CA2231101A1

CA2231101A1 - Process for the preparation of antimicrobial plastics

Info

Publication number: CA2231101A1
Application number: CA002231101A
Authority: CA
Inventors: Peter Ottersbach; Frank Hill; Christine Anders
Original assignee: Huls Aktiengesellschaft; Peter Ottersbach; Frank Hill; Christine Anders; Degussa-Huls Aktiengesellschaft; Degussa Ag
Current assignee: Evonik Operations GmbH
Priority date: 1997-03-06
Filing date: 1998-03-04
Publication date: 1998-09-06
Also published as: DE19709075A1; NO980981L; EP0862858A1; EP0862858B1; US6203856B1; NO980981D0; US5967714A; JPH10251350A; DE59804617D1; DK0862858T3; ATE219881T1

Abstract

The invention relates to antimicrobial polymers which are obtained by copolymerization of tert-butylaminoethyl methacrylate with one or more other aliphatically unsaturated monomers.

The invention furthermore relates to antimicrobial polymers which are obtained by grafting copolymerization of tert-butylaminoethyl methacrylate with one or more other aliphatically unsaturated monomers.

The invention moreover relates to processes for the preparation of antimicrobial polymers and their use.

Description

PRO('ESS FOR THE PREP.P~RATION O~ P~T.l~M:CCRO.Bl~L PI~ST~CS

The invention relates to antimicrobial polymers obtainable by copolymeriza-tion of tert-butylaminoethyl methacrylate with one or more aliphatically unsaturated monomers, a process for their preparation and their use.

S The invention furthermore relates to antimicrobial polymers obtainable by grafting copolymerization cf tert-butylaminoethyl methacrylate with one or more aliphatically unsaturate~d monomers on a substrate, a process for their preparation and their use.

Colonizations and spreads oF bacteria on surfaces of pipelines, containers or pack,aging are highly unde-sirable. Layers of slime often form, which allow the micropopulations to rise to extreme levels, lastingly impair the quality of water, drinks and foodstuffs, and can even lead to decay of the goods and damage to the health of consumers.

Bacteria are to be kept away from all areas of life where hygiene is of importance. ~his affects textiles for direct contact with the body, in particular for the intimate region, and for care of the sick and elderly. Bacteria are alsoto be! kept away from the surfaces of furniture and equipment in nursing wards, in particular in the intensive care and infant care sector, in hospitals,especially in rooms for medical operations, and in isolation wards for critical cases of infection, as well a.s in toilets.

Equipment, surfaces of fumiture and textiles are currently treated against bacteria as required or also preventively with chemicals or solutions and mixtures thereof which act i3S disinfectants with a more or less broad and masslve antimlcrobial action. Such chemical compositions have a non-2s specific action, are often themselves toxic or irritating, or form degredation products which are unacceptable to health. Intolerances are often also found O.Z. 5160 in appropriately sensitized persons.
Another procedure against spreads of bacteria on surfaces is incorporation of antimicrobially acting sulbstances into a matrix.

Tert-butylaminoethyl methacrylate is a commercially available monomer of ei methacrylate chemistry and is employed in particular as a hydrophilic consl:ituent in copolymerizations. Thus, EP 0 290 676 describes the use of valrioùs polyacrylates and polymethacrylates as a matrix for immobilization of bactericidal quaternary ammonium compounds.

US 3 592 805 discloses the preparation of systemic fungicides in which 10 perhalogenated acetone derivatives are reacted with methacrylate esters, such as, for example, tert-butylaminoethyl methacrylate.

US 4 515 910 describes the use of polymers of hydrogen fluoride saits of aminomethacrylates in dental medicine. The hydrogen fluoride bonded in the polyrners emerges slowly from the polymer matrix and is said to have actions 15 against karies.

From another technical he!ld, US 4 532 269 discloses a terpolymer of butyl methacrylate, tributyltin methacrylate and tert-butylaminoethyl metha-crylate. This polymer is used as an antimicrobial paint for ships, the hydro-philic, tert-butylaminoethyl methacrylate promoting slow erosion of the 20 polyrner and in this way liberating the highly toxic tributyltin methacrylate as an antimicrobial active compound.

In thlese applications, the copolymer prepared with amino-methacrylates is only a matrix or carrier substance for the added microbicidal active com-pounds, which can diffuse or migrate out of the carrier. Polymers of this type lose their action at a greater or lesser speed when the necessary "minimum inhibitory concsntration" (~/IIC) is no longer achieved on the surface.

o. z . 5160 EP 0 204 312 describes a process for the preparation of anti-microbially treated acrylonitrile fibers. The antimicrobial c~ction is based on a protonated amine as a comonomer unit, climethylarninoethyl methacrylate and tert-butylaminoethyl rnethacrylate, inter alia, being used as protonated species.
However, the antimicrobial action ofprotonated surfaces is severe]Ly reduced after loss of the H ions.
A major object oE the present invention is to develope rnaterials which have antimicrobial properties, which contain no :L0 active cornpounds which can be washed out, and in which the anti-rnicrobial action is pH-independent.
It has now been Eound, surprisingly, that polymers having a surface which is permanently microbicidal, is not attacked by solvents and physical stresses and shows no rnigration can be obtained by copolymerization of tert-butyl-aminoethy:L methacrylate with one or more other aliphatically unsaturated monomers or by grafting copolymerization of tert-butylaminoethyl methacrylate with one or more aliphatically unsaturated monomers on a substrate. It is not necessary here lo employ further biocidal active compounds.
The present invention therefore relates to anti-microbial polymers which are obtained by copolymerization of tert-butyLaminoethyl methacrylate and one or more other aliphatically unsaturated monomers.
The present invention furthermore relates to anti-microbial polymers which are obtained by grafting copolymeriza-tion of tert-butylaminoethyl methacrylate with one or more other aliphatically unsaturated monomers on a substrate.

O.Z. 5160 The present invention also relates to a process for the preparation of antimicrobial polymers, which comprises subjecting tert-butylaminoethyl methacrylate to grafting copolymerization with one or more other aliphatically unsaturated monomers on a substrate.
The present invention furthermore relates to a process for the preparation of antimicrobial polymers, which comprises copolymerizing tert-butylaminoethyl methacrylate with one or more other aliphatically unsaturated monomers.
The present invention furthermore relates to the use of the above-mentioned antimicrobial polymers for the production of products with an antimicrobial coating from the polymer.
The present invention moreover provides articles having a coating layer of the antimicrobial polymers.
The copolymerization of tert-butylaminoethyl methacrylate and one or more other aliphatically unsaturated monomers can be carried out by graft copolymerization on a substrate. When the copolymerization is carried out in this way, the microbicidal property is largely retained. Any usual aliphatic~lly unsaturated monomers are suitable for this purpose. They are preferably nonicnic. Examples of the monomers include (meth)acrylates and (meth)acrylamides of the general formula:

/ R

\ CONR R

o.z. 5160 in which :Rl is a hydrogen atom or a methyl group and R and R
are each a hydrogen atom, a metal atom or a linear or branched aliphatic, cycloaliphatic or aromatic hydrocarbon group having up to 20, preferably up to 10 carbon atoms or a heterocyclic group or such a hydrocarbon or heterocyclic group which contains a carboxyl group, a carboxylate group, a sulfonate group, an alkylamino group, an alkoxy group, halogen, a hydroxyl group, an amino group, a dialkyl amino group, a phosphate group, a phosphonate group, a sulfate group, a carboxami(lo group, a sulfonamido group, a phosphonamido group or a combination of these groupings.
It is furthermore possible to employ vinyl compounds of the general formula:
R CH _ CHR
vinyl esters of the general formula:

H C- C / H
2 ~ O2CR

and maleic and fumaric acid derivatives of the general formula:
R O2C-HC=CH-CO2R

in which :R is a hydrogen atom, an aromatic radical (such as phenyl) o:r a lower alkyl (such as methyl) group or may have the same meaning as R .
R5 is a hydrogen atom, a methyl group or a hydroxyl group, or may have the same meaning as R , or may be OR .

O.Z. 5160 Among these alipl~atically unsaturated mo~omers, preferred are (meth)acrylates (i. e~ esters) having a linear or branched alkyl group containing up to 10 carbon atoms and optionallv containing a hy~roxyl group. Particularly preferred is methyl methacrylate. ALso preferred are styrene and its derivative~s such as methylstyrene.
The ratio of tert-butylaminoethyl methacrylate and the aliphatically unsaturated monomers is not critical in general as far as the copolymer has an antimicrobial property.
:L0 Preferably, the content of units derived from tert-butylamino-ethyl methacrylate is from about 30 to about 98 mol %, more preferably from about 40 to 85 mol ~.
Suitable substrate materials are, above all, any polymeric plastics, such as, for example, polyurethanes, poly-amides, polyesters, polyetlhers, polyether-block amides, poly-styrene, polyvinyl chlorid~e, polycarbonates, polyorgano-siloxanes, polyolefins, polysulfones, polyisoprene, polychloro-prene, po:Lytetrafluoroethylene (PTFE), corresponding copolymers and blend;, as well as natural and synthetic rubbers, with or without r~diation-sensitive groups. The process according to the inven-tion may also be applied to surfaces of metal, glass or wooden bodies which are painted or are otherwise coated with the polymeric plastics.
The substrates' surfaces may be activated by a number of methods before the grafting copolymerization. They are preferably freed from oils, greases or other impurities before-hand in a known manner by means of a solvent.

o.Z. 5160 The standard polymers may be activated by UV
radiation. A suitable source of radiation is, for example, a UV-excime:r apparatus HERAEUS Noblelight, Hanau, Germany.
However, mercury vapor lamps are also suitable for activation of the substrate if they emit considerable proportions of the radiation in the ranges mentioned. The exposure time is in general 0.1 second to 20 minutes, preferably 1 second to 10 minutes.
The activation of the standard pGlymers with UV
radiation may furthermore be carried out with an additional photosensitizer. For this purpose, the photosensitizer, such as, for example, benzophenone, is applied to the surface of the subst:rate and irradiated. This can likewise be carried out with ~ mercury vapor lamp using exposure times of from 0.1 second to 20 minutes, preferably from 1 second to 10 minutes.
According to the invention, the activation may also be achieved by a high-frequency or microwave plasma (Hexagon , Technics Plasma, 85551 Kirchheim, Germany) in air or a nitrogen or argon atmosphere. The exposure times are in general from 30 seconds to 30 minutes, preferakly from 2 to 10 minutes.
The energy input of laboratory apparatus is generally between 100 and 500 W, preferably between 200 and 300 W.
Corona apparatus (SOFTAL, Hamburg, Germany) may furthermore be used for the activation by corona discharge.
In this c~se, the exposure times are in general from 1 to 10 minutes, preferably from 1 to 60 seconds.

Trade-mark O.Z. 5160 The activation by electron beams or y rays (for example from a cobalt-60 source) and the ozonization allows short exposure times which are in general from 0.1 to 60 seconds.
Flaming of surfaces likewise leads to activation thereof. Suitable apparat:us, in particular those having a barrier flame front, may be constructed in a simple manner or obtained, for example, from ARCOTEC, 7129 Monsheim, Germany.
They can be operated with hydrocarbons or hydrogen as the combustible gas. In all cases, harmful overheating of the substrate must be avoided, which is easily achieved by intimate contact with a cooled metal surface on the substrate surface facing away from the flaming side. Activation by flaming is accordingly limited to relatively thin, flat substrates. The exposure times are in general 0.1 second to 1 minute, prefer-ably 0.5 to 2 seconds, the flames without exception being non-luminant and the distances between the substrate surfaces and the outer flame front being 0.2 to 5 cm, preferably 0.5 to 2 cm.
The substrate surfaces activated in this way are coated with tert-butylaminGethyl methacrylate and one Gr more other aliphatically unsaturated monomers, if appropriate in solution, by known methods, such as dipping, spraying or brushing. Suitable solvents have proved to be water and water/ethanol mixtures although other solvents can also be used if they have a sufficient dissolving power for the monomers and wet the substrate surfaces thoroughly. Solutions O.Z. 5160 having monomer contents of 1 to 10% by weight, for example akout 5% by weight, have proved suitable in practice and in general give continuous coatings which cover the substrate surface and have coating thicknesses which can be more than 0.1 llm in one pass.
The graft copolymerization of the monomers applied to the acl ivated surfaces is preferably caused by rays in the short wavelength segment of the visible range or in the long wavelength segment of the UV range of electromagnetic L0 radiation. The radiation of a UV-excimer of wavelengths 250 to 500 mm, preferably 290 to 320 mm, for example, is particularly suitable. Mercury vapor lamps are also suitable here if they emit considerable proportions of radiation in the ranges mentioned. The exposure times are in general 10 seconds to 30 minutes, preferably 2 to 15 minutes.
Copolymers with tert-butylaminoethyl methacrylate as the comonomer unit also show intrinsic microbicidal properties without grafting to a substrate surface.
The polymers according to the invention of tert-butylaminoethyl methacrylate and one or more other aliphatically unsaturated monomers can b~e applied to the substrate in solution.
Suitable solvents are, for example, water, ethanol, methanol, methyl ethyl ketone, diethyl ether, dioxane, hexane, heptane, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran and acetonitrile.
The solution of the polymers according to the invention is applied to the standard polymers, for example, by o.z. 5160 dipping, spraying or painting. Then the solvent is evaporated.
When the polymers according to the invention are produced directly on the substrate surface without grafting, suitable initiators are added.
Initiators which can be used are, inter alia, azonitrilrs, alkyl peroxides, hydroperoxides, acyl peroxides, peroxoketones, peresters, peroxocarbGnates, peroxodisulfate, persulfate and all the customary photoinitiators, such as, for example, acetophenones and benzophenone.
The initiation of the polymerization can be carried out by means of heat or by electromagnetic radiation, such as, for example, UV light or ~-radiation.
The products coated with the polymers according to the inven-tion can be medical articles or hygiene articles.
Products according to the invention which are obtained by grafting copolymerization can likewise be medical articles or hygiene articles.

O.Z. 5160 CA 0223ll0l l998-03-04 The products coated with the polymers according to the invention can be used for the production of rnedical articles, such as, for example, catheters, blood bags, drainages, guide wires and surc~ical instruments.

The polymers according to the invention can furthermore be used for the s production of hygiene articles, such as, for example, toothbrushes, toilet seats, combs and packaging materials.

The Following examples are intended to illustrate the invention:

Example 1:

19.2 9 of tertbutylaminoeth~l methacrylate, 2.6 9 of methyl methacrylate and 150 ml of tetrahydrofuran are heated to 60~C under an inert gas. When the temperature is reached, 0.:33 9 of azobisisobutyronitrile, dissolved in 10 ml of tetrahydrofuran, is added. At the end of 24 hours, the reaction is ended by stirring the mixture into 1 1 of a waterlice mixture. The reaction product is filtered off and washed ~ith 300 ml of n-hexane. The product is then distributed over several Soxhlets and extracted with water for 24 hours, and is then dried at 50~C in vac:uo for 12 hours.

Example 2:

4 9 of copolymer from Exarnple 1 are dissolved in 40 ml of tetrahydrofuran.
A polyamide 12 film is immersed in this solution for 5 seconds, removed from the solution for 10 seconds and them immersed again for 5 seconds, so that a uniform film of the copolymer on the polyamide film has formed after subsequent drying at room temperature under normal pressure. The film is then dried at 50~C in vacuo for 24 hours. The film is subsequently extracted in water at 30~C 5 times for 6 hours and then dried at 50~C for 12 hours.

O.~. 5160 ExampTe 3:

49 oF copolymer from Example 1 are dissolved in ~0 ml of tetrahydrofuran. A
polyvinyl chloride film is immersed in this solution for 2 seconds removed from the solution for 1 Cl seconds and then immersed again for 2 seconds so s that a unifonn film of the copolymer has formed on the polyvinyl chloride filmafter subsequent drying at room temperature under normal pressure The film is then dried at 50~C in vacuo for 24 hours. The film is subsequently extracted in water at 30~C .5 times for 6 hours and then dried at 50~C for 12 hours.

Example 4:

A polyamide 12 film is exposed to the 172 nm radiation of an excimer radiation source from Heraeus for 2 minutes under a pressure of 1 mbar. The film activated in this way is laid and fixed in an irradiation reactor under an inert gas. The film is then covered with a layer of 20 ml of a mixture of 3 9 oftert-butylaminoethyl methacrylate 2 g of methyl methacrylate and 95 9 of methanol in a countercurrent of inert gas. The irradiation chamber is closed and placed a distance of 10 cm underneath an excimer irradiation unit from Heraeus which has an emission of wavelength 308 nm. The irradiation is started and the exposure time is 15 minutes. The film is then removed and rinsed offwith 30 ml of methanol. The film is then dried at 50~C in vacuo for 12 hours. The film is subsequently extracted in water at 30~C 5 times for 6 hours and then dried at 50~C for 12 hours.

Measurement of the bactericidal action:

The bactericidal action of c:oated piastics was measured as follows:
100~1i of a cell suspension of Klebsiella pneumoniae were placed on a piece of film 2 x 2 cm in size. The bactena were suspended in PBS buffer o. z. 5160 (phosphate-buffered saline); the cell concentration was 105 cells per ml of buffer solution. This drop was incubated for up to 3 hours. So that any drying out is prevented, the piece of film was laid in a polystyrene Petri dish wetted with l ml of water. After the Isnd of the contact time, the 100 ,ul were taken up 5 with an Eppendorf tip ancl diluted in 1.9 ml of sterile PBS. 0.2 ml of this solution was plated out on nutrient agar. The rate of inactivation was calculated from the number of colonies which had grown.

Checking the resistance of the coatings:

Before the measurement of the bactericidal action, the coated films were 10 subjected to the following pretreatments:
A: Washing in boiling waterfor 10 minutes B: Washing in 96% strength ethanolic solution for 10 minutes C: Washing in warm ~ater at 25~C under ultrasonic treatment for 10 minutes :15 D: No pretreatment The results of the measurements, taking into account the particular pretre-atment, are listed in Table 1.
Rate of inactivation Example: A B C D
~o 2 2% < 10% 51 % 99.g%

3 2% < 10% 50 % 99.9%

4 99.9% 99.9% 99.9% 99.9%

Table 1 After therrnal, chemical or mechanical pretreatment. the antimicrobial layers produced by grafting of a substrate surface continue to show virtually complete inactivation of the bacteria applied. The physically adhered layers o. z . 5160 are less stable than the pn3~reatments accordfng to methods A, B and C.

In addition to the microbicidal activity against cells of Klebsiella pneumoniae which has been described above, all the coated films also showed a microbicidal action against cells of Pseudomonas aeru~inosa,. Staphylococ-s cus aureus, Escherichia coli~ Rhizopus oryzae, Candida tropicalis and Tetrahymena pyriformis. The rate of inactivation after treatment method D
was also more than 99% in these cases.

_ 14 --o. z . 5160 ~3443-647

Claims

1. A medical or hygiene article which comprises:
a substrate which is made of a polymeric plastic or is made of a metal, glass or wooden body coated with a polymeric plastic, and a coating layer on a surface of the substrate, wherein the coating layer is of an antimicrobial copolymer of tert-butylaminoethyl methacrylate and at least one other aliphatically unsaturated monomer.

2. The article as claimed in claim 1, wherein the other aliphatic unsaturated monomer is a nonionic monomer selected from the group consisting of:
(a) a (meth)acrylate ester having a linear or branched alkyl group containing up to 10 carbon atoms and optionally containing a hydroxyl group;
(b) a (meth)acrylamide of the formula:

(wherein R1 is a hydrogen atom or a methyl group, and R2 and R3 are each a hydrogen atom or a linear or branched aliphatic, cycloaliphatic or aromatic hydrocarbon group having up to 20 carbon atoms);
(c) a vinyl compound of the formula (wherein R4 is a hydrogen atom or a phenyl or lower alkyl group, and R5 is a hydrogen atom or a methyl group);
(d) a vinyl ester of the formula:

(wherein R4 is a lower alkyl group); and (e) a maleic or fumaric acid derivative of the formula:
(wherein R4 is a phenyl or lower alkyl group).

3. The article as claimed in claim 2, wherein the other aliphatic unsaturated monomer is a (meth)acrylate ester having a linear or branched alkyl group containing up to 10 carbon atoms.

4. The article as claimed in claim 3, wherein the other aliphatic unsaturated monomer is methyl methacrylate.

5. The article as claimed in any one of claims 1 to 4, wherein the copolymer has a content of units derived from tert-butylaminoethyl methacrylate of 30 to 98 mol %.

6. The article as claimed in any one of claims 1 to 5, which is a medical article selected from the group consisting of a catheter, a blood bag, a drainage, a guide wire and a surgical instrument.

7. The article as claimed in any one of claims 1 to 5, which is a hygiene article selected from the group consisting of a toothbrush, a toilet seat, a comb and a packaging material.

8. The article as claimed in any one of claims 1 to 7, wherein the coating layer of the copolymer is formed by graft copolymerization of tert-butylaminoethyl methacrylate and the other aliphatically unsaturated monomer onto the surface of the substrate.

9. A process for the preparation of the article as claimed in any one of claims 1 to 7, which comprises:
(I) copolymerizing tert-butylaminoethyl methacrylate and the other aliphatically unsaturated monomer using a polymerization initiator to produce the copolymer, and applying a solution of the copolymer in a solvent onto the surface of the substrate and evaporating the solvent;
or (II) applying a mixture of tert-butylaminoethyl methacrylate and the other aliphatically unsaturated monomer onto the surface of the substrate, and subjecting the mixture to graft copolymerization to the substrate surface by radiation of UV rays having a wave-length of from 250 to 500 nm.

10. The process according to claim 9, wherein process variant (I) is chosen; tetrahydrofuran is used as the solvent;

and after the solvent is evaporated, the article is extracted with water and then dried.

11. The process according to claim 9, wherein process variant (II) is chosen.

12. The process according to claim 11, which further comprises:
activating the substrate surface by UV radiation, microwave plasma, corona discharge, electron beams or .gamma.-rays, or flaming, prior to applying the mixture onto the substrate surface.

13. An antimicrobial polymer obtainable by copolymerization of tert-butylaminoethyl methacrylate with one or more other aliphatically unsaturated monomers.

14. An antimicrobial polymer as claimed in claim 13,obtainable by co-polymerization of tert-butylaminoethyl methacrylate with one or more aliphatically unsaturated monomers on a substrate.

15. An antimicrobial polymer obtainable by grafting copolymerization of tert-butylaminoethyl methacrylate with one or more aliphatically unsaturated monomers on a substrate.

16. An antimicrobial polymer as claimed in claim 15,obtainable by activation of the substrate before the grafting polymerization.

17. An antimicrobial polymer as claimed in claim 16,obtainable by activation of the substrate by UV radiation with and without an additional photosensitizer, plasma treatment, corona treatment, flaming, ozonization, electrical discharge or .gamma.-radiation.

18. A process for the preparation of an antimicrobial polymer as claimed in claim 1 or 2, wherein tert-butylaminoethyl methacrylate is copolymerized with one or more aliphatically unsaturated monomers.

19. The process as claimed in claim 18,wherein the copolymerization of tert-butylaminoethyl methacrylate with one or more aliphatically unsaturated monomers is carried out on a substrate.

20. A process for the preparation of an antimicrobial polymer as claimed in one of claims 15 to 17, which comprises subjecting tert-butylaminoethyl methacrylate to grafting copolymerization with one or more aliphatically unsaturated monomers on a substrate.

21. The process as claimed in claim 20,wherein the substrate is activated before the grafting copolymerization.

22. The process as claimed in claim 21,wherein the activation of the substrate is carried out with UV radiation with and without an additional photosensitizer, plasma treatment, corona treatment, flaming, ozonization, electrical discharge or .gamma.-radiation.

23. The use of an antimicrobial polymer as claimed in claim 1 or 2 for the production of products with an antimicrobial coating of the polymer.

24. The use of an antimicrobial polymer as claimed in claim 1 or 2 for the production of medical articles with an antimicrobial coating of the polymer.

25. The use of an antimicrobial polymer as claimed in claim 1 or 2 for the production of hygiene articles with an antimicrobial coating of the polymer.

26. The use of an antimicrobial polymer as claimed in claim 3, 4 or 5 for the production of products, with an antimicrobial coating of the polymer.

27. The use of an antimicrobial polymer as claimed in claim 3, 4 or 5 for the production of medical articles with an antimicrobial coating of the polymer.

28. The use of an antimicrobial polymer as claimed in claim 3, 4 or 5 for the production of hygiene articles with an antimicrobial coating of the polymer.