EP2120552A1

EP2120552A1 - Polymer molding compounds containing partially neutralized agents

Info

Publication number: EP2120552A1
Application number: EP08707393A
Authority: EP
Inventors: Ralf Dujardin; Achim Bertsch; Heinz Pudleiner
Original assignee: Bayer Innovation GmbH
Current assignee: Bayer Innovation GmbH
Priority date: 2007-02-12
Filing date: 2008-01-30
Publication date: 2009-11-25
Also published as: CA2677704A1; IL199653A0; AU2008214875A1; US20100094230A1; DE102007006761A1; MX2009007600A; CN101605454A; BRPI0807468A2; RU2009134058A; WO2008098679A1; JP2010518246A

Abstract

The invention relates to polymer molding compounds that are antibacterially, antiprotozoally, or antimycotically equipped with partially neutralized agents, methods for the production thereof, and the use thereof in molded articles, particularly medical articles.

Description

Partially neutralized active ingredients containing polymer molding compositions

The invention relates to partially unneutralized active ingredients antibacterial, antiprotozoic or antimycotic treated polymer molding compositions, processes for their preparation and their use in moldings, in particular medical articles.

The use of polymeric organic materials has become an indispensable part of life. Of course, workpieces made of organic materials under different conditions whose use is susceptible to the colonization of microorganisms of various kinds such as bacteria, viruses or fungi. This leads to hygienic and medical risks in the environment of the workpiece as well as in the serviceability of the workpiece itself, the latter in the case of unwanted microbiological degradation of the material.

In particular, the use of polymeric materials for diagnostic and therapeutic purposes has led to a significant technological leap in modern medicine. On the other hand, the frequent use of these materials in medicine has led to a dramatic increase in so-called foreign body infections and / or polymer-associated infections.

In addition to traumatic and thromboembolic complications, catheter-associated infections through to sepsis are a serious problem when using central venous catheters in intensive care.

Numerous studies have shown that coagulase negative staphylococci, the transient germ Staphylococcus aureus, Staphylococcus epidermis, and various Candida species are the major contributors to catheter associated infections. These ubiquitous microorganisms on the skin penetrate the physiological skin barrier during the application of the catheter and thus reach the subcutaneous area and ultimately the bloodstream. The adhesion of bacteria to the plastic surface is considered to be an essential step in the pathogenesis of foreign body infections. After the adhesion of the skin germs to the polymer surface, the metabolically active proliferation of the bacteria begins with the colonization of the polymer. This is accompanied by the production of a biofilm by bacterial excretion of extracellular glycocalix.

The biofilm supports the adhesion of the pathogens and protects them from the attack of certain cells of the immune system. In addition, the film forms a for many antibiotics impenetrable

Barrier. After increased proliferation of pathogenic germs on the polymer surface, it may - - finally come to a septic bacteremia. For the treatment of such infections removal of the infected catheter is necessary because chemotherapy with antibiotics would require unphysiologically high doses.

The incidence of bacterially induced infections in central venous catheters is approximately 5% on average. Overall, central venous catheters account for approximately 90% of all cases of sepsis in intensive care. The use of central venous catheters therefore not only involves a high risk of infection for the patients, but also causes enormously high subsequent therapeutic costs (post-treatment, longer residence times in the clinic).

Pre-, peri- or postoperative measures (eg hygienic measures, etc.) can only partially solve this problem. A rational strategy for the prevention of polymer-associated infections is the modification of the polymeric materials used. The aim of this modification must be the inhibition of bacterial adhesion or the proliferation of already adhered bacteria, thus avoiding causally foreign body infections. This can be z. B. by incorporation of a suitable chemotherapeutic agent in the polymer matrix (eg., Antibiotics) succeed, provided that the incorporated drug can also diffuse out of the polymer matrix. In this case, the release of the antibiotic may be extended to a longer period of time to prevent bacterial adhesion or proliferation on the polymer for a correspondingly longer period of time.

Methods for producing antimicrobially finished polymers are already known. Here, the microbicides are applied to the surface or a surface layer or introduced into the polymeric material. For the thermoplastic polyurethanes used in particular for medical applications, the following techniques are described:

a) adsorption on the polymer surface (passively or via surfactants) b) introduction into a polymer coating which is applied to the surface of a shaped article c) incorporation into the bulk phase of the polymeric support material d) covalent bonding to the polymer surface e) mixing with a Polyurethane-forming component before the reaction to the finished polymer

EP 0 550 875 Bl, for example, discloses a process for introducing active substances into the outer layer of medical articles (impregnation). This is the implantable device swollen from polymeric material in a suitable solvent. The polymer matrix is modified so that a pharmaceutical active substance or a combination of active substances can penetrate into the polymeric material of the implant. After removal of the solvent, the active ingredient is entrapped in the polymer matrix. After contact with the physiological medium, the active substance contained in the implantable device is released again by diffusion. The release profile can be adjusted within certain limits by the choice of solvent and by varying the experimental conditions.

Polymeric materials for medical applications having active-agent-containing coatings are mentioned, for example, in US Pat. No. 5,019,096. Described are methods for

Preparation of antimicrobial coatings and methods for application to the surfaces of medical equipment. The coatings consist of a

Polymer matrix, in particular of polyurethanes, silicones or biodegradable polymers, and an antimicrobial substance, preferably a synergistic combination of a silver salt with chlorhexidine or an antibiotic.

EP 927 222 B1 describes the introduction of antithrombic or antibiotically active substances into the reaction mixture for producing a TPU.

WO 03/009879 A1 describes medical products with microbicides in the polymer matrix, the surface being modified with biological surface active substances (English, biosurfactants). The active substances can be introduced into the polymer with different techniques. The surface active substances serve to reduce the adhesion of the bacteria on the surface of the molding.

No. 5,906,825 describes polymers, including polyurethanes, in which biocides or antimicrobials (specifically described exclusively plant ingredients) are dispersed in such an amount that the growth of microorganisms which come into contact with the polymer is prevented. This can be optimized by the addition of an agent which regulates the migration and / or release of the biocide. Mention is made of natural products such as e.g. Vitamin E. Applications focus on food packaging.

In ZbI. Bakt. 284, 390-401 (1996), the better long-term effect of in a silicone or

Polyurethane polymer matrix distributed antibiotics to deposited by precipitation technique on the surface or introduced by swelling technique near the surface

Antibiotics described. The initially high rate of delivery of the antibiotic is subject to the surface in a surrounding aqueous medium very strong, irreproducible fluctuations.

US 6,641,831 describes medical devices with retarded pharmacological activity, which is controlled by the introduction of two substances of different lipophilicity. Of the

The core of the invention is the effect that the release rate of an antimicrobial agent is reduced by the addition of a more lipophilic substance and thus the delivery is maintained over a longer period of time. It is preferable that the active ingredient is not high

Solubility in aqueous media show. It is disclosed that one can lipophilize drugs by covalent or non-covalent modifications such as complex or salt formation.

For example, one could modify gentamicin salt or base with a lipophilic fatty acid.

All of the mentioned methods have in common that equipping the medical work equipment with a pharmacologically active substance requires an additional work step, namely either a pretreatment of the polymer material before processing or an aftertreatment of the moldings produced. This causes additional costs and involves an increased production time. Another problem of the method consists in the use of organic solvents, which can not be completely removed from the material usually. In addition, all of the methods mentioned here have in common that the temporally limited long-term effect of the antimicrobial finish of the shaped bodies of polymeric material, in particular of medical devices when used on or in the patient, is optimized. This and the avoidance of the risk of microbial initial infection of the molding itself or of man and animal by the molding are not guaranteed here but at the same time satisfying.

The medical devices referred to here are predominantly used intracorporally. For example, catheters penetrate the body surface for the entire time of application and therefore present a particularly high risk of microbial infection, as stated earlier. The risk of initial infection when introducing the medical devices into the body through microbial contamination is not sufficiently reduced by the known antimicrobial equipment.

It thus turns out, based on the prior art, the object of providing an antimicrobially finished polymer material for the production of medical moldings for implants, in particular catheters, which is suitable for the healing process Long-term effect in the prevention of surface colonization by germs and thereby minimizes the risk of microbial Erstinfektion on entry into the biological tissue by microbiocidal immediate effect, has suitable mechanical properties and is easy and inexpensive to manufacture. Surprisingly, it has now been found that the molding compositions according to the invention or the moldings produced therefrom both at the surface have a high initial concentration of active ingredients, which effectively prevents initial colonization of microorganisms by high drug delivery when wetted with an aqueous medium, as well as a long-lasting ensure adequate release of active ingredient for long-term use.

Accordingly, a first subject of the present invention are molding compositions comprising at least one thermoplastically processable polymer, in particular thermoplastic polyurethanes (TPU), copolyesters and polyether block amides, and at least one partially neutralized active ingredient.

A second object of the present invention are moldings which contain novel molding materials.

The active substances used according to the invention have antibacterial, antiprotozoic or antifungal or fungicidal activity and are therefore counted from their action to the antibiotics, respectively anti-infective agents, as well as antimycotics, respectively fungicides.

In the context of this invention, a partially neutralized drug is either an agent with basic functionality that is partially neutralized with an acid, or an agent with acidic functionality that is partially neutralized with a base. The terms basic or acidic functionality as well as acid and base include the well-known terms in the meaning as proton acceptor and donor according to Brönstedt.

Furthermore, in the context of this invention, the term partially neutralized active ingredient is understood in particular also to mean those active ingredients which simultaneously have basic and acidic functionalities, such as, for example, betaines and zwitterions with quaternized nitrogen. The acid functionality is partially neutralized in this case with a base and the basic functionality with an acid. Active substances with basic functionality which are suitable according to the invention are organic-chemical aliphatic and cyclic, in particular heterocyclic, compounds which carry, for example, a nitrogen functionality as substituent or in the chain or the ring. Preference is given to active substances such as β-lactam antibiotics such as penicillins, in particular 6-aminopenicillin esters such as bacampicillin such as cephalosporins, in particular cefotiam, 7-aminocephalosporanic acid esters such as cefpodoxime proxetil and cefetamet-pivoxil, gyrase inhibitor antiinfectives such as derivatized quinolones, in particular derivatized on the carboxylic acid function

Fluoroquinolonecarboxylic acid derivatives, aminoglycoside antibiotics, in particular streptomycin, neomycin, gentamicin, tobramycin, netylmycin, and amikacin, tetracycline antibiotics, in particular docycycline and minocycline, chloramphenicol and derivatives, in particular as succinate monosodium salt, macrolide antibiotics, such as desosamine macrolides, in particular erythromycin, Clarithromycin, roxithromycin, azithromycin, erythromycin, dirithromycin and their esters such as ketolides, lincosamide antibiotics such as lincomycin and clindamycin, oxazolidinone antibiotics, sulfonamide antimicrobials, especially sulfisoxazole, sulfadiazine, sulfamethoxazole, sulfamethoxydiazine, sulfa and sulfadoxine, diaminopyrimidine antimicrobials such as in particular trimethoprim, pyrimethamine, basic ansamycin antibiotics such as in particular rifampicin and rifabutin, and azole antifungals such as imidazole derivatives such as in particular bifonazole, clotrimazole, econazole, miconazole and isoconazole, and tri azole derivatives, in particular itraconazole, and voriconazole.

Active ingredients with acidic functionality which are suitable according to the invention are organic-chemical aliphatic and cyclic, in particular heterocyclic, compounds which are substituted, for example, by one or more carboxyl groups and / or a sulfo group. Preference is given to active substances such as β-lactam antibiotics such as penicillins, in particular 6-aminopenicillan acids such as, for example, penicillin G, propicillin, amoxicillin, ampicillin, mezlocillin, oxacillin and flucloxacillin, such as clavulanic acid, such as cephalosporins, in particular substituted 7-aminocephalosporanic acids, such as cefazolin, cefuroxime, cefoxitin , Cefotetan, cefotaxime and ceftriaxone, and oxacephems such as latamoxef and flomoxef such as carbapenems, especially imipenem, and monobactams, especially aztreonam, and gyrase inhibitor anti-infective agents such as nalixidic acid and derivatives, especially nalixidic acid itself, as well as fusidic acid.

According to the invention suitable agents with betaine or zwitterion structure are, for example, cephalosporins especially cefotiam and the cefalexin group such as cefaclor, the ceftazidime group such as ceftazidime, cefpirome and cefepime, carbapenems, in particular meropenems, quinolonecarboxylic acids, in particular substituted 6-fluoro-l , 4-dihydro-4-oxo-7- (1-piperazinil) -quinoline-3-carboxylic acids such as, for example, norfloxacin, ciprofloxacin, ofloxacin, Sparfloxacin, grepafloxacin and enrofloxacin, substituted 6-fluoro-l, 4-dihydro-4-oxo-7- (1-pyrrolidine) quinoline-3-carboxylic acids such as clinafloxacin, moxifloxacin and trovafloxacin, as well as cyclic peptide antibiotics such as glycopeptides such as in particular vancomycin and teicoplanin, such as streptograms such as in particular pristinamycins.

Very particularly preferred active ingredients are norfloxacin, ciprofloxacin, clinafloxacin, and moxifloxacin.

The partially neutralized active compounds can also be used according to the invention as active ingredient combinations, even with structurally or functionally different and / or with non-neutralized active substances from the substance classes used according to the invention in the shaped bodies, provided their effects do not antagonize.

Acids which can be used according to the invention are generally all customary inorganic or organic acids or proton donors. For example, one uses, depending on the basicity and stability of the partially neutralized active ingredient and, in medical applications, the physiological compatibility of mineral acids, mono- di-, tri- and polyfunctional aliphatic and aromatic carboxylic acids and hydroxycarboxylic acids, polyfunctional carboxylic acid partially with short - And long-chain alcohols, hydroxycarboxylic acids may be esterified with carboxylic acids, hydroxycarboxylic acids with glycoside bound carbohydrates, acidic amino acids, sulfonic acids such as in particular aliphatic perfluorosulfonic acids and phenols. Preference is given to using hydrogen chloride, sulfuric acid, phosphoric acid, phosphoric mono- and diesters, acetic acid, stearic acid, palmitic acid, malonic acid, succinic acid, glutaric acid, adipic acid, malic acid, tartaric acid, ethyl hydrogen succinate (succinic monoester), citric acid, acetylsalicylic acid, glutamic acid and perfluorobutanesulfonic acid. Hydrogen chloride is particularly preferably used.

Bases which can be used according to the invention are generally all customary inorganic or organic proton acceptors. For example, depending on the acidity and stability of the partially neutralized active ingredient and, in medical applications, the physiological compatibility of alkali metal hydrides, alkali metal alkoxides, alkali metal, alkaline earth metal, alkali metal, Erdalkalimetallhydrogencarbonate and nitrogen bases such as primary, secondary and tertiary aliphatic, cycloaliphatic and aromatic amines. Preference is given to using sodium hydride, sodium methoxide, - -

Sodium hydroxides, magnesium hydroxide, calcium hydroxide, sodium and potassium carbonate, sodium and potassium bicarbonate, triethylamine, dibenzylamine, diisopropylamine, pyridine, quinoline, diazabicyclooctane (DABCO), diazabicyclononene (DBN) and diazabicycloundecene (DBU).

The active substances with betaine or Zwitterrionenstruktur can according to the invention either with acids or bases, for example, from the o. A. Lists are partially neutralized. The partial neutralization can be done in a wide range of equivalents. For example, 0.01 to 0.95 equivalents of acid are used per equivalent of basic functionality in the active ingredient, or 0.01 to 0.95 equivalents of base per equivalent of acidic functionality in the active ingredient. Preference is given to 0.01 to 0.95, particularly preferably 0.2 to 0.8 equivalents of acid or base per mole of active ingredient.

In a particularly preferred embodiment of the invention is used with 0.1 to 0.9 mol of hydrogen chloride per mole of active ingredient neutralized quinolone anti-infective agents, more preferably ciprofloxacin.

The neutralization of the active ingredients for use according to the invention in the polymer is carried out by the well-known classical or newer methods of organic chemistry. Thus, for example, it is possible to dissolve or suspend the active ingredient in a suitable solvent and to add the acid or base in pure or dissolved form. After this, the partially neutralized active substance can then be obtained by crystallization or evaporation of the solvent. However, it is also possible to carry out the neutralization by means of an adsorbent loaded with the relevant acid or base, for example silica gel or aluminum oxide, or anionic or cationic ion exchanger. In general, this is carried out analogously to a column chromatograph by dissolving the active ingredient in a suitable solvent as mobile phase and continuous discontinuous contact with the loaded with the acid or base stationary phase.

In this case, it is in principle also possible to obtain the partially neutralized active substance only in a second step by mixing the equimolar neutralized with non-neutralized active ingredient. This can be done in homogeneous solution and / or liquid form, but also in solid form, for example, crystalline or amorphous powder form.

The partially neutralized active ingredient used must have sufficient (chemical) stability in the polymer matrix. In addition, the microbiological activity of the active substance in the - - polymer matrix and under the process conditions of incorporation are not impaired, the active ingredient must therefore be sufficiently stable at the required for the thermoplastic processing of the polymeric material temperatures of 150 to 200 ⁰ C and residence times of 2 to 5 min.

The incorporation of the pharmaceutically active substance should not affect the biocompatibility of the polymer surface or other desirable polymer-specific properties of the polymeric material (elasticity, tear resistance, etc.).

The active compounds are preferably incorporated in a concentration corresponding to their activity. The proportion of active ingredient (calculated as non-neutralized active ingredient) in the molding composition is preferably in a concentration range of 0.1 to 5.0 wt .-%, particularly preferably 0.5 to 2 wt .-%, based in each case on the molding composition. Very particular preference is given to using 1 to 2% by weight of ciprofloxacin.

Suitable thermoplastically processable polymers are in particular thermoplastic polyurethanes, polyether block amides and copolyesters, preferably thermoplastic polyurethanes and polyether block amides and particularly preferably thermoplastic polyurethanes.

The thermoplastically processable polyurethanes which can be used according to the invention are prepared by reacting the polyurethane-forming components

(A) organic diisocyanate,

(B) linear hydroxyl terminated polyol having a molecular weight of 500 to 10,000,

(C) chain extenders having a molecular weight of 60 to 500,

wherein the molar ratio of the NCO groups in (A) to the isocyanate-reactive groups in (B) u. (C) 0.9 to 1.2 is available.

Suitable organic diisocyanates (A) are, for example, aliphatic, cycloaliphatic, heterocyclic and aromatic diisocyanates, as described in Justus Liebigs Annalen der Chemie, 562, pp. 75-136. Preference is given to aliphatic and cycloaliphatic diisocyanates.

Specific examples are: aliphatic diisocyanates, such as hexamethylene diisocyanate, cycloaliphatic diisocyanates, such as isophorone diisocyanate, 1, 4-cyclohexane diisocyanate, 1-methyl

2,4-cyclohexane diisocyanate and 1-methyl-2,6-cyclohexane diisocyanate and the corresponding Isomer mixtures, 4,4'-dicyclohexylmethane diisocyanate, 2,4'-dicyclohexylmethane diisocyanate and 2,2'-dicyclohexylmethane diisocyanate and the corresponding isomer mixtures, aromatic diisocyanates such as 2,4-tolylene diisocyanate, mixtures of 2,4-tolylene diisocyanate and 2,6-tolylene diisocyanate, 4,4'-diphenylmethane diisocyanate, 2,4'-diphenylmethane diisocyanate and 2,2'-diphenylmethane diisocyanate, mixtures of 2,4'-diphenylmethane diisocyanate and 4,4'-diphenylmethane diisocyanate, urethane-modified liquid 4,4 ' Diphenylmethane diisocyanates and 2,4'-diphenylmethane diisocyanates, 4,4'-diisocyanatodiphenyl-ethane (1,2) and 1,5-diphenylmethane diisocyanates.

Naphthylene. Preferably used are 1 ₅ 6-hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane diisocyanate, diphenylmethane diisocyanate isomer mixtures having a 4,4'-diphenylmethane diisocyanate content of> 96 wt .-% and in particular 4,4'-diphenylmethane diisocyanate and 1,5-naphthylene diisocyanate. The diisocyanates mentioned can be used individually or in the form of mixtures with one another. They may also be used together with up to 15% by weight (calculated on the total amount of diisocyanate) of a polyisocyanate, for example triphenylmethane-4,4 ', 4 "-triisocyanate or polyphenyl-polymethylene-polyisocyanates.

Component (B) used is linear hydroxyl-terminated polyols having an average molecular weight Mn of from 500 to 10,000, preferably from 500 to 5,000, particularly preferably from 600 to 2,000. For production reasons, these often contain small amounts of branched compounds. Therefore, one often speaks of "substantially linear polyols". Preference is given to polyether diols, polycarbonate diols, sterically hindered polyester diols, hydroxyl-terminated polybutadienes or mixtures of these.

As soft segments, polysiloxane diols of the formula (I) can be used alone or in admixture with the abovementioned diols.

HO- (CH ₂ ) _n - [Si (R ¹ ) ₂ -O-] _m Si (R ¹ ) ₂ - (CH ₂ ) _n -OH (I)

in which

R ^{1 is} an alkyl group having 1 to 6 C atoms or a phenyl group, m is 1 to 30, preferably 10 to 25 and particularly preferably 15 to 25, and n is 3 to 6,

be used. They are known products and can be prepared by synthesis methods known per se, for example by reacting a silane of the formula (II) H- [Si (R ¹ ) ₂ ] O-] _m Si (R ¹ ) ₂ -H (II)

in which R ¹ and m have the meanings given above,

in the ratio 1: 2 with an unsaturated, aliphatic or cycloaliphatic alcohol such as allyl alcohol, butene- (l) -ol or penten- (l) -ol in the presence of a catalyst, for. B. hexachloroplatinic acid.

Suitable polyether diols can be prepared by reacting one or more alkylene oxides having 2 to 4 carbon atoms in the alkylene radical with a starter molecule containing two active hydrogen atoms bonded. As alkylene oxides may be mentioned, for example:

Ethylene oxide, 1,2-propylene oxide, epichlorohydrin and 1, 2-butylene oxide and 2,3-butylene oxide. Preferably, ethylene oxide, propylene oxide and mixtures of 1, 2-propylene oxide and ethylene oxide are used. The alkylene oxides can be used individually, alternately in succession or as mixtures. Suitable starter molecules are, for example: water, amino alcohols, such as N-alkyl-diethanolamines, for example N-methyl-diethanolamine, and diols, such as ethylene glycol, 1,3-propylene glycol, 1,4-butanediol and 1,6-hexanediol , Optionally, mixtures of starter molecules can be used. Suitable polyether diols are also the hydroxyl-containing polymerization of tetrahydrofuran. It is also possible to use trifunctional polyethers in proportions of from 0 to 30% by weight, based on the bifunctional polyethers, but at most in such an amount that a thermoplastically processable product is formed. The substantially linear polyether diols can be used both individually and in the form of mixtures with one another.

Suitable sterically hindered polyester diols can be prepared, for example, from dicarboxylic acids having 2 to 12 carbon atoms, preferably 4 to 6 carbon atoms, and polyhydric alcohols. Suitable dicarboxylic acids are, for example: aliphatic dicarboxylic acids, such as succinic acid, glutaric acid, adipic acid, suberic acid, azelaic acid and sebacic acid, and aromatic dicarboxylic acids, such as phthalic acid, isophthalic acid and terephthalic acid. The dicarboxylic acids can be used individually or as mixtures, eg. In the form of an amber, glutaric and adipic acid mixture. For the preparation of the polyester diols, it may optionally be advantageous, instead of the dicarboxylic acids, to use the corresponding dicarboxylic acid derivatives, such as carbonic acid diesters having 1 to 4 carbon atoms in the alcohol radical, - -

Carboxylic anhydrides or carboxylic acid chlorides to use. Examples of polyhydric alcohols are sterically hindered glycols having 2 to 10, preferably 2 to 6, carbon atoms which have at least one alkyl radical in the beta position relative to the hydroxyl group, such as 2,2-dimethyl-1,3-propanediol, 2-methyl-2-one propyl-l, 3-propanediol, 2,2-diethyl-l, 3-propanediol, 2-ethyl-l, 3-hexanediol, 2,5-dimethyl-2,5-hexanediol, 2,2,4-trimethyl- l, 3-pentanediol, or mixtures with ethylene glycol, diethylene glycol, 1,4-butanediol, 1,5-pentanediol, 1, 6-hexanediol, 1,10-decanediol, 1,3-propanediol and dipropylene glycol. Depending on the desired properties, the polyhydric alcohols may be used alone or optionally mixed with each other. Also suitable are esters of carbonic acid with the diols mentioned, in particular those having 3 to 6 carbon atoms, such as 2,2-dimethyl-l, 3-propanediol or 1,6-hexanediol, condensation products of hydroxycarboxylic acids, for example hydroxycaproic acid and polymerization products of lactones, for example optionally substituted caprolactones. As polyester diols are preferably used, neopentyl glycol polyadipate 1,6-hexanediol neopentylglykol- polyadipate. The polyester diols can be used individually or in the form of mixtures with one another.

As chain extenders (C) diols, diamines or amino alcohols having a molecular weight of 60 to 500 are used, preferably aliphatic diols having 2 to 14 carbon atoms, such as. As ethanediol, 1, 6-hexanediol, diethylene glycol, dipropylene glycol and in particular 1,4-butanediol. However, also suitable are diesters of terephthalic acid with glycols having 2 to 4 carbon atoms, such as. B. terephthalic acid-bis-ethylene glycol or terephthalic acid bis-l, 4-butanediol, hydroxyalkylene ethers of hydroquinone, such as. B. l, 4-di (hydroxyethyl) - hydroquinone, ethoxylated bisphenols, (cyclo) aliphatic diamines, such as. B. isophoronediamine, ethylenediamine, 1,2-propylenediamine, 1,3-propylenediamine, N-methyl-propylene-1,3-diamine, 1,6-hexamethylenediamine, 1,4-diaminocyclohexane, 1,3- Diaminocyclohexane, N, N'-

Dimethylethylenediamine and 4,4'-dicyclohexylmethanediamine and aromatic diamines, such as. B. 2,4-toluenediamine and 2,6-toluenediamine, 3,5-diethyl-2,4-toluylenediamine and 3,5-diethyl-2,6-toluylenediamine and primary mono-, di-, tri- or tetraalkylsubstituierte 4th , 4'-Diaminodiphenylmethane or amino alcohols such as ethanolamine, 1-aminopropanol, 2-aminopropanol. It is also possible to use mixtures of the abovementioned chain extenders. In addition, smaller amounts of tri- or higher-functional crosslinkers can be added, for. As glycerol, trimethylolpropane, pentaerythritol, sorbitol. Particular preference is given to using 1,4-butanediol, 1,6-hexanediol, isophoronediamine and mixtures thereof. Furthermore, customary monofunctional compounds can also be used in small amounts, for. B. as chain terminators or demoulding. Examples include alcohols such as octanol and stearyl alcohol or amines such as butylamine and stearylamine.

The molar ratios of the constituent components can be varied over a wide range, which can adjust the properties of the product. Molar ratios of polyols to chain extenders of 1: 1 to 1: 12 have proven useful. The molar ratio of diisocyanates and polyols is preferably 1.2: 1 to 30: 1. Particular preference is given to ratios of 2: 1 to 12: 1 To prepare the TPU, the synthesis components, if appropriate in the presence of catalysts, auxiliaries and additives, can be reacted in amounts such that the equivalence ratio of NCO groups to the sum of the NCO-reactive groups, in particular the hydroxyl or amino groups of the low molecular weight diols / Triols, amines and polyols 0.9: 1 to 1.2: 1, preferably 0.98: 1 to 1, 05: 1, more preferably 1.005: 1 to 1.01: 1.

The polyurethanes which can be used according to the invention can be prepared without catalysts; however, in some cases, the use of catalysts may be indicated. In general, the catalysts are used in amounts of up to 100 ppm, based on the total amount of starting materials. Suitable inventive catalysts are known and customary in the prior art tertiary amines, such as. For example, triethylamine, dimethylcyclohexylamine, N-methylmorpholine, N, N'-dimethyl-piperazine, 2- (dimethylaminoethoxy) ethanol, diazabicyclo- (2,2,2) octane and the like and in particular organic metal compounds such as titanic acid esters, iron compounds , Tin compounds, e.g. As tin diacetate, tin dioctoate, tin dilaurate or Zinndialkylsalze aliphatic carboxylic acids. Preferred are dibutyltin diacetate and dibutyltin dilaurate; Of these, 1 to 10 ppm are enough to catalyze the reaction.

In addition to the TPU components and the catalysts, other auxiliaries and additives may also be added. Examples which may be mentioned are lubricants such as fatty acid esters, their metal soaps, fatty acid amides and silicone compounds, antiblocking agents, inhibitors, hydrolysis stabilizers, light, heat and discoloration, flame retardants, dyes, pigments, inorganic or organic fillers and reinforcing agents. Reinforcing agents are, in particular, fibrous reinforcing materials, such as inorganic fibers, which are produced according to the prior art and can also be treated with a sizing agent. Further details of the abovementioned auxiliaries and additives can be found in the specialist literature, for example JH Saunders, KC Frisch: "High Polymers", Volume XVI, Polyurethanes, Part 1 and 2, Interscience Publishers 1962 and 1964, R. Gächter, H. Müller (Ed.): Paperback of the plastic additives, 3rd edition, Hanser Verlag, Munich 1989, or DE-A 29 01 774.

The structure of the thermoplastically processable polyurethane elastomers is preferably carried out stepwise in the so-called prepolymer process. In the prepolymer process, an isocyanate-containing prepolymer is formed from the polyol and the diisocyanate, which is reacted in a second step with the chain extender. The TPUs can be produced continuously or discontinuously. The best known technical production methods are the belt process and the extruder process.

Polyether block amides suitable according to the invention are, for example, those which consist of polymer chains which are built up from recurring units of the formula I.

in which

A is the polyamide chain derived from a polyamide having 2 carboxyl end groups by loss of the latter, and B is the polyoxyalkylene glycol chain derived from a OH-terminated polyoxyalkylene glycol by loss of the latter and n is the number of polymer chain forming units. As end groups are preferably OH groups or residues of compounds which terminate the polymerization.

The dicarboxylic acid polyamides having the terminal carboxyl groups are obtained in a known manner, e.g. by polycondensation of one or more lactams and / or one or more amino acids, furthermore by polycondensation of a dicarboxylic acid with a diamine, in each case in the presence of an excess of an organic dicarboxylic acid, preferably with terminal carboxyl groups. These carboxylic acids become part of the polyamide chain during the polycondensation and are deposited, in particular, at the end of the polyamide chain, giving a polycarbamide having a polycarboxylic acid. Furthermore, the dicarboxylic acid acts as a chain terminator, which is why it is also used in excess.

The polyamide can be obtained starting from lactams and / or amino acids having a hydrocarbon chain consisting of 4-14 C atoms, such as caprolactam, enantholactam, dodecalactam, undecanolactam, decanolactam, 11-amino undecano or 12-aminododecanoic acid. Examples of polyamides formed by polycondensation of a dicarboxylic acid with a diamine include the condensation products of hexamethylenediamine with adipic, azelaic, sebacic, and 1,12-dodecanedioic acid, and the condensation products of nonamethylenediamine and adipic acid.

In the case of the dicarboxylic acid used for the synthesis of the polyamide, that is, on the one hand for fixing in each case one carboxyl group at each end of the polyamide chain and on the other hand as chain terminating agents, those having 4-20 C atoms are suitable, in particular alkanedioic acids such as succinic, adipic, cork -, azelaic, sebacic, undecanedioic or dodecanedioic acid, also cycloaliphatic or aromatic dicarboxylic acid, such as terephthalic or isophthalic or cyclohexane-l, 4-dicarboxylic acid.

The terminal OH-containing polyoxyalkylene glycols are unbranched or branched and have an alkylene radical having at least 2 C atoms. In particular, these are polyoxyethylene, polyoxypropylene and polyoxytetramethylene glycol, as well as copolymers thereof.

The average molecular weight of these OH group-terminated polyoxyalkylene glycols can be in a wide range, it is advantageously between 100 and 6000, in particular between 200 and 3000.

The proportion by weight of the polyoxyalkylene glycol, based on the total weight of the polyoxyalkylene glycol and dicarboxylic acid polyamide used to prepare the PEBA polymer, is 5-85%, preferably 10-50%.

Processes for the synthesis of such PEBA polymers are known from FR-PS 7 418 913, DE-OS 28 02 989, DE-OS 28 37 687, DE-OS 25 23 991, EP-A 095 893, DE-OS 27 12 987 and DE-OS 27 16 004 known.

Preferably suitable according to the invention are those PEBA polymers which, in contrast to those described above, have a statistical structure. To prepare these polymers, a mixture of 1. one or more polyamide-forming compounds from the group of aminocarboxylic acids or lactams having at least 10 carbon atoms, 2. an α, ω-dihydroxy-polyoxyalkylene glycol, 3. at least one organic dicarboxylic acid in a weight ratio of 1: (2 + 3) between 30:70 and 98: 2, wherein in (2 + 3) hydroxyl and carbonyl groups are present in equivalent amounts, in the presence of 2 to 30% by weight of water, based on the polyamide-forming compounds the group 1, under which self-adjusting pressure is heated to temperatures between 23 ° C and 3O ⁰ C and then further treated after removal of the water with exclusion of oxygen at atmospheric pressure or under reduced pressure at 250 to 28O ⁰ C.

Such preferred suitable PEBA polymers are e.g. described in DE-OS 27 12 987.

Suitable and preferably suitable PEBA polymers are e.g. Atochem, Vestamid from Hüls AG, Grilamid from EMS-Chemie and Kellaflex from DSM are available under the trade names PEBAX.

The active substance-containing polyether block amides according to the invention can furthermore contain the additives customary for plastics. Typical additives are, for example, pigments, stabilizers, flow agents, lubricants, mold release agents.

Suitable copolyesters (segmented polyester elastomers) are constructed, for example, from a variety of recurring, short chain ester units and long chain ester units joined together by ester linkages, the short chain ester units being about 15-65% by weight of the copolyester and having the formula (I).

wherein R is a divalent radical of a dicarboxylic acid having a molecular weight below about 350, D is a divalent radical of an organic diol having a molecular weight of less than about 250; the long-chain ester units make up about 35-85% by weight of the copolyester and have the formula II

in which

R is a divalent radical of a dicarboxylic acid having a molecular weight below about 350; G is a divalent radical of a long chain glycol having an average molecular weight of about 350 to 6,000. The copolyesters which can be used according to the invention can be prepared by polymerizing together a) one or more dicarboxylic acids, b) one or more linear, long-chain glycols and c) one or more low molecular weight diols.

The dicarboxylic acids for the preparation of the copolyester are the aromatic acids having 8-16 C-atoms, in particular phenylenedicarboxylic acids, such as phthalic, terephthalic and isophthalic acid.

The low molecular weight diols for the reaction to form the short chain ester units of the copolyesters belong to the classes of acyclic, alicyclic and aromatic dihydroxy compounds. The preferred diols have 2-15 C-atoms, such as ethylene, propylene, tetramethylene, isobutylene, pentamethylene, 2,2-dimethyltrimethylene, hexamethylene and deca methylene glycols, dihydroxycyclohexane, cyclohexanedimethanol, resorcinol, hydroquinone and the like , Bisphenols for the present purpose include bis (p-hydroxy) diphenyl, bis (p-hydroxyphenyl) methane, bis (p-hydroxyphenyl) ethane, and bis (p-hydroxyphenyl) propane. The long-chain glycols for preparing the soft segments of the copolyesters preferably have molecular weights of about 600 to 3,000. These include poly (alkylene ether) -glycols in which the alkylene groups have 2-9 carbon atoms.

Glycol esters of poly (alkylene oxide) dicarboxylic acids or polyester glycols can also be used as long-chain glycol.

The long-chain glycols also include polyformals obtained by reacting formaldehyde with glycols. Polythioether glycols are also suitable. Polybutadiene and polyisoprene glycols, mixed polymers thereof and saturated hydrogenation products of these materials are satisfactory long chain polymeric glycols.

Processes for the synthesis of such copolyesters are known from DE-OS 2 239 271, DE-OS 2 213 128, DE-OS 2 449 343 and US Pat. No. 3,023,192.

The active ingredient-containing copolyesters according to the invention may furthermore contain the additives customary for plastics. Typical additives are, for example, lubricants such as fatty acid esters, their metal soaps, fatty acid amides and silicone compounds, antiblocking agents, inhibitors, hydrolysis stabilizers, light, heat and discoloration, flame retardants, dyes, pigments, inorganic or organic fillers and reinforcing agents. Reinforcing agents are, in particular, fibrous reinforcing materials, such as inorganic fibers, which are produced according to the prior art and can also be treated with a sizing agent. Details The technical references on the abovementioned excipients and additives can be found, for example, JH Saunders, KC Frisch: "High Polymers", Volume XVI, Polyurethanes, Parts 1 and 2, Interscience Publishers 1962 and 1964, R.Gächter, H.Müller ( Ed.): Paperback of the plastic additives, 3rd edition, Hanser Verlag, Munich 1989, or DE-A 29 01 774.

The molding compositions of the invention can be prepared by extruding a melt consisting of the polymer and the active ingredient. The melt may contain 0.01 to 10 wt .-%, preferably 0.1 to 5 wt .-% active ingredient. The mixing of the components can be done by known techniques in any way. The active ingredient can for example be introduced directly into the polymer melt in solid form. It is also possible for an active ingredient-containing masterbatch to be fused directly to the polymer or mixed with the polymer melt already present. The active ingredient may also be applied to the polymer prior to melting of the polymer by known techniques (tumbling, spraying, etc.).

Incidentally, the mixing / homogenization can be carried out of the components by known techniques on kneaders or extruders, preferably in single or twin screw extruders in a temperature range between 150 and 200 ⁰ C.

By mixing the components during the extrusion process, a homogeneous, molecularly disperse distribution of the active ingredient in the polymer matrix is achieved without requiring additional operations.

Investigations have shown that a homogeneous distribution of the active ingredient in the polymer matrix is necessary in order to be able to use the active ingredient diffusion as an adjustable release mechanism. The active ingredient and the polymer should therefore have high physicochemical compatibility. With good physicochemical compatibility of active ingredient and polymer, a high diffusion coefficient of the active ingredient in the polymer is achieved. The amount of the release rate of the antibiotically active substance can be regulated in this case by varying the incorporated amount of active ingredient, since then the amount of active substance released is proportional to the concentration in the matrix.

The active ingredient-containing granules obtained in this way can be further processed by the known techniques of thermoplastic processing (injection molding, extrusion, etc.). The moldings are free of specks, flexible, do not stick and can be easily sterilized by the usual methods. Shaped bodies produced from the molding compositions according to the invention are preferably medical products such as, for example, central venous catheters (CVC), urotheraphytes, hoses, shunts, cannulas, connectors, plugs or distributor taps, particularly preferred are CVCs.

The following examples are intended to illustrate the invention without, however, limiting it.

Examples

example 1

4,950 g of lens granules of the commercial aromatic polyether polyurethane Pellethane 2363-80AE, filled with 20 wt .-% barium sulfate, the Shore hardness 85 A (Dow Chemical, Midland MI) were dried for 24 hours at 80 ° C and then with 50 g Ciprofloxacin (betaine) mixed thoroughly on a Rhönrad mixer.

Compounding For the compounding of this mixture, it was carried out on an extruder from Brabender, which is constructed as follows:

- A 4-zone extruder with a double screw of 20 mm diameter (D) and a length of 25xD. The screw has a degassing zone;

- a one-hole round rod nozzle with 3.2 mm diameter; - A 2.5 m long water-filled cooling trough with about 20 ° C Temperautr

- A differential dosing scale

- a withdrawal device with strand granulation;

The above mixture is conveyed by means of the differential dosing into the cold task housing of the extruder. From the nozzle, the melt is withdrawn and pulled through the cooling trough for cooling. Ln granulator is the strand granulation of the round strand.

Process parameters:

Table 1: Compounding conditions

The drug-free cylindrical granules were extruded on a twin-screw extruder ZSK. A white, homogeneous, speck-free melt was obtained which, after cooling in a water / air bath and strand granulation, gave a homogeneous cylindrical granulate.

injection molding

An Arburg 270S-500-60 with a screw diameter of 18 mm was used. After drying, the granules were injection-molded into test specimens (plates 60 × 60 × 2 mm). For this the following parameters were chosen:

Table 2: Injection molding conditions

For microbiological in vitro investigations, platelets of 5 mm

Punched out diameter. These platelets were sterilized with 25 kGr gamma.

Example 2 (comparative example)

4,950 g of lens granules of the commercial aromatic polyether polyurethane Pellethane 2363-80AE filled with 20 wt .-% barium sulfate, the Shore hardness 85 A (Dow Chemical, Midland MI) were dried for 24 hours at 80 ° C and then with 50 g of ciprofloxacin hydrochloride are mixed thoroughly on a Rhönrad mixer. Analogously to the material from Example 1, the active ingredient-containing cylindrical granules were extruded on a twin-screw extruder ZSK. A white, speck-free melt was obtained which, after cooling in a water / air bath and strand granulation, gave a homogeneous cylindrical granulate. For in vitro microbiological examinations, platelets of 5 mm diameter were punched out of the plates. These platelets were sterilized with 25 kGr gamma.

Example 3

Preparation of the masterbatch for compounding the samples of Examples 7 to 11

Tecothane TT2085A-B20 in the form of commercially available lens granules with a size of about 2 mm was ground at -40 ° C to a powder, which was then sieved in two fractions. A 1st fraction with d ₅₀ = 300 μm was used for the examples according to the invention. 1,000 g of ciprofloxacin hydrochloride (d ₅₀ = 9.13 μm) were mixed in an intensive mixer with 2,000 g of drug-free Tecothane TT2085A-B20 powder (d ₅₀ = 300 μm). This polymer-active ingredient powder mixture and a further 2,000 g of Tecothane TT2085A-B20 lentil granules were metered separately into the housing 1 of the extruder by means of two differential metering scales. As in Example 1, the active ingredient-containing cylindrical granules were extruded on a twin-screw extruder ZSK Fa. Brabender. A speck-free white melt was obtained which, after cooling in a water / air bath and strand granulation, gave a cylindrical granulate containing 20% by weight of ciprofloxacin hydrochloride.

Example 4

Preparation of the masterbatch for compounding the samples of Examples 12 to 16

Tecothane TT2085A-B20 in the form of commercially available lens granules with a size of about 2 mm was ground at -40 ° C to a powder, which was then sieved in two fractions. A 1st fraction with d ₅₀ = 300 μm was used for the examples according to the invention.

1,000 g of ciprofloxacin (betaine) (d ₅ o = 5.77 microns) were mixed in an intensive mixer with 2,000 g of drug-free Tecothane TT2085A-B20 powder (d ₅₀ = 300 microns). This polymer-active ingredient powder mixture and a further 2,000 g of Tecothane TT2085A-B20 lentil granules were metered separately into housing 1 of the extruder by means of two differential metering scales. As in Example 1, the active ingredient-containing cylindrical granules were extruded on a twin-screw extruder ZSK from Brabender. A speck-free white melt was obtained which, after cooling in a water / air bath and strand granulation, gave a cylindrical granulate containing 20% by weight of ciprofloxacin (betaine).

Example 5

From the granules of Example 1, ciprofloxacin was obtained from an external manufacturer.

(Betain) -containing three-lumen catheter tubing extruded with an outer diameter of 2 mm. These catheter tubes were sterilized with 25 kGr gamma.

The catheter tubing was used in the Dynamic Model to detect antimicrobial effects of materials and to determine the elution profile of the incorporated drug Example 6 (comparative example)

From the granules of Example 2, ciprofloxacin hydrochloride-containing three-lumen catheter tubing having an outer diameter of 2 mm was extruded from an external manufacturer. These catheter tubes were sterilized with 25 kGr gamma.

The catheter tubing was used in the Dynamic Model to detect antimicrobial effects of materials and to determine the elution profile of the incorporated drug d

Example 7 (comparative example)

12.5 g of masterbatch granules from Example 3 were mixed in an intensive mixer with 987.5 g of drug-free Tecothane TT2085A-B20 granules. The active ingredient-containing cylindrical granules were extruded on a twin-screw extruder ZSK from Brabender. A homogeneous white melt was obtained which, after cooling in the water / air bath and strand granulation, gave a readily flowing cylindrical granulate with 0.25% by weight of ciprofloxacin hydrochloride.

For the determination of the elution profile of the incorporated active substance in the dynamic model for the detection of antimicrobial effects of materials, extruded samples (2 mm diameter and ca. 17 cm long) were taken and the granules were injection-molded into test pieces (plates) for the agar diffusion test.

For in vitro microbiological examinations, platelets of 5 mm diameter were punched out of the plates. These platelets were sterilized with 25 kGr gamma. Analogously to Example 7, the following granules were obtained:

Table 3: Composition of Comparative Examples 8 to 11

Example 12

12.5 g of masterbatch granules from Example 4 were mixed in an intensive mixer with 987.5 g of drug-free Tecothane TT2085A-B20 granules. The active ingredient-containing cylindrical granules were extruded on a twin-screw extruder ZSK from Brabender. A homogeneous white melt was obtained which, after cooling in the water / air bath and strand granulation, gave a readily flowing cylindrical granulate with 0.25% by weight of ciprofloxacin (betaine).

For in vitro microbiological examinations, platelets of 5 mm diameter were punched out of the plates. These platelets were sterilized with 25 kGr gamma. Analogously to Example 12, the following granules were obtained:

Table 4: Composition of Examples 13 to 16 according to the invention

Example 17

To test the effectiveness, the following experimental set-up was chosen: Dynamic model for the detection of antimicrobial effects of materials

The presented model is intended to demonstrate the antimicrobial effect of materials and to demonstrate the prevention of biofilm formation on the materials and to record the elution profile of the respective active substances from the materials. The experimental apparatus consists of the following components (see also Fig. 4 and Fig. 5):

In a reaction chamber, a strand piece of the sample to be examined was introduced and firmly fixed by shrink tubing on both sides. The reaction chamber is positioned in the incubator during the experimental period.

The tube system continues to the nutrient medium exchanger. With a three-way cock can be pumped out of the circulation nutrient medium at the outlet position, with the second can be supplied at inlet position in the circulation of nutrient medium.

The tubing continues to flow across the sample chamber to collect samples for germ counts and add the bacterial suspension, then back to the reaction chamber via the peristaltic pump. 1st method

Investigations on the long-term effect of antimicrobial activity of samples

(Strangproben) and catheters was carried out using the dynamic biofilm model.

1.1. test panels

Mueller-Hinton agar plates were used for the culture of germ count determination. For this purpose, Petri dishes of 9 cm diameter were poured with 18 ml Mueller-Hinton agar (Merck KGaA Darmstadt / Lot VMl 32437 339).

1.2. medium

Mueller-Hinton Broth (Merck KgaA Darmstadt / Lot VM205593 347) was used as the medium for the Dynamic Biofilm Model.

1.3. Bacterial suspension The addition of the test strain Staphylococcus aureus ATTC 29213 to the Dynamic Biofilm Model was carried out as a suspension. From an overnight culture of the test strain on Columbia blood agar, a suspension with the density of McFarland 0.5 in NaCl solution 0.85% was prepared. For the suspension, a "colony pool" of 3 to 4 colonies spotted with the inoculum was used and the suspension was diluted 2 times in the ratio of 1: 100. From this dilution step the model was filled.

2.1. assay

Each individual model circuit (reaction chamber + tube system) was filled with approximately 16 ml of medium from the reservoir (medium 1.2) connected to it. Thereafter, 100 μl of the bacterial suspension (1.3) were added to the model circulation via the sample chamber using a pipette. Parallel to this, the plating out of 100 .mu.l of the bacterial suspension for germ counts (1.1) was carried out.

On average, bacterial counts of at least 200 CPU / ml were present in the model cycle after each addition of the bacterial suspension.

The peristaltic pump was set to a speed of 5 / min (revolutions per minute), giving a flow rate of 0.47 ml / min for the tubing used in the experiment. The content of a model cycle was thus exchanged once in the reaction chamber in a good half hour or passed by the catheter.

For the first time after 24 hours, then daily or at varying intervals, 4 ml (25% of the total liquid) were taken from the model cycle and replaced with new medium.

In the removed medium, the ciprofloxacin concentration was determined by HPLC and the elution profile was determined (3.1 elution profile).

In the samples taken, the bacterial concentration was determined in each individual model cycle. From the sample 50 μl were spread on a test plate with a loop and incubated for 24 hours at 37 ° C. Germ counts were estimated according to growth in the smear or 50 μl were inoculated onto a test plate with a pipette, spatulated, incubated at 37 ° C for 24 hours and calculated by colony count.

In addition to the media exchange, 100 μl of the bacterial suspension was added to the model cycle with a pipette daily or at varying intervals across the sample chamber. The germ counts of the added bacterial suspension varied between 1800 and 15,000 bacteria per ml. The addition of a constant, always the same amount of bacteria was deliberately omitted, since in practical use also different numbers of pathogens that could have contact with the catheter, must be assumed. 2. Material

2.1. Material samples

The catheter tubes from Examples 5 and 6 were tested to demonstrate the antimicrobial effect and to prevent biofilm formation on the materials and to determine the elution profile of the respective active substances from the catheter tubes.

Table 5: Catheter tubing used in the dynamic model

The strand samples from the examples below were tested to determine the elution profile of the respective active ingredients

Table 6: Strand samples used in the dynamic model 2.2. test strains

The test strain for the dynamic biofilm model used was a Staphylococcus aureus strain ATCC 29213 designated for biofilm formation. The strain was provided by the Hannover Medical School. 3. Evaluation

3.1 elution profile Table 7: Eluted Wirkstoffseinge from the catheter tubes with daily sampling

Fig. 1 shows the temporal of the ciprofloxacin hydrochloride-containing catheter tube of Example 6 (comparative example) and the ciprofloxacin (betaine) -containing catheter tube (according to the invention). The eluted amounts were summed up.

Table 8: Eluierte amount of active ingredient from the strand samples of Comparative Examples 7 to 11 with daily sampling

Table 9: Eluierte amount of active ingredient from the strand samples of Comparative Examples 12 to 16 with daily sampling 3.2 Biofilm formation

Only the catheter tubes from Examples 5 and 6 were tested to demonstrate the antimicrobial effect and to prevent biofilm formation on the materials.

Table 10: Germ number on the catheter tubing Significantly reduced or no bacterial colonization was detected in the ciprofloxacin hydrochloride-containing catheter tubes of the comparative sample and in the ciprofloxacin betaine-containing catheter tubes according to the invention. 3.3 Discussion of Results The Dynamic Biofilm Model provides evidence of biofilm formation or evidence of prevention of biofilm formation by the antimicrobial effect of a material or a finished catheter.

With the experimental design, the natural situation of the catheter in the skin can be approximated.

The following factors can be approximately simulated:

• The medium contains all factors for bacterial growth according to the tissue fluid of the skin.

• The drug can be slowly released from the catheter into the environment and become antimicrobial there or directly on the catheter.

Significantly reduced or no bacterial colonization was detected in the ciprofloxacin hydrochloride-containing catheter tubes of the comparative sample and in the ciprofloxacin betaine-containing catheter tubes according to the invention. The temporal elution profile of the catheter tubes shows a markedly low profile for the ciprofloxacin betaine-containing catheter tube, i. Over time, this tube elutes significantly less drug than the ciprofloxacin hydrochloride-containing catheter tube. However, the biofilm studies surprisingly prove that colonization of the catheter tube surface is not detectable despite the significantly lower elution.

In the extrudates it is also clear that the dependence of the elution on the active substance concentration in the material is present (the higher the content, the higher the elution), but that the samples according to the invention elute significantly less active substance than the comparison samples. It follows that the samples of the invention with the same active ingredient content due to their lower elution rate significantly longer the catheter tube surface from bacterial colonization, ie biofilm formation, can protect.

Example 18

agar diffusion test

1st method

The antimicrobial study was carried out with the aid of the agar diffusion test.

1.1. test panels

Petri dishes 9 cm in diameter were cast with 18 ml of Mueller-Hinton agar according to NCCLS (Merck KGaA Darmstadt / Lot ZC217935 430).

1.2. bacterial suspension

From an overnight culture of the test strain Staphylococcus aureus ATTC 29213 on Columbia blood agar a suspension with the density of McFarland 0.5 in NaCl solution 0.85% was prepared. For the suspension, a "colony pool" of 3 to 4 colonies spotted with the inoculum was used.

1.3. assay

A sterile cotton swab is dipped into the suspension. The excess liquid is expressed at the edge of the glass. The swab is used to inoculate the Mueller-Hinton agar plate evenly in three directions at 60 ° each. Thereafter, the material platelets and test slides are placed on the test plate. The test plates were incubated at 37 ° C for 24 hours.

The antimicrobial effect of the samples was evaluated by means of inhibition sites. The plates punched out of the injection-molded plates are used.

Table 11: Microbiological activity in Agardifusion Test against Staphylococcus aureus ATTC 29213

The samples from Examples 12 to 14 according to the invention have smaller Hemmhöfe than the comparative samples from Examples 7 to 9. When comparing the material samples with each other can be made by means of Hemmhöfe a statement about the intensity or quantity of the released active ingredients. The results of the elution profiles are hereby confirmed. Example 19

Of the catheter tubes of Examples 5 (according to the invention) and 6 (Comparative Example) were each about 1 mm long piece cut in about 1 cm intervals. As described in Example 18 "Agar diffusion test plates were prepared. The catheter tube sections were placed with the cut surfaces on the agar plates. Subsequently, the test mixtures were treated further as in Example 18.

Figures 2 and 3 each show agar plates overgrown with Staphylococcus aureas ATTC 29213. Around the deployed catheter tube sections has formed a Hemmhof. FIG. 2: Sections of the catheter tubes from Example 5 (according to the invention), FIG. 3: Sections of the catheter tubes from Example 6 (Comparative Example) In the agar diffusion test, it can be seen that all Kather tubes result in a zone of inhibition and have antibacterial activity demonstrate. At the same concentration less active ingredient is eluted in the inventive catheter tube of Example 5 than in the catheter tube of Example 6. Thus, the catheter tube according to the invention remains significantly longer protected against Biofümbildung. In both tubes, it is also clear from the same Hemmhofdurchmesser all samples on a plate, that over the entire length of the catheter tubes, the drug is homogeneously distributed.

Claims

claims

1. molding compositions comprising at least one thermoplastically processable polymer and at least one partially neutralized active ingredient having antibacterial, antiprotozoal or antimycotic activity.

2. Molding compositions according to claim 1, characterized in that the partially neutralized active ingredient is an active substance with basic functionality and this basic functionality is partially neutralized with an acid.

3. Molding compositions according to claim 1, characterized in that the partially neutralized active ingredient is an active ingredient with acidic functionality and this acidic functionality is partially neutralized with a base.

4. Molding compositions according to claim 1, characterized in that the partially neutralized active ingredient is one with betaine or zwitterion structure and is partially neutralized with a base or acid.

5. Molding compositions according to one of claims 1 to 4, characterized in that one equivalent of basic functionality in the active ingredient with 0.01 to 0.95 equivalents of acid or an equivalent of acidic functionality in the active ingredient partially neutralized with 0.01 to 0.95 equivalents of base is.

6. Molding compositions according to one of claims 1 to 5, characterized in that the thermoplastically processable polymer is selected from the group consisting of thermoplastic polyurethanes, polyether block amides and copolyesters.

7. Molding compositions according to one of claims 1 to 6, characterized in that the active ingredient is ciprofloxacin.

8. Molding compositions according to claim 7, characterized in that the partially neutralized active substance with hydrogen chloride is partially neutralized ciprofloxacin.

9. Molding compositions according to one of claims 1 to 8, characterized in that the partially neutralized active substance (as non-neutralized active ingredient) is used in a concentration range of 0.5 to 2.0 wt .-% based on the molding composition. - -

10. Use of molding compositions according to any one of claims 1 to 9 for the production of moldings, in particular medical devices.

1 1. Medical devices, in particular central venous catheters, urotheraphy, hoses, shunts, cannulas, connectors, plugs or distributor taps containing a molding compositions according to any one of claims 1 to 9.