DE2325169A1 - PROCESS FOR MANUFACTURING NEW BIOLOGICALLY COMPATIBLE POLYMERS - Google Patents

Description

.. sDe. {Z-beeltaeeL

PATENT ADVOCATE * \ O *) IZ 1 £ Q

.17. May 1973 application file 75.583

PATENT APPLICATION

Applicant's Ceskoslovenska akademie v§d ·, Prαha 1, -C _e S «, SR ~

Title; Process for the preparation of new biocompatible polymers

The invention relates to a method for producing new biologically compatible polymers.

Discloses the preparation of a number of hydrophilic polymers based on methacrylic acid bz% i _a Acrylsäureestern or based on acrylamide, methacrylamide or .. their N-substituted derivatives or their copolymers with a range of comonomers dies® "types are All® mainly because of their mechanical properties

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unsuitable for a number of applications. So far it is Manufacture of a hydrophilic elastomer that also contains the meet the requirements placed on biomedical polymers, did not succeed

The polymers produced according to the present invention are biologically tolerated, are elastic thanks to the conjugated double bond system, and since their molecule contains one or two OH groups, they are also hydrophilic. They are prepared by polymerization of hydrophilic monomers (dienols whose molecule 5 to 10 carbon atoms and at least one OH group) in a solvent (C.- to C ₅ alcohols, dimethylformamide, benzene, etc.) or prepared without solvent. Soluble polymers can be prepared by polymerization to a low degree of conversion or polymerization in high dilution or in the presence of supercarriers (CBr., Mercaptans, etc.). Through polymerization to high conversions or polymerization in the presence of a crosslinking agent, such as glycol dimethacrylate, 1,6-heptadien-4-ol, divinylcarbinol, methylene-bis-acrylamide, 1,1,1-trimethylpropane triacrylate, bisphenol-A-dimethylacrylate and 1 , 5-hexadien-l-ol, in an amount of 0.1-30% you can prepare three-dimensional crosslinked polymers. Given the presence of both the OH group and the double bonds in the macromolecules of the soluble polymers, one can also go through

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their subsequent cross-linking of three-dimensional polymers Prepare · The subsequent crosslinking can be done with Diisoeyanaten, ammonium dichromate, dialdehydes, dicarboxylic acids and with a number of other difunctional compounds capable of with the in the Macromolecules present OH groups or C = C bonds to react. .

The polymerization or copolymerization of the dienols is advantageously carried out according to the radical mechanism using azo initiators, peroxides, UV light, and others. If the free OH group in the monomeric compound is blocked, for example by reaction with Cl-Si (CHo) 3 or (CH- ^ CO) ₂ O, the compound formed can also be polymerized ionically coordinatively using initiators such as diethylaluminum chloride + Rh-acetylacetonate, diethylaluminum chloride + Co-acetylacetonate, triisobutylaluminum + TiCl -, It is also possible to use ionic catalysts, for example CH3OL1, butyllithium and naphthalene sodium. After the end of the polymerization, the polymer formed can be hydrolyzed with liberation of the OH groups and a stereoregulated hydrophilic elastomer can thus be obtained.

The biological compatibility would be examined by subcutaneous implantation of the polymers, for example of poly-2,4-pentadien-1-ol, in 50 rats and 5 pigs. Samples were taken 1, 2, 3 and 4 weeks and after -2, 3, 4, 5, 6 and 12 months

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taken from the implantation. The implants are in The organism is successively encapsulated by a connective tissue sleeve, which is made up of positively colored collagen fibers and from there are few fibrocytes that are embedded in the basic substance and stain positive with Aleian blue and one give positive reaction to glycoproteins. The collagen fibers are positioned parallel to the surface of the implant. Large polynuclear cells were not found in the vicinity of the implant the biological compatibility of the polymers examined was rated as positive.

The dienols can be copolymerized with a number of monomers, for example, with glycol methacrylates, the designation glycol not only denoting the simple ethylene glycol, but also diethylene glycol, triethylene glycol and other homologous polyglycols, i.e. all hydrophilic diols of this type, also with N- substituted methacrylic acid and acrylic acid amides, methacrylonitrile, acrylonitrile and with monomers containing ionogenic groups, such as methacrylic acid, acrylic acid, β- vinyl acrylic acid, vinyl pyridine and diethylaminoethyl methacrylate, and with a number of other compounds that contain a polymerizable double bond.

The polymers prepared according to the invention are particularly suitable for the production of biomedical molded parts, such as tubular implants, heart valves, contact

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lenses, cosmetic implants, membranes for hemodialysis and reverse osmosis. The soluble polymer can In view of the excellent elastic properties of the film formed from it, apply it to elastic coverings or subject them to a subsequent crosslinking · Their applications are manifold - from the coating for catheters to stress and building material protection

example 1

A mixture of 98 parts of 2,4-pentadien-1-ol, 1.9 parts. Ethylene dimethacrylate and 0.1 part azo-bis-eisobutyronitril was weighed into a mold made of Teflon, sparged with nitrogen and under inert atmosphere polymerized for 20 hours at 70 ⁰ C · The polymer obtained is dimensionally stable, and after swelling in a physiological solution and Sterilieierung (ζ · Β · 30 minutes in an autoclave at 120 ⁰ G or by irradiation) it can be used as an artificial heart valve. -

Example 2

A mixture of 75 parts of 2,4-pentadiene-1- © l _f 20 parts of hydroxyethyl methacrylate, 4.8 parts of methylene bis-acryl amide and 0.2 part of diisopropyl percarbonate is weighed into a polypropylene mold and flushed with catalytically purified nitrogen and 14 hours b @ i 55 ⁰ G polymerized

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After the equilibrium swelling of the polymer formed in physiological solution, it is suitable as an implant in plastic operations to compensate for deformations the forehead and nose.

Example 3

A mixture of 69 parts of 2,4-pentadien-l-ol, 15 parts of methacrylic acid, 15 parts of dimethylaminoethyl methacrylate, 3 parts of ethylene dimethacrylate and 1 part of diisopropyl percarbonate is placed under an inert atmosphere between two glass plates, which are made with a 0.5 mm thick insert to keep the distance between them Silicone rubber are provided, ^{polymerized at 60 0} C for 18 hours. After swelling in water, the membrane obtained is a suitable separation barrier in the separation of low molecular weight substances (eg inorganic salts, urea and lactose) from protein, polypeptide and nucleic acid solutions, among others

I example 4

A mixture of 95 parts of 2,4-hexadiene-l-ol, 4.8 parts of vinyl propylene glycol and 0.2 parts of tert-butyl peracetate was polymerized in a mold made of Teflon for 12 hours at 75 ⁰ C. The resulting polymer, which is dimensionally stable, can be used as a tendon replacement.

Example 5

A mixture of 69 parts of 1,3-heptadien-5-ol, 20 parts Diglycol monomethacrylate, 10 parts divinyl carbinol and

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1 part Cyclohexanolperoxid was polymerized between two Teflon plates which were provided with a 0.4 mm thick insert for distance attitude, 10 hours at 60 ⁰ C ". The membrane obtained is suitable for the reversosmotische separation of inorganic salts.

Example 6

A device for binding biologically active substances (antibiotics, Cytostatics, vitamins, etc.) suitable polymer is made by Copolymerization of 58 parts of 2,4-pentadien-1-ol, 20 parts

CH ₃
CH ₂ = C-COOCH ₂ CH ₂ OCH ₂ Ch ₂ OCOCI, 20 parts of dimethylformamide, 1 part of triethylene glycol dimethacrylate and 1 part of benzoyl peroxide in an inert atmosphere for 10 hours at 60 ° C. The biologically active substance binds to the polymer formed by a polymer-analogous reaction with the OH or NH ₂ group with the formation of a -CO-OR- or

-CO-NH-R bond. In the reaction mixture becomes binding

of the hydrogen chloride formed an equivalent amount of e.g. triethylamine added. After thorough washing, the polymer is added to a physiological solution and after Implanted sterilization.

Example 7

A mixture of 76 parts of 2-Hydroxyaiethylbutadien-l, 3, 3 parts of l, 6-heptadiene-4-ol _s 20 parts of benzene and 1 part

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Dibenzoyl peroxide is used in an inert atmosphere for 15 hours

70 ⁰ G polymerized · The polymer formed is first

conditioned in ethanol and then in water and finally stored in physiological solution

Example 8

A mixture of 65 parts of 1,3-decadiene-8,9-diol, 10 parts of β- vinyl acrylic acid, 10 parts of diethylaminoethyl methacrylate, 10 parts of triglycol dimethacrylate and 5 parts of azo-bis-isobutyronitrile is in a glass form under an inert atmosphere for 10 hours at 80 ⁰ C polymerized. After equilibrium swelling in physiological solution and sterilization, the polymer can be used for implantations

Example 9

A mixture of 73 parts of 2,4-0ctedien-6-ol, 5 parts 1,5-heptsdien-4-ol, 20 parts of pyridine and 2 parts of cumene hydroperoxide is polymerized according to the method described in Example 1.

Example 10

10 parts of 2,4-pentadienoxytrimethylsilane (prepared by Reaction of 2,4-pentadien-l-ol with chloromethylsilane in Benzene solution) are sealed in a rubber seal Glass ampoule mixed with 90 parts of benzene and the mixture

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5 * 10 KoI diethylaluminum chloride are added per liter. Then, the oxygen radicals are by evacuation removed and under inert atmosphere 10 "* ^ mol of rhodium (III) -aeetylacetonat added per liter and 10 hours at 20 ⁰ G polymerized · The polymer formed is filled with ether, dissolved in ethanol and by addition of a kelinen Amount of alcoholic alkali hydrolyzed. By neutralization and reprecipitation, stereoregulated poly-2,4-pentadien-l-ol is obtained.

Example 11

60 parts of 2,4-pentadienoxytrimethylsilane and 10 parts Divinyl methoxysilane are mixed with 30 parts of benzene, 10 moles of diethylaluminum diloride, ΙΟ "** moles of cobalt aeetylacetonate and contains 10 moles of water per liter of total volume of the reaction mixture, mixed and then 10 hours at room temperature polymerized. The three-dimensional polymer formed is left first in ethanol and then left swell in alcoholic lye. Because it is made with alcohol-water mixture (1: 1) and water washed and stored in physiological solution.

Example 12

A 2,2'-azo-bis-dimethoxyvaleronitril existing mixture of 80 parts acetone, 17 parts of 2,4 ~ pentadiene-l-ol _f 2 parts of ethylene dimethacrylate and 1 part in a thick-

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-walled glass vessel filled, sparged with nitrogen, then sealed glass vessel and polymerized for 25 hours at 45 ⁰ C. A macroporous copolymer is "obtained"

Example 13

A 10 per cent 2,4-pentadien-1-ol solution in ethanol with a content of 1% by weight methyl azo-bis-isobutyrate is weighed into a glass vessel and placed in an inert atmosphere 15. Polymerized at 65 ⁰ C hours. From the obtained solution one can prepare an insoluble film by the addition of 1 mass% of diisocyanate (for example, 2,4-toluene diisocyanate), pouring the solution onto a glass substrate and 30 minutes of heating at 120 ⁰ C. The film obtained can be used, for example, to separate salt solutions by means of reverse osmosis or to treat the surface of the pavement of motorways and other building materials.

Example 14

A 5 percent Solution of a mixture of 2,4-pentadien-l-ol and glycerol methacrylate (4ϊ1) in pyridine with a content of 1% by weight methyl azo-bis-isobutyrate and 0.1% CBr. is polymerized in a glass kettle under an inert atmosphere at 60 ⁰ C for 10 hours. By pouring the solution into excess diethyl ether, the polymer is precipitated and, after drying in vacuo, in ethanol to a 7proz. Solution

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dissolved · This solution can be used for the production of highly elastic films by evaporation of the solvent, and this film can optionally be obtained in insoluble form by subsequent crosslinking. For this purpose, for example, 100% by mass of a solution of the above composition is admixed with 0.8% by mass (NH ^ gCr-pO ”(based on the weight of the polymer) in the form of a 20% aqueous solution room temperature obtain a crosslinked film. The method described can be also used for making coatings ^v on catheters and other medical instruments to use ·

Example 15

80 parts of dimethyl sulfoxide, 15 parts of 2 »Hydroxyäthylbutadien-rl, 3i 3 parts of butyl mercaptan and 2 parts of diisopropyl be in an inert atmosphere for 10 hours at 70 ⁰ C polymerisiert- · By ßingiessen the solution in excess ether is precipitated the polymer. This is suction filtered, dried, dissolved in benzene and nachträglieh with adipic acid at 80 ⁰ C by a similar method crosslinked 14 ° as in Examples 13 and ·

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Claims (4)

23251S9 Claims \ i Process for the production of new biologically compatible polymers, characterized in that dienols, the molecule of which contains 5 to 10 carbon atoms and at least one OH group, are polymerized. 2. The method according to claim 1, characterized in that the polymerization in a solvent such as for example in C, - to C = alcohols, dimethylformamide, Dimethyl sulfoxide, glycol monoethyl ether, pyridine or Benzene. 3. Process according to Claims 1 and 2, characterized in that the polymerization is carried out in the presence of chain transfer agents like, for example, tetrabromomethane or mercaptan. 4. Process according to Claims 1 to 3ι, characterized in that that the polymerization in the presence of a crosslinking agent, such as glycol dimethacrylate, l, 6-heptadien-4-ol, mvinylcarbinol, methylenebisacrylamide, 1,1,1-trimethylpropane triacrylate, bisphenol-A- dimethacrylate or 1,5-hexadien-3-ol. 5. The method according to claims 1 to 3, characterized in that after the end of the polymerization, the polymer is subsequently treated with bifunctional compounds, 309881/0782 ■ such as diisocyanates ^ ammonium dichromate, dialdehydes or .dicarboxylic acids crosslinked ₉ which are able to react with the OH groups "or ~ G ^s O <= bonds in _{the polymer 0} βο - A method according to claims 1 to § _s characterized marked in °> _s records that the polymerization in the presence of other unsaturated vinyl compound makes wherein the Dienolgehalt ₉ besogon least on DA® © 60 moles of "=% amounts to _e 7ο Bae naefe claim β prepares® polymer © al © Binäung · ψ & η biologiüefe akti ^ © n substance © no ' OO @ Pi 51