DE2528068C2 - - Google Patents

Description

The invention relates to cross-linked water-insoluble hydrophilic Gels which are suitable for use as carriers for Medicines and other active substances are suitable; further than hydrophilic membranes for separation processes, as wound dressing volumes, as body implants, e.g. B. artificial veins; as Cover layers for glass, metal, wood or ceramic and ins especially for use in cases where Festig speed and high water permeability of the polymer object of the required and as a carrier material for biological active connections, e.g. B. drugs, herbicides, insects cides, fungicides, bactericides and fragrances.

It is known weakly cross-linked, water-insoluble, but hydrophilic polymers as a carrier material for biological active, at least slightly water-soluble substances Copolymerization of a predominant part of hydrophilic 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. As mono-olefinic monomers are especially monoesters of acrylic or methacrylic acid with polyfunctional alcohols, such as. B. Ethylene glycol mono methacrylate, and in particular as a crosslinking agent special diesters of the acids mentioned with the alcohols mentioned,  such as B. ethylene glycol bis methacrylate, and the copoly merisation is carried out in the presence of water, see US Pat 32 20 960 or in an anhydrous system, see U.S. Patent 35 20 949 executed. Both low molecular weight and macro molecular, water-soluble compounds, such as. B. polyethylene oxide mono-methacrylate together with a small amount of the corresponding Bis-methacrylate were used according to US Pat. No. 3,220,960 Monomers and crosslinking agents used. The water-insoluble, but hydrophilic copolymers and their manufacturing process have been modified in various ways and to meet special needs adjusted, e.g. B. for the production of soft contact lenses (US PS 32 00 960 and Reissue No. 27 401) and the copolymers sation in the presence of linear polyamide resin to the mechanical Properties of articles molded from polymers thus obtained to improve or change (US-PS 35 20 949). Nevertheless, low molecular weight poly olefinic crosslinking agents, especially ethylene glycol bis methacrylate, used, in very small to moderate Amounts that never exceed 20% of the mono-olefinic monomer content steps. Although the copolymers of the type described above can be adapted to the various usage requirements ten, it was not possible to change the mechanical properties both in the unswollen, d. H. anhydrous state as well as swollen nen, d. H. be in equilibrium with water adapt peacefully to all purposes.  

It was also known from US-PS 32 97 745, hydrophobic Di to homopolymerize vinyl macromers or copolymers thereof To produce hydrophobic ethylenically unsaturated monomers. Find indications of copolymerization with hydrophilic monomers not there. On the other hand, it was e.g. B. also from DE-AS 10 65 621 known, exclusively water-soluble polymers or crosslink monomeric starting materials to form a hydrogel.

It is known that hydrophilic polymers, the main of which Component of monoesters of acrylic acid and methacrylic acid and a bifunctional alcohol, glass conversion system temperatures or softening points between 55 ° C and 80 ° C point. For this reason, objects are the state of the art Technology correspond, at temperatures below 55 ° C in the dry condition brittle and similar to glass. After reaching equilibrium state in water are those known in the prior art Objects soft and deformable, but also weak in terms of the bending strength; they also have low tear and shear strength what makes them sensitive to kinking or otherwise Stress. To this undesirable disadvantageous property the objects manufactured according to the prior art to avoid, they are made of deposits of stronger polymer Reinforced material, or the prepolymerized mixture is with an insoluble material such as silica gel. These aids to a certain extent increase toughness (kohäsi ven forces) (because the hydrogel acts as a putty), yet they are items thus obtained are susceptible to glassy when dry  Fracture and shear fracture in the swollen state in the Verengun (spaces) of these objects. It has a disadvantageous effect also the addition of filler material to the prepolymer by the diffusion properties and the water permeability of the Articles are changed.

The invention relates to u. a. the production of cross-linked water-insoluble hydrophilic gels with high Flexibility and elasticity both in predominantly anhydrous, as well as in the swollen state, d. H. in balance with Water or aqueous liquids such as body fluids.

Another object of the invention is the manufacture of cross-linked hydrophilic copolymers with high tensile strength in swollen condition for the uses defined above.

Another object of the invention is the production cross-linked hydrophilic copolymers with the verbs mentioned above serter properties, with a variable, effective content of  biologically active material, in particular with a therapeutic effect seed substances.

It has now been found that water-insoluble hydrophilic Copolymers consisting predominantly of a hydrophilic polymer mono-olefinic monomers exist that predominate with one the proportion of a diolefinic, non-hydrophilic macromer are networked and contain a biologically active substance ten, the above-mentioned and other desired properties own properties. The proportion is in the new copolymers terminally diolefinic hydrophobic macromers higher than that that of crosslinking agents in the known hydrophilic copolymers, and it is a predominant part of the system with about 10 to about 70% of the hydrophilic polymer, or preferably about 15 to about 50% of the same. The above-mentioned diolefinic non-hydrophilic macromers have a molecular weight between about 400 and about 8000, or preferably between unge for 600 and 5000.

In particular, the invention includes an unsolvable Lich polymeric hydrogel, which can be used as a carrier for drugs suitable, which is administered orally or buccally or use in the form of subcutaneous or intramuscular implants be det. The hydrogels according to the invention can also be used in Kör perimplants, such as artificial veins, insertion devices formed in the urethra, vagina or intestinal exit,  or they can take the form of controlled dispensing associations of medicines used through the skin. Other applications Forms of application of the new, water-swellable gels are membranes for reverse osmosis or semi-permeable membranes; hydro phile membranes for separation processes; Dressings for wound treatment lung; Cover layers on glass, metal, wood or ceramics and, entirely general, applications where both hydrophilicity and toughness are the same be requested in time.

The new hydrogels are manufactured in Gegen were or absence of solvents due to free radical Copolymerization of a water-soluble monomer (As) that is forming a water-soluble, or in water swellable polymers, d. H. a hydrophilic polymer (Ap) net, with a di-olefinic non-hydrophilic macromere (B), e.g. B. a divinyl compound with a long, linear polycondensate chain, such as B. polytetramethylene ether, with a polymerisable vinyl group on both sides. That way formed a three-dimensional macromolecular network that two types of segments are composed, each segment its specific physical properties to the whole system contributed. The A segment gives water solubility, the hydro phobe B segment forms the flexible networks. Through distances The appropriate proportions of each compound the mechanical and diffusion properties in a wide range Range can be varied. It can e.g. B. a polymer with out  excellent toughness, strength and ductility, which nevertheless absorb approximately their own weight of water can; this polymer is available using the appropriate ones Quantities of A and B. This possibility is known at hydrogels do not exist because their cross-links are short and are inelastic, and these hydrogels are hard when dry and are fragile.

The incorporation is in the polymers of the invention of the bifunctional macromolecule (B) in predominant quantities ratio in the system novel. In this way, the bifunk serves tional macromers not only as a structural crosslinker, but also also as a mediator of unique physical properties to 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 monomers and, at most 50% of the Total amount of the monomer, a water-insoluble mono-olefinic monomers, Ai. The water soluble monomers are preferably acrylic and / or methacrylic acid (2-methyl acrylic acid) or water-soluble derivatives thereof, such as. B. their Hydroxyalkyl esters, e.g. B. 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy propyl or 2,3-dihydroxypropyl ester; also ethoxylated and polyethoxylated hydroxyalkyl esters, such as esters of alcohols  of the formula

HO-C _m H _{2 m} -O- (CH₂-CH₂O) _n -R

where R is hydrogen or methyl, m is the number 2 to 5 and n is the number 1 to 20, or esters of analog alcohols in which part of the ethylene oxide unit has been replaced by propylene oxide units. Suitable esters are also dialkylaminoalkyl acrylates and methacrylates, such as the 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl and 3- (dimethylamino) -2-hydroxypropyl esters. Another class of suitable derivatives of such acids are their water-soluble amides, such as the unsubstituted amides and amides substituted by lower hydroxyalkyl, lower oxaalkyl or lower dialkylaminoalkyl groups, such as N- (hydroxymethyl) acrylamides and methacrylamides, N- (3 -Hydroxypropyl) acrylamide, N- (2-hydroxyethyl) methacrylamide, N- (1,1-dimethyl-3-oxabutyl) acrylamide and N- [1,1-dimethyl- 2- (hydroxymethyl) -3- oxabutyl] acrylamide; water-soluble hydrazine derivatives, such as. B. trialkylamino methacrylimides, e.g. B. Trimethyl amino methacrylimide and dimethyl (2-hydroxypropyl) amino meth acrylimide and the corresponding derivatives of acrylic acid; mono-olefinic sulfonic acids and their salts, such as sodium ethylene sulfonate, sodium styrene sulfonates and 2-acrylamido-2-methylpropanesulfonic acid; N- [2- (dimethylamino) ethyl] acrylamide and methacrylamide, N- [3- (dimethylamino) -2-hydroxypropyl] methacrylamide or mono-olefinic derivatives of heterocyclic nitrogen-containing monomers, such as, for. B. N-vinyl-pyrrole, N-vinyl-succinimide, 1-vinyl-2-pyrrolidone, 1-vinyl-imidazole, 1-vinyl-indole, 2-vinyl-imidazole, 4 (5) -vinyl-imidazole, 2 -Vinyl-1-methyl-imidazole, 5-vinyl-pyrazoline, 3-methyl- 5-isopropenyl-pyrazole, 5-methylene-hydantoin, 3-vinyl-2-oxazolone, 3-methacrylyl-2-oxazolidone, 3- Methacrylyl-5-methyl-2-oxazolidone, 3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinyl-pyridine, 5-vinyl-2-methyl-pyridine, 2-vinyl-pyridine-1- oxide, 3-isopropenyl-pyridine, 2- and 4-vinyl-piperidine, 2- and 4-vinyl-quinoline, 2,4-dimethyl-6-vinyl-s-triazine, 4-acrylic morpholine.

These monomers can be used alone or in combination other or with other suitable vinyl monomers, which are also hydro phob can be applied. The proportion of this hydropho Ben monomers should preferably 60% of the total composition 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. B. methyl and ethyl methacrylate or acrylate; of alkane carboxylic acids with 1 to 5 carbon atoms derived vinyl esters, e.g. B. 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. B. (methyl, ethyl, propyl, butyl or amyl) vinyl ether.

Water-soluble monomers that are used to polymerize a Comono Mereses are maleates, fumarates and vinyl ethers; the fol The following monomer combinations can be used, for example:  Di (hydroxyalkyl) maleates such as e.g. B. Di- (2-hydroxyethyl) maleate and ethoxylated hydroxyalkyl maleates, hydroxyalkylmonomaleates, such as B. 2-hydroxyethyl monomaleate and hydroxylated hydroxy alkyl monomaleates with vinyl ethers, vinyl esters, styrene or all common monomers that easily copoly with maleates or fumarates merize; Hydroxyalkyl vinyl ether, such as. B. 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether with maleates, fumarates or generally all monomers that easily copolymerize with Vinyl ethers.

Are particularly valuable as water-soluble monomers Hydroxyalkyl acrylates and methacrylates, such as. B. 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate, N-vinyl pyrrolidone, acrylic acid, methacrylic acid and a tert. Amino methacrylimide, e.g. B. trimethylamino methacrylimide, as in US-PS 36 27 802 described.

The most preferred monomers are 2-hydroxyethyl metha crylate and N-vinyl pyrrolidone.

In the di-olefinic, non-hydrophilic macromers (B), the olefinic part is preferably an acyl radical of a lower α, β- unsaturated aliphatic monocarboxylic or dicarboxylic acid or a vinyloxy radical. These residues are connected by a macromolecular, non-hydrophilic chain with repeated ether groups. The molecular weight of the chain can vary from approximately 400 to 8000, but preferably between 600 and 5000, and very particularly between 1500 and 3000. Accordingly, component (B) corresponds to the formulas

as defined in claim 1.  

In the terminal radicals of the compounds of the formula B₁ is derived, according to the definitions of R₂ and R₃ and when X is -COO- or -CONR₅, the acyl radical from acrylic or methacrylic acid or the monoacyl radicals of maleic, fumaric or Itacon acid or of monoalkyl esters of these acids with straight or ver branched chain alkanols having 1 to 10 carbon atoms, such as methanol, ethanol, butanol, diisobutyl alcohol or decanol, or if X is oxygen, from the vinyloxy radical of vinyl ethers. Ver compounds of formula B₁, wherein Y is a direct bond, are diesters of macromolecular diols in which two hydroxy groups are bonded to the polycondensate chain R₁ in opposite terminal or nearly terminal positions, with a, β -unsaturated acids. Such diesters can be prepared from the above-mentioned macro-molecular diols by known acylation processes by using reactive functional derivatives of suitable acids, e.g. As acrylic or methacrylic acid chloride, or of monoalkyl esters of maleic, fumaric or itaconic acid can be used. Compounds of formula B₁ with the amide group X are diamides obtained from macromolecular diamines by known acylation processes, for. B. by using the above acid chlorides or anhydrides. The macromolecular diamines are e.g. B. made from the corresponding macromolecular diols with twice the molar amount of alkyleneimine, for. B. propyleneimine.

The macromolecular bis-maleic acids are obtained according to the above-described reaction by using malein Acid anhydride as an acylating agent for macromolecular diamines while heating or reacting with dewatering agents provision of macromolecular bis-maleimido compounds of For mel B₂.

According to the definition of formula B₁, Y can also be a divalent rest

-R₆-Z₁-CONH-R₇-NH-CO-Z₂-

mean. In it R₆ z. B. methylene, propylene, trimethylene, tetramethylene, penta methylene, neopentylene (2,2-dimethyltrimethylene), 2-hydroxytri methylene, 1,1-dimethyl-2- (1-oxoethyl) trimethylene or 1- (di methylenaminomethyl) ethylene and especially ethylene. The divalent radical R₇ is derived from an organic diiso cyanate and is an aliphatic radical such as alkylene, e.g. B. Aethy len, tetramethylene, hexamethylene, 2,2,4-trimethylhexamethylene, 2,4,4-trimethylhexamethylene, fumaroyldiethylene or 1-carboxy pentamethylene; a cycloaliphatic residue,  e.g. B. 1,4-cyclohexylene or 2-methyl-1,4-cyclohexylene; an aromatic radical, such as m-phenylene, p-phenylene, 2-methyl-m- phenylene, 1,2-, 1,3-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,7- Naphthylene, 4-chloro-1,2- and 4-chloro-1,8-naphthylene, 1-methyl 2,4-, 1-methyl-2,7-, 4-methyl-1,2-, 6-methyl-1,3- and 7-methyl-1,3- naphthylene, 1,8-dinitro-2,7-naphthylene, 4,4'-diphenylene, 3,3'-di chloro-4,4'-diphenylene, 3,3'-dimethoxy-4,4'-diphenylene, 2,2'-di methyl- and 3,3'-dimethyl-4,4'-diphenylene, 2,2'-dichloro-5,5'- dimethoxy-4,4'-diphenylene, methylene-di-p-phenylene, methylene-bis- (3-chlorophenylene), ethylenedi-p-phenylene or hydroxydiphenylene.

If in the formula part B₁ the symbol Y has no direct link R₆ must always be connected to X.

There are therefore compounds of formula B₁, in which Y the bivalent radical mentioned means bis-vinyl ether if X Means oxygen, or bis-acrylates, bis-methacrylates, bis- maleate, bis-fumarate and bis-itaconate when X -COO- or

is.

The more preferred divinyl macromers (B) consist of poly tetramethylene oxide glycols of approximately a molecular weight 1000 to about 4000 end-saturated with 2,4-toluene diisocyanate and with 2 moles of a 2-hydroxyalkyl acrylate or methacrylate set. The macromere made of polytetramethylene is particularly valuable oxide glycol of molecular weight from about 1500 to about 3000,  finally saturated with 2,4-toluenediisocyanate and reacted with unge for 2 moles of 2-hydroxyethyl methacrylate.

The new hydrophilic copolymers according to the invention by free radical copolymerization, either in solution or in the mass, of water-soluble mono-olefinic monomers As or a mixture of at least 50% water soluble monomers As with 10 to 70% macromers of the formula B₁ or B₂, based on the total weight of the hydrogel. The polymerization becomes advantageous with a free radical catalyst at temperatures in the range from about 40 ° C to about 150 ° C, preferably between about 50 ° C and about 100 ° C leads. The presence of a therapeutic or biological effective substance during the polymerization can with regard to the heat stability of the substance limits the polymerisation tion temperature.

A preferred laboratory manufacturing process for the Hydro Gel object involves dissolving the drug in the macro mer monomer solution before polymerization, being the desired one Drug concentration with the macromer-monomer ratio together is selected so that the hydrogel the desired mecha niche and water absorption properties, mixing together with from about 0.02% to about 1% (% by weight) of a suitable, free radical generating catalyst and polymerizing the Mix at z. B. 80 ° C for about 2 hours in a ge  closed form, so that the hydrogel obtained as a flat film containing the drug in a quasi-solid solution. These Film is then in a high vacuum for about 12 hours exposed to a temperature of approximately 100 ° C to residues of mono mer and remove catalyst decomposition products.

A preferred laboratory method for producing the Hydrogels in the shape of a cylinder consist of being flexible Polyethylene tube with the preferred mixture of macromer, monomer, Drug and catalyst fills and the mixture during un can react for 2 hours at 80 ° C. The Hydro made in this way Gel article is slit out of the tube lengthways and Stripped of it cleared.

Another preferred method of making the Hydrogel in the form of small balls or pearls consists in that the preferred blend of macromer, monomer, drug and Catalyst at about 90 ° C in a viscous medium that is not acts as a solvent for a component of the hydrogel mixture, is stirred at high speed. As examples of suitable ones Bead polymerization media are silicone oils or poly called fluorinated oils, e.g. B. mineral oil distillates and saturated aqueous salt solutions.

Yet another preferred method of manufacture of the hydrogel in the form of a foamed article is  that a blowing agent such as sodium bicarbonate, the preferred mixture added and at about Polymerized 80 ° C in a mold for about an hour becomes. The closed cell foam obtained is special suitable for rapid water absorption and drug release.

Compounds of formula B₁, wherein Y

-R₆-Z₁-CONHR₇-NH-CO-Z₂-

means are obtained in a 2-step implementation by adding only macromolecular diols or diamines, d. H. Connections the two Hydroxy or amino groups in opposite or terminal almost end position bound to the polycondensate chain R₁ contain, with at least twice the amount of an aliphatic, cycloaliphatic or aromatic diisocyanate implemented are, the diisocyanate consisting of the rest R₇, on the two Isocyanate groups are bound, and in the second reaction stage the macromolecular diisocyanates thus obtained with a verb the formula

wherein R₂, R₃, X, R₆ and Z₁ have the meaning given above (for B₁) have implemented.

If X is oxygen, (C) is a vinyl ether with active hydrogen, e.g. B. a hydroxyalkyl vinyl ether or an amino alkyl vinyl ether; if X

means, (C) is a  Acrylate, methacrylate, maleate, fumarate, itaconate or the ent speaking amide with active hydrogen in the alkyl group. The Macromolecular diol or diamine is preferably used in light Excess applied, d. H. that the ratio of Iso cyano groups to hydroxyl or amino groups in the first reaction level of macromolecular synthesis should be at least 1: 1, but preferably at least 1: 1.05 or lower. If the used in the second stage of implementation of the macromer synthesis Compound C can be identical to the hydrophilic monomer (As) a large excess of this compound can be applied, so that the solution of the macromere B₁, dissolved or dis Perges in the monomer (A), directly for the production of the final product tes, the hydrophilic copolymer can be used.

The preparation of the macromer (B) is advantageous at Tem temperatures in the range between approximately room temperature and approximately 80 ° C executed. The temperature used is preferably not above 40 ° C and preferably in the range between 30 to 45 ° C. The Conversion of the isocyano group is done using infrared spectroscopy or titration tracked.

Another process for the preparation of the macromer be stands in the implementation of a prepolymer with terminal Hydroxyl groups, e.g. B. polybutylene or polypropylene oxide with Acryloyl chloride, methacryloyl chloride or maleic anhydride, forming a macromer without urethane links,  such as B. a macromer of the formula B₂ or B₁, wherein Y is a direct bond means.

The free radical copolymerization is carried out by means of a Catalyst, the free peroxy or alkyl residues in sufficiently high Can produce concentration.

Examples of suitable catalysts are diisopropyl peroxydicarbonates, tert-butyl peroctoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert-butyl peroxyacetate and azoisobutyronitrile. If the Polymerization carried out in water can be water soluble Peroxy compounds such as sodium, potassium or ammonium persulfate, and free radical-producing redox systems, such as persulfate bisul fit combinations can be used. The catalyst becomes an advantage adheres in an amount of about 0.02 to 1% by weight of the reaction mix used. Other free radicals can also be generated de systems are applied, such as gamma rays, electron beam oil bundle and UV radiation.

The reaction is preferably carried out in an inert or acidic manner Substance-free atmosphere, provided open shapes are used.  When working with closed forms, the hydrogel To mold the object, the molds must be made of an inert material with low oxygen permeability and good removability stand. Examples of suitable mold material are polytetra fluorethylene, silicone rubber, polyethylene and polyester. Glass and metallic shapes can be used if an appropriate mold release agent is used.

Incorporation of the drug in the hydrogel counter is either by dissolving or dispersing in the macro mer solution, the monomer solution or a mixture of both before the back addition of the free radical catalyst, or by diffusion of the Drug in the object obtained after the polymerization achieved. If the drug is not attacked by free radicals it is advantageous to do the same before the polymerization the macromer solution, monomer solution or a mixture of both dissolve or disperse. If the drug is free radi kalen is attacked, it should finish after the polymerization incorporated object by diffusion from a solution will.  

Hydrogels with toughness similar to leather when dry and great elasticity when wet can be dependent on the implementation ratios of the above components manufactured with low to high water absorption capacity will.

For applications such as body implants, wound dressings and semi-permeable membranes are particularly hydrophilic membranes advantageous having a relatively high wet strength Combine equilibrium water contents of 5 to 50%. To have to for example subcutaneous and intramuscular implants apply drug delivery to a certain extent to what serabsorption (15 to 25 wt .-%) enabled, on the other hand in a dry and swollen state be firm enough to support the Endure insertion and extraction process.

In addition to their suitability as a drug carrier the hydrogels according to the invention can also be used as carriers for Antiseptics, flavors, colorants, nutrients, insecticides, Herbicides. The hydrogels according to the invention can in particular in a suitable solvent which is the one to be transferred Contains active ingredient to be swollen; the solvent is ver  vaporizes and leaves the active ingredient in the hydrogel particles. In contact with an aqueous environment, the active ingredient will open up emitted evenly.

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

The hydrogels according to the invention are also used Use as a hydrophilic and non-thrombogenic outer layer suitable because they adhere strongly to glass, metal and plastic. Because of their high strength and elasticity make them strong deck layers with high wear resistance and are therefore wear and tear cover boat hulls suitable for the growth of shells prevent; or to cover layers on lenses and glasses testify that fogging of the same in a damp environment other.

Another excellent property of the fiction moderate hydrogels are their pliability in the dry state, in which they already take the form they want to use.  In the swollen state, another advantage of the invention appropriate hydrogels in that they are not friable but maintain their strength and elasticity, too if they are in equilibrium in an aqueous environment (with Water). These properties are particularly valuable in the use of membranes under pressure, such as in apparatus for the reverse returned osmosis.

Medicinal hydrogels according to the invention are especially for use in the treatment of open Wounds and burns, thanks to their pliability and Adaptability to shape, combined with the possibility of drug bring tel directly to the affected areas. At this time Type of application is a special advantage of the hydrogel its smoothness saminess in the dry state. It is unnecessary to pre-hydrogel Pre-swell application to make it soft and pliable enough to cover large injured areas (wound areas); out of this Basically, the drug-containing hydrogel can be dry instead of swollen len are stored, which contains the shelf life of the therein a drug increased.

The copolymeric support material according to the invention can be any Medicines for body treatment, both local and system mixed used, can be 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 bio logical effect. For therapeutic use  are all suitable without limitation in US Pat. No. 3,732,865 (Columns 10 and 11) enumerated drugs.

Medicines other than those mentioned above, with the same Chen or various effects, can in inventive Carriers are used. There can be both suitable mixtures of drugs as well as individual substances can be administered well.

The drugs can be administered in different ways shapes are given, such. B. as a pure active substance, as a compo nenten of molecular complexes or as irritant, pharmacological acceptable salts, e.g. B. the hydrochloride, hydrobromide, sulfate, Phosphate, nitrate, borate, acetate, maleate, tartrate or salicylate. For acidic drugs, metal salts, amines or organic cations (e.g. quaternary ammonium salts) come. Furthermore, simple derivatives of drugs (such as Ethers, esters, amides) can be used, which are desired Have delay and release properties and by On effect of body pH, enzymes are easily hydrolyzed.

The amount of drug to be added to the carrier depends to a large extent on the special connection, on the desired therapeutic effect and the length of time required to release the medicine. There is no critical one upper limit for the amount of drug to be loaded into the carrier, because the diversity of the carriers and their most diverse  Sizes and shapes should allow for different Most diseases a whole range of administration forms and Build up dosages. The lower limit is also from the Effectiveness of the drug and the extent of its release depend on the carrier. It is therefore deliberately not an area for the therapeutically effective amount of drug by the carrier is released, defined.

Preferred drugs to use are those that are intended for long-term treatment, so that multiple daily doses can be avoided, such as e.g. B. the active substance types mentioned in claim 15 and in particular especially the active substances mentioned in claim 16.  

In addition to drugs, the copoly according to the invention also fragrances or flavors, such as orange oil, citral, Coffee, tea, lemon oil, synthetic lemon-lime aroma, earth beer 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 biologically active mentioned Additives are described in US Pat. No. 3,660,563 (columns 3 to 7) called.

The new hydrogels, especially the polyurethanes as Macromer component containing form due to their superior physical properties in the dry and wet state Cross between classic hydrogel and polyurethane especially as biomedical plastics with non-thrombo valuable properties. Therefore, they are excellent net for use as an artificial skin in the treatment of ver  burns, for the construction of artificial organs or as Top layers for the same. You can also use it as a surgical Sutures are used.

The composition of the hydrogels can range 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 before compositions contain about 15 to 50% macromer (B) and about 50 to 85% monomer (A), and their degree of swelling moves between 15 and 120%.

Experimental part

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

The release rate of a drug contained in a hydrogel is determined by continuously measuring the characteristic UV absorption of a stirred amount of water containing a hydrogel disk 16 mm in diameter and 0.8 to 1.0 mm in thickness. The degree of swelling DS is defined as:

In the following examples, the term "end polytetramethylene oxide continuously reacted with isocyanate "(with Iso cyanate end-saturated polytetramethylene oxide) a polytetra methylene oxide chain, at both ends with 2,4-toluene diisocyanate was implemented. These connections can be made easily and are commercially available under the trade name "ADIPRENE".

The first seven examples show the influence of changing amounts of macromeric, hydrophobic crosslinking agent on the physical properties of polyhydroxyethyl methacrylate gels and their preparation.
MW: molecular weight
As: water-soluble monomer A
Ai: water-insoluble monomer A

Example 1

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

Example 2

The procedure of Example 1 is repeated with the off assumed that 2.0 g of terminally reacted polyisocyanate with isocyanate 3000 molecular weight methylene oxide (ADIPRENE L-42) used will. A tough, transparent film is obtained, which after Soak in water for 2 days and then dry in vacuo is tested at 80 ° C as described in Example 1.  

Example 3

The procedure according to Example 1 is carried out using 5.0 g of ADIPRENE 167 (Molecular weight 1500) and 15.0 g of 2-hydroxyethyl methacrylate guided. The product obtained is a tough, transparent film, which is treated as described in Example 1.

Example 4

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

Example 6

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

Example 7 (comparative example)

A conventional poly (2-hydroxyethyl) metha crylate gel made from 1.2% ethylene glycol dimetha crylate as a crosslinking agent; otherwise the same procedure applied as for the previously described gels. It will be a har preserved, fragile, translucent leaf that is immediately treated delt and checked as described above. Table 1 shows one decreasing degree of swelling with increasing amount of hydrophobic Macromers (B). The tensile strength when the products are dry according to Examples 1 to 6 is higher than that of the usual Poly-HEMA Example 7. Wet tensile strength and elongation in the dry and moist state increase with increasing amount from (B).  

Table 1

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

Examples 8 to 12

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

Example 8: N-vinyl pyrrolidone (NVP)
Example 9: Ethyl Acrylate (EA)
Example 10: Dimethyl maleate (DMM)
Example 11: Vinyl acetate (VA)
Example 12: Ethyl Acrylate (EA)

0.1 g of tert-butyl per are added to all five mixtures octoat added and the solutions in a mold for foils cast of 1 mm thickness. It is around at 80 ° C for two hours set, removed from the mold and at 100 ° C for 15 hours kept in a vacuum of 0.25 mm. The foils created in this way are clear and tough and their degree of swelling was determined as follows (see table 2).  

Table 2

In the following two examples, the macromere (B) a bis vinyl ether (Example 13) and a bis maleate (Example 14).

Example 13

According to the procedure described in Examples 8 to 12 30 g isocyanate-end-saturated polytetramethylene oxide (MW: 3000) and 10 g of 4-hydroxybutyl vinyl ether (HBVE) in 30 g of N-vinyl pyrrolidone implemented until all free isocyanate has disappeared. To the Mi 30 g of ethyl acrylate and 0.4 g tert-butyl peroctoate. The mixture is ge in foil molds brought and after two hours at 80 ° C the cross-linked foils removed from the mold and in a vacuum oven for 16 hours (33 Pa) kept at 100 ° C. The pattern is a tough, clear one Sheet whose degree of swelling has been determined (see Table 3).  

Example 14

According to the procedure described in Examples 8 to 12 40 g of isocyanate end-saturated polytetramethylene oxide (MW: 3000) and 10 g of 3-hydroxypropyl butyl maleate (HPBM) in 50 g N-vinyl pyrrolidone reacted until all free isocyanate is removed has been. 0.4 g of tert-butyl per are then added to the mixture octoat added. The mixture is placed in foil molds and exposed to a temperature of 80 ° C for two hours. The ver net film is removed from the mold and for 16 hours (33 Pa) kept at 100 ° C. The pattern is a tough, clear one Sheet whose degree of swelling has been determined (see Table 3).

Table 3

Examples 15 to 16

A bis-maleimide-type macromer (B) with a molecular weight of approximately 2200 (polypropylene oxide-bismaleimide) obtained by reacting 2 moles of maleic anhydride with one mole of polypropylene oxide, finally saturated with primary amino groups, is dissolved in 2-hydroxyethyl methacrylate in two proportions:
Example 15: 20% polypropylene oxide bis-maleimide (80% HEMA)
Example 16: 35% polypropylene oxide bis-maleimide (65% HEMA)
0.1% tert-butyl peroctoate are added and the solutions in film casting mold are converted at 80 ° C. for 2 hours; the films are removed and kept in a vacuum oven (33 Pa) for 16 hours at 100 ° C .; they are tough and supple; their degree of swelling is recorded in Table 4.

Table 4

Example 17

53.0 g of polypropylene oxide-bis-maleimide according to Examples 15 and 16 are dissolved in 47.0 g of N-vinylpyrrolidone; After adding 0.4 g of tert-butyl peroctoate, the mixture is poured into molds and reacted as described in Example 15. A tough, light brown colored gel is obtained which absorbs 46.0% of its weight in water (DS = 46.0).

Example 18

59.8 g of polypropylene oxide-bis-maleimide according to Examples 15 and 16 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 15. The gel forms a tough, very slightly yellowish film that absorbs 26.5% of its weight in water (DS = 26.5).

Example 19

Example 18 is repeated, but with amounts of 3.10 g of N-vinylpyrrolidone and 26.4 g of ethyl acrylate. The product obtained is a tough, colorless gel which absorbs 23.0% of its weight in water (DS = 23.0).

Example 20

Example 18 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 (DS = 15.8).

Examples 21 to 23

The procedure according to Example 2 is repeated with the Exception that the isocyanate end-saturated polytetramethylene oxide of molecular weight 3000 (ADIPRENE L-42) in concentrations of 15% for Example 21, 25% for Example 22 and 33% for Bei game 23 is used and 2.0% by weight pyribenzamine HCl, a medicine with an antihistamine effect, in every pattern telbar is dissolved before the polymerization.

Example 24 (comparative example)

The procedure according to Example 7 is repeated with the off assumed that immediately before the polymerization 4% by weight of pyribenz amine · HCl can be dissolved in the monomeric mixture.

Film samples of the same thickness, obtained according to examples 21 to 24, are at 37 ° C for 16 hours in an HCl / NaCl Solution (pH 2.15) extracted. The one extracted from each slide Amount of drug is in solution during the procedure 314 nm determined with a UV spectrometer at different times, by the amplitude of the Ab sorption peak is measured.  

The one needed to extract 50% of the pyribenzamine Time is 2 hours, or 4 hours, or 6½ hours for the samples obtained according to Examples 21, 22 and 23, respectively. This illustrates the adaptability of the diffusion ge speed in the products produced according to the invention. For comparison, a material sample of the same thickness resulted Example 24 50% drug release in less than one Hour.

Examples 25-26

The procedure according to Example 1 is repeated with the Exception that the isocyanate end-saturated polytetramethylene oxide has a molecular weight of 600 (ADIPRENE L-315) and in Concentrations of 20% by weight for example 25 or 40% by weight used for Example 26, using 3.7% dexamethasone dissolved in each batch immediately prior to polymerization becomes.

Example 27 (comparative example)

The procedure of Example 7 is repeated, with the Aus assumed that 3.7% dexamethasone in the monomer mixture immediately bar is dissolved before the polymerization.

Foil samples of approximately the same thickness, obtained after Examples 25 to 27 are in water at 25 ° C for 240 hours  extracted. The amount of drug extracted from each slide becomes during the procedure at different times with one UV spectrophotometer by determining the ampli tude of the characteristic absorption peak of dexamethasone in of the solution measured at 242 nm.

It was found that more than 95% of the original in a material sample according to Example 27 dissolved steroid be extracted half of 140 hours while in the same Time only 33% of that included in the sample according to Example 25 Drug extract and only 12% of the steroid from the Pattern according to Example 26, which shows the valuable applicability of the Lang time release by the water-insoluble material according to the invention illustrated.

Example 28

200 g of isocyanate end to 150 g of N-vinylpyrrolidone saturated polytetramethylene oxide (MW 3000) and 50 g of 2-hydroxy given ethyl methacrylate. The solution becomes inert at 25 ° C Atmosphere stirred for a week. After this time will stop the reaction between diisocyanate and HEMA by determining the disappearance of the NCO band in the IR Spectrum of the final product confirmed. This is kept and serves as the starting material for the manufacturing process according to Examples 29 to 41.  

Example 29

20.0 g of the starting material according to Example 28 mixed with (sufficient) tert-butyl peroctoate catalyst (to get the Bring final concentration of catalyst to 0.4% by weight). The mixture is made in a closed mold to produce a Given film of 1 mm thickness. The mold comes in a hot air oven brought to polymerization at 80 ° C for 2 hours to accomplish. The polymer film is removed from the mold and for 18 hours at a temperature of 80 ° C under a vacuum exposed to 13 Pa. The product is a clear, tough film, whose degree of swelling is determined.

Example 30

The procedure of Example 29 is repeated with the off took that 1.0 g of HEMA and 4 g of N-vinyl pyrrolidone before the addition of the peroxide can be added.

Example 31

The procedure of Example 29 is repeated with the off took that 2.0 g of HEMA and 3.0 g of N-vinyl pyrrolidone before the peroxide addition can be added.  

Example 32

The procedure of Example 29 is repeated with the Exception that before the peroxide addition 4.0 g HEMA and 1.0 g N-VP be added to the starting material (according to Example 29).

Example 33

The procedure of Example 29 is repeated with the Exception that 5.0 g of HEMA are added before the peroxide addition the.

Example 34

The procedure of Example 29 is repeated with the Exception that 3.0 g N-VP and 27.0 g HEMA before the peroxide addition be added.

Example 35

The procedure of Example 29 is repeated with the Exception that 24.0 g HEMA and 6.0 g N-VP before the peroxide addition be attached.

Example 36

The procedure of Example 29 is repeated with the  Exception that 15.0 g HEMA and N-VP each before the peroxide addition to be added.

Example 37

The procedure of Example 29 is repeated with the Exception that 5.0 g N-VP and 25.0 g HEMA before the peroxide addition be added.

Example 38

The procedure of Example 29 is repeated with the Exception that 3.53 g of ethyl acrylate beige before the peroxide addition be added.

Example 39

The procedure of Example 29 is repeated with the Exception that 6.67 g of ethyl acrylate was added before the peroxide addition be added.

Example 40

The procedure of Example 29 is repeated with the Exception that 10.8 g of ethyl acrylate beige before the peroxide addition to be mixed.  

Example 41

The procedure of Example 29 is repeated with the off took that 20.0 g of ethyl acrylate added before the peroxide addition will.

Composition and degree of swelling of the gels according to Example 29 to 41 are summarized in Table 5.

Table 5

Example 42

The polymer product according to Example 5 is sliced from Cut 2.5 mm in diameter and 1.0 mm in thickness. 5.8 g of this Slices are stirred for 48 hours at room temperature Ren in a solution of 30 wt .-% pyribenzamine HCl in water feasted. The final weight of the swollen slices is 9.6 g. They are washed with distilled water and in a vacuum (13 Pa) dried at 60 ° C to constant weight, the 6.85 g gives what a pyribenzamine HCl content of 15.3% in Corresponds to polymers.

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

Example 43 A. Preparation of the macromeric base substance

2000 parts (1 mole) molecular weight polytetramethylene oxide 2000 (Polymeg 2000) are melted into a 5 liter three neck flask and vacuumed at 80 ° C for 1 hour heats to remove any remaining moisture. The vacuum is canceled by introducing dried nitrogen gas and the contents of the flask cooled down to 40 ° C. To do this 444.6 parts (2 moles) of isophorone diisocyanate and 1 g of triethylamine added, increasing the temperature to 80 ° C. After this  the isocyanate content after 5 hours to approximately 3.5% (the Be mood has been decreased by titration), the reak tion mixture cooled to 40 ° C and then with 1630 parts HEMA (2-hydroxyethyl methacrylate) and 0.24 g dibutylbis (lauroyloxy) tin (DBTL) offset. The reaction mixture is left in with stirring a nitrogen atmosphere until the Cool residual isocyanate (IR) to room temperature.

B. Preparation of Crosslinked, Hydrophilic Polymers

The macromere starting compound prepared according to A) is used to monomer-macromere mixtures of the following composition to obtain:

Table 6

For each monomer-macromeric mixture obtained 0.2 parts of tert-butyl peroctoate are added, dissolved and the he solutions in casting molds (30 cm × 30 cm) made of glass splashes, which are lined with polyester films,  using 1.6 mm wide silicone tapes as a distance holder. The polymerization is carried out in a hot air oven 3 hours of heating at 80 ° C and 1 hour of heating at 100 ° C executed. The molds are taken out, on room cooled and the hydrogel films obtained characterized.

Degree of swelling, tensile strength (wet and dry) and stretch Availability (wet and dry) of the hydrogel obtained according to a) to g) are given in Table 7 below:

Table 7

Example 44

125.0 g (0.13 mol) of polyoxypropylene (MW 995) are in poured into a 500 ml three-necked flask and at 80 ° C for 1 hour / 265 Pa dried. The vacuum is dried by introducing nitrogen gas and the contents of the flask to 40 ° C cooled down. 55.9 g (0.25 mol) of isophorone diisocyanate are added and 127 mg of triethylamine are added, the reaction temperature  is increased to 80 ° C. After 18 hours of reaction the isocyanate content 5.8% (theoretical value = 5.84% isocyanate). The reaction mixture is cooled to 40 ° C. 172.8 g (1.3 mol) 2-hydroxyethyl methacrylate (HEMA) become 115.2 g of the above reaction mixture and added with 9.6 mg DBTL offset. The reaction mixture is complete Disappearance of the residual isocyanate at a temperature of 40 ° C. held.

Example 45

150.0 g (0.074 mol) of polyoxypropylene (MW 2015) are in poured a 500 ml three-necked flask and at 80 ° C / 265 Pa for 1 hour dried long. The vacuum is dried by introducing Nitrogen gas lifted and the contents of the flask to 40 ° C hypothermic. 33.1 g (0.15 mol) of isophorone diisocyanate are added and 83 mg of 1,4-diazabicyclo [2,2,2] octane (1 mol%) give, the reaction temperature is increased to 80 ° C. To 16 hours reaction time, the isocyanate content is 3.44% (theoretical value = 3.42% isocyanate). The reaction mixture is cooled to 40 ° C. 179.3 g (1.4 mol) of 2-hydroxyethyl methacrylate (HEMA) become 119.5 g of the reaction mixture obtained above added and mixed with 190 mg DBTL. The reak tion mixture until the restiso completely disappears cyanates kept at a temperature of 40 ° C.  

Example 46

143.9 g (0.50 mol) of polyoxypropylene, MW 2878, are in poured a 500 ml three-necked flask and at 80 ° C / 265 Pa for 1 hour dried long. The vacuum is dried by introducing Nitrogen gas lifted and the contents of the flask to 40 ° C chilled. 22.2 g (0.10 mol) of isophorone diisocyanate and 56 mg 1,4-diazabicyclo [2,2,2] octane (1 mol%) added, the reaction temperature being raised to 80 ° C. After 12 hours the reaction time, the isocyanate content is 2.44% (theor shear value = 2.53% isocyanate). The reaction mixture is at 40 ° C 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 adds and treated with 17 mg DBTL. The reaction mixture is until to completely disappear the residual isocyanate on a Temperature maintained at 40 ° C.  

Example 47

To 50.0 g of each obtained in Examples 44 to 46 Reaction mixtures (compounds) are 0.1 g tert-butyl peroctate added and dissolved with stirring. The result Mixture is ent at room temperature in a vacuum of 133 Pa gas until no rising bubbles can be observed, and then poured into a glass mold, which with Lined with polyester film and covered with 1 mm wide silicone tape has been sealed. The molds are placed in a hot air oven 3 hours at 80 ° C and then 1 hour at 100 ° C heated. The films obtained are from the cooled casting forms stripped out and in samples for analysis and physika cut the test.

The degree of swelling (DS) and tensile strength for the hydrogels obtained according to Examples 44 to 46 are given in Table 8 below:

Table 8

Example 48

The reaction mixture obtained according to Example 43 d) is polymerized to films with a thickness of 0.5 to 1.5 mm. The slides be in flowing water at a temperature of 40 ° C for 3 days washed long. These foils become tablets when wet of different diameters. After drying at 80 ° C in a vacuum tablets from 1.2 to 4.0 mm in diameter are obtained.

Example 49

The reaction mixture obtained according to Example 43 c) is polymerized as in Example 48 and the obtained Film in a shredding machine to form multiform particles of various average diameters. These Particles are then in the flowing water for 3 days at 40 ° C washed, dried and the particles on the different Particle sizes using a set of standard sieves with open rated between 0.18 and 2.4 mm. All particles that have a smaller diameter than 0.18 mm are discarded.  

Example 50

A tablet is made from those obtained in Example 48 Picked tablets and in a 40% aqueous solution of tripelennamine hydrochloride (2- [benzyl (2-dimethylaminoethyl) - amino] pyridine) for a period of 48 hours sen. Then the tablet is swung into water and until Dried to achieve a constant weight. The weight gain Taking the tablet indicates that 30.7% of tripelennamine hydrochloride has been added as the last component. The The thickness of this specimen increased to 1.9 mm. The tablet that Containing 37.2 mg of tripelennamine hydrochloride becomes one amount of 1 liter of artificial gastric juice at a temperature of 37 ° C added. The amount of drug released is called Function of time measured spectrophotometrically. The course of the Release behaves such that 25% of the total drug stop within half an hour, 50% after 2.2 hours, 75% after 5.5 hours and 90% after 10.5 hours.

Example 51

The particles which averaged according to Example 49 Liche diameter of 1.4 mm, are in a 40% aqueous tripelennamine hydrochloride solution for a period of Soaked for 48 hours. After that, the tablet is in water pivoted and ge until a constant weight is reached dries. The weight gain of the particles indicates that the last component was 17.5% of tripelennamine hydrochloride  has been taken. The amount of particles that are 30 mg of active Component corresponds to that in a rapidly dissolving Capsule weighed and added to an amount of 1 liter of artificial stomach juice at a temperature of 37 ° C added. The released Amount of drug is spectralphoto as a function of time measured metrically. The course of the release is so that 25% of the total drug content after 0.17 hours, 50% after 0.81 hours, 75% after 2.9 hours and 90% after 7.8 hours he follows.

Example 52

The particles which according to Example 49 have an average Chen diameter of 1.7 mm, are in a 22% Solution of phenformin hydrochloride for a period of 48 hours let the springs. As a solvent system, an ethanol Water mixture (3: 1) used. After drying, put through the weight gain found that overall drug intake 18% of phenformin hydrochloride. The amount of particles that 50 mg of the active component is equivalent in a quick turn dissolving capsule weighed and artificially to a quantity of 1 liter chem gastric juice at a temperature of 37 ° C added. The free set amount of drug becomes spectral as a function of time measured photometrically. The course of the release is so that 25% of the total drug content after 0.75 hours, 50% after 2.25 hours, 75% after 5 hours and 90% after 9 hours follows.  

Example 53

A tablet is made from those obtained in Example 48 Picked tablets and in a 30% aqueous solution Let swell of imipramine hydrochloride for 72 hours. To after drying it is found that the tablet has a thickness of 0.75 mm reached, and the weight gain indicates that a Ge total drug intake of 33.6% imipramine hydrochloride has taken place. The tablet, the 50 mg imipramine hydrochloride contains, to an amount of 1 liter of artificial gastric juice one Temperature of 37 ° C added. The released amount of Drug is spectrophotometric as a function of time measured. The course of the release is such that 25% of the total drug content after 1 hour, 50% after 2.5 hours 75% after 5 hours and 90% after 8.75 hours.

Example 54

The particles which according to Example 49 have an average Chen diameter of 0.425 mm, are in a 50% Solution of sulfinpyrazone in chloroform for a period of Soaked for 48 hours. These particles are flowing Washed water and until a constant weight is reached dried. The weight gain of the polymer particles indicates this indicating that 10.3% of sulfinpyrazone was added as the last component has been. The amount of particles that are 11.7 mg of active Component corresponds to that in a rapidly dissolving  Capsule weighed and added to an amount of 1 liter of artificial stomach juice at a temperature of 37 ° C added. The released Amount of sulfinpyrazone is spectrophotographed as a function of time determined metrically. The course of the release is so that 25% of the total drug content after 0.21 hours, 50% after 1.20 hours, 75% after 4.94 hours and 90% after 10.20 hours that takes place.

Example 55

A tablet is made from those obtained in Example 48 Picked tablets and in a 21% aqueous solution let swell from hydralazine. The hydralazine solution is obtained provides by adding 10 g of hydralazine hydrochloride in 2N sodium hydroxide solution for a complete solution to reach pH 8 be solved. The adsorption of the tablet continues for 72 hours set. After drying, the weight gain indicates that as last component 10.7% of hydralazine has been added. The tablet, which contains 11 mg hydralazine, becomes one quantity of 1 liter of artificial gastric juice at a temperature of 37 ° C given. The amount of hydralazine released is a function of Time determined spectrophotometrically. The course of the release behaves such that 25% of the total drug content after 0.53 hours, 50% after 3.33 hours, 75% after 7.87 hours and 90% after 13.3 hours.  

Example 56

The particles which averaged according to Example 49 Liche diameter of 1.4 mm, are in a 21% aqueous solution of hydralazine swelled. The Hydralazin solution is prepared as described in Example 55. The Adsorp The tablet is continued for 72 hours. After drying weight indicates that the last component is 4.2% of hydralazine has been taken up. It will then be the amount of Particles that correspond to 20 mg of the active substance in one quickly dissolving capsule weighed and to an amount of 1 liter added artificial gastric juice at a temperature of 37 ° C. The amount of hydralazine released is a function of time determined spectrophotometrically. The course of the release ver keeps so that 25% of the total drug content after 0.2 hours den, 50% after 0.68 hours, 75% after 2.50 hours and 90% after 4.94 hours.

Example 57

The particles which according to Example 49 have an average Have a diameter of 0.7 mm in a 22% solution swelled by maprotiline hydrochloride. The solution is here put by putting 10 g of maprotilin hydrochloride in 45 g of a metha nol / chloroform mixture (33: 67). The adsorption is for 48 hours continued. After swiveling in water and dry overnight, the weight gain indicates that the last com  component 12.8% of Maprotilin hydrochloride has been added. It will then be the amount of particles that contain 90 mg of the active sub punch corresponds, inserted in a rapidly dissolving capsule weighed and added to a quantity of 1 liter of artificial gastric juice Temperature of 37 ° C added. The released amount of Mapro Tilin hydrochloride is spectrophotometric as a function of time certainly. The course of the release is such that 25% the total dose in 0.67 hours, 50% in 3.67 hours, 75% in 13.4 hours and 90% in 23.4 hours.

Example 58

The particles according to Example 49 have an average Have a diameter of 1.7 mm in a 26% solution Let swell of methylphenidate hydrochloride for 48 hours. As Solution system uses a mixture of methanol / water 27: 73). After swiveling in water and drying overnight, the shows Weight gain indicates that the last compound is 26.7% methyl phenidate hydrochloride has been added. Then it will be the Amount of particles corresponding to 270 mg of active substance weighed in a rapidly dissolving capsule and into a Amount of 0.5 liters of artificial gastric juice at a temperature of 37 ° C added. The amount of methylphenidate hydrochloride released is determined spectrophotometrically as a function of time. The The course of the release is such that 25% of the total dose in 0.67 hours, 50% in 3.0 hours, 75% in 7.8 hours and 90% done in 14.2 hours.  

Example 59

15 g of the monomer macrome described in Example 43 c) Renal mixtures are given with the following below Connections mixed. 0.08 g are added to this mixture added tert-butyl peroctoate, the solution obtained or dis persion is degassed and in a casting lined with polyester film molded from glass (30 × 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 Heating at 100 ° C was carried out for 1 hour. After cooling the sample foils are taken out and for diffusion measurements used.

Table 9

Example 60

15 g of the monomer macromers described in Example 43 f) are mixed with the following compounds given below mixed. 0.08 g of tert-butyl peroctoate are added to this mixture added, the solution obtained is degassed and in with poly casting molds lined with glass (30 × 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 guided. After the molds have cooled, the samples are prepared excepted and used for diffusion measurements.  

Table 10

Example 61

9.89 g of a hydrophilic polymer, prepared as described in Example 43 b), are dissolved in 20 g of N- (cyclopropylmethyl) - α, α, α -trifluoro-2,6-dinitro-N-propyl-p-toluidine (herbicide ) Immersed for 5 days. The polymer is then removed, washed with methanol, air dried and weighed. The dried polymer weighs 11.22 g which corresponds in its composition to a polymer which contains 11.8% of active substance.

The procedure described in Example 43 e) is described in an analogous manner Polymers in a 5% solution of sodium iron ethylenediamine di [o-hydroxyphenyl acetate] (iron preparation) immersed in methanol. The dried polymer contains 15% active substance.  

Example 62

Diffusion measurements are taken at a temperature of 25 ° C in water buffered with secondary sodium citrate (pH = 5) performed using a sample of the delivery system as shown in Table 11 indicated, is immersed in 1 liter of the stirred buffer solution. Abge Measured quantities are taken periodically and the proportion of the ge entire active substance released by polymers, is determined spectrophotometrically.

Table 11

Example 63

The component obtained according to Example 59 d) is in part size from 0.18 to 0.25 mm crushed and into a cylinder filled by the air in an amount of 20 liters per minute and at a temperature of 40 ° C to flow. The weight decrease becomes gravimetric and from this the proportion of the vaporized Active ingredient determined. The course of the release is so that 25% after 48 hours, 50% after 300 hours, 75% after 1050 hours and 90% after 2000 hours.  

Example 64

The procedure is repeated as described in Example 44 ben, but uses one instead of hydroxyethyl methacrylate equivalent amount of 3-hydroxypropyl methacrylate to make the macromer To produce a monomer mixture. The polymerization takes place as in Bei game 47. The film obtained is unbreakable, flexible  and translucent and adsorbs 15% water. (Degree of swelling = 15).

Example 65

The particles according to Example 49 have an average Have a diameter of 0.6 mm in a 20% solution swelled by clomipramine hydrochloride. The solution is here put by putting 10 g of clomipramine hydrochloride in 40.0 ml of water dissolves. Absorption continues for 72 hours. After Ab panning in water and drying indicates the weight gain that the last compound was 10.6% of clomipramine hydrochloride men has been. It will then be the amount of particles that are 45 mg of the corresponds to active substance in a rapidly dissolving chap weighed sel and added to a quantity of 1 liter of artificial gastric juice added. The amount of clomipramine released is called Funk tion of time determined spectrophotometrically. The course of the free setting behaves such that 25% of the total dose in 0.5 hours, 50% in 2.2 hours, 75% in 5.9 hours and 90% in 11.0 hours he follows.

Example 66

The procedure is repeated as in Example 43 f) wrote with the exception that the layer thickness of the manufactured th film is 1.15 mm. The foil is in the flowing water Washed for 3 days and tablets with a diameter of Cut 1.27 mm from it after drying.  

Example 67

A tablet produced according to example 66 is produced selected and in a 20% aqueous solution of imipramine Allow hydrochloride to swell for 48 hours. After drying it is found that the tablet is now 1.44 mm thick was enough. The weight gain indicates that the total intake of active substance is 22.6% imipramine hydrochloride. The pill, which contains 46.3 mg imipramine hydrochloride becomes an amount of Add 1 liter of artificial gastric juice at a temperature of 37 ° C given. The amount of imipramine hydrochloride released is called Function of time determined spectrophotometrically. The course of the Release behaves such that 25% of the total dose in 1.8 hours den, 50% in 3.72 hours, 75% in 9.40 hours and 90% in 17.3 Hours.

Example 68

A tablet produced according to Example 66 is made from chosen and in a 20% aqueous solution of clomipramine Allow hydrochloride to swell for 48 hours. After drying it is found that the tablet is now 1.38 mm thick was enough. The weight gain indicates that the total intake of active substance is 19.5% of clomipramine hydrochloride. The Tablet that contains 37.3 mg of active ingredient becomes one amount of 1 liter of artificial gastric juice at a temperature of 37 ° C admitted. The amount of clomipramine hydrochloride released will determined spectrophotometrically as a function of time. The history  the release behaves such that 25% of the total dose in 1.33 hours, 50% in 4.03 hours, 75% in 10.2 hours and 90% is done in 18.7 hours.

Example 69

Fragrances of known compounds are in the Hydrogel polymers, which according to the method of Example 43 c) is obtained, including by polymerization in In the presence of the following mixtures.

Table 12

All fragrances resulted in clear, translucent (translucent polymer films that release the fragrances in a long time return period.

Claims (18)

1. A crosslinked water-insoluble hydrophilic gel consisting of the copolymer

• A) 30 to 90 wt .-% of one
  • a) water-soluble mono-olefinic monomers, selected from the group consisting of acrylic and methacrylic acid, hydroxyalkyl and dialkylamino alkyl esters thereof, in which alkyl has 2 to 4 carbon atoms, esters of acrylic or methacrylic acid, which are derived from alcohols Formula HO-C _m H _{2 m} -O- (CH₂-CH₂O) _n -delivery, in which R is hydrogen or methyl, m is the number 2 to 5 and n is the number 1 to 20, unsubstituted or substituted amides and imides of acrylic or methacrylic acid, in which the nitrogen substituent is hydroxyalkyl, oxaalkyl or dialkylaminoalkyl, in which alkyl has 2 to 4 carbon atoms, hydroxyalkyl maleates or fumarates, in which alkyl has 2 to 4 carbon atoms, hydroxyalkylvinyl esters, in which alkyl has 2 to 4 carbon atoms, and mono-olefinic derivatives of monocyclic azacyclic monomers, or a mixture of the aforementioned monomers, or
  • b) a mixture of one or more of the above-mentioned water-soluble mono-olefinic monomers with 1 to 50% by weight of the same or different water-insoluble mono-olefinic monomers, selected from the group consisting of acrylonitrile, alkyl acrylates and alkyl methacrylates, in which alkyl up to Has 18 carbon atoms, vinyl esters derived from alkane carboxylic acids with up to 5 carbon atoms, styrene, and vinyl alkyl ethers, wherein alkyl has up to 5 carbon atoms, with
• B) 10 to 70% by weight of a hydrophobic macromer of the formula with a molecular weight of 400 to 8000,
  wherein R₁ is a polycondensate chain with a molecular weight of 200 to 8000, selected from poly propylene oxide and polytetramethylene oxide,
  R₂ is hydrogen or methyl; R₃ is hydrogen or COOR₄, wherein R₄ is hydrogen or alkyl of up to 10 carbon atoms; with the condition that at least one of R₂ and R₃ is hydrogen; X is oxygen, -COO- or -CONR₅-, wherein R₅ is hydrogen or alkyl having up to 5 carbon atoms, and Y is a direct bond or for the rest
  -R₆-Z₁-CO-NH-R₇-NH-CO-Z₂-
  in which R₆ is bonded to X and denotes a branched or linear alkylene radical having up to 7 carbon atoms; Z₁ and Z₂ are oxygen or -NR₅- and R₇ is the divalent radical of an aliphatic or aromatic diisocyanate, with the condition that if X is oxygen, Y must be different from a direct bond and R₂ and R₃ are hydrogen.

2. A gel according to claim 1, wherein said water soluble monomers acrylic acid, methacrylic acid, 2-hydroxy ethyl or 2- or 3-hydroxypropyl acrylate or methacrylate, Are N-vinylpyrrolidone or tert-amino-methacrylamide. 3. A gel according to claim 1, wherein said water soluble monomers is 2-hydroxyethyl methacrylate. 4. A gel according to claim 1, wherein said water soluble monomers is N-vinyl-2-pyrrolidone. 5. A gel according to claim 1, wherein R₁ is a polypropylene oxide or polytetramethylene oxide chain with a molecular weight from about 1000 to about 4000. 6. A gel according to claim 1, wherein said macromere (B) a polytetramethylene oxide glycol with a molecular weight of is about 1000 to about 4000, end saturated with Toluene diisocyanate and with 2 moles of a hydroxyalkyl acrylate or methacrylate implemented, wherein alkyl has 2 to 4 carbon atoms Has. 7. A gel according to claim 6, wherein the polytetramethylene oxide glycol has a molecular weight of from about 1500 to about 3000 and the hydroxyalkyl methacrylate 2-hydroxyethyl methacrylate is. 8. A gel according to claim 7, wherein the proportion of ge named macromers (B) about 15% to about 50% is. 9. Process for producing a cross-linked water soluble hydrophilic gel according to claim 1, characterized ge indicates that components A) and B), which like  are defined in claim 1, in the stated weight conditions copolymerized. 10. The method according to claim 9, characterized in that to co-polymerize a water-soluble monomer A) with a hydrophobic macromer B) in the presence or absence of Solvents. 11. The method according to claims 9 and 10, characterized in that the co-polymerization 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 40 ° C to 150 ° C. 12. The method according to claims 9 to 11, characterized in that the co-polymerization of a water-soluble monomer A) with a hydrophobic macromer B) in the presence of 0.02 to 1.0% by weight of a suitable free radical forming catalyst at a temperature of 50 to 100 ° C. leads. 13. The method according to claims 9 to 11, characterized in that as a free radical donating system gamma rays, Elek Tron rays or UV radiation used.   14. Use of a hydrogel according to one of the An Proverbs 1 to 8 for the manufacture of a pharmaceutical composition composition consisting of such a hydrogel and a active pharmaceutical ingredient. 15. Use of a hydrogel according to one of the An Proverbs 1 to 8 for the manufacture of a pharmaceutical composition 14 according to claim 14, consisting of such Hydrogel and an anabolic, analgetic, Androgen, antibiotic, antidepressant, Antidiabeticum, anticonvulsant, antihistaminicum, Antihypertensive, antimicrobial Agent, anti-parasitic agent, anti parkinson remedy, antiphlogisticum, antitussive, an appetite suppressant, bronchodilators, Coronary dilators, corticoid, cytostaticum, Diureticum, Hypnoticum, Neurolepticum, Psychoanalepticum, tranquilizer, uricosuricum or a vasodilator. 16. Use of a hydrogel according to one of the An Proverbs 1 to 8 for the manufacture of a pharmaceutical composition 15 according to claim 15, consisting of such Hydrogel and methandrostenolone as anabolic, acetylsalicyl acid, phenylbutazone or methadone as analgesic, methyl testosterone as an androgen, rifampin as an antibiotic, Imipramine or maprotiline as an antidepressant, phenformin as Antidiabeticum, carbamazepine as an anticonvulsant, tripeles namin as an antihistamine, hydralazine as an antihypertensive, Trimethoprim as an antimicrobial agent, nifurtimox as an anti-parasitic agent, levodopa as an anti Parkinson's drug, naproxen as an anti-inflammatory drug, benzonate as an antitussive, mazindol as an appetite suppressant, fenoterol as Bronchodilator, fenalcomin as coronary dilator, dexamethasone  as corticoid, floxuridine as cytostaticum, hydrochlorothia zid as a diuretic, glutethimide as a hypnotic, reserpine or Thioridazine as a neuroleptic, methylphenidate as a psycho analepticum, diazepam as a tranquilizer, sulfinpyrazone as Uricosuricum or isoproterenol as a vasodilator. 17. Use of a hydrogel according to one of the An Proverbs 1 to 8 to produce a fragrance Composition consisting of such a hydrogel and a fragrance, for the production of a pesticidal composition settlement consisting of such a hydrogel and a Pesticide, or for the preparation of a herbicidal composition settlement consisting of such a hydrogel and a Herbicide. 18. Use according to any one of claims 14 to 17, characterized characterized in that active pharmaceutical ingredients, pesticides Active ingredients, herbicidal active ingredients or fragrances in the monomer mixture dissolves before the polymerization, or before the polymerization is mixed with the monomer-macromeric mixture, or the aforementioned active ingredients or salts thereof in ge dissolved form of a hydrogel according to claims 1 to 8 can adsorb.