CH616694A5 - Process for the preparation of crosslinked, water-insoluble, hydrophilic copolymers - Google Patents

Description

The present invention relates to a process for the preparation of crosslinked water-insoluble hydrophilic copolymers which are suitable for use as carriers for medicaments and other active substances; also as hydrophilic membranes for separation processes, as wound dressings, as body implants, e.g. B. artificial veins; as cover layers for glass, metal, wood or ceramic and in particular for use in cases where strength and high water permeability of the polymer article are required at the same time.

It is known to use weakly crosslinked, water-insoluble but hydrophilic polymers as carrier material for biologically active, at least slightly water-soluble substances by copolymerizing a predominant proportion of hydrophilic mono-olefinic monomers and a small proportion, between 0.01 and 15%, based on the called mono-olefinic monomers to produce from a low molecular weight crosslinking agent. Mono-olefinic monomers used are in particular monoesters of acrylic or methacrylic acid with polyfunctional alcohols, such as e.g. Ethylene glycol mono methacrylate, and as a crosslinking agent in particular diesters of the acids mentioned with the alcohols mentioned, such as. B. ethylene glycol bis methacrylate, and the copolymerization is in the presence of water, see US 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. B. Polyethylene oxide mono-methacrylate together with a small amount of the corresponding bis-methacrylate have been described in US Pat. 3,220,960 used as monomers and crosslinking agents. The water-insoluble but hydrophilic copolymers and their production process have been modified in various ways and adapted to special needs, e.g. B. for the production of soft contact lenses (US Pat. No. 3,220,960 and Reissue No. 27,401) and copolymerization in the presence of linear polyamide resin in order to improve or change the mechanical properties of articles formed from polymers thus obtained (US - Patent No. 3 520 949). Nevertheless, low molecular weight polyolefinic crosslinking agents, in particular ethylene glycol bis-methacrylate, were used in all embodiments, in very small to massive amounts which never exceeded 20% of the mono-olefinic monomer content. Although the copolymers of the type described above could be adapted to the various usage requirements, it was not possible to use the mechanical s

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Properties both in the unswollen, i.e. H. anhydrous state as well as in the swollen, d. H. to be satisfactorily adapted to all uses in a state in equilibrium with water

It is known that hydrophilic polymers, the main components of which consist of monoesters of acrylic acid and methacrylic acid and a bifunctional alcohol, have glass transition temperatures or softening points between 55 and 80 ° C. For this reason, state-of-the-art items are brittle and glass-like when dry at temperatures below 55 ° C. After reaching equilibrium in water, the objects mentioned become soft and deformable according to the prior art, but also weak in terms of their bending strength; they also have low tear and shear strength, which makes them sensitive to kinking or other stress. In order to avoid these undesirable disadvantageous properties of the articles manufactured according to the state of the art, they are reinforced by inlays made of stronger polymeric material, or the prepolymerized mixture is filled with an insoluble material such as silica gel. Although these aids increase the toughness (cohesive forces) to a certain extent (because the hydrogel acts as a putty), the articles obtained in this way are susceptible to glassy breakage and to shear fracture in the swollen state in the constrictions (gaps) of these objects when dry . The addition of filler material to the prepolymer also has a disadvantageous effect by changing the diffusion properties and the water permeability of the articles.

Subject of the invention

The present invention relates to the production of crosslinked water-insoluble hydrophilic copolymers with high flexibility and elasticity both in the predominantly anhydrous and in the swollen state, i.e. H. in equilibrium with water or aqueous liquids such as body fluids. These copolymers are suitable for use as hydrophilic membranes for separation processes, as wound dressings, body implants, e.g. B. artificial veins, also as cover layers on glass, metal, wood or ceramic, and as a carrier material for biologically active compounds, for. B. drugs, herbicides, insecticides, fungicides, bacteri-cidc and fragrances.

Another object of the invention is the production of crosslinked hydrophilic copolymers with high tensile strength in the swollen state for the purposes defined above.

It has now been found that water-insoluble hydrophilic copolymers which consist predominantly of a hydrophilic polymer of mono-olefinic monomers which are crosslinked with a predominant proportion of a diolefinic, non-hydrophilic macromere and which can contain a biologically active substance, the above-mentioned and still have other desired properties. In the new copolymers, the level of terminal diolefinic macromers is higher than that of crosslinking agents in the known hydrophilic copolymers and is a major portion of the system with about 10 to about 70% of the hydrophilic polymer or preferably about 15 to about 50% of the same. Said terminal diolefinic non-hydrophilic macromers have a molecular weight between about 400 and about 9600 or preferably between about 600 and 5000.

The present invention comprises a method for producing an insoluble polymeric hydrogel which is suitable as a carrier for medicaments which are administered orally or buccally (through the mouth) or are used in the form of subcutaneous or intramuscular implants. The hydrogels produced according to the invention can also be shaped into body implants, such as artificial veins, devices for insertion into the urethra, vagina or intestinal exit, or they can be used in the form of dressings for the controlled delivery of drugs through the skin. Other forms of application of the new, water-swellable gels are membranes for reverse osmosis or semi-permeable membranes; hydrophilic membranes for separation processes; Dressings for wound treatment; Top layers on glass, metal, wood or ceramic and, more generally, applications where both hydrophilicity and toughness are required at the same time.

The new hydrogels according to the present process according to the invention are prepared, if appropriate in the presence or absence of solvents, by copolymerizing free radicals, a water-soluble monomer which forms a water-soluble or water-swellable polymer, ie. H. a hydrophilic polymer is suitable, with a di-olefinic non-hydrophilic macromers (B), e.g. B. a divinyl compound with a long, linear polycondate-sat chain, such as. B. polytetramethylene ether, with a polymerizable vinyl group terminal on both sides. In this way a three-dimensional macromolecular network is formed, which is composed of two types of segments, each segment contributing its specific physical properties to the entire system. The A segment confers water solubility, the hydrophobic B segment forms the flexible cross-links. By changing the corresponding proportions of each connection, the mechanical and diffusion properties can be varied within a wide range. For example, a polymer with excellent toughness, strength and ductility can be obtained, which can nevertheless absorb approximately its own weight of water; this polymer is available when using the appropriate proportions of A and B. This possibility is not available with known hydrogels,

because their cross-links are short and inelastic, and these hydrogels are hard and brittle when dry.

The incorporation of the bifunctional macromolecule B into the system in a predominant quantitative ratio is novel on the polymers produced according to the invention. In this way, the bifunctional macromere not only serves as a structural crosslinker, but also as a mediator of unique physical properties on the gel.

The hydrophilic polymer is a polymer of one or more water-soluble mono-olefinic monomers or a copolymer of a mono-olefinic water-soluble monomer and at most 70%, preferably at most 50% of the total amount of the monomer, of a 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. B. their hydroxyalkyl esters, e.g. B. 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl or 2,3-dihydroxypropyl ester; furthermore also ethoxylated and polyethoxylated hydroxyalkyl esters, such as esters of alcohols of the formula

HO - CmH2m - O - (CH2-CH20) n - R

wherein R is hydrogen or methyl, m is 2 to 5 and n is 1 to 20, or esters of analog alcohols in which part of the ethylene oxide unit has been replaced by propylene oxide units. Suitable esters are also dialkylaminoalkyl acrylates and methacrylates, such as the 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl and 3- (dimethylamino) -2-hydroxypropyl esters. Another class of suitable derivatives should

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Cher acids are their water-soluble amides, such as the unsubstituted amides and amides substituted by lower hydroxyalkyl, lower oxaalkyl or lower dialkylaminoalkyl groups, such as N- (hydroxymethyl) acrylamides and metha-crylamides,

N- (3-hydroxypropyl) acrylamide,

N- (2-hydroxyethyl) methacrylamide,

N- (l, l-dimethyl-3-oxabutyl) acrylamide,

and N- [l, l-dimethyl-2- (hydroxymethyl) -3-oxabutyl] acrylic-

amide;

water-soluble hydrazine derivatives,

such as B. trialkylamino methacrylimides, e.g. B. trimethylamino methacrylimide and dimethyl (2-hydroxypropyl) amino methacrylimide and the corresponding derivatives of acrylic acid;

mono-olefinic sulfonic acids and their salts, such as sodium ethylene sulfonate,

Sodium styrene sulfonates and 2-acrylamido-2-methylpropanesulfonic acid; N- [2- (DimethyIamino) ethyl] acrylamide and methacrylamide, N- [3- (DimethyIamino) -2-hydroxypropyl] methacrylamide or mono-olefinic derivatives of heterocyclic nitrogen-containing monomers, such as, for. B. N-vinyl pyrrole, N-vinyl succinimide, I-vinyl pyrrolidone, 1-vinyl imidazole, 1-vinyl indole, 2-vinyl imidazole, 4 (5) vinyl imidazole, 2-vinyl -l-methyl-imidazole, 5-vinyl-pyrazoline, 3-methyl-5-isopropenyl-pyrazole, 5-methylene hydantoin, 3-vinyl-2-oxazo-lidone, 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-l-oxide, 3-isopropenyl-pyridine, 2- and 4-vinyl-piperidine, 2- and 4-vinyl-quinoline, 2,4-dimethyl-6-vinyl-s-triazine, 4-acrylyl-morpholine.

These monomers can be used alone or in combination with one another or with other suitable vinyl monomers, which can also be hydrophobic. The proportion of these hydrophobic monomers should not exceed 60% of the total composition, preferably 40%.

Suitable hydrophobic monomers are, for example, water-insoluble olefinic monomers, such as alkyl acrylates or methacrylates, in which alkyl has 1 to 18 C atoms, e.g. B. methyl and ethyl methacrylate or acrylate; vinyl esters derived from alkane carboxylic acids with 1-5 C atoms, e.g. Vinyl acetate, acrylonitrile, styrene and vinyl alkyl ether, in which the alkyl group of the ether chain has 1 to 5 carbon atoms, e.g. B. (methyl, ethyl, propyl, butyl or amyl) vinyl ether.

Water-soluble monomers which require a comonomer for the polymerization are, for example, maleates, fumarates and vinyl ethers; the following monomer combinations can be used for example: di (hydroxyalkyl) maleates, such as. B. di (2-hydroxyethyl) maleate and ethoxylated hydroxyalkyl maleates, hydroxyalkyl monomaleates, such as. B. 2-hydroxyethyl monomaleate and hydroxylated hydroxylalkyl monomaleates with vinyl ethers, vinyl esters, styrene or generally monomers which easily copolymerize with maleates or fumarates; Hydroxyalkyl vinyl ether, such as. B. 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether with maleates, fumarates or generally all monomers that easily copolymerize with vinyl ether.

Hydroxyalkyl acrylates and methacrylates, such as, for example, are particularly valuable as water-soluble monomers. B. 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate, N-vinyl-pyrrolidone, acrylic acid, methacrylic acid and a tertiary amino methacrylimide, e.g. B. Trimethylamino methacrylic 1 imide, as in U.S. Patent No. 3,627,802.

The preferred monomers are 2-hydroxyethyl methacrylate and N-vinyl pyrrolidone.

In the di-olefinic non-hydrophilic macromers B, the olefinic part is preferably an acyl radical of a lower α, β-mono-unsaturated aliphatic monocarboxylic or dicarboxylic acid or a vinyloxy radical. These residues are connected to one another by a macromolecular, non-hydrophilic chain with preferably repeated ester, amide or urethane groups, but in particular ether groups. The molecular weight of the chain is approximately 400 to approximately 9600, but preferably between 600 and 5000, and very particularly between 1500 and 3000. Accordingly, component B preferably corresponds to the formulas

R3 R2 R2 R3

II II

HC = C-X-Y-Ri-Y-X-C = CH (Bi) or

HC-CO. / CO - CH

II N-Ri-N II (B2)

HC-CO 'xCO-CH

wherein Ri is a polycondensate chain with a molecular weight of about 200, means about 8000, which contains hydrocarbon residues bound ether, ester, amide, uretlian or urea residues, R2 is hydrogen, methyl or -CH2-COOR4, wherein R4 is hydrogen or a Alkyl group with up to 10 carbon atoms means R3 is hydrogen or COOR4 with the condition that at least one of the radicals R2 and R3 is hydrogen, X is oxo, -COO- or

-CONR5,

wherein R5 is hydrogen or alkyl having up to 5 carbon atoms and Y is a direct bond or the radical —Rn-Z 1-CO-NH-R7-NH-CO-Z2-, wherein Rr> is bonded to X and a branched one or straight-chain alkylene radical having up to 7 carbon atoms, Zi and Z2 is oxo or

—NRs,

and R7 is the divalent radical of an aliphatic or aromatic diisocyanate, provided that when X is oxo, Y is not a direct bond and R2 and R3 are hydrogen.

In the compounds of the formulas Ri and B2, Ri means in particular a polypropylene oxide or a polytetramethylene oxide chain, but it can also mean a chain derived from dicarboxylic acids, diols, diamines or diisocyanates, which are obtained by known polycondensation processes. The terminal radicals of the compounds of the formula B1 correspond to the definitions of R2 and R3 and if X is -COO- or

-CONR5

means, the acyl radical is derived from acrylic or methacrylic acid or the monoacyl radicals from maleic, fumaric or itaconic acid or from monoalkyl esters of these acids with straight or branched chain alkanols with 1 to

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10 carbon atoms, such as methanol, ethanol, butanol, diisobutyl alcohol or decanol, or if X is oxygen, with the vinyloxy radical of vinyl ethers. Compounds of the formula Bi, in which Y is a direct bond, are diesters of macromolecular diols, in which two hydroxyl groups are bonded to the poly-condensate chain Ri in opposite terminal or nearly terminal positions, with α, β-unsaturated acids. Such diesters can be prepared from the macromolecular diols mentioned by known acylation processes by using reactive functional derivatives of suitable acids, e.g. As acrylic or methacrylic acid chloride, or of monoalkyl esters of maleic, fumaric or itaconic acid can be used. Compounds of the formula B i with the amide group X are diamides obtained from macromolecular diamines by known acylation processes, for. B. by using the above acid chlorides or anhydrides. The macromolecular diamines are e.g. B. prepared from the corresponding macromolecular diols with twice the molar amount of alkyl enimine, for. B. propyleneimine.

The macromolecular bis-maleic acid acids are obtained according to the above-described reaction by using maleic anhydride as an acylating agent for macromolecular diamines with heating or reaction with dehydrating agents to produce macromolecular bis-maleimido compounds of the formula B2. In these compounds, Ri z. B. be one of the macromolecular polycondensate chains, which are mentioned as components of the compounds according to formula Bi.

According to the definition of formula Bi, Y can furthermore mean a divalent radical -R6-Z1-CONH-R7-NH-CO-Z1. In it is Rô z. B. methylene, propylene, trimethylene, tetramethylene, pentamethylene, neopentylene (2,2-dimethyltrimethylene), 2-hydroxytrimethylene, l, l-dimethyl-2- (l-oxo-ethyl) -trimethylene or l- (dimethyleneaminomethyl) -ethylene and especially ethylene. The divalent radical R7 is derived from an organic diisocyanate and is an aliphatic radical such as alkylene, e.g. B. ethylene, tetramethylene, hexamethylene, 2,2,4-trimethylhexamethylene, 2,4,4-trimethylhexamethylene, fumaroyldiethylene or 1-carboxypentamethylene; a cycloaliphatic radical, e.g. B. 1,4-cyclohexylene or 2-methyl-1,4-cyclohexylene; an aromatic radical, such as m-phenylene, p-phenylene, 2-methyl-m-phenylene, 1,2-, 1,3-, 1,5-, 1,6-, 1,7-, 1,8- , 2,3- and 2,7-naphthylene, 4-chloro-l, 2- and 4-chloro-l, 8-napthylene, l-methyl-2,4-, l-methyl-2,7-, 4 -Methyl-l, 2-, 6-methyl-1,3- and 7-methyl-l, 3-naphthylene, l, 8-dinitro-2,7-naphthylene, 4m4'-diphenylene, 3,3'-dichloro -4,4 / -diphenylene, 3,3'-dimethoxy-4,4'-diphenylene, 2,2'-dimethyl and 3,3'-dimethyl-4,4'-diphenylene, 2,2-dichloro- 5,5'-dimethoxy-4,4-diphenylene, methylene-di-p-phenylene, methylene-bis- (3-chlorophenylene), ethylenedi-p-phenylene or hydroxydiphenylene.

If the symbol Y in the formula part B1 is not a direct bond, Rs must always be connected to X.

There are therefore compounds of the formula Bi, in which Y is the bivalent radical mentioned, bis-vinyl ether if X is oxygen, or bis-acrylates, bis-methacrylate, bis-maleates, bis-fumarates and bis-itaconates, if X -COO— or

-CONR5

is.

The preferred divinyl macromers B consist of poly-tetramethylene oxide glycols with a molecular weight of about 1000 to about 4000, end-saturated with 2,4-

Toluene diisocyanate and reacted with 2 mol of a 2-hydroxyalkyl acrylate or methacrylate. The macromere of polytetramethyleneoxidiglycol with a molecular weight of approximately 1500 to approximately 3000, end-saturated with 2,4-toluenediisocyanate and reacted with approximately 2 mol of 2-hydroxyethyl methacrylate is particularly valuable.

The new hydrophilic copolymers produced according to the invention are obtained 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 Ai with 10 to 70% macromers of the formula Bi 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 about 40 to about 150 ° C, preferably between about 50 and about 100 ° C.

Compounds of the formula Bi, in which Y is -RG-Z-CONHR7-NH-CO-Z2-, are obtained in a 2-stage reaction by first macromolecular diols or diamines, i.e. H. Compounds which contain two hydroxyl or amino groups in the opposite terminal or almost terminal position bound to the polycondensate chain Ri, are reacted with at least twice the amount of an aliphatic, cyclo-aliphatic or aromatic diisocyanate, the diisocyanate consisting of the radical R7 to which two isocyanate groups are bonded, and in the second reaction stage the macromolecular diiso-eyanates thus obtained with a compound of the formula

R3 R2

I I

HC = C-X-Rô-ZIH (C)

where R2j R3, X, Rä and Zi have the meaning given above (for Bi).

When X is oxygen, (C) is a vinyl ether with active hydrogen, e.g. B. a hydroxyalkyl vinyl ether or an aminoalkyl vinyl ether; if X-COO- or

-CONR5

means, (C) is an acrylate, methacrylate, maleate, fumarate, itaconate or the corresponding amide with active hydrogen in the alkyl group. The macromolecular diol or diamine is preferably used in a slight excess, i.e. H. that the ratio of isocyano groups to hydroxyl or amino groups in the first stage of the macromolecular synthesis should be at least 1: 1, but preferably at least 1: 1.05 or less. If the compound C used in the second reaction stage of the Macromersynthesis is identical to the hydrophilic monomer As, a large excess of this compound can be used, so that the solution of the Macromeren Bi obtained, dissolved or dispersed in the monomer A, directly for the preparation the end product, the hydrophilic copolymer, can be used.

Macromere B is advantageously produced at temperatures in the range between approximately room temperature and approximately 80 ° C. The temperature used is preferably not more than 40 ° C and most preferably in the range between 30-45 ° C. The conversion of the isocyano group is followed by infrared spectroscopy or titration.

Another process for the preparation of the macromer consists in the reaction of a prepolymer with terminal hydroxyl groups, e.g. B. polybutylene or polypropylene oxide, with acryloyl chloride, methacryloyl chloride ormalein5

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reanhydride, whereby a macromer is formed without urethane intermediate, such as B. a macromer of the formula B2 or Bi, wherein Y is a direct bond.

The free radical copolymerization is initiated by means of a catalyst which can generate free peroxy or alkyl radicals in a sufficiently high concentration in order to bring about the polymerization of the vinyl monomer used at the synthesis temperature.

Examples of suitable catalysts are diisopropyl peroxydicarbonate, tert-butyl peroctoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert-butyl peroxyacetate and azoisobutyronitrile. If the polymerization is carried out in water, water-soluble peroxy compounds, such as sodium, potassium or ammonium persulfate, and free radical-generating redox systems, such as persulfate-bisulfite combinations, can be used. The catalyst is advantageously used in an amount of approximately 0.02-1% by weight of the reaction mixture. Other free radical generating systems can also be used, such as gamma rays, electron beams and UV radiation.

The reaction is preferably carried out in an inert or oxygen-free atmosphere, provided open forms are used. It is known that oxygen inhibits polymerization and extends polymerization times until the reaction is complete.

When working with closed molds to form the hydrogel article, the molds must be made of an inert material with low oxygen permeability and good removability. Examples of suitable molding material are Teflon®, silicone rubber, polyethylene and Mylar®. Glass and metallic molds can be used if a suitable mold release agent is used.

The incorporation of the drug into the hydrogel article is accomplished either by dissolving or dispersing it in the macromer solution, the monomer solution, or a mixture of both prior to the addition of the free radical catalyst, or by diffusing the drug into the article obtained after the polymerization. If the drug is not attacked by free radicals, it is advantageous to dissolve or disperse it in the macromer solution, monomer solution, or a mixture of both, prior to polymerization. If the drug is attacked by free radicals, it should be incorporated into the finished article by diffusion from a solution after the polymerization.

The hydrogel system, which mainly consists of the hydrophobic macromeric segment B and the hydrophilic segment Ap, can be of very different compositions, and accordingly the degree of hydrophilicity and mechanical strength can be balanced against one another in such a way that there is a wide variety of possible uses, such as Delivery systems for drugs, insecticides, herbicides, etc., semi-permeable membranes for reverse osmosis, body implants and wound dressings.

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

For applications such as body implants, wound dressings and semi-permeable membranes, hydrophilic membranes that combine a relatively high wet strength with equilibrium water contents of 5-50% are particularly advantageous. For example, subcutaneous and intramuscular implants for regulated drug delivery must be used to a certain extent for water absorption (15-25% by weight)

capable, but on the other hand, when dry and swollen, be firm enough to withstand the insertion and extraction process.

In addition to their suitability as pharmaceutical carriers, the hydrogels produced according to the invention can also be used as carriers for antiseptics, flavors, colorants, nutrients, insecticides, herbicides, etc. The hydrogels obtained according to the invention can in particular be swollen in a suitable solvent which contains the active ingredient to be transferred; the solvent is evaporated, leaving the active ingredient in the hydrogel particles. The active ingredient is released in a uniform manner in contact with an aqueous environment.

For the wide range of their water absorption, strength and elasticity properties, the hydrogels produced according to the invention are particularly suitable for use as intramuscular and subcutaneous implants in warm-blooded animals. For the same reasons, the hydrogels produced according to the invention can be used as a replacement material for blood vessels or extracorporeal connections without a supporting matrix being necessary, as is the case with relatively weak hydrogel materials.

The hydrogel substances produced according to the invention are also suitable for use as hydrophilic and non-thrombogenic surface layers because they adhere strongly to glass, metal and plastic. Because of their high strength and elasticity, they form strong cover layers with high wear resistance and are therefore suitable for covering boat hulls to prevent the growth of shells; or to create cover layers on lenses and glasses that prevent them from fogging up in a humid environment.

Another outstanding property of the hydrogels produced according to the invention is their pliability in the dry state, in which they already assume the shape desired in their application.

A further advantage of the hydrogels produced according to the invention can be seen in the swollen state, insofar as they do not become friable, but retain their strength and elasticity, even if they are in equilibrium (with water) in an aqueous environment. These properties are particularly valuable when using membranes under pressure, such as in reverse osmosis apparatus, for which the hydrogels produced according to the invention are suitable.

Drug-containing hydrogels are also particularly suitable for use in the treatment of open wounds and burns, thanks to their pliability and conformability, combined with the possibility of applying medication directly to the affected Sellien. A particular advantage of the hydro-gel in this type of application is its pliability in the dry state. It is unnecessary to swell the hydrogel before use to make it soft and pliable enough to cover large injured areas (wound areas); for this reason, the drug-containing hydrogel can be stored dry instead of swollen, which increases the shelf life of the drug contained therein.

Any medicinal product for body treatment, applied both locally and systemically, can be incorporated into the copolymer carrier material produced according to the invention as an active substance. The term “medicinal product” is used here in the broadest sense and encompasses any substance or mixture of substances with a pharmacological or biological effect.

The amount of drug to be administered to the carrier depends to a large extent on the particular compound, the desired therapeutic effect and the time5

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span of time needed to release the medicine. There is no critical upper limit for the amount of medicament to be introduced into the carrier, because the diversity of the carriers and their various sizes and shapes should make it possible to build up a whole range of administration forms and dosages for the most diverse diseases. The lower limit will also depend on the effectiveness of the drug and the degree of release from the carrier. There is therefore no need to define a range for the therapeutically effective amount of drug released by the carrier.

In addition to medicinal products, the copolymers produced according to the invention can also contain fragrances or flavors, such as orange oil, citral, coffee, tea, lemon oil, synthetic lemon-lime aroma, strawberry aroma, vanilla, diacetyl, anise, lilac scent, spruce scent, peppermint oil, orchid oil or essence, Anethole, ethylene propionate, ethyl acetate, acetaldehyde, menthol and garden mint, as well as pesticides including bactericides, fungicides, insecticides and nematocides can be incorporated.

The new hydrogels, in particular those containing polyurethanes as macromer components, form a cross between classic hydrogels and polyurethanes due to their superior physical properties in the dry and wet state and are particularly valuable as biomedical plastics with non-thrombogenic properties.

They are therefore particularly suitable for use as artificial skin in the treatment of burns, for the construction of artificial organs or as cover layers for the same. They can also be used as surgical sutures.

The composition of the hydrogels varies from 30 to 90% of component (A) and 10 to 70% macromers (B), with a corresponding degree of swelling of approximately 10 to 250%. The preferred compositions contain about 15-50% macromer (B) and about 50-85% of ingredient (A) and their degree of swelling is between 15 and 120%.

Experimental part 15 After the gel has been prepared, a piece weighing 3 g is cut off, weighed and stored in a bottle with approximately 50 ml of water at room temperature. After 96 hours, the swollen sample is removed, the excess surface water is removed with filter paper and weighed again in order to determine the degree of swelling (DS). 6 test strips are punched out of the remaining hydrogel film, 3 of which are left to swell in water until the equilibrium water content is reached. The tensile strength and elongation of the dry and wet samples are determined in an Instron testing machine according to ASM test method D-638 using a type IV test strip.

Degree of swelling DS =

Gew. D. wet pattern - Gew. d. dry pattern ^ qq

Weight of the dry sample

In the following examples, the term “polytetramethylene oxide reacted terminally with isocyanate” (polytetramethylene oxide saturated with isocyanate) means a polytetramethylene oxide chain which was reacted at both ends with 2,4-toluene diisocyanate. These compounds can be easily prepared and are also commercially available from DuPont de Nemours Chemical Comp., Wilming-ton, Del., Under the trade name "ADIPRENE".

The first seven examples show the influence of changing amounts of macromeric, hydrophobic crosslinking agent on the physical properties of polyhydroxyethyl methacrylate gels and their production. A: 2-hydroxyethyl methacrylate (HEMA)

B: Polytetramethylene oxide + HEMA reacted with isocyanate at the end

example 1

20 g of an isocyanate-reacted polytetra-methylene oxide of molecular weight 1500 (ADIPRENE 167) are dissolved in 18 g of 2-hydroxyethyl methacrylate and reacted for 72 hours at room temperature. After 72 hours, the disappearance of all of the isocyanate is confirmed by noting the lack of the characteristic infrared band of isocyanate at 2270 cm- 'in the infrared spectrum. After the addition of 0.08 g of diisopropyl percarbonate, this mixture is then injected into a casting mold for foils of 1 mm thickness and kept in a rotary oven at 60 ° C. for 2 hours. The solid, transparent film obtained is placed in water for 2 days and then dried in vacuo at 80 ° C. The equilibrium water content, the tensile strength and elongation in the dry and moist state are measured.

Example 2

The procedure of Example 1 is repeated with the exception that 2.0 g of polytetramethylene oxide of molecular weight 3000 (ADIPRENE L-42) which has been terminally reacted with isocyanate are used. A tough, transparent film is obtained which is tested after soaking in water for 2 days and then drying in vacuo at 80 ° C. as described in example 35.

Example 3

The process according to Example 1 is carried out using 5.0 g of ADIPRENE 167 (molecular weight 1500) and 15.5 g of 2-hydroxy-40 ethyl methacrylate. The product obtained is a tough, transparent film which is treated as described in Example 1.

Example 4

45 The procedure according to Example 1 is repeated, but the composition of the reaction mixture is changed to 10.0 g ADIPRENE 167 (molecular weight 1500) and 10.0 g 2-hydroxyethyl methacrylate. A tough, transparent film is obtained and treated as described in Example 1.

Example 5

The procedure according to Example 2 is repeated with a changed composition of the reaction mixture by reacting 55 5.0 ADIPRENE L-42 (molecular weight 3000) and 15.0 g 2-hydroxyethyl methacrylate. A tough, transparent film is obtained and treated as in Example 1.

Example 6

60 The procedure according to Example 2 is repeated with the mixture of 10.0 g of ADIPRENE L-42 (mol. Wt. 3000) and 10.0 g of 2-hydroxyethyl methacrylate. A tough, transparent film is obtained, treated and tested as in Example 1.

65

Example 7

As a control, a conventional poly (2-hydroxyethyl) methacrylate gel is produced, starting from 1.2% ethylene glycol

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dimethacrylate as a crosslinking agent; otherwise the same procedure is used as for the gels previously described.

A hard, brittle, transparent sheet is obtained which is treated and tested in the same way as described above.

Table 1 shows a decreasing degree of swelling with increasing amount of the hydrophobic macromere B. The tensile

Table

Macromeric Monomeric Tensile Strain Elongation (B)% (As) dry moist

ADIPRENE *

HEMA

HEMA%

DS

1

L-167:

11.6

88.4

52

4560/41

185/99

2nd

L-42:

10.8

89.2

42

5343/39

150/108

3rd

L-167:

29

71

22

4760/89

409/113

4th

L-167:

58

42

12

4123/144

1055/150

5

L-42:

27th

73

30th

4453/120

258/95

6

L-42:

54

46

20th

3167/246

557/214

7

98.5

45

2320/15

69/83

* ADIPRENEL-167: MW = 1500

* ADIPRENE L-42: NW = 3000

Stability in the dry state of the products according to Example 1-6 is higher than with the conventional poly-HEMA according to Example 7. The tensile strength in the moist state and the elongation in the dry and moist state increase with increasing amount 5 of B.

The following examples show the usability of N-vinylpyrrolidone as hydrophilic monomer (A) and the use of hydrophobic comonomers for adaptation: the equilibrium water content.

Examples 8-12

30 g of a polytetramethylene oxide, end-saturated with isocyanate, of molecular weight 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 monomer are added:

Example 8: N-vinyl pyrrolidone (NVP)

Example 9: Ethyl Acrylate (EA)

Example 10: Dimethyl maleate (DMM)

Example 11: Vinyl acetate (VA)

Example 12: Ethyl Acrylate (EA)

0.1 g butyl peroctoate is added to each of the five mixtures and the solutions are poured into a casting mold for foils 1 mm thick. It is reacted at 80 ° C for two hours, removed from the mold and kept at 100 ° C for 15 hours in a vacuum of 0.25 mm. The films produced in this way are clear and tough and their degree of swelling was determined as follows (see Table II).

Table II

At

Macromeres (B)%

Monomeric

System (A)

game

ADIPRENE L-42 +

% +% (A)

% (Ai)

DS

HEMA

NVP + HEMA

Comonomer

8th

32.4

60 + 7.6

-

101

9

32.4

40 + 7.6

EA: 20

75

10th

32.4

40 + 7.6

DMM: 20

78

11

32.4

40 + 7.6

VA: 20

91

12

22.6

29 + 5.4

EA: 43

42

In the following two examples, the macromere (B) is a bis-vinyl ether (Example 12) and a bis-maleate (Example 14).

Example 13

According to the process described in Examples 8-12, 30 g of isocyanate-end-saturated polytetramethylene oxide (MW: 3000) and 10 g of hydroxybutyl vinyl ether (HBVE) are reacted in 30 g of N-vinylpyrrolidone until all free isocyanate has disappeared. 30 g of ethyl acrylate and 0.4 g of tert-butyl peroctoate are then added to the mixture. The mixture is placed in film casting molds and after two hours at 80 ° C. the crosslinked films are removed from the mold and kept for 16 hours in a vacuum oven (0.25 mmHg) at 100 ° C. The pattern is a tough,

55

clear sheet, the degree of swelling of which was determined (see Table III).

Example 14

According to the procedure described in Examples 8-11, 40 g of isocyanate-end-saturated polytetramethylene oxide (MW: 3000) and 10 g of 3-hydroxypropyl-butyl-maleate (HPBM) are reacted in 50 g of N-vinylpyrrolidone until all free isocyanate has been removed. 0.4 g of tert-butyl peroctoate are then added to the mixture. The mixture is placed in film casting molds and exposed for 2 hours at a temperature of 80 ° C. The crosslinked film is removed from the mold and kept at 100 ° C. for 16 hours (0.25 mmHg). The pattern is a tough, clear sheet whose degree of swelling was determined (see Table III).

Table III

Example Macromeres (B)%

ADIPRENE + Terminal% As L-42 Monomer NVP + HBVE

Monomer system (A)

% Aj

HPBM comonomers

DS

13

14

32.4 43.1

HB VE HPBM

30 + 7.6 50 + -

30th

6.9

72 89

9

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In the following examples, the macromeric crosslinking agent contains linear polyesters and polypropylene oxide chains.

Examples 15-17

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

Example 15: 15 g of polyester diisocyanate + 85 g of HEMA io

Example 16: 25 g polyester diisocyanate +75 g HEMA Example 17: 40 g polyester diisocyanate + 60 g HEMA

The mixtures are left to stand at room temperature for 72 hours; after this time, all of the isocyanate 15 has been converted. 0.4 g of tert-butyl peroctoate is added to each of the batches and the same is then placed in 1 mm thick film casting molds. The specimens are heated to 80 ° C for two hours, removed from the molds and exposed to a temperature of 100 ° C for 16 hours in a vacuum oven (0.25 mmHg). The translucent foils are tough and flexible; their degree of swelling is shown in Table IV.

Table IV

example

% Macromeres (B)

Polyester (E-410) + HEMA

Monomer (A)%

HEMA

DS

15

April 23

76.6

30th

16

39

61

21st

17th

62

38

21st

Examples 18-19 35

A bis-maleimide-type macromer (B) of molecular weight approx. 2200 (polypropylene oxide-bis-maleimide) obtained by reacting 2 moles of maleic anhydride with one mole of polypropylene oxide, end-saturated with primary amino groups, is mixed in two amounts in 2-hydroxyethyl methacrylate "Relations dissolved:

Example 18: 20% polypropylene oxide bis-maleimide (80% HEMA) Example 19: 35% polypropylene oxide bis-maleimide (65% HEMA)

45

0.1% tert-butyl peroctoate is added and the solutions are reacted in foil molds at 80 ° C for 2 hours; the foils are removed and kept in a vacuum oven (0.25 mmHg) at 100 ° C for 16 hours; afterwards they are tough and supple; Their degree of swelling is shown in Table V.

Table V

example

Macromeres (B)

Monomer (A)

DS

%

%

Polypropylene oxide-bis-maleimide

HEMA

18th

20th

80

44

19th

35

65

33

60

Example 20

53.0 g of polypropylene oxide bis-maleimide according to Examples 18 and 19 are dissolved in 47.0 g of N-vinylpyrrolidone; After adding 0.4 g of tert-butyl peroctoate, the mixture is poured into 65 molds and reacted as described in Example 18. A tough, slightly brown colored gel is obtained which absorbs 46.0% of its weight in water (DS = 46.5).

Example 21

59.8 g of polypropylene oxide bis-maleimide according to Examples 18 and 19 are dissolved in 27.1 g of N-vinylpyrrolidone and 13.0 of ethyl acrylate; After adding 0.4 g of tert-butyl peroctoate, the mixture is filled into molds and reacted as described in Example 18. The gel forms a tough, very slightly yellowish film that absorbs 26.5% of its weight in water (DS = 26.5).

Example 22

Example 21 is repeated, but with amounts of 3.10 g of N-vinylpyrrolidone and 26.4 g of ethyl acrylate. The product obtained is a tough, colorless gel which absorbs 23.0% of its weight in water (DS = 23.0).

Example 23

Example 21 is repeated, but with amounts of 27.1 g of N-vinylpyrrolidone and 43.5 g of ethyl acrylate. The gel obtained is tough and colorless, it absorbs 15.8% of a weight of water (DS = 15.8).

Example 24

200 g of isocyanate-end-saturated polytetramethylene oxide (MW 3000) and 50 g of 2-hydroxyethyl methacrylate are added to 150 g of N-vinylpyrrolidone. The solution is stirred at 25 ° C in an inert atmosphere for one week. At the end of this time, the completion of the reaction between diisocyanate and HEMA is confirmed by determining the disappearance of the NCO band in the infrared spectrum of the end product. This is stored and serves as the starting material for the manufacturing processes according to Examples 25-37.

Example 25

20.0 g of the starting material according to Example 24 are mixed with (sufficient) tert-butyl peroctoate catalyst (in order to bring the final concentration of catalyst to 0.4% by weight). The mixture is placed in a closed mold to produce a film 1 mm thick. The mold is placed in a hot air oven to complete the polymerization at 80 ° C for 2 hours. The polymer film is removed from the mold and exposed to a temperature of 80 ° C under a vacuum of 0.1 mm for 18 hours. The product is a clear, tough film whose degree of swelling is determined.

Example 26

The procedure of Example 25 is repeated except that 1.0 g of HEMA and 4 g of N-vinyl pyrrolidone are added before the peroxide is added.

Example 27

The procedure of Example 25 is repeated except that 2.0 g of HEMA and 3.0 g of N-vinyl pyrrolidone are added before the peroxide addition.

Example 28

The procedure of Example 25 is repeated, except that 4.0 g of HEMA and 1.0 g of N-VP are added to the starting material (according to Example 25) before the peroxide addition.

Example 29

The procedure of Example 25 is repeated, except that 5.0 g of HEMA is added before the peroxide addition.

Example 30

The procedure of Example 25 is repeated with the

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10th

Exception that 3.0 g of N-VP and 27.0 g of HEMA are added before adding the peroxide.

Example 31

The procedure of Example 25 is repeated, except that 24.0 g of HEMA and 6.0 g of N-VP are added before the peroxide addition.

Example 32

The procedure of Example 25 is repeated, except that 15.0 g of HEMA and N-VP are added before the peroxide addition.

Example 33

The procedure of Example 25 is repeated, except that 5.0 g of N-VP and 25.0 g of HEMA are added before the peroxide addition.

Example 34

The procedure of Example 25 is repeated, except that 3.53 g of ethyl acrylate is added before the peroxide addition.

Example 35

The procedure of Example 25 is repeated, except that 6.67 g of ethyl acrylate is added before the peroxide addition.

Example 36

The procedure of Example 25 is repeated with the exception that 10.8 g of ethyl acrylate are added before the peroxide is added.

Example 37

The procedure of Example 25 is repeated, except that 20.0 g of ethyl acrylate are added before the peroxide addition.

The composition and degree of swelling of the gels according to Example 25-37 are summarized in Table VI.

Table VI

Example macromer (B)% monomer (A)% source

ADIPRENE L-42 + HEMA As Ai

NVP + HEMA EA grad

7

_

-

98.5

-

52

25th

54

37.5

8.5

-

26

26

43.2

46

11.8

-

71

27th

43.2

42

14.8

-

60

28

43.2

34

22.8

50

29

43.2

30th

August 26

-

41

30th

21.6

69

9.4

-

173

31

21.6

63

15.4

-

153

32

21.6

45

33.4

-

93

33

21.6

25th

53.4

-

55

34

39.1

31.9

7.2

15

82

35

34.5

28.1

6.4

25th

71

36

22.4

24.4

5.5

35

56

37

23

18.8

4.2

50

28

Example 38

A. Preparation of the macromeric base substance 2000 parts (1 mol) of polytetramethylene oxide of molecular weight 2000 (Polymeg 2000) are melted, poured into a 5 1 three-necked flask and heated under vacuum to 80 ° C. for 1 hour to remove any moisture which is still present. The vacuum is released by introducing dried nitrogen gas and the contents of the flask are cooled down to 40 ° C. 444.6 parts (2 mol) of isophorone diisoeyanate and 1 g of triethylamine are added, the temperature being raised to 80.degree. After the isocyanate content has dropped to approximately 3.5% after 5 hours (the determination was made by titration), the reaction mixture is cooled to 40 ° C. and then with 1630 parts of HEMA (2-hydroxyethyl methacrylate) and 0.24 g of dibutyltin dilaurate (DBTL). transferred. The reaction mixture is allowed to cool to room temperature with stirring in a nitrogen atmosphere until the residual isocyanate (IR) has completely disappeared.

B. Preparation of Crosslinked Hydrophilic Polymers The macromere starting compound prepared according to A) is used to obtain monomer-macromere mixtures of the following composition by adding either more HEMA or NVP:

composition

Example 38

Macromer (%)

HEMA {%)

NVP (%)

a

68

32

-

b

45

55

-

c

34

66

-

d

11

89

-

e

22

53

25th

f

22

33

45

G

22

15

63

0.2 part of tert-butyl peroctoate is added to each monomer-macromeric mixture obtained, dissolved and the solutions obtained are injected into casting molds (30 cm X 30 cm) made of glass, which are lined with Mylar® polyester films using 1.6 mm wide silicone bands as spacers. The polymerization is carried out in a hot air oven by heating at 80 ° C for 3 hours and heating at 100 ° C for 1 hour. The molds are removed, cooled to room temperature and the resulting hydrogel films are then characterized.

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

Example 38

Degree of swelling%

tensile strenght

Elasticity%

dry wet dry wet a

10th

2720

1140

170 210

b

20th

3460

490

130 160

c

27th

4290

340

110 145

d

47

5910

120

50 120

e

61

5950

110

58 73

f

96

6620

85

67 60

G

138

7100

24th

40 20

Example 39

125.0 g (0.13 mol) of polyoxypropylene, MW 995, are poured into a 500 ml three-necked flask and dried for 1 hour at 80 ° C./2 mm Hg. The vacuum is released by introducing dried nitrogen gas and the contents of the flask are cooled down to 40 ° C. 55.9 g (0.25 mol) of isophorone diisocyanate and 127 mg of triethylamine are added, the reaction temperature being raised to 80.degree. After 18 hours of reaction, the isocyanate content is 5.8% (theoretical value = 5.84% isocyanate). The reaction mixture is cooled to 40 ° C. 172.8 g (1.3 mol)

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

11

2-Hydroxyethyl methacrylate (HEMA) is added to 115.2 g of the reaction mixture obtained above, and 9.6 mg of dibutyltin dilaurate (dibutylbis-auroxyloxy (tin)) are added C held.

Example 40

150.0 g (0.074 mol) of polyoxypropylene, MW 2015, are poured into a 500 ml three-necked flask and dried at 80 ° C / 2 mm Hg for 1 hour. The vacuum is released by introducing dried nitrogen gas and the contents of the flask are cooled down to 40 ° C. 33.1 g (0.15 mol) of isophorone diisocyanate and 83 mg of 1,4-diazabicyclo [2.2.2] octane (Dabco, 1 mol%) are added, the reaction temperature being raised to 80.degree. After a reaction time of 16 hours, the isocyanate content is 3.44% (theoretical value = 3.42% isocyanate). The reaction mixture is cooled to 40 ° C. 179.3 g (1.4 mol) of 2-hydroxyethyl methacrylate (HEMA) are added to 119.5 g of the reaction mixture obtained above, and 190 mg of dibutyltin dilaudate are added. The reaction mixture is kept at a temperature of 40 ° C. until the residual isocyanate has completely disappeared.

Example 41 25

143.9 g (0.50 mol) of polyoxypropylene, MW 2878, are poured into a 500 ml three-necked flask and dried at 80 ° C./2 mm Hg for 1 hour. The vacuum is released by introducing dried nitrogen gas and the contents of the flask are cooled to 40 ° C. 22.2 g (0.10 mol) of 30 isophorone diisocyanate and 56 mg of 1,4-diazabicyclo [2.2.2] octane (Dabco, 1 mol%) are added, the reaction temperature being raised to 80.degree. After a reaction time of 12 hours, the isocyanate content is 2.44% (theoretical value = 2.53% isocyanate). The reaction mixture is cooled to 40 ° C. 3S. 308.0 g (2.37 mol) of 2-hydroxyethyl methacrylate (HEMA) are poured into 205.3 g of the reaction mixture obtained in a 500 ml three-necked flask and 2 mm Hg mixture is added at 80 ° C. and mixed with 17 mg of dibutyltin dilaurate (di-butylbis- (lauroyloxy ) -tin). The reaction mixture 40 is kept at a temperature of 40 ° C. until the residual isocyanate has completely disappeared.

Example 42

145.9 g (0.074 mol) of a melted polyester diol, 45 MW 1965, are poured into a 500 ml three-necked flask and dried at 80 ° C / 2 mmHg for 1 hour. The vacuum is released by introducing dried nitrogen gas and the contents are cooled to 40 ° C. 33.0 g (0.15 mol) of isophorone diisocyanate and 83 mg of 1,4-diazabicyclo [2.2.2] octane (Dabco) are added and the temperature is raised to 80.degree. After a reaction time of 7 hours, the isocyanate content is 3.48% (theoretical value = 3.49 isocyanate). The reaction mixture is cooled to 40 ° C., 222.0 g (1.7 mol) of 2-hydroxyethyl methacrylate (HEMA) are added to 148.0 g of the reaction mixture obtained above, and 12 mg of dibutyltin dilaurate are added. The reaction mixture is kept at a temperature of 40 ° C. until the residual isocyanate has completely disappeared.

60

Example 43

To 50.0 g of each obtained in Examples 39-42

616694

Reaction mixtures (compounds) are added 0.1 g of tert-butyl peroctoate and dissolved with stirring. The resulting mixture is degassed at room temperature in a vacuum of 1 mm Hg until no more rising bubbles can be observed and then poured into a glass mold which has been lined with Mylar polyester film and sealed with a 1 mm wide silicone tape. The molds are heated in a hot air oven at 80 ° C for 3 hours and then at 100 ° C for 1 hour. The films obtained are stripped from the cooled molds and cut into samples for analysis and physical testing.

The degree of swelling (DS) and tensile strength for the hydrogels obtained according to Examples 39-42 are given in the following table:

example

Degree of swelling%

tensile strenght

Elasticity%

dry wet dry wet

39

20th

3980

433

89 111

40

22

3750

280

112 180

41

29

3600

250

113 126

42

19th

4600

656

131 191

Example 44

The reaction mixture obtained according to Example 46 d) is polymerized to give films having a thickness of 0.5-1.5 mm. The films are washed in flowing water at a temperature of 40 ° C for 3 days. Tablets of various diameters are cut from these foils when wet. After drying at 80 ° C. under vacuum, tablets with a diameter of 1.2-4.0 mm are obtained.

Example 45

The reaction mixture obtained according to Example 38 c) is polymerized analogously as in Example 44 and the film obtained is ground in a comminution machine to form multifaceted particles of various average diameters. These particles are then washed in flowing water at 40 ° C. for 3 days, dried and the particles are classified on the basis of the different particle sizes using a set of standard sieves with openings between 0.18 and 2.4 mm. All particles smaller than 0.18 mm in diameter are discarded.

Example 46

15 g of the monomer-macro mixture described in Example 38c are mixed with the following compounds as listed below and listed. 0.08 g of tert-butyl peroctoate is added to this mixture and the solution or dispersion obtained is degassed and injected into casting molds made of glass (30 × 30 cm) which are 1.4 mm thick and sealed with silicone tape and lined with Mylar polyester film . The polymerization is carried out in a hot air oven by heating at 80 ° C. for 3 hours and heating at 100 ° C. for 1 hour. After cooling, the sample foils are removed and used for diffusion measurements.

Active substances

Example 46 Code amount in g Appearance of the product a A 15 transparent, yellow, flexible layer b B 15 transparent, white, flexible layer c C 15 tarnished, yellow, hard film

616 694

12

Example 46

code

Active substances

Quantity in g appearance of the product d

D

15

transparent, amber, flexible layer e

E

10th

clear, white, hard film f

F

3.8

tarnished, almost white, hard film g

G

3.8

semi-transparent, yellow, hard film h

H

5.0

cloudy, white, hard film i

I.

15

clear, yellow, hard layer

Explanations of the code:

A ethyl 4,4'-dichlorobenzilate (Miticid, Acaricid)

B 0- [5-chloro-l- (l-methylethyl) -lH-l, 2,4-triazol-3-yl] 0.0-diethyl phosphorothioate (insecticide)

C 2,6-DimethyI-N-ß-methoxyethyl chloroacetanilide (herbicide) D N '- (4-chloro-o-tolyl) -N, N-dimethylformamidine (insecticide) E 0.0-dimethyl-phosphorodithioate S-ester with 4- (mercaptomethyl) -

2-methoxy-A2 ~ l, 3,4-thiadiazolin-5-one (insecticide) F 2- [4-chloro-6- (cyclopropylamino) -l, 3,5-triazin-2-yl-amino] -2 -methyl-propanenitrile (herbicide)

G S - [(6-chloro-2-oxooxazolo (4,5-b) pyridin-3 (2H) -yl) ethyI] 0.0dimethyl phosphorothioate (insecticide)

H 2- (tert-butylamino) -4- (ethylamino) -6- (methylthio) -s-triazine (herbicide) I 0.0-diethyl-0- (2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate (insecticide, nematocide)

Example 47 molded from glass (30X30 cm), which is 1.4 mm thick

15 g of the monomer macro described in Example 38 f and are sealed with silicone tape. The polymer mixes are mixed with the following 30 ion below in a hot air oven by heating for 3 hours on compounds. 0.08 g of 80 ° C. and actual heating to 100 ° C. are carried out on this mixture. After tert-butyl peroctoate is added and the solution obtained after cooling the molds, the samples are removed

degassed and used in castings lined with Mylar polyester film and used for diffusion measurements.

Active substance

Example 47 Code amount in g Appearance of the product a K 10 tarnished, white, hard foils b L 1.7 transparent, yellow, stretchable foils c M 3.8 white, tarnished, hard foils

Explanation of the code:

K disodium zinc ethylenediaminetetraacetate dihydrate (zinc preparation) L 3-methyl-5-methylsulfonyl-l, 2,4-thiadiazole (fungicide) M 2-chloro-4,6-bis (ethylamino) -s-triazine (herbicide)

Example 48

9.89 g of a hydrophilic polymer, prepared as described in Example 38 b, are dissolved in 20 g of N- (cyclopropylmethyl) -a, a, a-trifluoro-2,6-dinitro-N-propyl-p-toluidine ( a herbicide) for 5 days. The polymer is then removed, washed with methanol, air dried and weighed. The dried polymer weighs 11.22 g, which corresponds in its composition to a polymer which contains 11.8% of active substance.

In an analogous manner, the polymer described in Example 38e is immersed in a 5% solution of sodium formic acid diamine di- [o-hydroxyphenylacetate] (an iron preparation) in methanol. The dried polymer contains 15% active substance.

Example 49

Diffusion measurements are carried out at a temperature of 25 ° C in water buffered with secondary sodium citrate (pH = 5) by immersing a sample of the delivery system as shown in the table in 11 of the stirred buffer solution. Measured amounts are taken periodically and the proportion of the total active substance that is released by polymers is determined spectrally-photometrically.

Example 46 Number of hours required 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

i

12.0

48.0

72

72

Example 50

The component obtained according to Example 46d is crushed in a particle size of 0.18 to 0.25 mm and filled into a cylinder through which air flows at a rate of 20 liters per minute and a temperature of 40 ° C. The weight loss is determined gravimetrically and from this the proportion of the vaporized active ingredient is determined. The course of the release is such that 25% after 48 hours,

55

60

13

616 694

50% after 300 hours, 75% after 1050 hours and 90% after 2000 hours.

Example 51

Fragrances (aroma) of known compounds are in the

Hydrogel polymers obtained by Method 38c included by carrying out the polymerization in the presence of the following mixtures.

Formulas

Fragrances

lilac

Phenylethyl alcohol 30 35 15

Hydroxycitronellal 30-45

Geraniol 2 48 20

Amyl cinnamaldehyde 4 2 5

Benzyl acetate 5 4 5

Ionon 3 4 5

Eugenol 1 2 -

Terpinoel 25 5 5

Jasman

violet

clove

5

20th

25th

6

5

5

2nd

4th

5

45

1

1

40

10th

3rd

-

60

4th

-

-

55

2nd

-

2nd

All fragrances resulted in clear, translucent (translucent) polymer films, which release the fragrances over a longer period of time.

Example 52

The procedure is repeated as described in Example 39, but an equivalent amount of 3-hydroxypropyl methacrylate is used instead of hydroxyethyl methacrylate to prepare the macromer-monomer mixture. The polymerization is carried out as described in Example 43. The received

The film is unbreakable, flexible and translucent and adsorbs 15% water (degree of swelling = 15).

Example 53

The procedure is repeated as described in Example 38 f, with the exception that the layer cover of the film produced is 1.15 mm. The film is washed in flowing water for 3 days and tablets with a diameter of 1.27 mm are cut from it after drying.

B

Claims (9)

616 694 1. A process for the preparation of a crosslinked water-insoluble hydrophilic copolymer, characterized in that that he A) 30% by weight to 90% by weight of a hydrophilic a) homo- or copolymer of the same or different water-soluble mono-olefinic monomers, or b) copolymers of a water-soluble mono-olefinic monomer with 1% by weight to 70% by weight of the same or various, water-insoluble mono-olefinic monomers with B) 10% to 70% by weight of a terminally diolefinic hydrophobic macromer having a molecular weight of about 400 to about 9600 copolymerized. 2. The method according to claim 1, characterized in that one carries out the co-polymerization of a water-soluble homo- or copolymer A) with a hydrophobic macromer B) in the presence or absence of solvents. 2nd PATENT CLAIMS 3. The method according to claim 2, characterized in that the copolymerization of a water-soluble homo- or copolymer A) with a hydrophobic macromer B) in the presence of a free radical-forming catalyst or system at a temperature in the range from 40 to 150 ° C. becomes. 4. The method according to claim 3, characterized in that the copolymerization of a water-soluble homo- or copolymer A) with a hydrophobic macromer B) in the presence of 0.02% to 1.0% by weight of a free radical-forming catalyst in a Temperature of 50-100 "C is running. 5. The method according to claim 4, characterized in that catalysts which give off peroxy radicals or alkyl radicals are used as catalysts which form free radicals. 6. The method according to claim 3, characterized in that gamma rays, electron beams or UV radiation are used as the system which emits free radicals. 7. Process according to claims 1-6, characterized in that a homo- or copolymer of a water-soluble monomer is used as component A, which is selected from group a) acrylic acid or methacrylic acid, or water-soluble esters, amides or imides thereof , b) mono-olefinic sulfonic acids or their salts or c) mono-olefinic derivatives of N-heterocyclic monocyclic monomers. 8. The method according to claims 1-4, characterized in that the hydrophobic macromers B) compounds of the formula R.3 R2 Rz R3 HC = C-X-Y -Ri -Y -X-C = CH or HC-CO / CO - CH II ^ N_R | _N II HC-CO ^ CO-CH used, wherein Ri is a polycondensate chain having a molecular weight of about 200 to about 8000 and containing hydrocarbon residues bonded via ethers, esters, amides, urethanes or ureas; R2 is hydrogen, methyl or -CH2-COOR4, where R4 is hydrogen or alkyl having up to 10 C atoms; R3 is hydrogen or COOR4, provided that at least one of R2 and R3 is hydrogen; X is oxo, -COO- or -CONR5, wherein Rs is hydrogen or alkyl having up to 5 carbon atoms, and Y is a direct bond or the radical -R6-Z1-CO-NH-R7-NH-CO-Z2-, wherein Rô is bonded to X and branched or means linear alkylene radicals with up to 7 carbon atoms; Zi and Z2 means oxo or I. -NR5 and R7 is the divalent residue of an aliphatic or aromatic diisocyanate, provided that if X is oxo, Y must be different from the direct bond, and R2 and R3 are hydrogen. 9. Use of the water-insoluble hydrophilic copolymers prepared by the process according to claim 1 as a carrier material for biologically active compounds.