CS234156B1 - Method of spongy synthetic hydrogel preparation - Google Patents

Abstract

Process for preparing spongy synthetic hydrogels with improved mechanical properties and biological properties suitable especially for medical purposes, marked in that the hydrophilic monomer or mixture monomers selected from the group of monomethacrylates, or diol monoacrylates or polyols or polyol ethers, below acrylamide or methacrylamide and their N-mono- or N, N-disubstituted alkyl derivatives, % containing up to 5 wt. competent crosslinking agents are subjected to homogeneous radical copolymerization in the presence crystalline substances well soluble in water but only slightly soluble in the monomer mixture or insoluble, and in the presence 50 to 95% by volume of an organic builder based on the total volume of the liquid components the polymerization mixture being organic the diluent is indefinitely miscible with water, has an interaction parameter with respect to to a polymerization product 9C of less than 0.5 and after the polymerization is completed from the hydrogels it is removed by washing with excess water.

Description

The invention relates to a process for the preparation of spongy, synthetic hydrogels with improved mechanical and biological properties which are particularly suitable for the replacement of soft tissues.

PolyHEMA (2-hydroxyethyl methacrylate) hydrophilic gels are hitherto an important prosthetic material for numerous medical applications. Their properties are well known, see for example Q. Wichterle: "Hydrogels" in the Encyclopedia of Polymer Science and Technology, vol.15, pp.273-291. Interscience, J. Wiley and Sons, New York 1971 prepared according to the original procedures in the form of a homogeneous, micro- or macroporous gel.

Sponge (macroporous) hydrogels are generally prepared according to U.S. Patent No. 92,010 by increasing the copolymerization of HEMA monomer and a small amount (up to 2% by weight) of ethylene dimethacrylate - EDMA, in the presence of a greater amount (65-85 vol.%) Of water as an inert diluent. The copolymerization process is heterogeneous, i.e. the insoluble (crosslinked) polymer product gradually falls out of the polymerization mixture, separating excess (non-equilibrium) water, which in the resulting spatial gel generates forces of interconnected channels with an average size of 50 ~ 80 micrometers. The aqueous medium is characteristic of the HEMA monomer, but the more hydrophilic monomers, such as acrylamide or diethylene glycol monomethacrylate, provide only homogeneous (heporous) gels under the same polymerization conditions.

The mechanical properties of said prosthetic material are not satisfactory, in particular because of the low structural strength and also some of its biological properties. Result2

Indeed, implantation into an experimental animal has repeatedly demonstrated its increased susceptibility to calcification. It is the gradual deposition of insoluble calcium salts within the implant (see L. Sprincl, J. Kopec and D.Lim: Effect on the structure of poly (glycol monomethacrylate) gels on the calculation of implants', Calcified Tissue Research 13, 63-72 ( 1973)) · These findings were partially confirmed even in the clinical use of this material in the form of a female mamma prosthesis, prepared according to Pat. No. 140 155 · Loss of elasticity of implanted material due to its calcification may in some cases completely impair the resulting effect of the plastic surgery . These problems generally do not occur in the implantation of homogeneous or microporous hydrogel types (cf. Sprincl et al.).

In order to improve the mechanical properties of polyHEMA hydrogels, processes have been proposed which can be used to prepare either non-porous thin crosslinked gels having increased swollen strength (cf. Pat. No. 131,188 and No. 153,762) or very solid macroporous. gels which, however, are not very swellable in water (cf. Pat. No. 131,449). However, none of these approaches addresses the problem of spongy hydrogels that are suitable for substituting soft tissues.

The process of the present invention provides sponge-like (macroporous) synthetic hydrogels which are particularly useful for soft tissue replacement. These prosthetic materials are more mechanically resistant than the spongy polyHEMA. hydrogels and are characterized by significantly reduced susceptibility to calcifications when implanted into the living environment of the organism.

The essence of the process for preparing spongy synthetic hydrogels with improved mechanical and biological properties, particularly suitable for medical purposes, consists in that a hydrophilic monomer or a mixture of monomers selected from the group of monomethacrylates or monoacrylates of diols or polyols or polyol ethers, acrylamide or methacrylamide and their N- of mono- or Ν, dis-disubstituted alkyl derivatives containing up to 5% by weight of the respective crosslinker are subjected to homogeneous radical copolymerization in the presence of a water-soluble crystalline substance but sparingly soluble or insoluble in the monomer mixture and in the presence of 50-95% % of the organic diluent based on the total volume of the liquid components of the polymerization mixture, wherein the organic diluent is unrestrictedly miscible with water, has an interaction parameter with respect to the polymerization product X of less than 0.5, removes the drugstore by washing it with excess washing water.

According to the process of the invention, sponge hydrogels can be prepared from hydrophilic monomers other than HEMA, for example based on acrylamide, methacrylamide and their N-monosubstituted or N, N-disubstituted derivatives such as Ν, Ν-diethyl acrylamide, N- (2-hydroxypropyl) methacrylamide. are described in U.S. Pat. No. 1,559,937 or higher homologous glycol esters or polyglycol esters of methacrylic or acrylic acid, for example, diethylene glycol methacrylate, glycerol methacrylate, or other hydrophilic monomers which, by free radical polymerization, provide sufficiently solid and physiologically acceptable polymer products. Said monomers may be used singly or in combination, optionally with a minor amount (up to 30 wt.% Max.) Based on the hydrophobic monomer mixture. however, hydrogels based on sparsely cross-linked poly (2-hydroxyethyl methacrylate) are the most proven.

The crosslinking agents used according to the invention are the known cross-linking monomers, which are typical of the type, such as ethylene dimethacrylate, ethylene-bis-methacrylamide, in an amount of up to 5% by weight, based on the starting monomer or monomer mixture. Azo-bis-isobutyronitrile and diisopropylpercarbonate have proven to be the most suitable for the initiation of free-radical polymerization for the preparation of healthy hydrogels.

As an inert organic diluent, in principle any organic solvent which meets the above requirements could be used, but due to the strict health requirements, the selection is limited to inert liquids such as ethyl alcohol, glycerol and diacetin (glycerol acetate diester). Their trace amounts contained in the washed hydrogel are physiologically harmless. The use of an inert diluent in the polymerization system (after its complete washing and replacement with pure water) results in a strongly relaxed polymeric network exhibiting higher structural strength, elasticity and penetration life.

Only inert compounds which are soluble in water but practically insoluble in the starting polymerization mixture are used as inert crystalline substances according to the invention. Of course, these substances must not adversely affect the polymerization process itself. The inert crystalline substance is in the solid state in said polymerization system, with all the free space between its particles being filled with the starting liquid polymerization mixture and the later swollen gel. Upon completion of the polymerization, the crystalline material used is removed from the gel by dissolving it and washing it in excess of wash water to form the sponge-like structure of the polymer product. The porosity of the gel can be controlled within wide limits by the choice of the size or distribution of the particles of the crystalline substance used. The pore dimensions roughly correspond to the original particle size. During elutriated _T ·· _{vol of} the crystalline substance is simultaneously removed from the gel, the hydrophilic organic zřeňovadlo and additional ballast materials, which are the residues of the monomer and initiator event.jiné extrabovatelné dopant. Overall, the porous structure of the gel facilitates the washing of excipients and ballasts from the polymer casting. The porous hydrogel can be leached without boiling water, which greatly speeds up the entire washing process. Convection of the washing water by a network of formed and interconnected tubes is advantageously used.

Due to strict medical requirements, their choice has been limited to completely harmless substances, for example sodium chloride, sucrose or glucose, sorbitol, etc. The said substances can also be used in finely powdered form, for example obtained by milling. These materials are preferably fractionated according to particle size prior to use, for example by means of a set of standardized stainless steel screens. Although it is generally known in the art to use crystalline substances to form spongy structures (e.g. viscose sponges), the inventive process achieves completely new properties in synthetic hydrogels for medical use. These spongy prosthetic materials with improved mechanical and biological properties have not been previously known.

The following examples serve to illustrate the process of the present invention and are not to be construed as limiting the scope thereof to possible combinations of starting monomers and excipients.

- 5 234 158

Example 1

First, a polymerization mixture with the following composition was prepared:

% by weight of HEMA monomer (diester content 0.3%), 70% by weight diacetine and 0.4% azobisisobutyronitrile (by mass HEMA) as polymerization initiator. An equal amount (50/50 parts by weight) of finely crystalline sodium chloride p.a. (pre-sieved through a 0.1 mm stainless steel mesh) and the slurry was briefly bubbled with pure nitrogen. The mixture was aspirated into soft PVC tubing (non-toxic) and the ends were sealed by sealing. Tubes were heated in a slightly rotating drum placed in a water bath at -5 ° C for 10 hours. At the end of the polymerization, both ends of the tubing were centrifuged and the polymer casting was pushed out with a syringe filled with water. Macroporous cylindrical castings having a diameter of 1.5 to 5 mm, a length of 250 mm and a porosity of 100 microns were prepared. These were thoroughly washed in boiling distilled water for 5 days, with a twice daily wash water change. Purely washed polymer sponge casts were wrapped in PE foil and sterilized by radiation using a Tesla linear electron accelerator, LINAC, dose 2.5 Mrad. Sponge gel pieces resterilized by boiling in saline were used for experimental embolisation in a dog after cooling to room temperature.

Example 2

The procedure of Example 1 was followed, but instead of diacetin, the pharmacopoeial glycerol was used, and instead of sodium chloride, finely powdered sucrose was used in the same weight ratios as indicated. The polymer mixture was sucked into a tube of 2 / 2.5 mm x 250 mm health-safe silicone rubber and both ends were then closed with stainless steel clamps. After the polymerization was completed, the inner gel pad was leached with thoroughly boiling distilled water until the last wash water showed no organic impurities in the spectroscopic control. A silicone tubing with a hydrogel sponge tube was sterilized in an autoclave and then used to drain the cerebrospinal fluid into the jugular vein, using a model hydrocephalus in the experimental rabbit.

AND

- 6 Example 3. ^{234 156}

10 g of recrystallized N- (2-hydroxypropyl) methacrylamide, 0.5 g of methylene-bis-methacrylamide and 0.05 g of azo-bis-isobutyronitrile were dissolved with stirring in 9θ ml of pure ethyl alcohol. 80 g of glucose were suspended to the monomer mixture and the mixture was briefly purged with pure nitrogen and then poured into a mold made of two pieces of 20 x 20 x 0.5 cm glass sheets of 2 cm wide silicon rubber and 1.5 mm thick. which was closed with 4 pieces of screw terminals. The polymerization was carried out under an inert atmosphere of CO 2 gas at 0 ° C for 10 hours. After thorough gel elimination with boiling distilled water, a porous foil having a pore size of 50-80 microns was obtained. Round discs with a diameter of 10 mm were cut from it. The targets were used after experimental sterilization for experimental implantation in an animal organism (rat). Preliminary results of monitoring the biological properties of the implanted material indicate its advantageous properties, its reduced susceptibility to calcifications. These properties, together with the good mechanical properties of the sponge hydrogel, make this material potentially useful in the field of reconstructive and plastic surgery.

Example 4.

Following the procedure of Example 3, but using a polymerization mixture of the following composition: 70% by weight of diethylene glycol monomethacrylate (containing 0.83% of the respective diester as crosslinker), 3% by weight of n-butyl methacrylates and 0.3% by weight of isopropylpercarbonate (based on said monomer mixture) ) was mixed with diacetin in a ratio of 20/80 parts by volume and the liquid mixture was mixed with an equal amount of (sorbent) sorbitol sieved in advance through a 0.05 mm stainless steel sieve. In the same manner as in Example 3, a macroporous material is obtained which exhibits elastic behavior even in the dried state and can be used in the external therapy of various injuries, for example burns, and can simultaneously serve as a carrier of suitable biologically active substances, e.g. cover of injured tissue against environmental influence (infection).

Claims (5)

SUBJECT OF THE INVENTION 234 156 Process for the preparation of spongy, synthetic hydrogels with improved mechanical and biological properties, particularly suitable for medical purposes, characterized in that a hydrophilic monomer or a mixture of monomers selected from the group consisting of monoacrylates monoacrylates of diols to polyols or polyolethers, acrylamide or methacrylamide The N-mono- or N, N-disubstituted alkyl derivatives containing up to 5% by weight of the respective crosslinker are subjected to homogeneous free-radical copolymerization in the presence of a crystalline substance which is readily soluble in water but only slightly soluble or insoluble in the monomer mixture. 95 vol of organic diluent based on the total volume of liquid components of the polymerization mixture, the organic diluent being unrestrictedly miscible with water, having an interaction parameter relative to the polymerization product of 3C of less than 0.5, and removal of the hydrogels from the hydrogels Rani excess wash water. 2. A process according to claim 1, wherein the crystalline solid is selected from the group of non-toxic compounds such as sodium chloride, sucrose, glucose and sorbitol. 3. The process of claim 1 wherein the organic hydrophilic diluent is selected from the group of non-toxic compounds such as ethyl alcohol, glycerol and glycerol diacetate. 4. Process according to claim 1 or 2, characterized in that the crystalline solid is first fractionated prior to its use according to the particle size or distribution of its particles and optionally fined first. grinds. J 5. The process of claim 1, wherein a portion of the base hydrophilic monomer in an amount of up to 30% by weight is replaced by a hydrophobic monomer such as methyl methacrylate or n-butyl methacrylate.