DE2528068A1 - WATER-INSOLUBLE HYDROPHILIC COPOLYMERS - Google Patents

Description

Case 4-9472 / SU 613 / + 2528068

GERMANY

Water-insoluble hydrophilic copolymers

The present invention relates to crosslinked hydrophilic polymers which are suitable for use as carriers for Medicines and other active substances are suitable; also as hydrophilic membranes for separation processes, as wound dressings, as body implants such as artificial veins; as cover layers for glass, metal, wood or ceramics and in particular for use in cases where both strength and high water permeability of the polymer article are required are required.

It is known to have weakly cross-linked, water-insoluble, but hydrophilic polymers as a carrier material for biologically active, at least slightly water-soluble substances Copolymerization of a predominantly hydrophilic part

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70.01.334

mono-olefinic monomers and a small proportion, between 0.01 and 15%, based on the mono-olefinic monomers mentioned, from a low molecular weight crosslinking agent. Monoesters of acrylic monomers in particular are used as mono-olefinic monomers or methacrylic acid with polyfunctional alcohols, such as ethylene glycol mono-methacrylate, and in particular as a crosslinking agent Diesters of the acids mentioned with the alcohols mentioned, such as ethylene glycol bis-methacrylate, and the copolymerization is used in the presence of water, see U.S. Patent No. 3,220,960 or in an anhydrous system, see U.S. patent No. 3,520,949 executed. Both low-molecular and macromolecular, water-soluble compounds, such as polyethylene oxide mono-methacrylate along with a small amount of the corresponding bis-methacrylate were soaked in U.S. Pat. Patent No. 3,220,960 as Monomers and crosslinking agents used. The water-insoluble but hydrophilic copolymers and their manufacturing process were modified in various ways and adapted to special needs, e.g. for the manufacture of soft contact lenses (U.S. Patent No. 3.200.960 and Reissue No. 27.401) and the copolymerization in the presence of linear polyamide resin to improve the mechanical To improve or change properties of articles molded from polymers obtained in this way (U.S. Patent No. 3,520,949). Nevertheless, low molecular weight polyolefinic ones were used in all embodiments Crosslinking agents, especially ethylene glycol bismethacrylate, are used, in very small to massive amounts Quantities that never exceed 20% of the mono-olefinic monomer content

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stepped. Although the copolymers of the type described above could be adapted to the various requirements of use, it was not possible to measure the mechanical properties both in the unswollen, i.e. anhydrous state and in the swollen, i.e. the state in equilibrium with water can be adapted satisfactorily to all purposes.

It is known that hydrophilic polymers, the main components of which consist of monoesters of acrylic acid and methacrylic acid and a bifunctional alcohol, glass transition temperatures or have softening points between 55 ° C and 80 ° C. For this reason, objects that correspond to the state of the art are in the dry state at temperatures below 55 C. brittle and glass-like. After the equilibrium has been reached in water, the items mentioned are technically soft and malleable, but also weak in terms of flexural strength; they also have low tear and shear strength, which makes them sensitive to kinking or other stresses. To these undesirable adverse properties To avoid the objects manufactured according to the state of the art, they are replaced by inserts made of stronger polymer Material is reinforced, or the prepolymerized mixture is filled with an insoluble material such as silica gel. These devices increase the toughness (cohesive forces) to a certain extent (because the hydrogel acts as a putty), nevertheless they are Articles thus obtained are susceptible to glassy appearance when dry

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Fracture and shear fracture in the swollen state in the constrictions (Spaces) of these objects. The addition of filler material to the prepolymer also has a disadvantageous effect in that the diffusion properties and the water permeability of the articles can be changed.

Subject of the invention

One of the objects of the present invention is the production of crosslinked hydrophilic copolymers having high flexibility and elasticity both in the predominantly anhydrous as well as in the swollen state, i.e. in equilibrium with water or aqueous fluids such as body fluids. These copolymers are suitable for use as hydrophilic membranes too Separation methods, as wound dressings, body implants, e.g. artificial veins, also as cover layers on glass, metal, wood or ceramics, and as a carrier material for biologically active compounds, e.g. drugs, herbicides, insecticides, fungicides, bactericides and fragrances.

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

Another object of the invention is the production of crosslinked hydrophilic copolymers with the improved copolymers mentioned above Properties, with a variable, effective content of

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- £ Γ- 252 * 068

biologically active material, especially therapeutically effective material Substances.

It has now been found that water-insoluble hydrophilic copolymers, which are predominantly composed of a hydrophilic polymer of mono-olefinic monomers exist with a predominant Share of a diolefinic, non-hydrophilic macromer are crosslinked and which contain a biologically active substance may have the above-mentioned and other desirable properties. In the new copolymers the proportion of terminal diolefinic macromer is higher than that of crosslinking agents in the known hydrophilic copolymers, and it is a predominant part of the system with about 10 bis about 70% of the hydrophilic polymer, or preferably about 15 to about 50% of the same. The said terminally diolefinic non-hydrophilic macromers have a molecular weight between about 400 and about 8,000, or preferably between about 600 and 5000.

In particular, the present invention encompasses an insoluble polymeric hydrogel that can be used as a carrier for drugs suitable, administered orally or buccally (through the mouth) or applied in the form of subcutaneous or intramuscular implants will. The hydrogels according to the invention can also be used in body implants, such as artificial veins, devices for insertion into the urethra, vagina or anus are shaped,

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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 reverse osmosis or semi-permeable membranes; hydrophilic Membranes for separation processes; Dressings for wound treatment; Top layers on glass, metal, wood or ceramics and, in general, applications where both hydrophilicity and toughness are at the same time are required.

The new hydrogels according to the present invention are produced in the presence or absence of solvents by free radical copolymerization, a water-soluble monomer (As), which is suitable for the formation of a water-soluble or water-swellable polymer, i.e. a hydrophilic polymer (Ap), with a di-olefinic non-hydrophilic macromer (B), e.g. a divinyl compound with a long, linear polycondensate chain, such as polytetramethylene ether, with a polymerizable Vinyl group terminal on both sides. In this way, a three-dimensional macromolecular network is formed that consists of is composed of two types of segments, each segment having its specific physical properties for the whole system contributed. The Α segment gives water solubility, the hydrophobic B segment forms the flexible cross-links. By amendment the corresponding proportions of each compound can improve the mechanical and diffusion properties to a large extent Range can be varied. For example, a polymer with

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excellent toughness, strength and elasticity can be obtained, which still take up approximately their own weight in water can; this polymer is obtainable using the appropriate proportions of A and B. This possibility is known Hydrogels do not exist because their cross-links are short and inelastic, and these hydrogels are hard when dry and are brittle.

In the polymers according to the invention, the incorporation of the bifunctional macromolecule B is predominantly proportionate in the system novel. In this way, the bifunctional macromer not only serves as a structural crosslinker, but also as a mediator of unique physical properties in the gel.

The hydrophilic polymer, Ap, 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 Be monomers and at most 70%, preferably at most 50% of the total amount of the monomer, of a water-insoluble be mono-olefinic monomers Ai. The water-soluble monomers are preferably acrylic and / or methacrylic acid (2-methylacrylic acid) or water-soluble derivatives thereof, such as their 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

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the formula

vr \ _ c vs _ r> _ / cn cn r \\ D.

IHJ - Kj Hn KJ - ILlUn ^- VJtInU) "" K.

m / m z zn

where R is hydrogen or methyl, m is 2 to 5 and η is 1 to 20, or esters of analogous alcohols in which part of the ethylene oxide unit has been replaced by propylene oxide units. Also suitable esters are dialkylaminoalkyl acrylates and methacrylates, such as 2- (dimethylamine) ethyl, 2- (diethylamino) ethyl and 3- (dimethylamino) -2-hydroxypropyl ester. Another class of suitable derivatives of such acids are their water-soluble ones Amides, such as the unsubstituted amides and by lower hydroxyalkyl, lower oxaalkyl or lower dialkylaminoalkyl groups substituted amides, such as N- (hydroxymethyl) acrylamides and methacrylamides, N- (3-Hydroxypropyl) -acrylamide, N- (2-HydroxyäthyI) -methacrylamid, N- (1,1-dimethyl-3-oxabutyl) acrylamide and N- [1,1-dimethy1-2- (hydroxymethyl) -3-oxabutyl] acrylamide; water-soluble hydrazine derivatives such as trialkylamino-methacrylimides, e.g. trimethylamino-methacrylimides and dimethyl (2-hydroxypropyl) amino methacrylimide and the corresponding derivatives of acrylic acid; monoolefinic Sulphonic acids and their salts, such as sodium ethylene sulphonate, sodium styrene sulphonate and 2-acrylamido-2-methylpropanesulphonic acid; N- [2- (dimethylamino) ethyl] acrylamide and methacrylamide, N- [3- (dimethylamino) -2-hydroxypropyl] methacrylamide or mono-olefinic derivatives of heterocyclic nitrogen-containing monomers, such as e.g. N-vinyl-pyrrole, N-vinyl-succinimide, l-vinyl-2-pyrrolidone, 1-vinyl-imidazole, 1-vinyl-indole, 2-vinyl-imidazole, 4 (5) -vinyl-

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imidazole, 2-vinyl-l-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-isopropenylpyridine, 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 that are also hydrophobic can be applied. The proportion of these hydrophobic monomers should be 60% of the total composition, preferably 40%, do not exceed.

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

Water-soluble monomers that require a comonomer for polymerization are maleates, fumarates and vinyl ethers; the following Monomer combinations can be used, for example:

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Di- (hydroxyalkyl) maleates, such as di- (2-hydroxyethyl) maleate and ethoxylated hydroxyalkyl maleates, hydroxyalkyl monomaleates, such as 2-hydroxyethyl monomaleate and hydroxylated hydroxyalkyl monomaleate with vinyl ethers, vinyl esters, styrene or, in general, monomers which easily copolymerize with maleates or fumarates; Hydroxyalkyl vinyl ethers, such as 2-hydroxyethyl vinyl ether, 4-Hydroxybutyl vinyl ether with maleates, fumarates or in general all monomers that easily copolymerize with Vinyl ethers.

Hydroxyalkyl acrylates and methacrylates, such as 2-hydroxyethyl acrylate, are particularly valuable as water-soluble monomers. 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate, N-vinyl-pyrrolidone, acrylic acid, methacrylic acid and a tert. Amino-methacrylimide, e.g., trimethylann.no-methacrylamide, as in U.S. Patent No. 3,627,802.

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

In the di-olefinic non-hydrophilic macromers B the olefinic part is preferably an acyl radical of a lower α, ß-mono-unsaturated aliphatic monocarboxylic or dicarboxylic acid or a vinyloxy radical. These remnants are connected to one another through a macromolecular, non-hydrophilic chain with

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repeating ester, amide or urethane groups, in particular but ether groups. The molecular weight of the chain can be from about 400 to about 8000, but preferably between 600 and 5000, and most particularly between 1500 and 3000. Accordingly, component B corresponds to the formulas

Rn 0 0 Q

Il It

HC = CXYR ₁ -YXC = CH (B ₁ ) or

HC-C 'NR ₁ -N O CO - CH
Il ti
Il Il HC-C CH

(B ₂ )

wherein R, denotes a polycondensate chain with a molecular weight of about 200 to about 8000, the hydrocarbon radicals contains ether, ester, amide, urethane or urea radicals bonded, R ₂ is hydrogen, methyl or -CH ₂ -COOR ,, where R / Means hydrogen or an alkyl group with up to 10 carbon atoms, Ro is hydrogen or COOR, with the condition that at least one of the radicals R ₂ and R ~ is hydrogen, X is oxo,

-COO- or -CONR _1. , In which R- is hydrogen or alkyl with up to 5 carbon atoms and Y is a direct bond or the radical -R ₆ -Z ₁ -CO-NH-R ₇ -NH-CO-Z ₂ - means in which R 1 is bonded to X and a branched or straight-chain alkylene radical with up to

7 denotes carbon atoms, Z, and Z ₂ is oxo or -NR _n ., And R ₇ is the divalent radical of an aliphatic or aromatic diisocyanate with the proviso that when X denotes oxo, Y is none

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is a direct bond and R ₂ and R ^ are hydrogen.

In the compounds of the formulas B and B ″, R ₁ denotes in particular a polypropylene oxide or a polytetramethylene oxide chain, but it can also denote 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 B correspond to the definitions of R ₂ and R "and if X is -COO- or -CONR ₅ , the acyl radical is derived from acrylic or methacrylic acid or the monoacyl radicals of maleic, fumaric or itaconic acid or monoalkyl esters of these acids with straight or branched chain alkanols having 1 to 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 B ,, in which Y is a direct bond, are diesters of macromolecular diols in which two hydroxyl groups are bonded to the polycondensate chain R in opposite terminal or nearly terminal positions, with α, ß-unsaturated acids. Such diesters can be prepared from the macromolecular diols mentioned by known acylation processes by using reactive functional derivatives of suitable acids, for example acrylic or methacrylic acid chloride, or of monoalkyl esters of maleic, fumaric or itaconic acid. Compounds of the formula B with the amide group X are diamides obtained from macromolecular diamines by known methods

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Acylation methods, e.g., using those noted above Acid chlorides or anhydrides. The macromolecular diamines are e.g. produced from the corresponding macromolecular diamines Diols with twice the molar amount of alkyleneimine, e.g. propyleneimine.

The macromolecular bis-maleamic acids are obtained according to the reaction described above by using maleic anhydride as acylating agent for macromolecular diamines with heating or reaction with dehydrating agents to produce macromolecular bis-maleimido compounds of the formula B _? . In these compounds, R can be, for example, one of the macromolecular polycondensate chains which are mentioned as constituents of the compounds according to formula B.

According to the definition of formula B ₁ , Y can also be a divalent radical -R ₆ -Z ₁ -CONH-R ₇ -NH-CO-Z ₁ . R / - e.g. methylene, propylene, trimethylene, tetramethylene, pentamethylene, neopentylene (2,2-dimethyltrimethylene), 2-hydroxytrimethylene, 1,1-dimethyl-2- (1-oxo-ethyl) -trimethylene or 1- ( Dimethylenaminomethyl) ethylene and especially ethylene. The divalent radical Ry is derived from an organic diisocyanate and is an aliphatic radical such as alkylene, for example ethylene, tetramethylene, hexamethylene, 2,2,4-trimethylhexamethylene, 2,4,4-trimethylhexamethylene, fumaroyldiethylene or 1-carboxypentamethylene; a cycloaliphatic radical,

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for example 1,4-cyclohexylene or 2-methyl-1,4-eyelohexylene; an aromatic radical such as m-phenylene, p-phenylene, 2-methyl-mphenylene, 1,2-, 1,3-, 1,5-, 1,6-, 1,7-, 1,8-, 2 , 3- and 2,7-naphthylene, 4-chloro-1,2 and 4-chloro-1,8-naphthylene, 1-methyl-2,4-, 1-methyl-2,7-, 4-methyl -l, 2-, 6-methyl-1,3 and 7-methyl-1,3-naphthylene, 1,8-dinitro-2,7-naphthylene, 4,4'-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 -SjS ¹ -dimethoxy-4,4'-diphenylene, methylene-di-p-phenylene, methylene-bis- (3-chlorophenylene), ethylenedi-p-phenylene or hydroxydiphenylene.

If the symbol Y is not a direct bond in formula part B _{1, Rß must always be connected to X.}

There are therefore compounds of the formula B ,, in which Y the divalent radical mentioned is bis-vinyl ether when X Means oxygen, or bis-acrylates, bis-methacrylates, bismaleates, Bis-fumarate and bis-itaconate when X - COO- or

-CONR is ₅ .

The more preferred divinyl macromers B consist of polytetramethylene oxide glycols from about 1000 to about 4000 molecular weight end-saturated with 2,4-toluene diisocyanate and reacted with 2 moles of a 2-hydroxyalkyl acrylate or methacrylate. The macromer made from polytetramethylene oxide glycol is particularly valuable from a molecular weight of about 1500 to about 3000,

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End-saturated with 2,4-toluene diisocyanate and reacted with approximately 2 moles of 2-hydroxyethyl methacrylate.

The novel hydrophilic copolymers 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 B or B ₂ based on the total weight of the hydrogel. The polymerization is advantageously carried out with a catalyst which forms free radicals at temperatures in the range from about 40.degree. C. to about 150.degree. C., preferably between about 50.degree. C. and about 100.degree. The presence of a therapeutically or otherwise biologically active substance during the polymerization can necessitate a limitation of the polymerization temperature in view of the heat stability of the substance.

A preferred laboratory manufacturing process for the hydrogel article includes dissolving the drug in the macromer monomer solution prior to polymerization, with the desired Drug concentration is selected together with the macromer monomer ratio so that the hydrogel has the desired mechanical and maintains water absorption properties, mixing together with from about 0.02% to about 1% (weight%) of a suitable, free radical-forming catalyst and polymerizing the mixture at e.g. 80 ° C for about 2 hours in a

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closed shape, so that the hydrogel is obtained as a flat film that contains the drug in a quasi-solid solution. These The film is then exposed to a temperature of about 100 ° C. in a high vacuum for about 12 hours in order to remove residues of monomers and to remove catalyst decomposition products.

A preferred laboratory method for making the cylindrical hydrogel is by having a pliable Fill polyethylene tube with the preferred mixture of macromer, monomer, drug and catalyst and keep the mixture in for about Reacts for 2 hours at 80 ° C. The hydrogel article manufactured in this way is made free of the pipe by slitting it open lengthways and stripping it off.

Another preferred process for producing the hydrogel in the form of small spheres or beads is that the preferred mixture of macromer, monomer, drug and catalyst at about 90 C in a viscous medium that does not acts as a solvent for a component of the hydrogel mixture, is stirred at high speed. As examples of suitable Media for bead polymerization are silicone oils, polyfluorinated oils and the like, e.g. mineral oil distillates and saturated ones aqueous salt solutions.

Yet another preferred method for producing the hydrogel in the form of a foamed article consists in

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that a gas generating agent (propellant), such as sodium bicarbonate, is added to the preferred mixture and polymerized at about 80 C in a mold for about an hour will. The resulting closed cell foam is particularly suitable for rapid water absorption and drug release.

Compounds of the formula B ,, in which Y is - R ₆ -Z ₁ , are obtained in a 2-stage reaction by first adding macromolecular diols or diamines, ie compounds which have two hydroxyl or amino groups in opposite terminal or almost terminal positions to the Polycondensate chain R, contain bound, are reacted with at least twice the amount of an aliphatic, cycloaliphatic or aromatic diisocyanate, the diisocyanate consisting of the radical R ₇ , to which two isocyanate groups are bonded, and in the second reaction stage the macromolecular diisocyanates thus obtained with one Compound of formula

R ₃ R ₂
HC = C - X - R ₆ - Z ₁ H (C)

wherein R ₂ , R ₃ , X, R ₆ and Z, have the meaning given above (for B ^), converts.

When X is oxygen, (C) is a vinyl ether with

active hydrogen, e.g. a hydroxyalkyl vinyl ether or an amino

alkyl vinyl ethers; when X is - COO- or CONR ₅ , (C) is a

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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 light Excess applied, i.e. that the quantitative ratio of isocyano groups to hydroxyl or amino groups in the first conversion stage of the macromolecular synthesis should be at least 1: 1, but preferably at least 1: 1.05 or lower. If that used in the second conversion stage of the macromer synthesis Compound C is identical to the hydrophilic monomer As, a large excess of this compound can be used, see above that the resulting solution of the macromer B ,, dissolved or dispersed in the monomer A, directly for the production of the end product, of the hydrophilic copolymer can be used.

The preparation of the macromer B is advantageous at temperatures carried out in the range between about room temperature and about 80 ° C. The temperature used is preferably not above 40 ° C and preferably in the range between 30-45 C. The Conversion of the isocyano group is carried out by means of infrared spectroscopy or titration followed.

Another process for the preparation of the macromer consists in the reaction of a prepolymer with terminal ones Hydroxyl groups, e.g. polybutylene or polypropylene oxide, with acryloyl chloride, methacryloyl chloride or maleic anhydride, thereby forming a macromeric with no urethane spacers.

such as, for example, a macromer of the formula B ₂ or B ,, in which Y is a direct bond.

The free radical copolymerization becomes sufficiently high by means of a catalyst, the free peroxy or alkyl radicals Can generate concentration, initiated to bring about the polymerization of the vinyl monomer used at the synthesis temperature.

Examples of suitable catalysts are diisopropyl peroxide! Carbonates, 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 redox systems that generate free radicals, such as persulfate-bisulfite combinations be used. The catalyst is advantageously used in an amount of about 0.02-1% by weight of the reaction mixture used. Other systems that generate free radicals 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 manner Atmosphere, provided that open forms are used. It is known that oxygen inhibits the polymerization and the Polymerization times extended to the end of the reaction.

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When working with closed molds, around the hydrogel article To mold, the molds must be made of inert material with low oxygen permeability and good removability. Examples of suitable mold 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 the mixture of both before the addition of the free radical catalyst, or by diffusion of the Drug achieved in the article obtained after the polymerization. When the drug is not attacked by free radicals it is advantageous to dissolve the same in the macromer solution, monomer solution or a mixture of both before the polymerization or to disperse. If the drug is attacked by free radicals, it should be finished after polymerization Object can be incorporated by diffusion from a solution.

The hydrogel system, which consists primarily of the hydrophobic macromeric segment B and the hydrophilic segment Ap, can be of very different composition, and accordingly the degree of hydrophilicity and mechanical strength can be balanced against each other in such a way that a great variety

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of applications, such as delivery systems for medicines, insecticides, herbicides, etc., semi-permeable reverse osmosis membranes, body implants and wound dressings.

Hydrogels with leather-like toughness in the dry state and great extensibility in the wet state can depend on made of the conversion ratios of the above components with low to high water absorbency will.

For applications such as body implants, wound dressings, and semi-permeable membranes, hydrophilic membranes are particularly useful advantageous, which have a relatively high wet strength Combine equilibrium water contents of 5-50%. For example, subcutaneous and intramuscular implants have to be regulated Drug delivery on the one hand capable of water absorption (15-25 percent by weight) to a certain extent, but on the other hand be firm enough when dry and swollen to withstand the introduction and extraction process.

In addition to their suitability as drug carriers, the hydrogels according to the invention can also be used as carriers for Antiseptics, flavorings, colorants, nutrients, insecticides, herbicides, etc. The hydrogels according to the invention can in particular swollen in a suitable solvent containing the active ingredient to be transferred; the solvent is

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steams and leaves the active ingredient in the hydrogel particles. In contact with an aqueous environment, the active ingredient is released in a uniform manner.

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

The inventive hydrogel substances are also for Suitable for use as hydrophilic and non-thrombogenic cover layers because they adhere strongly to glass, metal and plastic. Because Their high strength and elasticity make them strong cover layers with high wear resistance and are therefore ideal for covering suitable for boat hulls to prevent the growth of mussels; or to create top layers on lenses and glasses, which prevent fogging of the same in a damp environment.

Another excellent property of the hydrogels according to the invention is their flexibility in the dry state, in which they already take on the shape desired in their application.

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In the swollen state, a further advantage of the inventive Hydrogels can be seen in that they do not become crumbly but retain their strength and elasticity, too when they are in equilibrium (with water) in an aqueous environment. These properties are particularly valuable at the use of membranes under pressure, such as in apparatus for reverse osmosis, for which the hydrogels according to the invention are suitable.

According to the invention, drug-containing hydrogels are Particularly suitable for use in the treatment of open wounds and burns thanks to their flexibility and Adaptability to shape, combined with the possibility of applying drugs directly to the affected areas. In this type of application A particular advantage of the hydrogel is its flexibility when dry. It is unnecessary to put the hydrogel on before Pre-swell application to make it soft and pliable enough to cover large injured areas (wound areas); from this Basically, the drug-containing hydrogel can be stored dry instead of swollen, which increases the shelf life of the contained therein Drug increases.

Any medicament for body treatment, both topical and systemic, can be incorporated into the copolymeric carrier material according to the invention applied, incorporated as an active ingredient. The term "medicament" is used and encompassed here in the broadest sense any substance or mixture of substances with pharmacological or biological Effect. For therapeutic use according to the present

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of the invention are, without limitation, all disclosed in U.S. Patent No. 3,732,865 (columns 10 and 11) listed medicinal products.

Medicines other than those mentioned above, having the same or different effects, can be used in the present invention Straps are used. Suitable mixtures of drugs can be administered just as well as individual substances.

The medicaments can be given in various forms of administration, such as, for example, as a pure active substance or as components of molecular complexes or as non-irritating, pharmacological acceptable salts, e.g. the hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc. Metal salts, amines or organic cations (e.g. quaternary ammonium salts) can be used for acidic drugs come. Further, simple derivatives of drugs (such as ethers, esters, amides, etc.) can be used as desired Have retarding and releasing properties and are easily hydrolyzed by exposure to body pH, enzymes, etc.

The amount of drug to be incorporated into the carrier depends to a large extent on the particular compound, the desired therapeutic effect and the length of time it takes to release the medicine. There is no critical upper limit for the amount of drug to be introduced into the vehicle, because the diversity of the carriers and their most diverse

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Sizes and shapes should make it possible for the most diverse Diseases a whole range of forms of administration and Build up dosages. The lower limit is also based on the effectiveness of the drug and the degree of its release depend on the carrier. There is, therefore, no range for the therapeutically effective amount of drug that may be consumed by the wearer is released to define.

Preferred medicaments according to the present invention are intended for long-term treatment so that multiple daily dosing is avoided such as anabolic steroids, such as methandrostenolone, Analgesics, for example acetylsalicylic acid, phenylbutazone or methadone, androgens, for example methyltestosterone, antibiotics, for example rifampin, antidepressants, for example imipramine or maprotiline, antidiabetics, for example phenoformin, Anticonvulsants, e.g. carbamazepine, antihistamines, for example tripelennamine, antihypertensive agents, for example hydralazine, antimicrobial agents, for example trimethoprim, antiparasitic agents, for example nifurtimox, antiparkinsonian agents, for example levodopa, antiphlogistics, for example naproxen, antitussives, for example benzonatate, appetite suppressants, for example mazindol, bronchodilators, for example fenoterol, coronary dilators, for example fenalcomin, corticoids, for example dexamethasone, cytostatics, for example floxuridine, diuretics, for example hydrochloric

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thiazid, hypnotics, for example glutethimide, neuroleptics, for example Reserpine or thioridazine, psycho-analeptics, for example methylphenidate, tranquilizers (tranquilizers), for example Diazepam, Uricosurica, for example sulfinpyrazone, vasodilators, for example isoproterenol.

In addition to drugs, the copolymers according to the invention also 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, ethyl propionate, Ethyl acetate, acetaldehyde, menthol and garden mint, as well as pesticides including bactericides, fungicides, insecticides and nematocides be incorporated.

Other examples of the mentioned biologically active additives are found in U.S. Patent No. 3,660,563 (columns 3 to 7) called.

The new hydrogels, in particular those containing polyurethanes as macromer components, form because of their superiority physical properties in the dry and wet state are a cross between classic hydrogel and polyurethane especially as biomedical plastics with non-thrombogenic Properties valuable. They are therefore eminently suitable for use as artificial skin in the treatment of

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burns, for the construction of artificial organs or as cover layers for the same. You can also use it as a surgical one Sewing material can be used.

The composition of the hydrogels can be from 30 to 90% Monomer (A) and 10 to 70% macromer (B) vary, with one corresponding degree of swelling of approximately 10 to 250%. The preferred compositions contain about 15-50% macromers (B) and about 50-85% of monomer (A) and their degree of swelling ranges between 15 and 120%.

Experimental part

After the gel has been prepared, a 3 g heavy Cut, weigh and store in a bottle with approximately 50 ml of water at room temperature. After 96 hours it will the swollen specimen taken out, with filter paper from the excess Surface water freed and reweighed to determine the degree of swelling (DS). From the remaining hydrogel film 6 test strips are punched out, 3 of which are allowed to swell in water until the equilibrium water content is reached. Tensile strength and elongation of the dry and the wet samples will be in an Instron testing machine according to ASM test method D-638 under Use of a type IV test strip is determined.

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-2g _φ 2b2Ö068

The rate of release of a drug contained in a hydrogel is determined by continuous measurement of the characteristic UV absorption of a stirred amount of water containing a hydrogel disk 16 mm in diameter and 0.8-1.0 mm thick, certainly.

Weight d. wet sample - wt. d. dry pattern

Degree of swelling DS = x

Weight of the dry sample

In the following examples, the term "terminally isocyanate-reacted polytetramethylene oxide" (polytetramethylene oxide terminally saturated with isocyanate) means a polytetramethylene oxide chain which has been reacted at both ends with 2,4-toluene diisocyanate. These compounds are easily made and are also commercially available from DuPont de Nemours Chemical Comp., Wilmington, Del., Under the tradename "ADIPRENE ¹¹ .

The first seven examples show the influence of varying amounts of macromeric, hydrophobic crosslinking agent on the physical Properties of polyhydroxyethyl methacrylate gels as well their manufacture.

A: 2-hydroxyethyl methacrylate (HEMA)
B: Polytetramethylene oxide terminally reacted with isocyanate + HEMA

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example 1

20 g of a polytetramethylene oxide reacted at the end with isocyanate of molecular weight 1500 (ADIPRENE 167) are dissolved in 18 g of 2-hydroxyethyl methacrylate and held for 72 hours reacted at room temperature. After 72 hours, the disappearance of all of the isocyanate is confirmed by finding the absence the characteristic infrared band of isocyanate at 2270 cm in the infrared spectrum. This mixture is then added of 0.08 g of diisopropyl percarbonate was injected into a mold for films of 1 mm thickness and placed in a rotary kiln for 2 hours held at 60 C. The solid, transparent film obtained is placed in water for 2 days and then dried at 80 ° C. in vacuo. The equilibrium water content, tensile strength and elongation in dry and wet conditions are measured.

Example 2

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

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Example 3

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

Example 4.

The process of 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 of 2-hydroxyethyl methacrylate. A tough, transparent film is obtained and treated as described in Example 1.

Example 5

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

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Example 6

The process according to Example 2 is repeated with a mixture of 10.0 g of ADIPRENE L-42 (mol. Wt. 3000) and 10.0 g 2-hydroxyethyl methacrylate. A tough, transparent film will received, treated and tested as in example 1.

Example 7

A customary poly (2-hydroxyethyl) methacrylate gel is used as a control produced, starting from 1.2% ethylene glycol dimethacrylate as a crosslinking agent; otherwise the same procedure is used applied as for the previously described gels. A hard, brittle, transparent sheet is obtained which is treated in the same way and is checked as described above. Table 1 shows a decreasing degree of swelling with increasing amount of the hydrophobic Macromers B. The tensile strength in the dry state of the products according to Example 1-6 is higher than that of the customary Poly-HEMA according to Example 7. The tensile strength in the wet state and the elongation in the dry and wet state increase as the amount increases from B.

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Macromeres Table I. HEMA% DS 25th 28068 Moist ADIPRENE * 88.4 185/99 example L-167: 89.2 52 Tensile strength elongation 150/108 L-42: (B)% monomer (A) 71 42 Dry 409/113 1 L-167: HEMA 42 22nd 4560/41 1055/150 2 L-167: 11.6 73 12th 5343/39 258/95 3 L-42: 10.8 46 30th 4760/89 557/214 4th L-42: 29 98.5 20th 4123/144 69/83 5 58 45 4453/120 6th 27 3167/246 7th 54 2320/15

* ADIPRENE L-167: MW = 1500
¹¹ L-42: MW = 3000

The following examples show the utility of N-vinylpyrrolidone as a hydrophilic monomer (A), as well as the use of hydrophobic comonomers to adjust the equilibrium water content.

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Examples 8-12

30 g of a polytetramethylene oxide, end-saturated with Isocyanate with 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 des the following monomers are added:

Example 8: N-vinylpyrrolidone (NVP)

Example 9: ethyl acrylate (EA)

Example 10: Dimethyl Maleate (DMM)

Example 11: vinyl acetate (VA)

Example 12: ethyl acrylate (EA)

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

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Table II

Example Macromeres (B)% ADIPRENE L-42 + HEMA

Monomer system (A)% +% (A) % (A ₁ ) NVP + HEMA comonomer

32.4 32.4 32.4 32.4 22.6

60 - - 20th 101 40 H. EA: 20th 75 40 H. DMM: 20th 78 40 H. VA: 43 91 29 H. EA: 42 l · 7.6 h 7.6 l · 7.6 h 7.6 l · 5.4

In the following two examples, the macromer (B) is a bis-vinyl ether (example 12) and a bis-maleate (example 14)

Example 13

According to the method described in Examples 8-12, 30 g of isocyanate-end-saturated polytetramethylene oxide (MW: 3000) and 10 g of 4-hydroxybutyl vinyl ether (HBVE) in 30 g of N-vinylpyrrolidone implemented until all free isocyanate has disappeared. 30 g of ethyl acrylate and 0.4 g are then added to the mixture tert-butyl peroctoate. The mixture is placed in foil casting molds and after two hours at 80 C the crosslinked sheets are removed from the mold and placed in a vacuum oven for 16 hours (0.25 mmHg) held at 100 ° C. The pattern is a tough, clear sheet, the degree of swelling of which has been determined (see Table III).

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-IS

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

Table III

Example Macromeric (B) % Monomeric System (A) DS

ADIPRENE Final% A _s % A ^

L-42 monomer NVP + HBVE HPBM comonomers

13 32.4 HBVE 30 + 7.6 - 30

14 43.1 HPBM 50 + --- 6.9 -

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

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Examples 15-17

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

Example 15: 15 g polyester diisocyanate + 85 g HEMA Example 16: 25 g "" + 75 g HEMA Example 17: 40g "" + 60g HEMA

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

Table IV

Example% Macromeres (B) Monomer (A) DS Polyester (E-410) + HEMA ^

15th 23.4 16 39 17th 62

76.6 30

61 21

38 21

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One by reacting 2 moles of maleic anhydride with one mole of polypropylene oxide, end-saturated with primary amino groups, obtained bis-maleimide-type macromers (B) of molecular weight approx. 2200 (polypropylene oxide-bis-maleimide) is in 2-hydroxyethyl methacrylate Dissolved in two proportions: Example 18: 20% polypropylene oxide-bis-maleimide (80% HEMA) Example 19: 35% "" "(65% HEMA)

0.1% tert-butyl peroctoate are added and the Solutions in film casting molds reacted at 80 C for 2 hours; the foils are removed and kept in a vacuum oven (0.25 mmHg) for 16 hours at 100 ° C .; they are afterwards tough and pliable; their degree of swelling is recorded in Table V.

Table V

Example Macromeres (B) Monomer (A) DS

7 7

la la

Polypropylene oxide-to-maleimide HEMA

18 20 80 44

19 35 65 33

Example 20

53.Og polypropylene oxide-bis-maleimide according to the example and 19 are dissolved in 47.0 g of N-vinylpyrrolidone; after adding

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The mixture is poured from 0.4 g of tert-butyl peroctoate into molds and implemented as described in Example 18. A tough, slightly brown colored gel is obtained which is 46.0% of its weight absorbed in water (DS = 46.0).

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 g 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 quantities of 3.10 g of N-vinylpyrrolidone and 26.4 g of ethyl acrylate. The product obtained is a tough, colorless gel that absorbs 23.0% of its weight in water (DS = 23.O).

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 its weight in water

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Examples 24-26

The process according to Example 2 is repeated, with the exception that the polytetramethylene which is end-saturated with isocyanate 3000 molecular weight oxide (ADIPRENE L-42) at concentrations of 15% for Example 24, 25% for Example 25 and 33% for Example 26 is used and 2.0 percent by weight pyribenzamine HC1 ^ -% a drug with anti-axstamine action, is dissolved in each sample just before polymerization.

Example 27

The process according to Example 7 is repeated with the exception that immediately before the polymerization, 4% by weight of pyribenzamine · HCl to be dissolved in the monomeric mixture.

Foil samples of the same thickness, obtained according to Examples 24 27, are at 37 ° C for 16 hours in an HCl / NaCl solution (pH 2.15) extracted. The amount of drug extracted from each slide is included in the solution at 314 during the process a Beckman Acta C III ultraviolet spectrometer determined at different times by determining the amplitude of that characteristic of pyribenzamine Absorption peak is measured.

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The one needed to extract 50% of the pyribenzamine The time is 2 hours, or 4 hours, or 6 1/2 hours for the samples obtained according to Examples 24, 25 and 26, respectively. This illustrates the adaptability of the diffusion rate in the products produced according to the invention. For comparison, a sample of material of the same thickness from Example 27 gave 50% drug release in less than one Hour.

Examples 28-29

The process according to Example 1 is repeated with the exception that the polytetramethylene oxide which is end-saturated with isocyanate has a molecular weight of 600 (ADIPRENE L-315) and in concentrations of 20% by weight for example 28 and 40% by weight for example 29 is used, 3.7 % dexamethasone ·., A synthetic steroid hormone, being dissolved in each batch immediately before polymerization.

Example 30

The process according to Example 7 is repeated, with the exception that 3.7% dexamethasone is immediately in the monomer mixture is dissolved prior to polymerization.

Foil samples of approximately the same thickness, obtained according to Examples 28-30, are placed in water at 25 ° C. for 240 hours

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' 2529068

extracted. The amount of drug withdrawn from each slide will be during the procedure at various times with a Beckman

Acta III ultraviolet spectrophotometer by determining the amplitude the characteristic absorption peak of dexamethasone in the solution was measured at 242 nm.

It was found that more than 95% of the steroid originally dissolved in a sample of material according to Example 30 is extracted within 140 hours, while in the same time only 33 % of the drug included in the sample according to Example 28 is extracted and only 12 % of the steroid from the sample according to Example 29, which illustrates the valuable applicability of the long-term release by the water-insoluble material obtained according to the present invention.

Example 31

To 150 g of N-vinylpyrrolidone, 200 g of isocyanate end-saturated Polytetramethylene oxide (MW 3000) and 50 g of 2-hydroxyethyl methacrylate given. The solution is stirred at 25 ° C. in an inert atmosphere for one week. After this time has elapsed the termination of the reaction between diisocyanate and HEMA is determined by the disappearance of the NCO band in the infrared spectrum of the final product confirmed. This is kept and serves as the starting material for the manufacturing process according to Examples 32-44.

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Example 32

20.0 g of the starting material according to Example 31 are mixed with (enough) tert-butyl peroctoate catalyst (to the Bring final concentration of catalyst to 0.4% by weight). The mixture is put into a closed mold for making a Foil 1 mm thick given. The mold is placed in a hot air oven to polymerize at 80 ° C. for 2 hours to complete. The polymer film is removed from the casting mold and kept at a temperature of 80 ° C. in a vacuum for 18 hours exposed by 0.1 mm. The product is a clear, tough film, the degree of swelling of which is determined.

Example 33

The procedure of Example 32 is repeated except that 1.0 g of HEMA and 4 g of N-vinylpyrrolidone are added before the addition of the peroxide can be added.

Example 34

The procedure of Example 32 is repeated except that 2.0 g of HEMA and 3.0 g of N-vinylpyrrolidone are added before the peroxide is added to be added.

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Example 35

The procedure of Example 32 is repeated with the exception that 4.0 g of HEMA and 1.0 g of N-VP to the starting material (according to Example 32) are added.

Example 36

The procedure of Example 32 is repeated with the exception that 5.0 g of HEMA is added before the peroxide is added.

Example 37

The procedure of Example 32 is repeated except that 3.0 g of N-VP and 27.0 g of HEMA are added prior to the peroxide addition be added.

Example 38

The procedure of Example 32 is repeated except that 24.0 g of HEMA and 6.0 g of N-VP are added prior to the peroxide addition attached.

Example 39

The procedure of Example 32 is repeated with the

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-Jim -

Exception that 15.0 g each of HEMA and N-VP are added before the peroxide is added.

Example 40

The procedure of Example 32 is repeated except that 5.0 g of N-VP and 25.0 g of HEMA are added prior to the peroxide addition be added.

Example 41

The procedure of Example 32 is repeated with the exception that 3.53 g of ethyl acrylate are added before the peroxide is added will.

Example 42

The process according to Example 32 is repeated with the exception that 6.67 g of ethyl acrylate are added before the peroxide is added will.

Example 43

The process according to Example 32 is repeated with the exception that 10.8 g of ethyl acrylate are added before the peroxide is added will.

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-VS-

Example 44

The procedure of Example 32 is repeated with the exception that 20.0 g of ethyl acrylate are added before the peroxide is added will.

The composition and degree of swelling of the gels according to Examples 32-44 are summarized in Table VI.

Table VI NVP Monomer (A)% Swelling - ^A s ^A i Degree example Macromeres (B)% 37.5 + HEMA EA ADIPRENE L-42 + HEMA 46 98.5 - 52 42 8.5 - 26th 7th - 34 11.8 - 71 32 54 30th 14.8 - 60 33 43.2 69 22.8 - 50 34 43.2 63 26.8 - 41 35 43.2 45 9.4 - 173 36 43.2 25th 15.4 - 153 37 21.6 31.9 33.4 - 93 38 21.6 28.1 53.4 - 55 39 21.6 24.4 7.2 15th 82 40 21.6 18.8 6.4 25th 71 41 39.1 5.5 35 56 42 34.5 4.2 50 28 43 22.4 44 23

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The polymer product according to Example 5 is sliced from 2.5 mm in diameter and 1.Ö mm thick. 5.8 g of this Discs are suspended for 48 hours at room temperature while stirring in a solution of 30% by weight pyribenzamine HCl in water * The final weight of the swollen slices is 9.6 g » They are washed with distilled water and dried in vacuo (0.1 mmHg) at 60 ° C until the weight is equal to that 6.85 g results, which corresponds to a pyribettzamine HCl content of 15.3% im Polymers corresponds to *

The pattern is in an artificial hag sap at 37 ° C 50% of its drug content in 2 hours, and 85% in 9 hours.

Example 46

A. Production of "the macrpmeren basic substance :

2000 parts (1 mole) molecular weight polytetramethylene oxide 2000 (Polymeg 2Ö0Ö) are melted in a 5 liter three-necked flask poured and heated under vacuum to 80 C for 1 hour to remove any moisture that was 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 moles) of isophorone dilsocyanate and 1 g of triethylamine were added, the temperature being increased to 80.degree. After this

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the isocyanate content after 5 hours to approximately 3.5% (the determination done by titration), the reaction mixture is cooled to 40 ° C. and then with 1630 parts HEMA (2-hydroxyethyl methacrylate) and 0.24 g of dibutyltin dilaurate (DBTL) offset. The reaction mixture is left with stirring in a nitrogen atmosphere until the Cool residual isocyanate (IR) to room temperature.

B. Production of crosslinked, hydrophilic polymers :

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

Composition Example 46 Macromer (%) HEMA (%) NVP (%)

a b c d

For each monomer-macromeric mixture obtained, 0.2 part of tert-butyl peroctoate was added, dissolved and the resulting Solutions are injected into casting molds (30 cm χ 30 cm) made of glass, which are lined with Mylar ^ - polyester films,

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68 32 - 45 55 - 34 66 - 11 89 - 22nd 53 25th 22nd 33 45 22nd 15th 63

using 1.6 mm wide silicone strips as spacers. The polymerization is done in a hot air oven
3 hours of heating to 80 ° C and 1 hour of heating to 100 ° C carried out. The casting molds are removed, cooled to room temperature and the hydrogel films obtained are then characterized.

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 46 Degree of swelling I ₀ example tensile strenght
dry wet 1140 Extensibility%
dry wet 210 a 10 2720 490 170 160 b 20th 3460 340 130 145 C. 27 4290 120 110 120 d 47 5910 110 50 73 e 61 5950 85 58 60 f 96 6620 24 67 20th G 138 7100 40 47

125.0 g (0.13 mol) of polyoxypropylene, MW 995, are in
Poured into a 500 ml three-necked flask and dried for 1 hour at 80 C / 2 mmHg. 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

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door is increased to 80 ° C. After 18 hours of reaction time is the isocyanate content 5.8% (theoretical value = 5.84% isocyanate). The reaction mixture is cooled to 40 ° C. 172.8 g (1.3 mol) of 2-hydroxyethyl methacrylate (HEMA) are added to 115.2 g of the above The reaction mixture is added and 9.6 mg of dibutyltin dilaurate (dibutylbis (lauroyloxy) tin) are added. The reaction mixture is kept at a temperature of 40 C until the residual isocyanate has completely disappeared.

Example 48

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 mmHg 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 increased 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 dilaurate are added. The reaction mixture is kept at a temperature of 40 ° C. until the residual isocyanate has completely disappeared.

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Example 49

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 mmHg 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 isophorone diisocyanate and 56 mg of 1,4-diazabicyclo [2.2.2] octane (Dabco, 1 mol%) are added, the reaction temperature being increased 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 heated to 40.degree. cooled down. 308.0 g (2.37 mol) of 2-hydroxyethyl methacrylate (HEMA) are added to 205.3 g of the reaction mixture obtained above, and 17 mg of dibutyltin dilaurate (dibutylbis (lauroyloxy) tin) are added. The reaction mixture is kept at a temperature of 40 ° C. until the residual isocyanate has completely disappeared.

Example 50

145.9 g (0.074 mol) of a molten polyester diol, MW 1965, are poured into a 500 ml three-necked flask and dried at 80 ° C / 2 mmHg for 1 hour. The vacuum is through Introduction of dried nitrogen gas, and the contents lifted cooled to 40 ° C. To this end, 33.0 g (0.15 mol) of isophorone diisocyanate are added and 83 mg of 1,4-diazabicyclo [2.2.2] octane (Dabco) added and the temperature increased to 80 ° C. After 7 hours of reaction

2/0988

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) will be added to 148.0 g of the reaction mixture obtained above and mixed with 12 mg of dibutyltin dilaurate. The reaction mixture is Maintained at a temperature of 40 ° C. until the residual isocyanate has completely disappeared.

Example 51

0.1 g of tert-butyl peroctate are added to 50.0 g of the reaction mixtures (compounds) obtained in each case in Examples 47-50 added and dissolved with stirring. The resulting mixture is degassed at room temperature in a vacuum of 1 mmHg until no more rising bubbles can be observed and then poured into a mold made of glass, which is covered with Mylar polyester film lined and sealed with 1 mm wide silicone tape. The molds are made in a hot air oven At 80 ° C for 3 hours and then at 100 ° C for 1 hour heated. The films obtained are removed from the cooled casting molds stripped out and cut into samples for analysis and physical testing.

The degree of swelling (DS) and tensile strength for the hydrogels obtained according to Examples 47-50 are as follows Table specified:

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-SZ-

ZS? 8O68

Example Degree of swelling% Tensile strength Extensibility%

dry wet dry wet

47 20th 48 22nd 49 29 50 19th

3980 433 89 111 3750 280 112 180 3600 250 113 126 4600 656 131 191

Example 52

The reaction mixture obtained according to Example 46 d) is polymerized to form sheets 0.5-1.5 mm thick. The films are kept in running water at a temperature of 40 ° C. for 3 days long washed. When wet, tablets of various diameters are cut from these foils. After drying at 80 ° C in a vacuum, tablets with a diameter of 1.2-4.0 mm are obtained,

Example 53

The reaction mixture obtained according to Example 46 c) is polymerized analogously to Example 52 and the resulting Foil ground in a grinder into polyhedral particles of various average diameters. These Particles are then washed in running water for 3 days at 40 C, dried and the particles on the hand of the various Particle sizes using a set of standard sieves with openings classified between 0.18 and 2.4 mm. All particles smaller than 0.18 mm in diameter are discarded.

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-Si '

Example 54

A tablet is selected from the tablets obtained according to Example 52 and placed in a 40% aqueous solution of triple amine hydrochloride (2- [benzyl (2-dimethylaminoethyl) amino] pyridine) allowed to swell for a period of 48 hours. Then the tablet is swiveled in water and up to Achieving a constant weight when dried. The weight gain of the tablet indicates that 30.7% is tripelennamine hydrochloride was added as the last component. The thickness of this specimen increased to 1.9 mm. The tablet that Contains 37.2 mg tripelennamine hydrochloride is added to an amount of 1 liter of artificial gastric juice at a temperature of 37 ° C added. The amount of drug released is measured spectrophotometrically as a function of time. The course of the Release behaves in such a way that 25% of the total drug content within half an hour, 50% after 2.2 hours, 75% after 5.5 hours and 90% after 10.5 hours.

Example 55

The particles, which according to Example 53 have an average diameter of 1.4 mm, are in a 40% strength aqueous tripelennamine hydrochloride solution for a period of Left to swell for 48 hours. The tablet is then swiveled in water and dried until it has a constant weight. The increase in weight of the particles indicates that 17.5% of tripleennamine hydrochloride was the last component.

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has been taken. The amount of the particles, which corresponds to 30 mg of the active component, is weighed into a rapidly dissolving capsule and added to an amount of 1 liter of artificial gastric juice at a temperature of 37 ° C. The amount of drug released is measured spectrophotometrically as a function of time. The course of the release is such that 25% of the total drug content occurs after 0.17 hours, 50% after 0.81 hours, 75% after 2.9 hours and 90% after 7.8 hours.

Example 56

The particles, which according to Example 53 have an average diameter of 1.7 mm, are left to swell in a 22% strength solution of phenformin hydrochloride for a period of 48 hours. An ethanol-water mixture (3: 1) is used as the solvent system. After drying, the increase in weight shows that the total drug uptake is 18% of phenformin hydrochloride. The amount of the particles, which corresponds to 50 mg of the active component, is weighed into a rapidly dissolving capsule and added to an amount of 1 liter of artificial gastric juice at a temperature of 37 ° C. The amount of drug released is measured spectrophotometrically as a function of time. The course of the release is such that 25 % of the total drug content occurs after 0.75 hours, 50% after 2.25 hours, 75% after 5 hours and 90 % after 9 hours.

509882 / 098S

A tablet is selected from the tablets obtained according to Example 52 and placed in a 30% aqueous solution swelled by imipramine hydrochloride for 72 hours. After drying, it is found that the tablet has a thickness of Reached 0.75 mm and the weight gain indicates a total drug intake of 33.6% imipramine hydrochloride took place. The tablet containing 50 mg imipramine hydrochloride contains, is added to an amount of 1 liter of artificial gastric juice at a temperature of 37 ° C. The amount of the Drug is determined spectrophotometrically as a function of time. The course of the release behaves in such a way that 25% of the total drug content takes place after 1 hour, 50% after 2.5 hours, 75% after 5 hours and 90% after 8.75 hours.

Example 58

The particles, which according to Example 53 have an average diameter of 0.425 mm, are in a 50% strength Solution of sulfinpyrazone in chloroform left to swell for a period of 48 hours. These particles are in the flowing Washed with water and dried to constant weight. The increase in weight of the polymer particles indicates this indicate that 10.3% sulfinpyrazone was absorbed as the last component. The amount of particles containing 11.7 mg of the active Component is equivalent to being in a rapidly dissolving

S09882 / 0988

Capsule weighed in and added to an amount of 1 liter of artificial gastric juice at a temperature of 37 C. The amount of sulfinpyrazone released is determined spectrophotometrically as a function of time. The course of the release is such that 25% of the total drug content occurs after 0.21 hours, 50% after 1.20 hours, 75% after 4.94 hours and 90 % after 10.20 hours.

Example 59

A tablet is selected from the tablets obtained according to Example 52 and allowed to swell in a 21% strength aqueous solution of hydralazine. The hydralazine solution is prepared by dissolving 10 g of hydralazine hydrochloride in 2N sodium hydroxide solution until a pH value of 8 is reached. The tablet continues to adsorb for 72 hours. After drying, the increase in weight indicates that the last component was 10.7 % hydralazine. The tablet, which contains 11 mg of hydralazine, is added to an amount of 1 liter of artificial gastric juice at a temperature of 37 ° C. The amount of hydralazine released is determined spectrophotometrically as a function of time. The course of the release is such that 25% of the total drug content occurs after 0.53 hours, 50% after 3.33 hours, 75% after 7.87 hours and 90% after 13.3 hours.

5098 8 2/0988

Example 60

The particles, which according to Example 53 have an average diameter of 1.4 mm, are in a 21% strength left to swell aqueous solution of hydralazine. The hydralazine solution is prepared as described in Example 59. The adsorption the tablet is continued for 72 hours. After drying, the weight increase indicates that the last component is 4.2% has been added to hydralazine. It then becomes the amount of particles that corresponds to 20 mg of the active substance in one fast-dissolving capsule weighed in and added to an amount of 1 l of artificial gastric juice at a temperature of 37 C. The amount of hydralazine released is determined spectrophotometrically as a function of time. The course of the release is cautious so that 25% of the total drug content after 0.2 hours, 50% after 0.86 hours, 75% after 2.50 hours and 90% after 4.94 hours takes place.

Example 61

The particles, which according to Example 53 have an average diameter of 0.7 mm, are in a 22% solution swelled by maprotiline hydrochloride. The solution is prepared by adding 10 g of maprotiline hydrochloride in 45 g of a methanol / chloroform mixture (33:67) resolves. Adsorption continues for 48 hours. After swirling in water and drying overnight, indicates the weight gain that the last com-

509882/0988

2128068

component 12.8% has been added to maprotiline, is then the amount of particles containing 90 mg of active substance corresponds, in a quick-disintegrating capsule weighed into ~ and an amount of 1 1 artificial gastric juice a temperature of 37 ^Q C added. The amount of maprotiline hydrochloride released is determined spectrophotometrically as a function of time. The course of the release is such that 25% of the total dose takes place in 0.67 hours, 50 % in 3.67 hours, 75% in 13.4 hours and 90% in 23.4 hours,

Example 62

The particles, which according to Example 53 have an average diameter of 1.7 μm , are left to swell for 48 hours in a 26% strength solution of methylphenidate hydrochloride. A mixture of methanol / water (27:73) is used as the solution system. After swirling in water and drying overnight, the increase in weight indicates that 26.7 % of methylphenidate hydrochloride was the last compound to have been taken up. The amount of particles corresponding to 270 mg of the active substance is then weighed into a rapidly dissolving capsule and added to an amount of 0.5 l of artificial gastric juice at a temperature of 37 C. The amount of methylphenidate hydrochloride released is a function of time determined spectrophotometrically. The course of the release is such that 25% of the total dose takes place in 0.67 hours, 50% in 3.0 hours, 75% in 7.8 hours and 90% in 14.2 hours.

509382/0988

Example 63

15 g of the monomer-macromer mixture described in Example 46c are mixed with the following compounds as indicated and enumerated below. To this mixture, 0.08 g tert-Butyl peroctoate is added and the solution or dispersion obtained is degassed and poured into casting molds lined with Mylar polyester film Injected from glass (30 χ 30 cm), which are 1.4 mm thick and sealed with silicone tape. The polymerization will in a hot air oven by heating to 80 ° C for 3 hours and 1 hour heating at 100 ° C carried out. After cooling down the sample foils are taken out and used for diffusion measurements used.

Active substances Example 63 Code Amount in g Appearance of the product

transparent, yellow, flexible layer transparent, white, flexible layer tarnished, yellow, hard foil

transparent, amber-colored, pliable layer

transparent, white, hard film
cloudy, almost white, hard film
semi-transparent, yellow, hard film, cloudy, white, hard film
transparent, yellow, hard layer

a A. 15th b B. 15th C. C. 15th d D. 15th e E. 10 f F. 3.8 G G 3.8 H H 5.0 • I. 15th

509882/0988

Explanation of the code :

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

B 0- [5-talor-1- (1-methylethyl) -lH ~ l, 2,4 ^ triazol-3-yl] jD, 0-dimethyl-phosphorothioate (insecticide)

C 2,6-dimethyl-N-ß-methoxyethyl-chloroacetanilide (herbicide) D N '- (4-chloro-o-tolyl) -N, N-dimethylformamidine (insecticide)

E Ο, Ο-dimethyl phosphorodithioate S-ester with 4- (mercaptomethyl) -2-methoxy-A ^ -1,3,4-thiadiazolin-5-one (insecticide)

F 2- [4-chloro-6- (cyclopropylamino) - !, 3,5-triazin-2-yl-amino] -2-methylpropanenitrile (Herbicide)

G S - [(6-chloro-2-oxooxazolo (4,5-b) pyridin-3 (2H) -yl] ethyl) 0,0-dimethyl-phosphorothioate (Insecticide)

H 2- (tert-butylamino) -4- (ethylamino) -6- (methylthio) -s-triazine (Herbicide)

I 0,0-diethyl O- (2-isopropyl-6-raethyl-4-pyrimidinyl) phosphorothioate (Insecticide, nematocide)

Example 64

15 g of the monomer / macromer mixture described in Example 46 f are mixed with the following compounds listed below. 0.08 g of tert-butyl peroctoate are added to this mixture and the resulting solution degassed and covered with Mylar polyester film Lined molds made of glass (30 χ 30 cm) injected, which are 1.4 mm thick and sealed with silicone tape will. The polymerization is carried out in a hot air oven for 3 hours Heating to 80 ° C and heating to 100 ° C for 1 hour carried out. After the molds have cooled down, the samples are removed and used for diffusion measurements.

509882/0 9 88

a K 10 b L. 1.7 C. M. 3.8

Active substance example 64 Code Amount in g Appearance of the product

cloudy, white, hard foils, transparent, yellow, stretchy foils white, cloudy, hard foils

Explanation of the code:

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

Example 65

9.89 g of a hydrophilic polymer, prepared as described in Example 46b, are added to 20 g of N- (cyclopropylmethyl) -a, a, cc-trifluoro-2,6-dinitro-N-propyl-p-toluidine (a herbicide) immersed for 5 days. Then the polymer is removed, washed with methanol, air dried and weighed. The dried polymer weighs 11.22 g, which in its composition is a polymer corresponds, which contains 11.8% active ingredient.

In an analogous manner, the polymer described in Example 46e is dissolved in a 5% strength solution of sodium iron ethylenediamine di- [o-hydroxyphenyl acetate] (a Iron preparation) immersed in methanol. The dried polymer contains 15% active substance.

509882/0988

2528061

Example 66

Diffusion measurements are made at a temperature of 25 C in water buffered with secondary sodium citrate (pH = 5) carried out, iii a sample of the delivery system as in the table indicated iii 1 1 of the stirred buffer solution is immersed. Measured Quantities are taken periodically and the proportion of the total active ingredient ^ released by polymers, is determined spectrophotometrically.

Example 63 number the necessary Hours to release 25 % 50% ' 75 % 90 % a 60 b 3.0 7.5 18.0 30.0 e 4.2 16.5 50.0 17O.0 H 9.0 35.0 120.0 300 i 12.0 48.0 72 72 Example 67

The component obtained according to Example 63 d) is comminuted to particle sizes of 0.18 to 0.25 mm and filled into a cylinder through which air flows in an amount of 20 liters per minute and at 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% takes place after 48 hours, 50% after 300 hours, 75 % after 1050 hours and 90 % after 2000 hours.

509 8 82/0 988

Example 68

Fragrances (aromas) of known compounds are incorporated into the hydrogel polymer, which is obtained according to method 46 c), included by carrying out the polymerization in the presence of the following mixtures.

Formulas lilac Roses Fragrances jasmine violet clove 30th 35 lily of the valley 5 20th 25th Phenylethyl alcohol 30th - 15th 6th 5 5 Hydroxycitronellal 2 48 45 2 4th 5 Geraniol 4th 2 20th 45 1 1 Amylcinnamaldehyde 5 4th 5 40 10 3 Benzyl acetate 3 4th 5 - 60 4th Ionon 1 2 5 - - 55 Eugenol 25th 5 - 2 - 2 Terpineol 5

All of the fragrances yielded clear, see-through (translucent) polymer films that held the fragrances in a prolonged period of time return.

Example 69

The procedure described in Example 47 is repeated, but using one instead of hydroxyethyl methacrylate equivalent amount of 3-hydroxypropyl methacrylate to the macromer monomer mixture to manufacture. The polymerization takes place as described in Example 51. The film obtained is unbreakable and flexible

509882/0988

and translucent and adsorbs 15% water. (Degree of swelling = 15)

Example 70

The particles, which according to Example 53 have an average diameter of 0.6 mm, are allowed to swell in a 20% strength solution of chloinipramine hydrochloride. The solution is prepared by dissolving 10 g of chlomipramine hydrochloride in 40.0 ml of water. The absorption continues for 72 hours. After swirling in water and drying, the increase in weight indicates that 10.6% of chlomipramine hydrochloride was taken up as the last compound. The amount of particles corresponding to 45 mg of the active substance is then 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 spectrophotometrically as a function of time. The course of the release is such that 25 % of the total dose occurs in 0.5 hours, 50% in 2.2 hours, 75% in 5.9 hours and 90 % in 11.0 hours.

Example 71

The procedure is repeated as described in Example 46 ^ with the exception that the layer cover of the film produced is 1.15 mm. The slide is in running water Washed for 3 days and cut tablets with a diameter of 1.27 mm from it after drying.

509882/0988

Example 72

A tablet produced according to Example 71 is picked out and left to swell for 48 hours in a 20/0 strength aqueous solution of imipramine hydrochloride. After drying, it is found that the tablet has now reached a thickness of 1.44 mm. The increase in weight indicates that the total uptake of active substance is 22.6% imipramine hydrochloride. The tablet, which contains 46.3 mg of imipramine hydrochloride, is added to an amount of 1 liter of artificial gastric juice at a temperature of 37.degree. The amount of imipramine hydrochloride released is determined spectrophotometrically as a function of time. The course of the release behaves so that 25% of the total dose is carried out in 1.8 hours, 50% in 3.72 hours, 75% in 9:40 hours and 90 _O 7 in 17.3 hours.

Example 73

A tablet prepared according to Example 71 is selected and in a 207 _o aqueous solution of Chlomipraminhydrochlorid long 48 hours allowed to swell. After drying, it is found that the tablet has now reached a thickness of 1.38 mm. The increase in weight indicates that the total uptake of active substance is 19.5% of chlomipramine hydrochloride. The tablet, which contains 37.3 mg of active substance, is added to an amount of 1% artificial gastric juice at a temperature of 37 ° C. The amount of chlomipramine hydrochloride released is determined spectrophotometrically as a function of time. The history

509802/0388

the release is such that 25% of the total dose in 1.33 hours, 50% in 4.03 hours, 75% in 10.2 hours and 90% done in 18.7 hours.

509882/0988

Claims (114)

Claims 1. Process for the production of a water-insoluble hydro- /
phile gels, characterized in that one A) about 30% to about 90% of a hydrophilic a) Polymers from identical or different water-soluble mono-olefinic monomers, or b) copolymers of said water-soluble monomer with 1 % to 70 % of the same or different, water-insoluble mono-olefinic monomers with B) about 10 % to about 70 % of a terminal diolefinic hydrophobic macromer having a molecular weight of about 400 to about 8,000 is co-polymerized. 2. The method according to claim 1, characterized in that the copolymerization of a water-soluble monomer A) is carried out with a hydrophobic macromer B) in the presence or absence of solvents. 3. The method according to claims 1 and 2, characterized in that the copolymerization of a water-soluble monomer A) with a hydrophobic macromer B) in the presence of a free radical forming catalyst or system at a temperature in the range from approx. 40 ° C to 150 ° C. 5 09882/0988 4. Process according to claims 1-3, characterized in that the co-polymerization of a water-soluble monomer A) with a hydrophobic macromer B) in the presence of about 0.02% to 1.0 % (Too by weight) of a suitable, free radical-forming catalyst at a temperature of 50-100 ° C. 5. Process according to Claims 1-4, characterized in that the free radical-forming catalysts are peroxy or Catalysts which donate alkyl radicals are used. 6. Process according to Claims 1-5, characterized in that the catalysts which form free radicals are diisopropyl perdicarbonate, tert-butyl peroctate, benzoyl peroxide, decanoyl peroxide, Lauroyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert-butyl peroxyacetate or azoisobutyronitrile is used. 7. The method according to claims 1-5, characterized in that for the copolymerization as free radicals forming Catalysts used water-soluble peroxy compounds. 8. Process according to Claims 1-5 and 7, characterized in that the water-soluble peroxy compounds used are sodium, Potassium or ammonium persulfate is used. 509882/0988 9. The method according to claims 1-3, characterized in that the free radical-releasing system is gamma rays, electron beam blind or UV radiation is used. 10. The method according to claims 1-9, characterized in that that the water-soluble monomers A) a) acrylic acid or methacrylic acid, or water-soluble esters,
Amides or imides thereof, b) mono-olefinic salts thereof or c) Polymers of a mono-olefinic, monocyclic-azacyclic Monomers used. 11. The method according to claims 1-10, characterized in that the water-soluble monomers acrylic acid or methacrylic acid, Hydroxyalkyl or dialkylaminoalkyl esters of the same with 2-4 carbon atoms in the alkyl radical are used. 12. The method according to claims 1-10, characterized in that the water-soluble monomers acrylic or methacrylic acid esters, which differs from an alcohol formula ^H0 - ^C m ^H 2m - ° - (CH ₂ -CH ₂ -O) _n - R, where R is hydrogen or methyl, m is an integer from 2-5 and η is a number from 1-20, derived, used. 509882/0988 13. The method according to claims 1-12, characterized in that that the water-soluble monomers amides or imides of acrylic or methacrylic acid, in which the N-substituent is hydroxyalkyl, oxaalkyl or dialkylaminoalkyl with 2-4 C atoms in the alkyl radical is used. 14. The method according to claims 1-13, characterized in that the water-soluble monomers acrylic acid, methacrylic acid, 2-hydroxyethyl or 2- or 3-hydroxypropyl acrylate or methacrylate, N-vinylpyrrolidone or tert-amino-methacrylamide is used. 15. The method according to claims 1-14, characterized in that the water-soluble monomers 2-hydroxyethyl methacrylate used. 16. The method according to claims 1-14, characterized in that the water-soluble monomer used is N-vinyl-2-pyrrolidone. 17. The method according to claims 1-10, characterized in that the water-soluble monomers or hydroxyalkyl maleates -fumarates with 2-4 carbon atoms in the alkyl radical are used. 18. Process according to Claims 1-10, characterized in that the water-soluble monomers used are hydroxyalkyl vinyl esters 2-4 carbon atoms are used in the alkyl radical. 509882/0988 19. The method according to claims 1-10, characterized in that that the water-soluble monomers acrylonitrile or an alkyl acrylate or an alkyl methacrylate with up to 18 carbon atoms in the alkyl radical used. 20. The method according to claims 1-10, characterized in that the water-soluble monomers vinyl esters, which differ from Derive alkanecarboxylic acids with up to 5 carbon atoms, used. 21. Process according to Claims 1-9, characterized in that the hydrophobic macromers B) are compounds of the formula R ₃ R ₂ R ₂ R ₃ ti Il HC = CXYR ₁ -YXC = CH or HC - CO CO - CH "NR ^ HC - CO '"CO-CH used in which R, a polycondensate chain with a molecular weight of about 200 to about 8000, which contain hydrocarbon radicals bound via ethers, esters, amides, urethanes or urea; R ₂ is hydrogen, methyl or -CH ₂ -COOR ,, in which R is hydrogen or alkyl with up to 10 carbon atoms; R ₃ is hydrogen or COOR, with the proviso that at least one 3 8 2/0968 of R ₂ and R “denotes hydrogen; X is oxo, -COO- or -CONR ₁ -, in which R _{5 is} hydrogen or alkyl with up to 5 carbon atoms, and Y is a direct bond or the radical -R ₆ -Z ₁ -CO-NH-R ₇ -NH-CO-Z ₂ -wherein R _{fi is} bonded to X and denotes branched or linear alkylene radicals with up to 7 carbon atoms; Z, and Z ~ denotes Oxo or NR ₁ - and R ₇ is the divalent radical of an aliphatic or aromatic diisocyanate, with the proviso that if X is Oxo, Y must be different from the direct bond and R 1 and R 2 are Hydrogen. 22. The method according to claims 1-9 and 21, characterized in that that as hydrophobic macromers compounds in which R is a polypropylene oxide or polytetramethylene oxide chain with means a molecular weight of from about 1000 to about 4000 is used. 23. The method according to claims 1-9 and 21, characterized in that that as hydrophobic macromer compounds, in which R, a co-condensation of an aliphatic or carbocyclic, aromatic dicarboxylic acid or a diisocyanate with an aliphatic diol or diamine means chain, used. 24. The method according to claims 1-9, 21-23, characterized in that that a polytetramethylene oxide glycol with a molar weight of approx. 1000 to approx. 4000 is end-saturated as macromers 5098S2 / 0988 with toluene diisocyanate and with 2 moles of a hydroxyalkyl acrylate or methacrylate reacted with 2-4 carbon atoms in the alkyl radical, used. 25. The method according to claims 1-9, 21-24, characterized in that that a polytetramethylene oxide glycol with a molar weight of approx. 1500 to approx. 3000 is end-saturated as macromers with 2,4-toluene diisocyanate and reacted with about 2 moles of 2-hydroxyethyl methacrylate, used. 26. A water-insoluble hydrophilic gel consisting of: A) about 30% to about 90% of a hydrophilic a) Polymers from identical or different water-soluble mono-olefinic monomers, or b) Copolymers of the water-soluble monomers mentioned with 1 to 70% of identical or different, water-insoluble mono-olefinic monomers Monomers, the polymer or copolymer being crosslinked with B) about 10% to about 70% of a terminally diolefinic hydrophobic macromers having a molecular weight of from about 400 to about 8,000. 27. A gel according to claim 26, wherein said water-soluble Monomers a) Acrylic acid or methacrylic acid, or water-soluble esters, amides or imides thereof, or 309882/0988 b) mono-olefin salts thereof or c) are polymers of a monoolefinic, monocyclic-azacyclic monomer. 28) A gel according to claim 26, wherein said water-soluble Monomers are acrylic acid or methacrylic acid, hydroxyalkyl or dialkylaminoalkyl esters thereof, where alkyl is 2 to 4 Has carbon atoms. 29) A gel according to claim 26, wherein said water-soluble Monomers are acrylic or methacrylic acid esters that differ from an alcohol of the formula HO - CH ₀ - O - (CH ₀ -CH ₀ -O) - R, m Zm Z Zn where R denotes hydrogen or methyl 2 to 5 and η 1 to 20 is derived. 30) A gel according to claim 26, wherein said water-soluble Monomeric amides or imides of acrylic or methacrylic acid, in which the N-substituent is hydroxyalkyl, oxaalkyl or dialkylaminoalkyl is wherein alkyl has 2 to 4 carbon atoms. 31) A gel according to claim 26, wherein said water-soluble Monomers acrylic acid, methacrylic acid, 2-hydroxyethyl or 2- or 3-hydroxypropyl acrylate or methacrylate, N-vinylpyrrolidone or tert-amino methacrylamide. 9882/0988 32) A gel as claimed in claim 26, wherein said water soluble monomer is 2-hydroxyethyl methacrylate. 33) A gel as claimed in claim 26, wherein said water soluble monomer is N-vinyl-2-pyrrolidone. 34) A gel according to claim 26, wherein said water-soluble monomers are hydroxyalkyl maleates or fumarates, wherein
Alkyl has 2 to 4 carbon atoms. 35) A gel according to claim 26, wherein said water-soluble Monomers are hydroxyalkyl vinyl esters, where alkyl is 2 to Has 4 carbon atoms. 36) A gel according to claim 26, wherein said water-soluble Monomers are acrylonitrile or an alkyl acrylate or methacrylate, where alkyl has up to 18 carbon atoms. 37) A gel according to claim 26, wherein said water-soluble monomers are vinyl esters which are different from alkanecarboxylic acids
derive with up to 5 carbon atoms. 38) A gel according to claim 26, wherein said water-soluble Monomers are styrene or a vinyl alkyl ether, where alkyl has up to 5 carbon atoms. 5098Ö2 / 0988 39) A gel enjoyed claim 26 wherein said macromers the formula Rn RO "-O " 3 Il It HC = CXYR ₁ -YXC = CH or HC - CO. CO - CH ¹¹ ^ NR, -KC " HC - CO '"' * ^ CO-CH has, wherein R _{1 has} a polycondensate chain with a molecular weight of about 200 to about 8000, which contain hydrocarbon radicals bound via ethers, esters, amides, urethanes or urea; R ₂ is hydrogen, methyl or -CH ₂ -COOR ,, in which R is hydrogen or alkyl with up to 10 carbon atoms; R- is hydrogen or COOR ,, with the proviso that at least one of R ₂ and R "is hydrogen; X is oxo, -COO- or -CONR ₅ , in which R ₁ - is hydrogen or alkyl with up to 5 carbon atoms, and Y is a direct bond or the radical -R ₆ -Z ₁ -CO-NH-R ₇ -NH-CO-Z ₂ -, in which R 1 is bonded to X and denotes branched or linear alkylene radicals with up to 7 carbon atoms; Z ₁ and Z ₂ denote oxo or NRc and R ₇ is the divalent radical of an aliphatic or aromatic diisocyanate, with the proviso that if X is oxo, Y must be different from the direct bond, and R ₉ and R "are hydrogen. 50900270980 40) A gel as claimed in claim 39, wherein R, a polypropylene oxide or polytetramethylene oxide chain with a Molecular weight is from about 1000 to about 4000. 41) A gel as claimed in claim 39, wherein R .. a by co-condensation of an aliphatic or carbocyclic, aromatic dicarboxylic acid or a diisocyanate, with a aliphatic diol or diamine containing chain. 42) A gel as claimed in claim 26, wherein said macromer is a polytetramethylene oxide glycol of molecular weight is from about 1000 to about 4000 endcapped with toluene diisocyanate and with 2 moles of a hydroxyalkyl acrylate or methacrylate implemented, wherein alkyl has 2 to 4 carbon atoms. 43) A gel as claimed in claim 42, wherein the polytetramethylene oxide glycol has a molar weight of about 1500 to about 3000 and the hydroxyalkyl methacrylate is 2-hydroxyethyl methacrylate. 44) A gel as claimed in claim 43, wherein approximately 15% to about 50% of said macromers can be used. 45) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a pharmaceutical active substance consists. 5Ö98S2 / 0986 46) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an anabolic. 47) Pharmaceutical composition according to claim 46, characterized characterized that methandrostenolone is used as an anabolic. 48) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an analgesic. 49) Pharmaceutical composition according to claim 48, characterized characterized in that acetylsalicylic acid is used as an analgesic. 50) Pharmaceutical composition according to claim 48, characterized characterized in that one uses phenylbutazone as an analgesic. 51) Pharmaceutical composition according to claim 48, characterized in that the analgesic used is methadone. 52) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an androgen. 9082/0966 53) Pharmaceutical composition according to claim 52,
characterized in that the androgen used is methyltestosterone. 54) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antibiotic. 55) Pharmaceutical composition according to claim 54, characterized in that the antibiotic used is rifampin, 56) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antidepressant. 57) Pharmaceutical composition according to claim 56, characterized characterized by using imipramine as an antidepressant. 58) Pharmaceutical composition according to claim 56, characterized in that the antidepressant is maprotiline
used. 59) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antidiabetic. 60) A pharmaceutical composition according to claim 59, characterized in that the antidiabetic used is phenformin. 509B62 / 0988 61) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an anticonvulsant. 62) A pharmaceutical composition according to claim 61, characterized in that the anticonvulsant is carbamazepine used. 63) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antihistamine. 64) A pharmaceutical composition according to claim 63, characterized in that the antihistamine is tripelennamine used. 65) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antihypertensive agent. 66) Pharmaceutical composition according to claim 65, characterized in that the antihypertensive is hydralazine used. 67) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antimicrobial agent consists. 509882/0988 68) Pharmaceutical composition according to claim 67, characterized in that the antimicrobial agent used Tr imethopr in use. 69) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an anti-parasitic agent consists. 70) A pharmaceutical composition according to claim 69, characterized in that the antiparasitic agent Nifurtimox used. 71) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an anti-Parkinson agent. 72) A pharmaceutical composition according to claim 71, characterized in that the anti-Parkinson agent levodopa used. 73) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an anti-inflammatory agent. 74) A pharmaceutical composition according to claim 73, characterized in that naproxen is used as the antiphlogisticum. 509882/0988 75) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an antitussive. 76) Pharmaceutical composition according to claim 75, characterized in that the antitussive used is benzonatate. 77) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and an appetite suppressant. 78) Pharmaceutical composition according to claim 77, characterized marked that one uses Mazindol as an appetite suppressant. 79) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a bronchodilator. 80) Pharmaceutical composition according to claim 79, characterized in that the bronchodilators used are fenoterol
used. 81) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a coronary dilator. 82) 'Pharmaceutical composition according to claim 81, characterized in that the coronary dilators Fenalcomin
used. 82/0980 83) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a corticoid. 84) Pharmaceutical composition according to claim 83, characterized in that the corticoid used is dexamethasone. 85) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a cytostatic. 86) Pharmaceutical composition according to claim 85, characterized in that the cytostatic used is floxuridine, 87) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a diuretic. 88) Pharmaceutical composition according to claim 87, characterized in that the diuretic is hydrochlorothiazide used. 89) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a hypnoticum. 90) Pharmaceutical composition according to claim 89, characterized characterized in that glutethimide is used as a hypnotic. 50 9 882/0988 91) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a neuroleptic. 92) Pharmaceutical composition according to claim 91, characterized in that reserpine is used as the neuroleptic. 93) Pharmaceutical composition according to claim 91, characterized in that the neuroleptic used is thioridazine. 94) Pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a psychoanaleptic. 95) Pharmaceutical composition according to claim 94, characterized in that the psychoanaleptic is methylphenidate used. 96) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a tranquilizer. 97) Pharmaceutical composition according to claim 96, characterized in that the tranquilizer used is diazepam. 98) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a uricosuricum. 509882/0988 99) Pharmaceutical composition according to claim 98, characterized characterized in that one uses as Uricosuricum SuIfinpyrazon. 100) A pharmaceutical composition consisting of a hydrogel according to claims 26-44 and a vasodilator. 101) Pharmaceutical composition according to claim 100, characterized in that isoproterenol is used as the vasodilator used. 102) Fragrance-releasing compositions which consist of a fragrance and a hydrogel according to claims 26-44. 103) Pesticidal compositions that consist of a hydrcgel according to claims 26-44 and a pesticide exist. 104) Herbicidal compositions which consist of a hydrogel according to claims 26-44 and a herbicide. 105) Process for the preparation of pharmaceutical compositions according to claims 45-101, characterized in that pharmaceutical active ingredients in the monomeric mixture before the Polymerization dissolves. 509882/0988 106) Process for the preparation of pharmaceutical compositions according to claims 45-101, characterized in that
pharmaceutical active ingredients are added to the monomer macromeric mixture before the polymerization. 107) Process for the preparation of pharmaceutical compositions according to claims 45-101, characterized in that
active pharmaceutical ingredients or their salts in dissolved form
can be adsorbed by a hydrogel according to claims 26-44. 108) Process for the preparation of pesticidal compositions according to claim 103, characterized in that pesticides Dissolves active ingredients in the monomeric mixture before the polymerization. 109) Process for the preparation of pesticidal compositions according to claim 103, characterized in that pesticidal active ingredients are added to the monomer-macromeric mixture before the polymerization
added. 110) Process for the preparation of pesticidal compositions according to claim 103 ^ characterized in that pesticides Allow active ingredients or their salts to be adsorbed in dissolved form by a hydrogel according to claims 26-44. 111) Process for the preparation of herbicidal compositions according to claim 104, characterized in that herbicidal 509882/0988 Active ingredients in the monomeric mixture before the polymerization 112) Process for the preparation of herbicidal compositions according to claim 104, characterized in that herbicidal Active ingredients prior to polymerization to the monomer-macromer mixture added. 113) Process for the preparation of herbicidal compositions according to claim 104, characterized in that herbicidal Active ingredients or their salts in dissolved form of a hydrogel according to Claims 26-44 can be adsorbed. 114) Process for making fragrance-releasing compositions, characterized in that fragrances are added to the monomer-macromeric mixture before the polymerization. 509382/0988