CZ722389A3 - Hydrolytically degradable hydrophilic gels - Google Patents

Abstract

Hydrolytically degradeable hydrophilic gels (HG) formed from individual chains of hydrophilic polymers connected with crosslinks contg. a structural unit of formula (a). Pref. the gel contains N,O-dimethacryloylhydroxylamine as a crosslinking agent. The hydrophilic monomer is N-(2-hydroxypropyl) methacrylamide, N-isopropylacrylamide, N,N-diethylacrylamide, N-ethylmethacrylamide, vinylpyrrolidone, maleic anhydride, 2-hydroxyethyl methacrylate, 2-(2-hydroxyethoxy) ethylmethacrylate, acrylic acid and/or methacrylic acid. The hydrophobic monomer is dimethylaminoethyl methacrylate, n-butylmethacrylate, n-butyl acrylate, 2-acetoxyethyl methacrylate, t.-butylacrylamide, methylmethacrylate or hexylmethacrylate. The solvent is DMSO, DMF, lower alcohol, e.g., MeOH or EtOH, or mixts. of alcohol-water, or water.

Description

The invention relates to hydrolytically degradable hydrophilic gels.

Hydrophilic gels can be defined as polymeric materials capable of absorbing considerable amounts of water without dissolving them. They find application in many fields of medicine such as implants, membranes for hemodialysis and ultrafiltration, non-thrombogenic surfaces of artificial organs, contact lenses and components of drug release systems. They are hydrophilic polymers linked into a three-dimensional network by physical, ionic or covalent bonds. Although a number of hydrophilic gels resulting from ionic bonds and hydrolytically cleavage are known, there are relatively few data on hydrolytically cleavable gels where the cross-linking is covalent. These are mainly polymers containing ester bonds, after which hydrolysis results in the dissolution of the gel (for example, copolymers of vinylpyrrolidone or polyethylene glycol with fumaric acid), hydrolysis is pH dependent and the rate of hydrolysis is controlled both by the structure of the ester bond neighborhood and the density of the polymer network. Some other systems are based on hydrophilic synthetic polymers linked by a network consisting of biomolecules (carbohydrates, polypeptides) enzymatically or hydrolytically cleaved. The above mentioned systems are relatively little defined and do not guarantee reproducible results in the preparation. Our system is based on the preparation of a polymeric network by copolymerization of a monomeric monomer with a well-defined divinyial crosslinker containing a hydrolytically labile bond. In this way it is possible to reproducibly prepare gels where the density of the network can be controlled not only by the solvent content of the polymerization mixture, but also by the ratio of the two monomer components to each other, and thus the rate of hydrolytic degradation of the gel. Similar systems are not yet known.

It is an object of the present invention to hydrolyse degradable hydrophilic gels, which are characterized in that they contain bonds formed by a structural unit

The principle of the process for the preparation of the hydrolytic degradable hydrophilic gels according to the invention consists in the radical polymerization of hydrophilic monomers or their copolymerization with hydrophobic monomers in the presence of N, N-dimethacryloylhydroxylamine as crosslinker.

For the preparation of the hydrolytically degradable polymer gels according to the invention, suitable hydrophilic monomers are N- (2-hydroxypropyl) methacrylamide, vinylpyrrolidone, maleic anhydride, 2-hydroxyethyl methacrylate, diglycol methacrylate, acrylic acid, methacrylic acid and others. Hydrophilic monomers can be used in crosslinking homopolymerization in an amount of 90 to 98% by weight, in copolymerization with hydrophobic monomers in an amount of 50 to 99 mol%. in the polymerization mixture.

Suitable hydrophobic monomers are dimethylaminoethyl methacrylate, n-butyl methacrylate, n-butyl acrylate, methyl methacrylate and hexyl acrylate in an amount of 0 to 50 mol% in the polymerization mixture.

The polymerization may be carried out in solvents such as dimethylsulfoxide. dimethylformamide, alcohols such as methanol and ethanol or an ethanol-water mixture using conventional free radical polymerization initiators.

The hydrophilic gels thus prepared, cross-linked with N, O-dimethacryloylhydroxylamine, contain a structural unit

-C-O-NH-C-.

A ¹¹ 'in which it is hydrolytically labile. The most important component in the preparation of these gels is the crosslinker according to MS. AO ...... (PV) These hydrophilic gels are stable in acidic environments with a pH of 1 to 6.5. In neutral or slightly alkaline environments above pH 6.5 their degradation occurs, ie dissolution of the originally insoluble hydrophilic geium.

The accompanying figures show the solubility of the polymers of the invention as a function of time at various pH values. Fig. 1 shows the time dependence of the percentage of the cleaved hydrophilic gel prepared according to Example 1 at different pH values.

Curve 1 - shows the course at pH = 8,

Curve 2 - shows the course at ph = 7.4,

Curve 3 - shows the course at pH = 6.5.

Figure 2 shows the time dependence of the percentage of hydrophilic gel digested prepared according to Example 2:

Curve 1 - pH = 3,

Curve 2 - pH = 7.4,

Curve 3 - pH = 6.5.

The invention is further illustrated by the following non-limiting examples.

Example 1

The hydrophilic polymer gel was prepared by solution radical polymerization in dimethylsulfoxide. The polymerization was carried out in a mold consisting of two heated plates provided with a separation layer of polypropylene. The thickness of the hydrophilic polymer gel was controlled by the thickness of the silicone rubber spacer inserted between the heated plates.

Composition of the mixture for polymerization:

3.0 g of N- (2-hydroxypropyl) methacrylamide, 0.036 g of Ν, dim-dimethacryloylhydroxylamine, 0.060 g of azo-bis-isobutyronitrile, 10 ml of dimethyl sulfoxide

3.0 g of N- (2-hydroxypropyl) methacrylamide, 0.036 g of N, O-dimethacryloyihydroxylamine and 0.060 g of azo-bis-isobutyronitrile were dissolved in 10 ml of dimethylsulfoxide. Nitrogen was bubbled into the solution for 10 min and then sprayed into a 50 ° C mold (7 for 24 hours polymerization). After the polymerization was complete, the gel was removed from the mold, 1.5 cm diameter circles were punched out and conditioned in 200 ml of methanol for 24 minutes, and further unwashed in distilled water for 24 hours.

Example 2

A hydrophilic polymer gel based on N- (2-hydroxypropyl) methacrylamide was prepared in the same manner as in Example 1 except with the difference. The composition according to claim 1, characterized in that 0.073 g of N, O-dimethacryloylhydroxy lamin was used in the polymerization mixture.

Example 3

A hydrophilic polymeric gel based on N-vinylpyrrolidone was prepared in a similar manner to that described in Example 1.

The composition of the polymerization mixture is as follows:

3.0 g of N-vinyipyrrolidinone, 0.093 g of Ν, dim-dimethacryloyihynrexyamine. 0.132 g azobisisobutyronitrile, 10 ml dimethylsulfoxide.

Example 4

A hydrophilic polymer gel based on 2-hydroxyethyl methacrylate was prepared in a similar manner to that described in Example 1, except that a 1.5 cm internal diameter polypropylene tube was used as the polymerization form.

The composition of the polymerization mixture was as follows:

3.0 g hydroxyethyimethacrylate, 0.039 g Ν, Ν-dimethacryloylhydroxylamine, 0.142 g azo-bis-isobutyronitrile, 10 ml dimethylsulfoxide.

Example 5

A hydrophilic polymer gel based on copolymers of N- (2-hydroxypropyl) methacrylamide, methacrylic acid and dimethylaminoethyl methacrylate was prepared as described in Example 1.

The composition of the polymerization mixture was:

2.0 g N- (2-hydroxypropyl) methacrylamide, 0.41 g methacrylic acid, 0.73 g dimethylaminoethyl methacrylate, 0.04 g N, O-dimethacryloylhydroxylamine, 0.09 g azobis-isobutyronitrile, 5.0 ml dimethylsulfoxide

Example 6

A hydrophilic polymeric gel based on vinylpyrrolidone maleic anhydride copolymers was prepared as described in Example 1.

The composition of the polymerization mixture was as follows:

1.5 g N-vinyipyrrolidone, 1.3 g maleic anhydride, 0.093 g N, O-dimethacryloyihydroxylamine, 0.132 g azo-bis-isobutyronitrile, 10 ml dimethylsulfoxide

Example 7

A hydrophilic polymer gel based on copolymers of N- (2-hydroxypropyl) methacrylamide and n-butyl methacrylate was prepared as described in Example 1.

The composition of the polymerization mixture was as follows:

2.1 g of N- (2-hydroxypropyl) methacrylamide, 0.9 g of n-butyl methacrylate, 0.111 g of N, 0-dimethacryloylhydroxylamine, 0.143 g of azo-bis-isobutyronitrile, 10 ml of dimethylformamide

EXAMPLE 8 g \ - _K 2 Nýdr poiymerizcvano at xyÍpropyHmethakrylamidu were dissolved in 6625 ml of water and the coexistence of the red-ox initiator system consisting of a solution of 1.5 mL (VHI} zS _from OI (0.45 g) and a solution of 0.375 mi Ν, Ο-dimethacryloylhydroxylamine (0.150 g) in dimethylsulfoxide, then 1.5 ml of ascorbic acid solution (0.348 g) was added, polymerization was carried out at 30 ° (7 for 4 hours).

Claims (5)

Hydrolytically degradable hydrophilic gels characterized in that they consist of individual chains of hydrophilic polymer linked by cross-links containing a structural unit -C-O-NH-C- 2. A process for the preparation of hydrolytically degradable gels according to claim 1, characterized in that the hydrophilic monomers or mixtures thereof are subjected to radical polymerization or copolymerization or copolymerization with hydrophobic monomers in the presence of a Ν, Ο-dimethacryloylhydroxy lamin and optionally in the presence of a solvent. in the range of 50 to 99.8 mol%. 3. A process according to claim 2 wherein the hydrophilic monomer is a monomer selected from N- (2-hydroxypropyl) methacrylate, vinylpyrrolidone, maleic anhydride, 2-hydroxyethyl methacrylate, diglycol methacrylate, acrylic acid, methacrylic acid, or a mixture thereof. in " 4. The process of claim 2 wherein the hydrophobic monomer is a monomer selected from the group consisting of dimethylaminoethyl methacrylate, n-butyl methacrylate, n-butyl acrylate, methyl methacrylate, hexyl methacrylate. 5. A process according to any one of claims 2 to 4, wherein the solvents used are those selected from the group consisting of dimethylsulfoxide, dimethylformamide, lower alcohols such as methanol and ethanol, alcohol-water and science.