EP1373384A1

EP1373384A1 - Antibacterial and fungicidal polymer dispersions and polymer solutions

Info

Publication number: EP1373384A1
Application number: EP02704715A
Authority: EP
Inventors: Maximilian Angel; Bernhard Fussnegger; Silke Gebert
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2001-02-27
Filing date: 2002-02-14
Publication date: 2004-01-02
Also published as: US20040077748A1; CN1281666C; JP2004527605A; DE10109447A1; US7005145B2; CN1494569A; WO2002068518A1

Abstract

The invention relates to polymer dispersions or polymer solutions that are given antibacterial and fungicidal properties by metal ions of group Ib of the Periodic table. According to the invention, a) the polymer dispersions or polymer solutions are not produced using controllers that contain thiol groups, b) the metal ions have been introduced by means of an electrochemical process and c) said dispersions or solutions do not contain any active quantity of organic biocides.

Description

Antibacterial and fungicidal polymer dispersions and polymer solutions

description

The invention relates to aqueous polymer dispersions or polymer solutions which have been treated with antibacterial and antifungal agents by means of ions of metals from group Ib in the periodic table of the elements, the polymers being produced without regulators or without regulators containing thiol groups and the metal ions being introduced by an electrochemical process.

Polymers, especially water-containing polymer solutions and polymer dispersions are susceptible to bacterial, yeast or fungal attack. This can cause discoloration of the product, changes in viscosity, pH and smell. For polymers that are used for pharmaceutical purposes, certain maximum bacterial counts according to the applicable pharmacopoeia must also be observed.

Examples of microorganisms that attack polymers are, for example, the bacteria Alcaligenes faecalis, Escherichia coli, Micrococcus flavus, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, the yeasts Candida albicans, Rhodotorula albicans, Saccharomyces and Aspergillus aspergillus aspergillus terreus and Geotrichum candidum.

To protect the polymer solutions and polymer dispersions and products made from them against microbial attack, they must therefore be preserved so that the product properties remain constant over a defined period of time and limit values for the bacterial count are observed.

Numerous processes for the preservation of polymers against bacterial or fungal attack are already known. In addition to formaldehyde or generally aldehyde-releasing substances, a large number of substances having a bactericidal action, such as sodium hypochlorite, hydrogen peroxide, but also organic chemical bactericides, as are mentioned, for example, in US Pat. No. 5,736,591, are used against microbial attack. However, numerous proposals for solving the problem of bacterial, yeast and fungal infestation and infestation by other microorganisms based on antibiotic metal ions, such as silver, copper, zinc, are known from DE 197 07 221 AI. A special solution is described in DE 197 07 221 A1 with a process for the preparation of polymer dispersions containing metal ions which have antibacterial and fungicidal activity and which can be used to protect a large number of further polymer dispersions. It is mentioned as a particular advantage that the problem of adding metal ions, in particular in the form of metal salts, to polymer dispersions is solved by adding the silver-containing polymer dispersion instead of adding the silver salt. Polymer dispersions tend to irreversibly coagulate due to the local high concentration when electrolytes are added, irrespective of whether they are in pure or dissolved form, especially at the point of dropping. A clear disadvantage to be mentioned is that the addition of the silver-containing polymers to other dispersions in addition to the desired antibacterial and fungicidal metal ions inevitably introduces further components (polymeric protective polymer) into the antibacterial and fungicidal polymer dispersion. The introduction of further components with a fundamentally different composition than the polymer to be treated with antibacterial and fungicidal agents can be regarded as a considerable disadvantage for a variety of reasons, for example with regard to approval requirements as they apply to polymers in pharmaceutical, cosmetic but also other applications. An unfavorable influence on the properties of the antibacterial and anti-fungicidal polymers can also not be excluded.

In order to achieve effective antibacterial and fungicidal protection, it is therefore proposed in US Pat. No. 5,736,591 to use a combination of Group Ib metals and organic biocides. Despite this combination of inorganic and organic biocides, a concentration of the metal ions of 1 to 50 ppm is required. The metal ions are introduced in the examples in the form of a salt solution. However, it is also noted in column 3, left column, lines 37 to 39 "An electrolytic process for adding Group Ib metals to the latex can also be used".

In view of the prior art mentioned, the task remained unchanged to further reduce the required metal ion concentration without the use of organic biocides being necessary. This requirement applies particularly to cosmetic and pharmaceutical preparations.

This object has been solved according to the invention with polymer dispersions and polymer solutions prepared by metal ions of Group Ib of the Periodic Table of the Elements anti-bacterial and fungi ^~ Removing zid- are prepared, (a) the polymer dispersion or polymer solutions being prepared without a regulator or without a regulator having thiol groups, (b) the metal ions are introduced by an electrochemical process and without (c) organic biocides being required.

The new process advantageously manages with less than 1 ppm of the metal ions, in many cases with less than 0.6 ppm of the metal ions. This is particularly important for cosmetic and pharmaceutical preparations in which only small additions of metal are permitted or desirable.

The invention is based on the surprising finding that the small amounts of the metal ions of generally less than one ppm are sufficient if the dispersions are free from compounds containing thiol groups. It is assumed that the latex dispersions according to US Pat. No. 5,736,591 were produced with such thiol group-containing regulators and therefore higher concentrations of metal ions and additional organic biocides were required in order to achieve adequate antibacterial and fungicidal treatment.

Above all copper and in particular silver come into consideration as ions of metals of group Ib of the periodic table of the elements.

Suitable polymer dispersions or polymer solutions to be stabilized according to the invention are any small amounts or predominantly water-containing polymer dispersions or polymer solutions as dispersants or solvents, provided that they are not produced with regulators or with regulators which have no thiol groups.

In general, the polymer consists of at least 40% by weight, particularly preferably at least 60% by weight, very particularly preferably at least 80% by weight, of so-called main monomers.

The main monomers are selected from C ₂₀ -C ₂₀ alkyl (meth) acrylates, vinyl esters of carboxylic acids containing up to 20 C atoms, vinyl aromatics with up to 20 C atoms, ethylenically unsaturated nitriles, vinyl halides, vinyl ethers from 1 to Alcohols containing 10 carbon atoms, aliphatic hydrocarbons with 2 to 8 carbon atoms and 1 or 2 double bonds or mixtures of these monomers. The dispersions and solutions to be stabilized according to the invention are, in particular, those which have a pH of 4.5 to 9 and which contain unsaturated esters as main monomers, such as vinyl esters and in particular acrylic esters.

Particularly worth mentioning are (meth) acrylic acid alkyl esters with a C 1 -C 8 -alkyl radical, such as methyl methacrylate, methyl acrylate, n-butyl acrylate, ethyl acrylate and 2-ethylhexyl acrylate.

Mixtures of the (meth) acrylic acid alkyl esters are also suitable.

Vinyl esters of carboxylic acids with 1 to 20 carbon atoms are e.g. B.

Vinyl laurate, stearate, vinyl propionate, vinyl versatic acid and vinyl acetate.

Suitable vinyl aromatic compounds are vinyl toluene, o- and p-

Methyl styrene, o-butyl styrene, 4-n-butyl styrene, 4-n-decyl styrene and preferably styrene. Examples of nitriles are

Acrylonitrile and methacrylonitrile.

The vinyl halides are chlorine, fluorine or bromine-substituted ethylenically unsaturated compounds, preferably vinyl chloride and

Vinylidene chloride.

Examples of vinyl ethers include B. vinyl methyl ether or vinyl isobutyl ether. Vinyl ethers of alcohols containing 1 to 4 carbon atoms are preferred.

As hydrocarbons with 2 to 8 carbon atoms and two olefinic double bonds, butadiene, isoprene and chloroprene may be mentioned, with a double bond e.g. Ethylene or propylene.

The main monomers preferred are the Ci to Cio alkyl acrylates and methacrylates, in particular Ci to Cs alkyl acrylates and methacrylates and vinyl esters, in particular vinyl acetate and mixtures thereof.

Methyl acrylate, methyl methacrylate, ethyl acrylate and vinyl acetate and mixtures of these monomers are very particularly preferred.

In addition to the main monomers, the free-radically polymerized polymer may contain further monomers, e.g. B. monomers with carboxylic acid, sulfonic acid or phosphonic acid groups. Carboxylic acid groups are preferred. Examples include acrylic acid, methacrylic acid, itaconic acid, maleic acid or fumaric acid. Methacrylic acid and acrylic acid are preferred. Further monomers are, for example, monomers containing hydroxyl groups, in particular C 1 -C 8 -hydroxyalkyl (meth) acrylates, but also (meth) acrylamide.

Phenyloxyethylglycol ono (meth) acrylate, glycidyl acrylate, glycidyl methacrylate, amino (meth) acrylates such as 2-aminoethyl (meth) acrylate may also be mentioned as further monomers.

Crosslinking monomers and monomers with hydrolyzable Si groups may also be mentioned as further monomers.

In a preferred embodiment, the polymers are prepared by emulsion polymerization, so it is an emulsion polymer.

However, the manufacture can e.g. also by solution polymerization in water, mixed aqueous / non-aqueous solvents or non-aqueous solvents and subsequent dispersion in water.

In the emulsion polymerization, ionic and / or nonionic emulsifiers and / or protective colloids, such as polyvinylpyrrolidone or polyvinyl alcohol, or stabilizers, are used as surface-active compounds.

A detailed description of suitable protective colloids can be found in Houben-Weyl, Methods of Organic Chemistry, Volume XIV / 1, Macromolecular Substances, Georg-Thieme-Verlag, Stuttgart, 1961, pp. 411 to 420. Both anionic and cationic come as emulsifiers as well as nonionic emulsifiers. Preferably, only accompanying emulsifiers are used as accompanying surface-active substances, the molecular weight of which, in contrast to the protective colloids, is usually below 2000 g / mol. Of course, if mixtures of surface-active substances are used, the individual components must be compatible with one another, which can be checked with a few preliminary tests if in doubt. Anionic and nonionic emulsifiers are preferably used as surface-active substances. Common accompanying emulsifiers are, for example, ethoxylated fatty alcohols (EO grade: 3 to 50, alkyl radical: C ₈ - to C ₃₆ ), ethoxylated mono-, di- and tri-alkylphenols (EO degree: 3 to 50, alkyl radical: C - bis Cg), alkali metal salts of dialkyl esters of sulfosuccinic acid and alkali and ammonium salts of alkyl sulfates (alkyl radical: Cs ~ to Cχ), of ethoxylated alkanols (EO degree: 4 to 30, alkyl radical: Cι ₂ - to Cχ ₈ ), of ethoxylated Alkylphenols (EO grade: 3 to 100, alkyl radical: C ₄ - to C ₉ ), of alkyl sulfonic acids (alkyl radical: Cι ₂ - to Cis) and of alkylarylsulfonic acids (alkyl radical: Cg to C ₁₈ ).

Other suitable emulsifiers are compounds of the general formula II

wherein R and R 'are hydrogen or C - to Cχ-alkyl and are not simultaneously hydrogen, and X and Y can be alkali metal ions and / or ammonium ions. R, R 'are preferably linear or branched alkyl radicals having 6 to 18 carbon atoms or hydrogen and in particular having 6, 12 and 16 carbon atoms, where R and R' are not both hydrogen at the same time. X and Y are preferably sodium, potassium or ammonium ions, with sodium being particularly preferred. Connections are particularly advantageous

11 in which X and Y are sodium, R is a branched alkyl radical

12 C atoms and R 'is hydrogen or R. Technical mixtures are frequently used which have a proportion of 50 to 90% by weight of the monoalkylated product, for example Dowfax® 2A1 (trademark of the Dow Chemical Company).

Suitable emulsifiers can also be found in Houben-Weyl, Methods of Organic Chemistry, Volume 14/1, Macromolecular Substances, Georg Thieme Verlag, Stuttgart, 1961, pages 192 to 208.

Trade names of emulsifiers are e.g. B. Dowfax®2 AI, Emulan® NP 50, Dextrol® OC 50, Emulsifier 825, Emulsifier 825 S, Emulan® OG, Texapon®NSO, Nekanil® 904 S, Lumiten® I-RA, Lumiten E 3065, Disponil FES 77 , Lutensol AT 18, Steinapol VSL, Emulphor NPS 25.

The surface-active substance is usually used in amounts of 0.1 to 10% by weight, based on the monomers to be polymerized.

Water-soluble initiators for emulsion polymerization are e.g. B. Ammonium and alkali metal salts of peroxidic sulfuric acid, e.g. As sodium peroxodisulfate, hydrogen peroxide or organic peroxides, e.g. B. tert-butyl hydroperoxide. So-called reduction-oxidation (red-ox) initiator systems are also suitable.

The Red Ox initiator systems consist of at least one mostly 5 inorganic reducing agent and one inorganic or organic oxidizing agent.

The oxidation component is e.g. to the initiators for emulsion polymerization already mentioned above.

10

The reduction component is e.g. around ascorbic acid. The Red-Ox initiator systems can be used with the use of soluble metal compounds, the metallic component of which can occur in several valence levels.

15

Common red-ox initiator systems are e.g. Ascorbic acid / iron (II) sulfate together with sodium peroxydisulfate or hydrogen peroxide. The individual components, e.g. the reduction component can also be mixtures.

20

The compounds mentioned are mostly used in the form of aqueous solutions, the lower concentration being determined by the amount of water acceptable in the dispersion and the upper concentration being determined by the solubility of the compound in question in water. The concentration is generally 0.1 to 30% by weight, preferably 0.5 to 20% by weight, particularly preferably 1.0 to 10% by weight, based on the solution.

The amount of initiators is generally 0.1 to 30 10% by weight, preferably 0.5 to 5% by weight, based on the monomers to be polymerized. Several different initiators can also be used in emulsion polymerization.

Regulators can be used in the polymerization, e.g. in 35 amounts of 0 to 5% by weight, based on the monomers to be polymerized, preferably 0 to 0.8% by weight. Suitable controllers are e.g. in DE-A 197 12 247, page 4. However, regulators that contain a thiol group such as tert. -Butylmer- captan, thioglycolic acid ethyl acrylate, mercaptoethanol, Mer- 40 captopropyltrimethoxysilane or tert. -Dodecyl mercaptan included.

The emulsion polymerization of the antibacterial and fungicidal polymers according to the invention is generally carried out at 30 to 130, preferably 50 to 90 ° C. The polymerization medium can consist only of water as well as of mixtures of water and therefore miscible liquids such as methanol. Preferably only water is used. The emulsion polymerization can both as a batch process and in the form of a feed process, including a step or gradient procedure. Preference is given to the feed process, in which part of the polymerization batch is initially charged, heated to the polymerization temperature, polymerized and then the remainder of the polymerization batch, usually via a plurality of spatially separate feeds, one or more of which the monomers are pure or emulsified Contain form, continuously, stepwise or with superposition of a concentration gradient 10 while maintaining the polymerization feeds the polymerization zone. During the polymerization, a polymer seed can also be introduced, for example, for better adjustment of the particle size.

The manner in which the initiator is added to the polymerization vessel in the course of the free-radical aqueous emulsion polymerization is known to the person skilled in the art. It can either be completely introduced into the polymerization vessel or used continuously or in stages in the course of the free-radical aqueous emulsion polymerization, depending on its consumption. In particular, this depends on the chemical nature of the initiator system as well as on the polymerization temperature. A portion is preferably introduced and the remainder is fed to the polymerization zone in accordance with the consumption.

25 To remove the residual monomers, usually after the end of the actual emulsion polymerization, i.e. after a conversion of the monomers of at least 95%, initiator added.

The individual components can be added to the reactor in the feed process 30 from above, in the side or from below through the reactor floor.

In emulsion polymerization, aqueous dispersions of the polymer are generally obtained with solids contents of from 15 to 35 75% by weight, preferably from 30 to 50% by weight.

The glass transition temperature of the polymeric binder or of the emulsion polymer is preferably -60 to + 100 ° C, particularly preferably -20 to + 60 ° C and very particularly preferably -10 to 40 + 50 ° C.

The glass transition temperature can be determined by conventional methods such as differential thermal analysis or differentail scanning calorimetry (see, for example, ASTM 3418/82, so-called "midpoint temperature"). 45 The polymers produced in this way can contain, for example, 25 to 85% by weight of water as dispersant or solvent as dispersions or solutions.

The dispersions or solutions preferably contain 50 to 70% by weight of water.

The metal ions, preferably silver ions, are introduced into the dispersions or solutions by an electrochemical process. This is done with devices known per se, in which a current flows between silver electrons, the aqueous substrate to be loaded with silver serving as the electrolyte when flowing through.

There are basically two alternatives for loading. Either one loads (a) the water to be used later for the polymerization in advance in the desired concentration or, preferably (b) the silver ions are introduced into the finished polymer.

In case (b), the totality of the conditions (current strength, electrode surface, flow rate) is chosen so that an average local concentration of the silver ions in the volume element between the electrodes of 5 ppm, preferably 2 ppm, is not exceeded. In order to achieve the desired final concentration without local overconcentration, it may be expedient to pass the dispersions and solutions to be loaded with silver ions through the device again or several times. However, it is also possible to treat only a partial stream of the dispersion and then to mix it with the untreated stream.

Suitable devices are e.g. the devices called electric Katadyn from Katadyn® (Wallisellen, Switzerland).

Examples

a) Preparation of the polymers

Polymer 1

A solution of 500 g of deionized water, 3.5 g of sodium lauryl sulfate and 50 g of feed 1 is mixed with 7.5 g of sodium peroxodisulfate (7% in water) after heating to 80 ° C. and then added over a period of 2 hours Inlets 1 and 2 are continuously mixed at 80 ° C. Inlet 1

500 g demineralized water 23 g ethoxylated nonylphenol (100 EO units) 7 g sodium lauryl sulfate (15% in water) 370 g ethyl acrylate 160 g methyl methacrylate

Inlet 2

21 g sodium peroxodisulfate (2.5% in water)

The mixture is then polymerized for 2 h, cooled to room temperature and in succession with a solution of 0.2 g of hydrogen oxide (30% strength) in 9 g of fully demineralized water and a solution of 0.3 g of ascorbic acid and 0.5 g of iron-II -sulfate (1% in water) in 24 g of fully demineralized water. The pH is then adjusted to pH 7.5 by adding sodium pyrophosphate (3% in water) and sodium hydroxide solution (10% in water).

Polymer 2

The procedure is as for polymer 1, with the proviso that the feed 1 contains 10 g of isopropanol as a regulator.

b) Methods of introducing the silver

bl) Immediate electrochemical introduction of the silver into the dispersions

The dispersion to be provided with silver ions is passed through a device consisting of the electro-katadyn type EK4 silvering device from Katadyn Produkte AG CH-8304 Wallisellen and a pump. In order to set the desired silver dose, the flow of the pump must be determined. The silvering flow to be set is calculated using the flow rate and the desired silver dose. The Faraday formula is used for this.

The following correspond:

1 A = 4 g Ag ⁺ per hour

1 iaA = 4 mg Ag ⁺ per hour Calculation example:

Flow 2 m ³ / h

Desired silver dose (Ag) 0.2 ppm (0.2 mg / 1) silver for 2 m ³ dispersion according to Example 1 400 mg

1 mA = 4 mg Ag ⁺ / h

Silvering current 100 mA

(400: 4 = 100)

The calculated silvering current is set and, using the pump, the dispersion according to Example 1 is passed through the Electro-Katadyn EK-4 unit. As soon as the product is pumped through the electro-katadyn unit, the silvering current switches on and the desired amount of silver is added to the dispersion. The dispersion of polymer 1 was mixed with 0.2, 0.5 and 1 ppm silver.

The procedure for dispersion 2 was analogous.

b2) introducing the silver into the water used to prepare the dispersion.

The procedure is the same as for the preparation of polymer 1, but using demineralized water into which 1 ppm of silver ions have previously been introduced by the electrochemical process described under (c).

c) test method

20 g each of the polymers 1 and 2 were inoculated with 0.2 ml of the individual germ suspensions (Escherichia coli, Pseudomonas aeriginosa, Staphylococcus aurens, Candida albicans, Aspergillus niger) and homogenized, so that a sowing of 1.8 to 3. 4 x 10 ⁵ germs were present.

The number of bacteria was determined immediately and after 14 and after 28 days. The results are shown in Tables 1 to 7 below. Table 1

Evaluation:

According to the result of the microbiological test, the effectiveness of the preservation meets the requirements for preparations for oral use in Ph. Eur. 3, 2000.

Table 2

Evaluation:

According to the result of the microbiological test carried out, the effectiveness of the preservation meets the requirements for preparations for oral use in Ph. Eur. 3, 5 2000.

Repetitive inoculation with the 5 different test germs, i.e. A re-inoculation after the germs had died gave the following results for the dispersion of polymer 1, equipped with 0.5 ppm silver 0 and using the method described under c) test method:

Table 3

5

0

5

0

Evaluation:

According to the results of the microbiological test carried out, the effectiveness of the preservation meets the requirements for preparations for oral use in Ph. Eur. 3, 2000.

0 Table 4

Evaluation:

According to the result of the microbiological test, the effectiveness of the preservation after the 2nd exposure is sufficient. n / A. = cannot be evaluated

Table 5

Evaluation:

According to the result of the microbiological test, the effectiveness of the preservation after the 3rd exposure is sufficient. Table 6

Evaluation:

According to the result of the microbiological test, the effectiveness of the preservation after the 4th exposure is sufficient.

Table 7

Evaluation:

According to the result of the microbiological test, the effectiveness of the preservation after the 5th exposure is sufficient.

d) Production of preparations granules for matrix tablets

The dispersion 2 with a polymer content of 30% and with a silver content of 0.4 ppm is used as a granulation liquid in a fluidized bed granulator for the production of granules for Matrix tablets used. It is used for this purpose without further dilution or formulation.

Production of the granules

3.5 kg of paracetamol powder and 1.7 kg of lactose monohydrate as filler are placed in a fluidized bed granulator (e.g. Glatt WSG 15 device) as the active ingredient and granulated under the addition of 5.67 liters of the above-mentioned dispersion. Then it is dried to a residual moisture of <2%.

The following spraying and drying conditions were set:

The granules obtained have good flowability and can be compressed into matrix tablets under the conditions customary in the prior art.

tablet coating

The following formulation for coating for tablet cores was prepared and sprayed using dispersion 1, with a silver content of 0.2 ppm silver.

Composition of the spray formulation

₅ Preparation of the spray formulation

Triacetin is first dissolved in 1100 g of water. The dispersion is then slowly added and homogenized with constant stirring. 0

Separately, the ingredient Kollidon ^® 30 is first dissolved in 340 g of water, then titanium dioxide and talc are added to this solution, then treated with a homogenizer, for example an Ultra Turrax. The pigment suspension is finally _g stirred into the dispersion with a plasticizer and sprayed under the following conditions on tablet cores.

The white tablet coating obtained is absolutely uniform after drying and has no cracks or other defects. 5

Claims

claims

1. By metal ions of group Ib of the periodic table of the elements antibacterial and fungicidal polymer dispersions or polymer solutions, characterized in that

a) the polymer dispersions or polymer solutions are not prepared with regulators containing thiol groups,

b) the metal ions have been introduced by an electrochemical process and

c) they do not contain effective amounts of organic biocides.

2. Antibody and fungicidal polymer dispersions or polymer solutions according to claim 1, characterized by metal ions of group Ib of the periodic table of the elements, characterized in that

d) the group Ib metal ion content is less than 1 ppm.

3. polymer dispersions and polymer solutions according to claim 1, characterized in that the polymer dispersions and polymer solutions predominantly contain water as the dispersing or solvent.

4. polymer dispersions and polymer solutions according to claim 1, characterized in that they have a pH of 4.5 to 9.

5. polymer dispersions or polymer solutions according to claim 1, characterized in that the metal ions in the finished

Polymer dispersions or polymer solutions have been introduced.

6. polymer dispersions or polymer solutions according to claim 1, characterized in that the polymer dispersions or

Polymer solutions are prepared with water into which the metal ions have been introduced before the polymerization.

7. polymer dispersions or polymer solutions according to claim 1, characterized in that silver ions are used as metal ions.

8. polymer dispersions or polymer solutions according to claim 1, characterized in that the content of metal ions is less than 0.6 ppm.

9. Pharmaceutical or cosmetic preparations, characterized in that they contain polymer dispersions or polymer solutions according to claim 1.