strength in the moist state and the expansion in the dry and moist state increase with increasing amounts of B.

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Table I

Ex. Macromer (B) fo Monomer (As) Tensile strength Expansion ADIPRENE * HEMA HEMA fo DS dry moist 1 L-I67: 11.6 oz, 4 52 4560/41 165/99 2 L-42: 10, S 69.2 42 5343 / 39 150 / 10δ 3 L-167: 29 71 22 4760 / S9 409 / II3

4 L-167: 56 42 12 4123/144 IO55 / I5O

5 L-42: 27 73 30 4453/120 256/95 6 L-42: 54 46 20 3167/246 557/214 7 - 96.5 45 2320/15 69/63 * ADIPRENE L-167: molecular weight = 1500, f L-42: molecular weight = 3000

The following examples demonstrate the utility of N-vinylpyrrolidone as hydrophilic monomer (A) as well as the use of hydrophobic comonomers for adjusting the equilibrium water content.

Examples 7 - 11.

30 g of an isocyanate end saturated polyethylene ternide oxide having a molecular weight of 3000 (ADIPRENE L-42) are dissolved in 40 g of N-vinylpyrrolidone and 10 g of 2-hydroxyethyl methacrylate, after 72 hours all free isocyanate has disappeared. The solution is then divided into 4 equal parts and 5 g of the following monomers are added:

Example 7: N-vinylpyrrolidone (NVP)

Example δ: Ethyl acrylate (EA)

Example 9: Dimethyl maleate (DMM)

Example 10: Vinyl Acetate (VA)

Example 11: Ethyl acrylate (EA).

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22

To each of the five mixtures 0.1 g of tert.butyl peroctoate is added and the solutions are cast in a mold for foil having a thickness of 1 mm. React at 60 ° C for two hours; the foils are taken out of the mold and kept at 100 ° C for 15 hours in a vacuum of 0.25 mm. The films thus prepared are clear and tough, and their swelling rate was determined as follows (see Table II).

Table II

Ex. Macromer (B)% Monomer system (A)

ADIPRENE L-42 + HEMA fo + fo (A) fo (Ai) DS

NVP + HEMA Comonomer 7 32.4 60 + 7.6 - 101 8 32.4 40 + 7.6 EA: 20 75 9 32.4 40 + 7.6 DMM: 20 76 10 32.4 40 + 7.6 VA: 20 91 II · 22.6 29 + 5.4 EA: 43 42 In the following two examples, the macromer (B) is a bis-vinyl ether (Example 12) and a bis-maleate (Example 13).

Example 12.

Following the procedure described in Examples 7 to 11, 30 g of isocyanate end-saturated polytetramethylene oxide (molecular weight 3000) and 10 g of 4-hydroxybutyl vinyl ether (HBVE) are reacted in 30 g of N-vinyl pyrrolidone until all free isocyanate has disappeared. 30 g of ethyl acrylate and 0.4 g of tert.butyl peroctoate. The mixture is placed in foil molds and after two hours at 60 ° C the cross-linked foils are taken out of the mold and kept for 16 hours in a vacuum oven (0.25 mm Hg) at 100 ° C. The sample is a cool, clear leaf whose swelling rate was determined (see Table III).

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Example 13

Following the procedure described in Examples 7 to 11, 40 g of isocyanate end-saturated polytetramethylene oxide (molecular weight 3000) and 10 g of 3-hydroxypropyl-butyl maleate (HPBM) are reacted in 50 g of N-vinylpyrrolidone until all free isocyanate is removed. To this mixture is then added 0.4 g of tert-butyl peroctate. The mixture is brought into foil molds and kept for two hours at a temperature of # 0 ° C. The cross-linked film is taken out of the mold and held for 100 hours (0.25 mm Hg) at 100 ° C.

The sample is a cool, clear leaf whose swelling rate was determined (see Table III).

Table III

Ex. Macromer (B)% Monomer system (A)

ADIPRENE L-42 + Endpoint fo As fo Åj DS

monomeric NVP + HBVE HPBM Gomonomer 12 32.4 HBVE 30 + 7.6 - 30 72 13 43.1 HPBM 50 + - 6.9 - 39 In the following examples, the macromeric crosslinking agent contains linear polyesters and polypropylene oxide chains.

Examples 14 to 16 ·

An isocyanate end-saturated polyester (Mutrathane E-410, Mobay Chemical Corp.) having a molecular weight of 425 is mixed with 2-hydroxyethyl methacrylate (HEMA) in the following proportions:

Example 14: 15 g polyester diisocyanate + $ 5 g HEMA

Example 15: 25 g n, r + 75 g HEMA

Example 16: 40 g n n + 60 g HEMA

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24

The mixtures are allowed to stand for 72 hours at room temperature, after which time all isocyanate is reacted. 0.4 g of tert.butyl peroctoate are added to each of the batches, and these are then placed in foil molding having a thickness of 1 mm. The samples are heated for 2 hours to 50 ° C, taken out of the molds and subjected to a temperature of 100 ° C for 16 hours in a vacuum oven (0.25 mm Hg). The transparent foils are cool and flexible, their swelling degree is shown in Table ΓΥ.

Table IV

Ex. % Macromer (B) Monomer (A)

Polyester (E-410) + HEMA% HEMA DS

14 23.4 76.6 30 15 39 6l 21 16 62 36 21

Examples 17 to 18 «

A by reaction of 2 moles of maleic anhydride with a mole of polypropylene oxide, end-saturated with primary amino groups, obtained bis-maleimide-type macromer (B) having a molecular weight of approx. 2200 (polypropylene oxide bis-maleimide) is dissolved in 2-hydroxyethyl methacrylate in two proportions:

Example 17: $ 20 polypropylene oxide bis-maleimide ($ 0 HEMA)

Example 18: $ 35, T "($ 65 HEMA)

0.1 tert.butyl peroctate is added and the solutions are reacted in the foil mold at 0 ° C for 2 hours, the foils are taken out and kept in a vacuum oven (0.25 mm Hg) for 16 hours at 100 ° C. is then cool and supple; their degree of swelling is given in Table Y.

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25

Table V

Ex. Macromer (B) $ Monomer (A) $

DS

Polypropylene oxide-bis-maleimide HEMA

17 20 BO 44 18 35 65 33

Example 19.

53) 0 g of polypropylene oxide bis-maleimide of Examples 17 and 18 are dissolved in 47) 0 g of N-vinylpyrrolidone; after the addition of 0.4 g of tert.butyl peroctoate, the mixture is poured into the mold and reacted as described in Example 17. A cool, light brown colored gel is obtained which absorbs 1 + 6.0% of its weight of water (DS = 46.0).

Examples 20, 59.5 g of polypropylene oxide bis-maleimide of Examples 17 and 18 are dissolved in 27.1 g of N-vinylpyrrolidone and 13.0 g of ethyl acrylate; after the addition of 0.4 g of tert.butyl peroctoate, the mixture is filled into molds and reacted as described in Example 17. The gel forms a tough, slightly yellowish foil which absorbs $ 26.5 of its weight of water (DS = 26.5) .

Example 21.

Example 20 is repeated but with amounts of 3.10 g of N-vinylpyrrolidone and 26.4 g of ethyl acrylate. The product obtained is a cool, colorless gel that absorbs $ 23.0 of its weight of water (DS = 23.0).

Example 2 2,

Example 20 is repeated but with amounts of 27.1 g of N-vinylpyrrolidone and

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26 43.5 g of ethyl acrylate. The gel obtained is tough and colorless; it absorbs $ 15.8 of its weight of water (DS = 15.8).

Application Examples 1 to 3.

The procedure of Example 2 is repeated except that the isocyanate end-saturated polytetramethylene oxide having a molecular weight of 3000 (ADIPRENE L-42) is used at concentrations of $ 15 for e.g. 1, $ 25 for e.g. 2 and $ 33 for e.g. 3, and dissolving 2.0% by weight of Pyribenzamine HCl, a drug with antihistamine action, in each sample immediately prior to polymerization.

Application Example 4.

The method according to e.g. 1 is repeated except that immediately before polymerization, 4% by weight of Pyribenzamine HCl is dissolved in the monomeric mixture.

Foil samples of the same thickness, obtained according to e.g. 1 to 4, extracted at 37 ° C for 16 hours in a HCl / NaCl solution (pH 2.15).

The amount of drug extracted from each film is determined during the process in the solution at 314 nm with a Beckman Acta C III ultraviolet spectrometer at different times, measuring the amplitude of the absorption peak characteristic of Pyribenzamine.

The time required to extract $ 50 of the Pyribenzamine is 2 hours, 4 hours, 6 1/2 hours, respectively, according to the application. 1, 2 and 3 obtained samples. This illustrates the adaptability of the diffusion rate of the products produced. In comparison, a material sample of the same thickness as used in e.g. 4 a 50 $ 1 s drug release in less than an hour.

Application Examples 5 and 6.

The procedure of Example 1 is repeated except that the isocyanate end-saturated polytetramethylene oxide has a molecular weight of 600 (ADIPRENE L-315) and is used at concentrations of 20% by weight for example. 5 and 40% by weight for e.g. S, which dissolves $ 3.7 dexamethasone, a synthetic steroid hormone, in

27 DK 152740 B

each charge immediately prior to polymerization.

Comparative Example 2.

The method according to e.g. 1 is repeated except that 3.7 $ dexamethasone is dissolved in the monomer mixture immediately prior to polymerization.

Foil samples of approximately the same thickness obtained according to e.g. 5 and 6, extracted in water at 25 ° C for 240 hours. The amount of drug extracted from each film is measured during the process at various hot spots with a Beckman Acta III ultraviolet spectrophotometer by determining the amplitude of the characteristic absorption peak for dexamethasone in the solution at 242 nm.

It turned out that more than $ 95 of it originally in a material sample according to e.g. 2 dissolved steroids are extracted over 140 hours, while at the same time only $ 33 of it is dissolved in the sample according to e.g. 5 enclosed drug and only $ 12 of the steroid from the sample according to Example 1. 6 illustrating the valuable utility of the long-term release of the water-insoluble material obtained by the present invention.

Example. 23rd

To 150 g of N-vinylpyrrolidone are added 200 g of isocyanate end-saturated polytetramethylene oxide (molecular weight 3000) and 50 g of 2-hydroxyethyl methacrylate. The solution is stirred at 25 ° C in an inert atmosphere for one week. At the end of this time, the termination of the reaction between diisocyanate and HEMA is confirmed by the disappearance of the NCO band in the infrared spectrum of the final product. This is stored and serves as the starting material for the preparation methods of Examples 24 to 36.

Example 24.

20.0 g of the starting material of Example 23 are mixed with (sufficient) tert.butyl peroctate catalyst (to bring the final concentration of the catalyst to 0.4% by weight). The mixture is placed 28

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in a closed mold to produce a film of 1 mm * s thickness. The mold is placed in a hot air oven to complete the polymerization at 50 ° C for two hours. The polymer film is removed from the mold and exposed for 1 hour at a temperature of $ 0 ° C in a vacuum of 0.1 mm. The product is a clear, tough foil whose swelling rate is determined.

Example 25

The procedure of Example 24 is repeated except that 1.0 g of HEMA and 4 g of N-vinylpyrrolidone are added before the addition of the peroxide et.

Example 26

The procedure of Example 24 is repeated except that 2.0 g of HEMA and 3.0 g of N-vinylpyrrolidone are added before the peroxide addition.

Example 27

The procedure of Example 24 is repeated except that before the peroxide addition, 4> 0 g of HEMA and 1.0 g of N-VP are added to the starting material (according to Example 24).

Example 28.

The procedure of Example 24 is repeated except that 5.0 g of HEMA is added before the peroxide addition.

Example 29.

The procedure of Example 24 is repeated except that 3.0 g of N-VP and 27.0 g of HEMA are mixed before the peroxide addition.

Example 30.

The procedure of Example 24 is repeated except that 24.0 g of HEMA and 6.0 g of N-VP are added before the peroxide addition.

Example 31.

29 DK 152740 B

The procedure of Example 24 is repeated except that 15.0 g of HEMA and 15.0 g of N-VP are added before the peroxide addition.

Example 32.

The procedure of Example 24 is repeated except that 5.0 g N-VP and 25.0 g HEMA are pre-mixed before the peroxide addition.

Example 33

The procedure of Example 24 is repeated except that 3.53 g of ethyl acrylate is added before the peroxide addition.

Example 34.

The procedure of Example 24 is repeated except that 6.67 g of ethyl acrylate is added before the peroxide addition.

Example 35.

The procedure of Example 24 is repeated except that 10.7 g of ethyl acrylate are mixed before the peroxide addition.

Example 3f.

The procedure of Example 24 is repeated except that 20.0 g of ethyl acrylate is added before the peroxide addition.

The composition and swelling rate of the gels of Examples 24 to 36 are summarized in Table VI.

Table VI

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Ex. Macromer (B) fo Monomer (A) fo Swelling ADIPRENE L-42 + HEMA As Ai grade

NYP + HEMA EA

Sam. ex 1 - - 98.5 52 24 54 37.5 8.5 - 26 25 43.2 46 11, S - 71 26 43.2 42 14.8 - 60 27 43.2 34 22, S - 50 28 43.2 30 26.8 - 41 29 21.6 69 9.4 - 173 30 21.6 63 15.4 - 153 31 21.6 45 33.4 - 93 32 21.6 25 53.4 - 55 33 39.1 31.9 7.2 15 82 34 34.5 28.1 6.4 25 71 35 22.4 24.4 5.5 35 56 36 23 18.8 4.2 50 28

Application Example 7.

The polymer product of Example 5 is cut into slices having a diameter of 2.5 mm and a thickness of 1.0 mm. 5.8 g of these small slices are suspended for 48 hours at room temperature with stirring in a solution of 30% by weight Pyribenzamine · H01 in water. The final weight of the swollen slices is 9.6 g. content of $ 15.3 in the polymer.

The sample dispenses in an artificial gastric juice at 37 ° C over 2 hours

31 DK 152740B

$ 50 of its drug content and $ 5 $ in 9 hours.

Example 37.

A. Preparation of the Macromeric Ingredient: 2000 parts (1 mole) of polytetramethylene oxide having a molecular weight of 2000 (Polymeg 2000) are melted, poured into a 5 liter three-neck flask and heated for one hour under vacuum to 50 ° C to remove any moisture present. . The vacuum is removed by the supply of dry nitrogen gas and the contents of the flask are cooled to 40 ° C. 444 * 6 parts (2 moles) of isophorone diisocyanate and 1 g of triethylamine are added, raising the temperature to $ 0 ° C. After reducing the isocyanate content after 5 hours to approx. 3 * 5 $ (the determination was done by titration), the reaction mixture is cooled to 40 ° C and then 1363 parts of HEMA (2-hydroxyethyl methacrylate) and 0.24 g of dibutyltin dilaurate (DBTL) are added. The reaction mixture is allowed to cool to room temperature with stirring in a nitrogen atmosphere until complete removal of the residue isocyanate (IR).

B. Preparation of Crosslinked Hydrophilic Polymers:

The macromeric starting compound prepared according to A) is used to prepare monomer-macromeric mixtures of the following composition by the addition of either more HEMA or NVP:

composition

Example 37 Macromer ($) HEMA ($) NVP ($) a 6S 32 b 45 55 c 34 66 d 11 e 22 53 25 f 22 33 45 g 22 15 63 32

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To each of the obtained monomer-macromer mixtures, 0.2 parts of tert.butyl peroctoate are dissolved and the solutions obtained are injected into glass molds (30 cm x 30 cm) coated with Mylar polyester foils, using of 1.6 mm wide silicone bands as spacers. The polymerization is carried out in a hot air oven at 3 hours heating to 60 ° C and one hour heating to 100 ° C. The molds are taken out, cooled to room temperature, and then the obtained hydrogel films are characterized.

Swelling degree, tensile strength (wet and dry) and extensibility (wet and dry) of the hydrogel obtained according to (a) to (g) are given in the following table:

Example 37 Swelling degree $ Tensile extensibility% dry wet dry wet a 10 2720 1140 170 210 b 20 3460 490 130 l60 c 27 4290 340 110 145 d 47 5910 120 50 120 e 6l 5950 110 56 73 f 96 6620 65 67 60 g 13 $ 7100 24 40 20

Example 38

125.0 g (0.13 mol) of polyoxypropylene, molecular weight 995, is poured into a 500 ml three-neck flask and dried for one hour at 60 ° C / 2 mm Hg.

The vacuum is removed by the addition of dried nitrogen gas and the contents of the flask are cooled to 40 ° C. fertile 55.9 g (0.25 mol) of isophorone diisocyanate and 127 mg of triethylamine are added, raising the reaction temperature to 60 ° C. After hours of reaction time, the isoeyanate content was 5.6 $ (theoretical value = 5, 4I isocyanate). The reaction mixture is cooled to 40 ° C. 172.6 g (1.3 mol) of 2-hydroxyethyl methacrylate (HEMA) are added to 115.2 g of the reaction mixture obtained above, and then 9.6 mg of dibutyltin dilaurate (dibutylbis (lauroyl-oxy) -tin) is added. The reaction mixture is kept at a temperature of 40 ° C until complete disappearance of the residual isocyanate.

Examples 39, 33

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150.0 g (0.074 mol) of polyoxypropylene, molecular weight 2015, is poured into a 500 ml three-neck flask and dried at $ 0 ° C / 2 mm Hg for one hour.

The vacuum is removed by the addition of dried nitrogen gas and the contents of the flask are cooled to 40 ° G. To this is added 33.1 g (0.15 mol) of isophorone diisocyanate and $ 3 mg of 1,4-diazabicyclo [2,2,2] octane (Dabco, 1 mol fo), raising the reaction temperature to $ 0 ° C. After 16 hours of reaction time, the isocyanate content is 3.44% (theoretical value = 3.42% isocyanate). The reaction mixture is cooled to 40 ° C. 179.3 g (1.4 mole) of 2-hydroxyethyl methacrylate (HEMA) are added to 119.5 g of the above reaction mixture and 190 mg of dibutyltin dilaurate is added. The reaction mixture is kept at a temperature of 40 ° G until complete disappearance of the residual isocyanate.

Example 40.

143.9 g (0.50 mol) of polyoxypropylene, molecular weight $ 237, is poured into a 500 ml three-neck flask and dried at $ 0 ° C / 2 mm Hg for one hour.

The vacuum is removed by the addition of dried nitrogen gas and the contents of the flask are cooled to 40 ° C. To this is added 22.2 g (0.10 mole) of isophorone diisocyanate and 56 mg of 1,4-diazabicyclo [2,2,2] octane (Dabco, 1 mole fo), raising the reaction temperature to $ 0 ° C. After 12 hours of reaction time, the isocyanate content is 2.44% (theoretical value = 2.53 fo isocyanate). The reaction mixture is cooled to 101 ° C. 30 $, 0 g (2.37 mol) of 2-hydroxyethyl methacrylate (HEMA) is added to 205.3 g of the reaction mixture obtained above and 17 mg of dibutyltin dilaurate (dibutylbis- (lauroyloxy) -tin) is added. The reaction mixture is kept at a temperature of 40 ° C until complete disappearance of the residual isocyanate.

Example 41.

145.9 g (0.074 mol) of a molten polyester diol, molecular weight 1965, is poured into a 500 ml three-neck flask and dried at $ 0 ° C / 2 mm Hg for one hour. The vacuum is removed by adding dried nitrogen gas and the contents are cooled to 40 ° C. To this is added 33.0 g (0.15 mole) of isophorone diisocyanate and $ 3 mg of 1,4-diazabicyclo [2,2,2] octane (Dabco) and raise the temperature to $ 0 ° C. After 7 hours of reaction time, the iso-

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34 cyanate content 3, k & l (theoretical value = 3349 isocyanate). The reaction mixture is cooled to 4 ° C · 222.0 g (1.7 mol) of 2-hydroxyethyl methacrylate (HEMA) is added to 14 $ 30 g of the reaction mixture obtained above and 12 mg of dibutyltin dilaurate is added. The reaction mixture is kept at a temperature of 40 ° C until complete disappearance of the residual isocyanate.

Example 42

To 50.0 g of each of the reaction mixtures (compounds) obtained in Examples 38 to 41 is added 0.1 g of tert.butyl peroctate which is dissolved with stirring. The resulting mixture is degassed at room temperature in a vacuum of 1 mm Hg until no rising blisters can be observed, and then poured into a glass mold coated with mylar polyester foil and sealed with 1 mm wide silicone tape. The molds are heated in a hot air oven for 3 hours to $ 0 ° C and then for 1 hour to 100 ° C. The obtained foils are ironed out of the cooled molds and cut into samples for analysis and physical testing.

Swelling degree (DS) and tensile strength of the hydrogels obtained according to Examples 38 to 41 are given in the following table.

Example Swelling degree% Tensile strength Extensibility $ dry wet dry wet 38 20 39 ^ 0 433 39 hl 39 22 3730 230 112 l80 40 29 3600 250 113 126 41 19 46ΟΟ 656 131 191

Application Example 8.

The reaction mixture obtained according to Example 37 d) is polymerized into foils having a thickness of 0.5 to 1.5 mm. The films are washed in flowing water at a temperature of 40 ° C for 3 days. Of these films, tablets of different diameters are cut in wet condition. After drying at 80 ° C in vacuo, tablets having a diameter of 1.2 to 4 * 0 mm are obtained.

Application Example 9.

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Bones of Example 37 c) obtained reaction mixture are polymerized analogously to e.g. 8, and the resulting film is ground in a multi-particle comminuting machine with different average diameters. Pieces of particles are then washed in flowing water for 3 days at 40 ° C, dried, and the particles are classified into the various particle sizes using a set of standard sieves with openings between 0.1 $ and 2.4 mm. All particles having a diameter smaller than 0.1 mm are discarded.

Application Example 10.

A tablet is selected from those according to e.g. 8 obtained tablets and allowed to swell in a Ιβ% fs aqueous solution of tripelennamine hydrochloride (2- [benzyl (2-dimethylaminoethyl) -amino] -pyridine) for a period of $ 4 hours. Afterwards, the tablet is swirled in water and dried until a constant weight is obtained. The weight gain of the tablet shows that 30.7% of tripelennamine hydrochloride is taken up as the last component. The thickness of this specimen increased to 1.9 mm. The tablet containing 37.2 mg of tripelennamine hydrochloride is added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° C. Bone released amount of drug is measured spectrophotometrically as a function of time. The course of the release is such that 23% of the total drug content is released in half an hour, 30% after 2.2 hours, 73%> after 5.5 hours and 90%> after 10.5 hours.

Application Example 11.

The particles which, according to e.g. 9 has an average diameter of 1.4 mm, is allowed to swell in a 40 $ Ts aqueous tripelennamine hydrochloride solution for a period of 48 hours. Then, the particles are thrown in water and dried until a constant weight is obtained. The weight gain of the particles shows that, as a final component, $ 17.5 tripelennamine hydrochloride is taken up. An amount of the particles corresponding to 30 mg of the active component is weighed into a rapidly dissolving capsule and added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° C. Bone released amount of drug is measured spectrophotometrically as a function of time. The course of the liberation 36

DK 152740B

Thus, $ 25 of total drug content is released after 0.17 hours, $ 50 after 0.8l hours, $ 75 after 2.9 hours, and $ 90 after 7 hours.

Application Example 12.

The particles which, according to e.g. 9 has an average diameter of 1.7 mm, is allowed to swell in a 22 $ 1 s solution of phenformin hydrochloride for a period of 4 hours. As the solvent system, an ethanol-water mixture (3: 1) is used. After drying, by weight gain, it is found that the drug uptake amounts to a total of 10 $ phenformin hydrochloride. An amount of the particles corresponding to 50 mg of the active component is weighed into a rapidly dissolving capsule and added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° G. The amount of drug released is measured spectrally photometrically as a function of time. The course of release is such that $ 25 of total drug content is released after 0.75 hours, $ 50 after 2.25 hours, $ 75 after 5 hours and $ 90 after 9 hours.

Application Example 13.

*

A tablet is selected from those according to e.g. 8 tablets were obtained and allowed to swell in a 30 $ aqueous solution of imipramine hydrochloride for 72 hours. After drying, the tablet is found to have a thickness of 0.75 mm and the weight gain indicates that a total drug uptake of 33 µm of imipramine hydrochloride has occurred. The tablet containing 50 mg of imipramine hydrochloride is added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° C. The released amount of the drug is determined spectrally photometrically as a function of time. The course of release is such that $ 25 of total drug content is released after 1 hour, $ 50 after 2.5 hours, $ 75 after 5 hours and $ 90 after 8.75 hours.

Application Example 14.

The particles which, according to e.g. 9 has an average diameter of 0.425 mm, is allowed to swell in a 50 $ fs solution of sulfin-pyrazone in chloroform for a period of $ 4 hours. These particles are washed

37 DK 152740B

in flowing water and dried until constant weight is obtained. The weight gain of the polymer particles shows that as the last component, $ 10.3 sulfin pyrazone is taken up. An amount of the particles corresponding to 11.7 mg of the active component is weighed into a rapidly dissolving capsule and added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° C. The amount of sulfin pyrazone released is determined spectrally photometrically as a function of time. The course of release is such that $ 25 of total drug content is released after 0.21 hours, $ 50 after 1.20 hours, $ 75 after 4> 94 hours, and $ 90 after 10.20 hours.

Application Example 15.

A tablet is selected from among those of use. 8 'tablets obtained and allowed to swell in a 21 $ * aqueous solution of hydralazine. The hydralazin solution is prepared by dissolving 10 g of hydralazine hydrochloride in 2 L sodium hydroxide solution until complete dissolution to obtain a pH of S. The adsorption of the tablet is continued for 72 hours. After drying, the weight gain indicates that $ 10.7 of hydralazine is taken up as the last component. The tablet containing 11 mg of hydralazine is added to an amount of 1 liter of artificial gastric juice with a temperature of 37 ° 0. The amount of hydralazine released is determined spectrally photometrically as a function of time. The course of release is such that $ 25 of total drug content is released after 0.53 hours, $ 50 after 3> 33 hours, $ 75 after 7> 07 hours, and $ 90 after 13.3 hours.

Application Example 16.

The particles which, according to e.g. 9 has an average diameter of 1.4 mm, is allowed to swell in a 21 $ fs aqueous solution of hydralazine. The hydralazine solution is prepared as described in e.g. 15. The adsorption of the tablet is continued for 72 hours. After drying, the weight gain indicates that as a last component 4> 2 $ hydralazine is taken up. An amount of particles corresponding to 20 mg of active substance is weighed into a rapidly dissolving capsule and added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° C. The amount of hydralazine released is determined spectrophotometrically as a function of it. The process of release is such that $ 25 of total physician-

38 DK 152740B

the mean content is released after 0.2 hours, $ 50 after 0.86 hours, $ 75 after 2.50 hours, and $ 90 after 4.94 hours.

Application Example 17.

The particles which, according to e.g. 9 has an average diameter of 0.7 mm, is allowed to swell in a 22 $ * s solution of maprotiline hydrochloride. The solution is prepared by dissolving 10 g of maprotiline hydrochloride in 45 g of a methanol / chloroform mixture (33:67). Adsorption is continued for 46 hours. After soaking in water and drying for approx. At 16 hours, the weight gain indicates that as a last component $ 12.8 of maprotiline hydrochloride is taken up. Weigh a quantity of particles corresponding to 90 mg of the active substance into a rapidly dissolving capsule and add to an amount of 1 liter artificial gastric juice with a temperature of 37 ° G. The amount of maprotiline hydrochloride released is determined spectrophotometrically as a function of time. The process of release is such that $ 25 of total dose is released within 0.67 hours, $ 50 over 3.67 hours, $ 75 over 13.4 hours, and $ 90 over 23.4 hours .

Application Example 18.

The particles which, according to e.g. 9 bar, an average diameter of 1.7 mm, is allowed to swell in a solution of methylphenidate hydrochloride for 48 hours for 48 hours. A solution of methanol / water is used as a solution system (27:73). At 16 hours, the weight gain shows that as a last compound, $ 26.7 methylphenidate hydrochloride is taken up. An amount of particles corresponding to 270 mg of the active substance is weighed into a rapidly dissolving capsule and added to a quantity of 0.5 liters of artificial gastric juice with a temperature of 37 ° C. The amount of methylphenidate hydrochloride released is determined spectrally photometrically as a function of time. The process of release is such that $ 25 of total dose is released within 0.67 hours, $ 50 over 3.0 hours, $ 75 over 7.8 hours, and $ 90 over 14.2 hours .

Application Example 19.

15 g of the monomer-macrorner mixture described in Example 37 c)

39 DK 152740B

are mixed with the following compounds listed below. To this mixture is added 0.08 g of tert.butyl peroctate and the resulting solution or dispersion is sprayed with Mylar polyester film coated glass molds (30 x 30 cm) which are 1.4 mm thick and sealed with silicone tape. The polymerization is carried out in a hot air oven at 3 hours heating to $ 0 ° C and 1 hour heating to 100 ° G. After cooling, the sample films are taken out and used for diffusion measurements.

Active substances

Example.19 Code Quantity ig Product appearance a A 15 Transparent, yellow, flexible layer b B 15 transparent, white, flexible layer c C 13 cloudy, yellow, hard foil d D 15 transparent, amber, flexible layer e E 10 transparent , white, hard foil f F 3.3 cloudy, almost white, hard foil g G 3j $ semi-transparent, yellow, hard foil H H 5.0 fuzzy, white, hard foil $ 11 transparent, yellow, hard layer

Explanation of the code: A Ethyl AA-dichlorobenzylate (miticide, acaricide) B 0 - [$ - Chloro-1- (1-methylethyl) -1H-1,2,4-triazol-3-yl] - 0.0- diethyl phosphorothioate (insecticide) C 2,6-Dimethyl-NP-methoxyethyl chloroacetanilide (herbicide) D NT- (4-Chloro-o-tolyl) -N, N-dimethylformamidine (insecticide) E 0.0-Methyl phosphorodithioate S-ester with 4- (mercaptomethyl) -2-methoxy-A-1,3A-thiadiazolin-5-one (insecticide) F 2- [4-Chloro-6- (cyclopropylamino) -1,3, $ - triazine 2-yl-amino] -2-methylpropannitrile (herbicide) G S - [(6-Chloro-2-oxooxazolo (4, $ - b) pyridin-3 (2H) -yl] ethyl) -0,0-dimethyl phosphorothioate (insecticide)

40 DK 152740 B

Explanation of the code cont.

H 2- (tert.Butylamino) -4- (ethylamino) -6- (methylthio) -s-triazine (herbicide) 1.0 O-Diethyl-O- (2-isopropyl-6-methyl-4-pyrimidinyl) - phosphorothioate (insecticide, nematodicide).

Application Example 20.

15 g of the monomer-macromer mixture described in Example 37 'f) are mixed with the following compounds listed below. To this mixture is added 0.0S g of tert.butyl peroctoate and the resulting solution is degassed and sprayed with glass (30 x 30 cm) Mylar polyester film coated molds, which are 1.4 mm thick and sealed with silicone tape. The polymerization is carried out in a hot air oven at 3 hours heating to 50 ° C and 1 hour heating to 100 ° G. After cooling the molds, the samples are taken and used for diffusion measurements.

River> Active substance ex 20 Code Quantity in g Product appearance a K 10 Unclear, white, hard foil b L 1.7. transparent, yellow, expandable foils c M 3j8 white, hazy, hard foils

Explanation of the code: K Disodium zinc-ethylenediamine tetraacetate dihydrate (zinc preparation) 1 3-Methyl-5-methylsulfonyl-1,2,4-thiadiazole (fungicide) M 2-Chloro-4,6-bis (ethylamino) -s-triazine (herbicide) ).

Application Example 21.

9, $ 9 g of a hydrophilic polymer prepared as described in Example 37 b is immersed in 20 g of N- (cyclopropylmethyl) -α, α, α-trifluoro-2,6-dinitro-N-propyl-β-toluidine (a herbicide) for 5 days. Then it is removed

41 DK 152740B

polymers, washed with methanol, dried in air and weighed. The dried polymer weighs 11.22 g, which is similar in composition to one containing $ 11.8 active substance.

By analogy, the polymers described in Example 37 (e) are immersed in a 5 $ fs solution of sodium iron ethylenediamine di- [o-hydroxyphenyl acetate] (an iron preparation) in methanol. The dried polymer contains 15 $ active substance.

Application Example 22.

Diffusion measurements are performed at a temperature of 25 ° C in water buffered with secondary sodium citrate (pH = 5) by dipping a sample of the delivery system as indicated in the table into 1 liter of the stirred buffer solution. Measured amounts are sampled periodically and the amount of the total active substance released by polymers is determined by spectral tomometry.

Anv.eks. 19 Number of hours needed for release 25 $ 50 $ 75 $ 90 $ a 60 b 3.0 7.5 18.0 30.0 e 4.2 16.5 50.0 170.0 h 9.0 35.0 120.0 300.0 in 12.0 48.0 72.0 72.0

Application Example 23.

The appliance according to e.g. (D) the component obtained is comminuted to particle sizes of 0.18 to 0.25 mm and filled into a cylinder through which air is fed at an amount of 20 liters per liter. per minute and at a temperature of 40 ° C. The weight loss is determined gravimetrically and hence the amount of the vaporized active substance is determined. The process of release is such that $ 25 is released after 48 hours, $ 50 after 300 hours, $ 75 after 1050 hours and $ 90 after 2000 hours.

42 DK 152740 B

Application Example 24.

Fragrances (aroma) of known compounds are enclosed in the hydrogel polymer obtained according to process 37 c) by conducting the polymerization in the presence of the following mixtures:

Formulas Fragrances

Syren Rose Lily of the Valley Jasmin Viol Carnation

Phenylethyl alcohol 30 35 15 5 20 25

Hydroxycitronellal 30 - 45 655

Geraniol 2 4 $ 20 2 4.5

Amyl Cinnamaldehyde 42 5 45 1 1

Benzyl Acetate 54 5 40 10 3

Ionone 3 4 5 - 60 4

Eugenol 12 55

Terpineol 25 5 5 2 -2

All fragrances provide clear, transparent (translucent) polymer foils, which in turn deliver the fragrances over a longer period of time.

Example 43

However, the procedure as described in Example 38 is repeated, but instead of hydroxyethyl methacrylate, an equivalent amount of 3-hydroxy-propyl methacrylate is used to prepare the macromer monomer mixture. The polymerization is done as described in Example 42. The resulting film is fracture resistant, flexible and translucent and adsorbs 15 $ water.

(Swelling degree = 15) ·

Application Example 25.

The particles which, according to e.g. 9 has an average diameter of 0.6 mm is allowed to swell in a 20 $ * s solution of chlomipramine hydrochloride. The solution is prepared by dissolving 10 g of chromium pramine hydrochloride in 40.0 ml of water. The absorption is continued for 72 hours. After soaking in water and drying, the weight gain indicates that

43 DK 152 740 B

$ 10.6 of chloromipramine hydrochloride is taken up as a last compound. An amount of the particles corresponding to 45 mg of the active substance is weighed into a rapidly dissolving capsule and added to an amount of 1 liter of artificial gastric juice. The amount of chlomipramine released is determined spectrally photometrically as a function of time. The course of release is such that $ 25 of the total dose is released in 0.5 hours, $ 50 in 2.2 hours, $ 75 in 5.9 hours, and $ 90 in 11.0 hours .

Application Example 26.

The procedure is repeated as described in Example 37 (f), except that the layer thickness of the film produced is 1.15 mm. The film is washed in flowing water for 3 days, and after drying, tablets with a diameter of 1.27 mm are cut.

Application Example 27.

One according to e.g. 26 prepared tablets are selected and allowed to swell in a 20 $ fs aqueous solution of imipramine hydrochloride for 4 $ hours. After drying, it is found that the tablet now has a thickness of 1.44 mm. The weight gain indicates that the total uptake of the active substance is $ 22.6 imipramine hydrochloride. The tablet containing 46.3 mg of imipramine hydrochloride is added to an amount of 1 liter artificial gastric juice with a temperature of 37 ° C. The amount of imipramine hydrochloride released is determined spectrally photometrically as a function of time. The course of release is such that $ 25 of total dose is released within 1, $ hours, $ 50 over 3> 72 hours, $ 75 over 9.40 hours, and $ 90 over 17.3 hours .

Application Example 28.

One according to e.g. 26 tablets prepared are selected and allowed to swell in a 20 $ Ts aqueous solution of chlomipramine hydrochloride for $ 4 hours. After drying, it is found that the tablet has now reached a thickness of 1.36 mm. The weight gain indicates that the total uptake of active substance is $ 19.5 chlomipramine hydrochloride. The tablet containing 37.3 mg of active substance is added to an amount of 1 liter

44 DK 152740 B

artificial gastric juice with a temperature of 37 ° G. The amount of chlomipramine hydrochloride released is determined spectrally photometrically as a function of time. The course of release is such that $ 25 of total dose is released in 1.33 hours, $ 50 in 4.03 hours, $ 75 in 10.2 hours, and $ 90 in $ 1, 7 hours.

Claims (1)

Process for the preparation of a cross-linked water-insoluble hydrophilic copolymer, characterized by reacting A) 30-90% by weight of an a) water-soluble monoolefinic monomer selected from acrylic acid and methacrylic acid, hydroxyalkyl esters and dialkylaminoalkyl esters thereof, wherein the alkyl group contains 2-4 carbon atoms, esters of acrylic acid or methacrylic acid derived from alcohols of the formula H0 - CmH2m - 0 - (CH2 * CH2 °> n 'E where R means hydrogen or methyl, m is 2-5 and n is 1-20, unsubstituted or substituted amides and imides of acrylic acid or methacrylic acid, wherein the nitrogen substituent is hydroxyalkyl, oxaalkyl or dialkylaminoalkyl, wherein the alkyl group contains 2-4 carbon atoms, hydroxyalkyl maleate or fumarates wherein the alkyl group contains 2-4 carbonyl atoms, hydroxy wherein the alkyl group contains 2-4 carbon atoms and monoolefinic derivatives of heterocyclic nitrogen-containing monomers or a mixture of the above or b) a mixture of one or more of the above water-soluble monoolefinic monomers having 1-70% by weight of the same or different water-insoluble monoolefinic monomers selected from acrylonitrile, alkyl acrylates, alkyl methacrylates and alkyl maleate wherein the alkyl group contains not more than 18 carbon atoms , vinyl esters of alkane carboxylic acids having not more than 5 carbon atoms, styrene and vinyl alkyl ethers, wherein the alkyl group contains not more than 5 carbon atoms, having B) 10-70% by weight of a hydrophobic macromer of the formula DK 152740 B 3 2 2 3 h! = f - X - Y - R1 - Y - X - ^ = Ih (B1) or HC - CO, CO - CH) N - R - N ((B2) HC - CO CO - CH wherein R ^ is a polycondensate chain with a molecular weight of 200-8000 containing hydrocarbon groups bonded over ether or ester-2 bonds, R means hydrogen or methyl, R means hydrogen 4 4 or -C00R, where R means hydrogen or an alkyl group having 2 at most 10 carbon atoms, however, at least one of the groups R and R 5 is hydrogen, X is oxygen, -COO- or -CONR wherein R is hydrogen or an alkyl group having no more than 5 carbon atoms and Y is a direct bond or the group is -R®-Z -CO-NH-R 2 -NH-CO-Z 2 - wherein R 2 is bonded to X and represents a branched or linear alkylene group of not more than 7 carbon atoms, Z 2 OC * 7 and Z means oxygen or -NR -, and R represents a bivalent residue of an aliphatic or aromatic diisocyanate, however, when X is 2 3 oxygen, Y is different from a direct bond and R and R are hydrogen in the presence of a catalyst or a free radical system # at a temperature in the range of 40 to 150 ° C.