DE19723131A1 - Use of water-insoluble carboxyl- and sulphonic acid-containing polymers - Google Patents

Abstract

The use of water-insoluble polymers (P) is claimed as cell proliferation inhibitors. (P) are obtained by radical polymerisation of (a) at least one monomer of formula R-(A)a (I) and (b) at least one other aliphatically unsaturated monomer. R = an olefinic organic group; A = COOH, OSO3H, SO3H, OPO(OH)2, PO(OH)2, OP(OH)2, a phenolic OH group or a salt or ester of these groups; a = 1-3; provided that when A = COOH or carboxylate, then either this monomer contains another A group with a different definition, or the monomer is used with another monomer whose A group has a different meaning. Also claimed are (1) new polymers (P1) containing monomer components (a') and (b'). (a') comprises (a1) aliphatic, unsaturated monomers containing carboxyl and/or carboxylate groups or their functional derivatives; and (a2) aliphatic, unsaturated monomers containing sulphonic acid and/or sulphonate groups or their functional derivatives; or (a') comprises aliphatic, unsaturated monomers containing carboxyl and/or carboxylate groups, and sulphonic acid and/or sulphonate groups, or their functional derivatives; and (b') comprises one or more aliphatic, unsaturated monomers; (2) use of (P) and (P1) to manufacture medical articles with surfaces that inhibit cell proliferation; or to produce medical articles made of metal, ceramic or plastic with a coating of (P) or (P1) to inhibit cell proliferation; (3) articles with a cell-proliferation-inhibiting surface or coating of (P) or (P1). Preferably the ratio of carboxyl/carboxylate groups to sulphonic acid/sulphonate groups is 0.4 - 3.

Description

The invention relates to the use of certain water-insoluble Chen polymers as cell proliferation-inhibiting materials. the The invention further relates to certain novel water-insoluble polymers with cell proliferation-inhibiting properties and a method ren for their production. Finally, the invention relates to Er products made using the water-insoluble, the Zellpro liferation inhibiting polymers were produced.

State of the art

In numerous medical applications of materials such as poly mers, ceramics and metals, e.g. B. as sutures, stents, Implants, or prostheses, must be compatible with the Immune and complement systems as well as the blood are guaranteed.

This property, often referred to as biocompatibility, includes the Avoidance of degradation of the materials through physiological components such as enzymes and macrophages.

An improved biocompatibility of medically used Substitute materials can basically be found through the settlement reach human cells. The one described in EP 0 290 642 Procedure first requires the covalent attachment of a Zwi layer of so-called biopolymers on by carboxyl, ami no and hydroxyl groups functionalized polymer surfaces. the The desired biocompatibility of the material is then determined by a careful, extracorporeal endothelial cell colonization of the Zwi layer reached.

In certain cases of medical applications of biocompatible In contrast, plastics are completely undesirable for cell colonization. For example, cell colonization is intracorporal in the medium term ral applied catheters are just as harmful as with long-term implanted stents or heart valves. In WO 94/16648 a Ver drive described in which the cell sorption and cell spreading on eye implant lenses that cloud the lens subsequent chemical modification of the implant surface ver is prevented. According to EP 0 431 213, polymers are cell-repellent the properties endowed by the surfaces of the polymers be hydrophilized with strong mineral acids. This leads to a Reduction of cell adhesion.

The subsequent chemical modification of polymer surfaces Materials is mostly not uniform and / or uniform. It often untreated areas remain, the starting points can form for a cell colonization of the surface.

US Pat. No. 5,278,200 discloses another technical area Polymers known to have carboxylate and sulfonate groups in one contain natural heparin in a comparable ratio. These Polymers have anticoagulant properties with respect to thrombo cytes in the blood.

The present invention is therefore based on the object Prevent cell proliferation on polymer surfaces.

Description of the invention

An object of the present invention is the use of water-insoluble polymers according to claim I, obtainable by free-radical polymerization of

• (i) at least one monomer of the general formula
  Formula I: R- (A) _a ,
  in which R is an olefinically unsaturated organic radical with the valency a,
  A is a carboxyl group -COOH, sulfuric acid group -OSO ₂ OH. Sulphonic acid group -SO ₃ H, phosphoric acid group -OPO (OH) ₂ . Phosphonic acid group -PO (OH) ₂ , phosphorous acid group -OP (OH) ₂ , phenolic hydroxyl group or a salt or an ester of one of the groups mentioned, and
  a is 1, 2 or 3;
  with the proviso that if the monomer of the formula I has a carboxyl group -COOH or a carboxylate group, either this monomer contains at least one further radical A with one of the meanings given for A or at least one further monomer of the formula I in which A is one has other meanings given for A is also used; and
• (ii) at least one other aliphatically unsaturated monomer as a cell proliferation inhibiting material.

An aliphatically unsaturated radical R is intended here and in the Follow a C-C double and / or triple bond, preferably one or radical containing two olefinic double bonds will. The organic radical R can have a hydrocarbon structure zen or contain other atoms besides carbon and hydrogen, z. B. oxygen, nitrogen and / or silicon atoms.

Due to the restrictive condition above, they become few effective copolymers excluded, which only a carboxyl or Contain carboxylate group.

Among the groups mentioned for A are the acidic groups and the Salts are preferred, among the salts the alkali salts, in particular the Sodium salts.

The common characteristic of the monomers of formula I is that they are aliphatically unsaturated, preferably 1 or 2 olefinic Double bonds and at least one acidic group or salt have an acidic group, as said before the carboxyl and the carboxylate group cannot occur alone.

New cell proliferation inhibiting polymers

Another object of the invention are new water-insoluble, cell proliferation-inhibiting, carboxyl groups and / or carboxyl groups and sulfonic acid groups and / or sulfonate groups-containing polymers B according to claims 2 to 7, obtainable by radical polymerization of

• - one or more carboxyl groups and / or carboxylate groups hal term, aliphatically unsaturated monomers or the corresponding accordingly functionalized derivatives of the monomers as component I. with
• - one or more sulfonic acid groups and / or sulfonate groups hal term, aliphatically unsaturated monomers or the corresponding accordingly functionalized derivatives of the monomers as a component II and
• - a component III, which contains an aliphatically unsaturated monomer or several aliphatically unsaturated monomers,
  wherein the correspondingly functionalized derivatives are converted after the copolymerization, at least on the surface, into carboxyl or carboxylate groups or sulfonic acid or sulfonate groups.

The adhesion and growth of cells will be due to the new poly mers B, as well as on the aforementioned polymer B, excellent suppressed. The polymers A and B are also excellent physio logically compatible and are therefore particularly suitable for production of implants and other medical technology items which cell growth is to be avoided.

Another object of the present invention is a method for producing the water-insoluble, cell proliferation-inhibiting polymers B according to claims 8 to 13, which is characterized in that the polymers are polymerized by free radical copo

• - one or more carboxyl groups and / or carboxylate groups hal term, aliphatically unsaturated monomers or the corresponding accordingly functionalized derivatives of the monomers as component I. with
• - One or more sulfonic acid groups and / or sulfonate groups hal term, aliphatically unsaturated monomers or the corresponding accordingly functionalized derivatives of the monomers as a component II and
• - A component III, which is an aliphatically unsaturated monomer or contains several aliphatically unsaturated monomers, are obtained, the correspondingly functionalized Deri vate after the copolymerization at least on the surface in Carboxyl or carboxylate groups or sulfonic acid or sulfonate groups are convicted.

The new polymers B are a subset of those described above Polymers A, which according to claims 14 to 23 as cell prolifera ion-inhibiting. Materials are used. The information about the properties of the polymer A therefore also apply to the polymers ren B, and vice versa.

Functionalized derivatives of the groups mentioned are in particular Ester, amide and nitrile groups. You may be at the at least on the surface (and only this is what matters for the zellpro liferation-inhibiting effect on) subsequently in carboxyl or Carboxylate groups or sulfonic acid or sulfonate groups converted delt, for example by acidic or basic saponification.

Preferred polymers B contain carboxylate and sulfonate groups. To the extent that these groups do not enter through the choice of appropriate monomers can be brought in at a later date, at least at the waiter surface through neutralization of carboxyl groups or sulfonic acid groups with the solution of a base, such as caustic soda, or by ba generate sic saponification of ester groups.

For the polymers B according to the invention, both carboxy Lat- and sulfonate-group-containing aliphatically unsaturated Monomer or more can be both carboxylate and sulfonate group-containing aliphatically unsaturated monomers or equivalent functionalized derivatives of these monomers are used. Sol Some bifunctional monomers also act as components I and II.

The sum for the polymers B according to the invention is expediently the proportions of component I and component II 5 to 30 mol%, preferably 15 to 20 mole percent of the polymer.

The ratio is preferably that in the polymer according to the invention B containing carboxyl or carboxylate groups to sulfonic acid or Sulphonate groups 0.4 to 3, particularly preferably 0.4 to 2.

Monomers for the cell proliferation-inhibiting polymers A and B

As components I and II for the preparation of the polymers B according to the invention are, for. B. Monomers of the general formulas II and III,

Formula II: (C _n H _2n-qx ) (COOR ¹ ) _x (for component I)

Formula III: (C _n H _2n-qx ) (SO ₃ R ¹ ) _x (for component II)

which fall under the formula I and preferred monomers for the Her position of the polymers B are. In the formulas II and III stand

n each independently for an integer from 2 up to and including 6;
q each independently for 0 or 2,
x each independently for 1 or 2; and
each R ¹ independently denotes -H, an equivalent of a metal ion, in particular an alkali metal ion, or a residue of an aliphatic, cycloaliphatic or araliphatic alcohol, preferably an alkanol with 1 to 6, in particular with 1 to 4 carbon atoms, of a cycloalkanol with 5 to 12 carbon atoms, an arylalkanol with 7 to 10 carbon atoms or an alkanol with oxygen and / or nitrogen atoms in the chain and up to 12 carbon atoms.

If the groups COOR ¹ and SO ₃ R ^{1 are} ester groups, they are converted into carboxyl or carboxy lat groups or sulfonic acid or sulfonate groups by saponification after the polymerization.

According to the definitions given, the radical (C _n H _2n-qx ) - in each case independently means a straight-chain or branched monovalent alkenyl radical (q = 0, x = 1) or alkadienyl radical (q = 2, x = 1) or a straight-chain or branched one divalent alkylene radical (q = 0, x = 2) or alkadienylene radical (q = 2, x = 2).

Instead of two monomers of the formulas II and III, it is also possible to use only one bifunctional monomer (II + III) which contains the groups COOR ¹ and SO ₃ R ¹ in the same molecule.

As a special case of monomers that are suitable as component I, be the following, falling under the formula II monomers of Called formula IV;

Formula IV: (C _n H _2n-qx ) (COOR ² ) _x called, in the

R ² = (CH ₂ -CH ₂ -O) _d -H, (-CH ₂ -CH (CH ₃ ) -O) _d -H, - (CH ₂ -CH ₂ -CH ₂ -O) _d -H or - (CH ₂ ) _d -NH _2-e (R ³ ) _e , where R ³ = -CH ₃ or -C ₂ H ₅ ,
d = 0, 1, 2, 3 or 4 and
e = 0, 1 or 2 means
n = 2, 3, 4, 5 or 6,
q = 0 or 2,
x = 1 or 2 and

mean.

The carbon ester groups are saponified after the polymerization and are then present as carboxyl or carboxylate groups. The alipha Table unsaturated monomers can be both straight-chain and be branched.

As a special case of monomers which are suitable as component II, the following monomers of the general formula V falling under the formula III may be mentioned:

Formula V: (C _n H _2n-qx ) (SO ₃ R ² ) _x

in which R ² , n, g and x have the meanings given.

The sulfonic acid ester groups are saponified after the polymerization and then exist as sulfonic acid or sulfonate groups. The ali Phatically unsaturated monomers can be both straight-chain and be branched.

Also derived from benzene monomer components of the general formula VI

Formula VI: (C ₆ H _6-abc ) A _a B _b (OH) _c

are suitable as components I and II for polymer B, where A is independently a mono- or divalent straight-chain or branched radical of the formulas - (C _n H _2n-1-qx ) (COOR ¹ ) _x or (-C _n H _{2n -1-qx} ) (SO ₃ R ¹ ) _x denotes, where R ¹ , n , q and x are as defined above;
B each independently C _1-4 alkyl, -NH ₂ , -COOH, -SO ₃ H, -OSO ₃ H, -OPO (OH) ₂ , -PO (OH) ₂ , -OP (OH) ₂ , -OPO (O⁻) OCH ₂ CH ₂ N⁺ (CH ₃ ) ₃ , -PO (O⁻) OCH ₂ CH ₂ N⁺ (CH ₃ ) ₃ , -OP (O⁻) OCH ₂ CH ₂ N⁺ (CH ₃ ) ₃ or optionally a salt, in particular an alkali salt, or an ester of the groups mentioned;
a is 1, 2 or 3;
b is 0, 1, 2 or 3; and
c is 0, 1, 2 or 3;
with the proviso that a + b + c ≦ 6, advantageously ≦ 4.

Depending on the meaning of A, the monomers of the formula VI are as Component I or suitable as component II.

As a special case of monomers that come under the general formula VI and are suitable as component I, the following monomers of the general formula VII may be mentioned:

Formula VII: (C ₆ H _6-abc ) C _a D _b (OH) _c , in which mean

C = (C _n H _2n-qx-1 ) (COOR ² ) _x , where
R ² = - (CH ₂ -CH ₂ -O) _d -H, - (CH ₂ -CH (CH ₃ ) -O) _d -H, - (CH ₂ -CH ₂ -CH ₂ -O) _d -H or - (CH ₂ ) _d -NH _2-e (R ³ ) _e denotes, where R ³ = -CH ₃ or -C ₂ H ₅ denotes,
n = 2, 3, 4, 5 or 6,
q = 0 or 2,
x = 1 or 2,
d = 0, 1, 2, 3 or 4 and
e = 0, 1 or 2;
D = -COOH, -SO ₃ H, -NH ₂ , -N⁺ (CH ₃ ) ₃ , -O-PO ₃ H -, -OSO ₃ H, or -O-PO _2⁻ -CH ₂ -CH _2⁻ -N⁺ (CH ₃ ) ₃ ,
a = 1, 2 or 3,
b = 0, 1, 2 or 3 and
c = 0, 1, 2 or 3;
with the proviso that a + b + c ≦ 6, advantageously ≦ 4.

As a special case of monomers that come under the general formula VI and are suitable as component II, the following monomers of the general formula VIII may be mentioned:

Formula VIII: (C ₆ H _6-abc ) E _a D _b (OH) _c , in which:

E = (C _n H _2n-qx-1 ) (SO ₃ R ² ) _x , where
R ² = - (CH ₂ -CH ₂ -O) _d -H, - (CH ₂ -CH (CH ₃ ) -O) _d -H, - (CH ₂ -CH ₂ -CH ₂ -O) _d -H or - (CH ₂ ) _d -NH _2-e (R ³ ) _e where R ³ = -CH ₃ or -C ₂ H ₅ ,
n = 2, 3, 4, 5 or 6,
q = 0 or 2,
x = 1 or 2,
d = 0, 1, 2, 3 or 4 and
e = 0, 1 or 2;
D = -COOH, -SO ₃ H, -NH ₂ , -N⁺ (CH ₃ ) ₃ , -O-PO ₃ H -, -OSO ₃ H, -O-PO _2⁻ -CH ₂ -CH ₂ -N ⁺ (CH ₃ ) ₃
a = 1, 2 or 3,
b = 0, 1, 2 or 3 and
c = 0, 1, 2 or 3;
with the proviso that a + b + c ≦ 6, advantageously ≦ 4.

Ester groups are also used in the last two special cases mentioned saponified after polymerization and then lie as ionic carb oxyl or carboxylate or sulfonic acid or sulfonate groups.

Of those suitable for the preparation of the coating polymers Monomers of the general formulas I to VIII, one or more re same or different, current or potential (i.e. after Saponification current) residues A contained in the molecule, are for example wisely called:

Acrylic acid, sodium acrylate, isobutyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, 2- (2'-hydroxyethoxy) ethyl acrylate, 2-hydroxy-1-me ethyl ethyl acrylate, 2-N, N-dimethylaminoethyl acrylate, methacrylic acid, sodium methacrylate, n-propyl methacrylate, 2-hydroxyethyl meth acrylate, 2- (2'-hydroxyethoxy) ethyl methacrylate, 2-hydroxy-1-methyl ethyl methacrylate, 2-N, N-dimethylaminoethyl methacrylate, maleic acid, Diethylene glycol methacrylate, triethylene glycol diacrylate, sodium al lyl sulfate, sodium methallyl sulfate, 2-hydroxyethyl allyl sulfate, vinyl sulfonic acid, sodium vinyl sulfonate, vinyl sulfonic acid-2-hydroxyethyl ester, vinyl benzene sulfonic acid, sodium vinyl toluene sulfonate, 4-vinyl salicylic acid, butadiene (1,3) diol (1,4) diphosphate, sorbic acid, Caffeinic acid, 4- and 2-vinylphenol, 2-allylhydroquinone, 4-vinylre sorcin, carboxyl-styrenesulfonic acid.

Other monomers

As component III or as a further aliphatically unsaturated one Monomer (ii) are suitable for the polymers ß as well as for the above mentioned polymers A preferably monomers that are not ionic Groups wear. Component III mainly contributes to the fact that polymers A and B are insoluble in water. By orienting Tests can easily be determined which monomers in which Amount can be used as component III, so that the poly mers A and B are insoluble in water. They become insoluble in water viewed when in contact with aqueous media at determination appropriate use of the products made from them or with them stratified products are not visibly changed even after months change. In principle as component III (polymer b) or as aliphatically unsaturated monomer (ii) (polymer A) suitable mono mers include, for example, vinyl compounds such as vinyl ketones, z. Vinyl ethyl ketone and vinyl n-butyl ketone; Vinyl esters, such as vinyl acetate and propionate; Allyl compounds; (Meth) acrylic compounds, such as (meth) acrylic acid esters, e.g. B. methyl acrylate, methyl methacrylate, n-butyl acrylate and 2-ethylhexyl acrylate, also acrylonitrile and Acrylamide; Olefins and dienes, such as 1-butene, 1-hexene, 1,3-butadiene, Isoprene and chloroprene; unsaturated halogenated hydrocarbons, such as Vinyl chloride and vinylidene chloride; Vinylsiloxanes, such as Tris (trime thylsiloxy) methactyloylsilane and tris (trimethylsiloxy) acryloylpro pylsilane; or their correspondingly functionalized derivatives. if and as far as carbon ester, nitrile and carbonamide groups do not follow are hydrolyzed later, the corresponding monomers apply as such of component III or (ii).

Production of the cell proliferation-inhibiting polymers

The polymers according to the invention or to be used according to the invention Ren can for example with the help of emulsion polymerization are manufactured according to the state of the art. (Hans-Georg Elias, Macromolecules, Hüthig & Wepf Verlag, Heidelberg, 1981, p. 603 ff.).

Furthermore, for the production of the polymers according to the invention components I, II and III also in solution or in bulk the known methods are copolymerized. (Hans-Georg Elias, Macromolecules, Hüthig & Wepf Verlag, Heidelberg, 1981, p. 602 ff.).

For the copolymerization of components I, II and III in solution can for example, depending on the monomers used, the following solvents are used: water, ketones such as acetone, methyl ethyl ketone, Butanone and cyclohexanone; Ethers such as diethyl ether, tetrahydrofuran and dioxane; Alcohols such as methanol, ethanol, n- and iso-propanol, n- and iso-butanol and cyclohexanol; strongly polar solvents, such as Dimethylacetamide, dimethyl sulfoxide and dimethylformamide; Coal water substances such as heptane, cyclohexane, benzene and toluene; Halo hydrogens such as dichloromethane and trichloromethane; Ester like Ethyl acetate, propyl acetate and amyl acetate; and nitriles such as aceto nitrile.

The polymerization initiators that can be used include Azonitriles, alkyl peroxides, acyl peroxides, hydroperoxides, peroxoketones, peresters and Peroxocarbonate, Peroxodisulfat, Persulfat as well as all common Pho use initiators. The initiation of polymerization can ther mixed or by electromagnetic radiation, such as. B. UV light or gamma radiation.

Used for the production of the cell proliferation-inhibiting polymers no carboxylate or carboxylate from monomers of the formulas II to VI groups and / or sulfonic acid or sulfonate groups-containing mono mers used, but their functionalized derivatives, z. B. a Carboxylic acid ester instead of a carboxylic acid, the func nalized derivatives after polymerization in carboxyl or carb oxylate groups and / or sulfonic acid or sulfonate groups transferred will. In the case of the esters, this can be acidic or basic catalyzed saponification take place. The derivatization of polymers Materials can be prepared using generally known methods (Hans Beyer, Textbook of organic chemistry, S. Hirzel Verlag, Stuttgart, 1988, P. 260 ff.).

Use of the cell proliferation-inhibiting polymers

Another object of the present invention is the use generation of the water-insoluble, cell proliferation-inhibiting polymers Ren according to claims 14 to 23 as inhibiting cell proliferation de materials, d. H. for the manufacture of products with cellular proles fermentation-inhibiting surface. This includes products made from These polymers consist, and plastic products, ceramics or metal coated with the polymers. To the Beschich well-known methods such as dipping, spraying, Brush, doctor blade and spin coating. The coating with the polymers Ren according to the invention makes it possible to use well-known and proven mate continue to use materials and manufacturing processes. This is especially which is interesting when the mechanical properties of the work substances are of great importance or the production facilities according to the existing manufacturing processes require high investments.

Furthermore, the polymers are fixed by means of primer layers or intermediate layers made from bifunctional compounds activated standard polymers are also possible. Such a standard polymers are, for example, PVC, polystyrene, polyurethanes, poly acrylates, polymethacrylates, polyesters, polyethers, polyether blocks amides, polyamides, polycarbonates, polyolefins, silicones and polytes trafluoroethylene.

The products produced according to the invention with cell proliferati Onsinhibierenden surface are particularly for use on the Area of medical technology suitable and determined. Such products include intraocular lenses and drains. A preferred one Use of the cell proliferation-inhibiting materials according to The invention is for the manufacture of catheters.

Products according to the invention

Finally, the subject of the present invention are the gener nits with a cell proliferation-inhibiting surface according to the Claims 24 to 30, using the water-insoluble, Cell proliferation-inhibiting polymers according to claims 1 to 7 were prepared as previously described, in particular the medical technology products mentioned, preferably catheters.

Measurement method for determining cell proliferation Preparation of the cell suspension

Human fibroblasts (McCoy's) from ATCC NO CRL 1696 (Rockville, Maryland, USA) are grown in a DMEM medium (Dulbecco's Modified Eagles Medium) with the addition of antibiotics, L-glutamine and 10% by volume of a fetal calf serum at 37 ° C grown under an atmosphere of 5% CO ₂ and 95% air. After separating the cells from the nutrient medium, both the number of living cells with the MTT-Fär betest (MTT = 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) and their total number is determined.

Measurement of cell inhibition

Samples of the respective polymer according to the invention are placed in wells (wells of standard microtiter plates) and locked in place by means of special PTFE inserts that have previously been sterilized with ethanol. Samples, wells and PTFE inserts are also sterilized by exposure to ultraviolet light for 15 minutes. The polymer samples are then mixed with the cell suspension of known concentration and kept at 37 ° C. in an atmosphere of 95% air and 5% CO ₂ . After eight days, the cells were washed with a phosphate buffer solution, suspended with 0.05% by weight trypsin solution and 0.02% by weight EDTA solution at pH 7.4 and counted using a Coulter counter.

A sample prepared in the same way serves as a reference sample Sample obtained by polymerizing component III of the respective polymers according to the invention is obtained. The inhibition of the Cell proliferation is expressed as a percentage of the number of Cells on the reference samples to that on the invention Polymers determined.

The measurement results shown in the following examples show gene that cell proliferation on polymers according to the invention is practically completely prevented.

The following examples are intended to explain the invention in more detail.

Preparation of samples of the polymers according to the invention example 1

In a nitrogen atmosphere, 218.2 g of methacrylic acid methyl ester, 12.1 g methacrylic acid and 14.8 g sodium styrene sulfonate in 500 ml of dimethyl sulfoxide dissolved. The solution is heated to 70 ° C. with stirring heated. 2.3 g of azobisisobutyronitrile are then dissolved added dropwise in 30 ml of dimethyl sulfoxide within 2 minutes. the Polymerization is ge over a period of 16 hours at 70 ° C leads. Subsequently, the resulting product is fourfold Excess ice water is precipitated, then in the Soxhlet for 24 hours Extracted water and dried at 50 ° C in a vacuum.

A subsequent analysis of the composition via 1H-NMR shows:
Methacrylic acid: 14 mol%
Sodium styrene sulfonate: 11 mol%
Methacrylic acid methyl ester: 75 mol%
These values give a ratio of carboxylate groups to sulfonate groups of 1.27.

Example 2

216.3 g of methyl methacrylic acid are added in a nitrogen atmosphere ester, 13.8 g acrylic acid and 9.9 g sodium styrene sulfonate in 500 ml Dissolved dimethyl sulfoxide. The solution is heated to 70 ° C. with stirring heats. Then 2 g of azobisisobutyronitrile are dissolved in 30 ml Dimethyl sulfoxide was added dropwise within 2 minutes. The polymers rization is carried out over a period of 16 hours at 70 ° C. The resulting product is then in a fourfold over A shot of ice water was precipitated, then 24 hours in a Soxhlet with water extracted and dried at 50 ° C in vacuo.

A subsequent analysis of the composition via 1H-NMR shows:
Acrylic acid: 10 mol%
Sodium styrene sulfonate: 9 mol%
Methacrylic acid methyl ester: 81 mol%
These values give a ratio of carboxylate groups to sulfonate groups of 1.1.

Example 3

In a nitrogen atmosphere, 235.0 g of styrene, 6.1 g of meth acrylic acid and 14.8 g of sodium styrene sulfonate in 500 ml of dimethyl sulf oxide dissolved. The solution is heated to 70 ° C. while stirring. 2.3 g of azobisisobutyronitrile are then dissolved in 30 ml Dimethyl sulfoxide was added dropwise within 2 minutes. The Polymeri sation is carried out over a period of 20 hours at 70 ° C. in the Connection becomes the resulting product in a four-fold excess Ice water precipitated, then 24 hours in the Soxhlet with water extracted and dried at 50 ° C in vacuo.

A subsequent analysis of the composition via 1H-NMR shows:
Methacrylic acid: 15 mol%
Sodium styrene sulfonate. 7 mol%
Styrene: 78 mol%
These values give a ratio of carboxylate groups to sulfonate groups of 2.14.

Example 4

In a nitrogen atmosphere, 227.5 g of styrene and 8.1 g of acrylic acid and 24.7 g of sodium styrene sulfonate in 500 ml of dimethyl sulfoxide solved. The solution is heated to 70 ° C. while stirring. Afterward 2.3 g of azobisisobutyronitrile are dissolved in 30 ml of dimethyl sulfoxide added dropwise within 2 minutes. The polymerization is over performed for a period of 20 hours at 70 ° C. Afterwards ge the resulting product in a four-fold excess of ice water falls, then extracted with water in a Soxhlet for 24 hours and dried at 50 ° C in vacuo.

A subsequent analysis of the composition via 1H-NMR shows:
Acrylic acid: 11 mol%
Sodium styrene sulfonate: 12 mol%
Styrene: 77 mol%
These values give a ratio of carboxylate groups to sulfonate groups of 0.9.

Example 5

In a nitrogen atmosphere, 310.0 g of n-butyl methacrylate, 12.1 g methacrylic acid and 14.8 g sodium styrene sulfonate in 500 ml Dissolved dimethyl sulfoxide. The solution is heated to 70 ° C. with stirring heats. 2.3 g of azobisisobutyronitrile are then dissolved in 30 ml of dimethyl sulfoxide was added dropwise over the course of 2 minutes. The polymers rization is carried out over a period of 20 hours at 70 ° C. The resulting product is then in a fourfold over A shot of ice water was precipitated, then 24 hours in a Soxhlet with water extracted and dried at 50 ° C in vacuo.

A subsequent analysis of the composition via 1H-NMR shows:
Methacrylic acid: 14 mol%
Sodium styrene sulfonate: 9 mol%
n-butyl methacrylate: 77 mol%
These values give a ratio of carboxylate groups to sulfonate groups of 1.6.

Example 6

In a nitrogen atmosphere, 306.7 g of n-butyl methacrylate, 13.8 g of acrylic acid and 9.9 g of sodium styrene sulfonate in 500 ml of Dime dissolved ethyl sulfoxide. The solution is heated to 70 ° C. while stirring. 2.3 g of azobisisobutyronitrile are then dissolved in 30 ml Dimethyl sulfoxide was added dropwise within 2 minutes. The Polymeri sation is carried out over a period of 16 hours at 70 ° C. in the Connection becomes the resulting product in a four-fold excess Ice water precipitated, then 24 hours in the Soxhlet with water extracted and dried at 50 ° C in vacuo.

A subsequent analysis of the composition via 1H-NMR shows:
Acrylic acid: 10 mol%
Sodium styrene sulfonate: 8 mol%
n-butyl methacrylate: 82 mol%
These values give a ratio of carboxylate groups to sulfonate groups of 1.3.

Manufacture of membranes from polymers according to the invention Example 7

A 5% strength dimethyl sulfoxide solution of the polymer according to the invention according to Example 1 is prepared. The solution is poured into a Petri dish and the solvent is removed from the sample at 80 ° C. under reduced pressure. The membrane produced in this way is then comminuted into pieces of 0.5 cm ² each and extracted with water for 24 hours. Before the following biological investigations, the membrane pieces are washed three times in a Michaelis buffer solution (pH = 7.33) for three hours each time and stored at -4 ° C. until further investigation.

Production of coatings from polymers according to the invention Example 8

It is a 5% methyl ethyl ketone solution of the invention Polymers prepared according to Example 1. In this solution a 10 cm × 8 cm × 0.04 cm polyamide film for 10 seconds submerged. The film is removed and taken for 10 hours at 50 ° C dried under reduced pressure. Then the with the invent according to the polymer coated film in pieces of each Crushed 2 cm × 2 cm and extracted with water for 24 hours. Before The following biological tests are carried out on the samples Michaelis buffer solution (pH = 7.33) three times for three hours each time washed and stored at -4 ° C until further investigation.

Example 9

It is a 5% acetone solution of the polymer according to the invention according to Example 2 produced. A 10 cm × 8 cm × 0.03 cm large polyethylene film, the surface of which was previously through 3-minute exposure to the 172 nm radiation of an excimer beam lers was activated, immersed for 15 seconds. The slide is ent taken and dried for 10 hours at 50 ° C under reduced pressure. The coated film is then cut into pieces of 2 cm × 2 cm each crushed and extracted with water for 24 hours. Before The following biological tests are carried out on the samples Michaelis buffer solution (pH = 7.33) three times for three hours each time washed and stored at -4 ° C until further investigation.

Example 10

It is a 5% acetone solution of the polymer according to the invention according to Example 5 produced. A 10 cm × 8 cm × 0.04 cm large polyether block amide film dipped for 10 seconds. The film is removed and 10 hours at 50 ° C under reduced Print dried. Then the coated film is in Pieces of 2 cm × 2 cm each crushed and treated with water for 24 hours extracted. Before the following biological examinations are made the samples in a Michaelis buffer solution (pH = 7.33) three times Washed for three hours at a time and pending further examination stored at -4 ° C.

Conditioning of the samples from polymers according to the invention Example 11

The membrane according to Example 7 and with the Po according to the invention Polymeric coated films according to Examples 8 to 10 are used sterilized by exposure to ultraviolet light for 15 minutes. Subsequently, the samples pretreated in this way are used three times each kept in a 0.15 molar sodium chloride solution for three hours, then washed for three hours with distilled water. In the follow They are in the cleaning step three times for three hours each time a phosphate buffer solution of the following composition:

CaCl ₂ .H ₂ O 0.132 g / l KCl 0.2 g / l KH ₂ PO ₄ 0.2 g / l MgCl ₂ .6H ₂ O 0.1 g / l NaCl 8 g / l Na ₂ HPO ₄ 1.15 g / l

The samples are then irradiated again with ultraviolet light for 15 minutes. The samples thus present are stored for about 16 hours at 37 ° C. in a DMEM solution (Dulbecco's Modified Eagles Medium). Finally, the samples are kept for a further 16 hours in a DMEM solution mixed with antibiotics, L-glutamine and 10% by volume of a fetal calf serum at 37 ° C. and an atmosphere of 5% CO ₂ and 95% air.

The prepared according to Examples 1, 2 and 5 according to the invention Polymers were either made into a membrane (Example 7) or applied to standard polymers (Examples 8 to 10). These samples were then conditioned according to the example 11 carried out and the cell proliferation according to the described Procedure determined.

The inhibition of cell proliferation exceeded in all samples 98%.

Claims (30)

1. Use of water-insoluble polymers, obtainable by free radical polymerization of

• (i) at least one monomer of the general formula
  Formula I: R- (A) _a
  in which R is an olefinically unsaturated organic radical with the valency a ,
  A is a carboxyl group -COOH, sulfuric acid group -OSO ₂ OH, sulfonic acid group -SO ₃ H, phosphoric acid group -OPO (OH) ₂ . Phosphonic acid group -PO (OH) ₂ , phosphorous acid group -OP (OH) ₂ , phenolic hydroxyl group or a salt or an ester of one of the groups mentioned, and
  a is 1, 2 or 3;
  with the proviso that if the monomer of the formula I has a carboxyl group -COOH or a carboxylate group, either this monomer contains at least one further radical A with one of the meanings given for A or at least one further monomer of the formula I in which A is one has other meanings given for A, is also used; and
• (ii) at least one other aliphatically unsaturated monomer as a cell proliferation-inhibiting material.

2. Water-insoluble, cell proliferation-inhibiting, carboxyl and / or carboxylate groups and polymers containing sulfonic acid and / or sulfonate groups, obtainable by radical copolymerization of
one or more carboxyl groups and / or carboxylate groups-hal term, aliphatically unsaturated monomers or the correspondingly functionalized derivatives of the monomers as component I with
one or more sulfonic acid groups and / or sulfonate groups-hal term, aliphatically unsaturated monomers or the correspondingly functionalized derivatives of the monomers as component II and
a component III, which contains an aliphatically unsaturated monomer or several aliphatically unsaturated monomers,
wherein the correspondingly functionalized derivatives are converted into carboxylic acid or carboxylate groups or sulfonic acid or sulfonate groups after the copolymerization. 3. Polymers according to claim 2, characterized in that as com component I and at the same time as component II a carboxyl or Carboxylate groups and sulfonic acid or sulfonate groups, aliphatically unsaturated monomer or several such monomers the appropriately functionalized derivatives of the monomers are incorporated are set. 4. Polymers according to Claims 2 and 3, characterized in that that the sum of the proportions of component I and component II 5 to Is 30 mole percent of the polymer. 5. Polymers according to claim 4, characterized in that the sum the proportions of component I and component II 15 to 20 mol% of the Polymers is. 6. Polymers according to Claims 1 to 5, characterized in that that the ratio of the carboxyl and / or contained in the polymer Carboxylate groups to sulfonic acid and / or sulfonate groups 0.4 to 3 is. 7. Polymers according to claim 6, characterized in that the Ver ratio of the carboxyl and / or carboxylate contained in the polymer groups to sulfonic acid and / or sulfonate groups is 0.4 to 3. 8. A process for the preparation of water-insoluble, cell proliferation inhibiting, carboxylate and sulfonate groups contain the polymers according to claims 1 to 8, characterized in that the polymers by radical copolymerization of

• - One or more carboxyl groups and / or carboxylate groups-hal term, aliphatically unsaturated monomers or the appropriately functionalized derivatives of the monomers as component I with
• - One or more sulfonic acid groups and / or sulfonate groups-hal term, aliphatically unsaturated monomers or the appropriately functionalized derivatives of the monomers as component II and
• - A component III which contains an aliphatically unsaturated monomer or several aliphatically unsaturated monomers can be obtained, the correspondingly functionalized derivatives being converted into carboxyl or carboxylate groups and sulfonic acid or sulfonate groups after the copolymerization.

9. The method according to claim 8, characterized in that as Component I and at the same time as component II Carboxyl groups or carboxylate groups and sulfonic acid groups or Aliphatically unsaturated monomer containing sulfonate groups or more such monomers or the corresponding functionalized derivatives of the monomers are used. 10. The method according to claims 8 and 9, characterized in that that the sum of the proportions of component I and component II 5 to Is 30 mole percent of the polymer. 11. The method according to claims 8 and 9, characterized in that that the sum of the proportions of component I and component II 15 to Is 20 mole percent of the polymer. 12. The method according to claims 8 to 11, characterized in that that the ratio of the carboxylate groups contained in the polymer increases Sulfonate groups is 0.4 to 3. 13. The method according to claims 8 to 11, characterized in that that the ratio of the carboxylate groups contained in the polymer increases Sulfonate groups is 0.4 to 2. 14. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of products with a cell proliferation inhibiting Surface. 15. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of medical technology articles with a cell proliferation inhibiting surface. 16. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of intraocular lenses with a cell proliferation inhibitor Surface. 17. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of catheters with a cell proliferation-inhibiting upper area. 18. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of drainage with a cell proliferation inhibiting surface area. 19. Use of water-insoluble, cell proliferation inhi Bing polymers according to claims 1 to 7 for the production of products with a cell proliferation inhibiting Be layering from the polymer. 20. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of medical technology articles made of plastics, ceramics or Metals with a cell proliferation-inhibiting coating from the polymer. 21. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of intraocular lenses with a cell proliferation inhibitor Coating from the polymer. 22. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of catheters with a cell proliferation inhibitor Coating from the polymer. 23. Use of water-insoluble, cell proliferation inhi Bing polymers according to Claims 1 to 7 for the production of drainages with a cell proliferation inhibiting Be layering from the polymer. 24. Products with a cell proliferation inhibiting Be stratification of water-insoluble substances that inhibit cell proliferation the polymers according to claims 1 to 7. 25. Products according to claim 24, characterized in that the Products are medical technology articles. 26. Products according to claim 25, characterized in that the medical devices are catheters. 27. Products according to claim 26, characterized in that the medical-technical articles intraocular lenses, catheters or drains genes are. 28. Products with a cell proliferation-inhibiting upper surface of water-insoluble, cell proliferation inhibiting Polymers according to Claims 1 to 7. 29. Products according to claim 28, characterized in that the Products are medical technology articles. 30. Products according to claim 29, characterized in that the medical-technical articles intraocular lenses, catheters or drains genes are.