Antiseptic-containing silicone elastomers

Translation of description of equivalent WO 2007124855 A2

p0001Antiseptikahaltige silicone elastomers

p0002The invention relates to compositions containing silicone elastomers and antiseptics in a homogeneous distribution, methods for their preparation and their use in medical articles.

p0003Medical articles of plastics (eg catheters) are currently used in a variety of applications for diagnostic and therapeutic purposes. Central venous catheters are used for example in modern intensive care for invasive monitoring or treatment strategies, such as continuous hemofiltration. Urinary catheter are an essential component of modern medical care and are indispensable, for example in the treatment of urinary obstruction. Although modern medical products have improved the therapy of intensive care patients substantially, their application is associated with significant risks. The frequent use of plastic articles such as catheters has led to a dramatic increase in so-called polymer-associated infections. The main cause of polymer-associated infections are generally multiresistant nosocomial pathogens which adhere to the plastic surface of the article and then colonize (Urogenital infections, ed A. Hofstetter, Springer 1999, 241 -. 64).

p0004Catheter-associated infections now represent an important cause of morbidity and mortality of patients in intensive care Recent studies indicate that 70 -. 90% of nosocomial urinary tract infections with a Instrumentation (catheterization) associated urinary tract. After catheterization of the bladder occurs, for example at from 0.5 to 28% of patients on bacteriuria. The incidence of catheter associated urinary tract infection is dependent on the duration of catheterization and the age, sex and the disease condition (immunocompetence) of patients (Urogenital infections, ed A. Hofstetter, Springer 1999, 241 -. 64). The use of catheters but not only involves a high risk of infection for the patient, but also causes high therapeutic costs. Givens and Wenzel were able to show that nosocomial urinary tract infections increase the postoperative stay of a patient on average by 2.4 days and corresponding additional costs (J. Urol 1980 124: 646 - 4S.). The prevention of catheter associated infections therefore in modern medicine for both medical and economic reasons the highest priority.

p0005In addition to traumatic and thromboembolic complications are catheter-associated infections, including sepsis, a serious problem with the use of central venous catheters in intensive care. Numerous studies have shown that coagulase-negative staphylococci, the transient bacterium Staphylococcus aureus and various Candida species are the main causes of catheter-associated infections. This ubiquitously present on the skin microorganisms penetrate in the application of the catheter, the physiological skin barrier and thus reach the subcutaneous region and eventually into the bloodstream. Adhesion of the bacteria to the plastic surface is regarded as an essential step in the pathogenesis of foreign-body infections. Adhesion of the cutaneous organisms to the polymer surface of metabolically active proliferation of the bacteria begins with colonization of the polymer. This is accompanied by the production of a biofilm is caused by bacterial, excretion of extracellular glycocalyx. The biofilm supports adhesion of the pathogens and protects them from attack by certain cells of the immune system. In addition, the film forms an impenetrable barrier for many antibiotics. Extensive proliferation of the pathogenic microbes on the polymer surface may finally be followed by septic bacteraemia. Therapy of such infections requires removal of the infected catheter because chemotherapy with antibiotics would require supraphysiological.

p0006The incidence of bacterially induced infections with central venous catheters averages about 5%. Overall, central venous catheters for about 90% of all sepsis case in the intensive care unit are responsible. The use of central venous catheters therefore not only a high risk of infection for the patient, but also causes extremely high follow-up therapy costs (subsequent treatment, extended stays in clinics).

p0007By prophylactic measures such as hygienic measures (handling the catheter, training of staff) or routine endoluminal antibiotic applications the problems with urinary and central venous catheters can be solved only partially.

p0008A rational strategy for prevention of polymer-associated infections consists in the modi- fication of the polymeric materials used. The aim of this modification has the inhibition of

p0009already be bacterial adhesion and proliferation adherent bacteria, for causal

p0010to avoid foreign-body infections. This can be achieved eg microbially effective by incorporating a suitable anti-substance in the polymer matrix (eg antibiotics), provided that the active substance incorporated also from the polymer matrix in a controlled manner can diffuse out. An infection-resistant material should therefore have the following characteristics:

p00111) Broad spectrum of activity against the relevant in the corresponding catheter-associated infections microorganisms, particularly coagulase-negative staphylococci such as Staphylococcus aureus with central venous catheters and enterococcal, Proteus, Klebsiella, Enterobacter species with urethral catheters

p00122) Adequate duration of antimicrobial activity, said operating periods are required by more than 30 days

p00133) protection of the inner and outer surfaces of the materials

p00144) polymer modification should neither interfere with the biocompatibility (thrombogenicity, cytotoxicity) nor the mechanical properties (tensile strength, modulus, hardness) of the material.

p0015Methods for preparing antimicrobially modified polymers for medical applications are already known.

p0016From EP-A-0696604 will be apparent aliphatic thermoplastic polyurethane ureas which are hydrophilic by urea groups, but the bacterial adhesion and proliferation on the catheter surface can not be prevented. In EP A 1067974, EP A 0927222, EP A 1128724 and EP A 1128723 antibacterially effective thermoplastic compounds are described, the active ingredients are introduced in a sufficiently fine and homogeneous distribution in the by high-viscosity processing techniques. As Comparative experiments have shown, the shear forces in the extruder, however, are not sufficient to achieve the required distribution of the powdered ingredients in the silicone phase solid rubbers, which are used for the manufacture of catheter tubes.

p0017Polymer materials for medical applications, the agent-containing coatings aufwei- sen, are also mentioned in EP A 328 421. are described processes for preparing the antimicrobial coatings as well as methods for application to the surfaces of medical devices. The coatings consist of a polymer matrix, in particular from polyurethanes, silicones or biodegradable polymers, and an antimicrobially effective substance, preferably a synergistic combination of a silver salt (silver Sulfathiazin) with chlorhexidine or an antibiotic. In this publication are combinations of different polymers, including silicones, described with antibiotics. On the difficulties in the incorporation of powdery substances in silicone rubbers but will not be discussed. The inventive method is not described in this document.

p0018In the European Patent EP A 0,688,564 active ingredient-containing silicone elastomers are described, whose delivery rate can be controlled by the cross-linking density. The special one

p0019Importance of particle size of active ingredients in silicone elastomers and how to reach them No mention. Furthermore, the release of active ingredients supporting additives is described, is deliberately to the present in the invention.

p0020In the US patent 4,230,686 (Schöpflin et al) are room temperature crosslinking (RTV) silicone elastomers described containing nonionic, lipophilic active ingredients. According to this specification (column 5, line 57 to 59) are those of silicone elastomers suitable as active substance carriers for slow release lipophilic, non-ionic agents. It is further described in column 7, lines 51 to 60 that the active ingredients are mixed as dry powders in the silicone elastomers. The particle size should be selected so that each water-soluble the active ingredient is, the greater the blended particles must be (4 to 400 .mu.m).

p0021The object of the invention to provide novel silicone elastomers, which are suitable for the production of medical moldings for temporary implants, in particular catheters, and for a longer period of time efficiently prevent (more than 30 days) a surface colonization by microorganisms.

p0022Moreover, it was an object of the invention to provide a method that the incorporation of active ingredients in fine distribution allows in silicone elastomers.

p0023Surprisingly, it has now been found that silicone elastomers of the invention, the antiseptics, and in particular those selected from the group of bispyridinium-alkanes, the polymeric Amidobiguanide, the quaternary ammonium compounds, in particular benzalkonium chloride and chlorhexidine, taurolidine and triclosan, with very small particle size (ca . 3 microns) contained several weeks resulted in a very good activity against bacterial colonization on catheter surfaces.

p0024A first subject of the invention are thus silicone elastomers containing at least an antiseptic agent in a homogeneous distribution, said antiseptic, in particular in the form of a suspension, a mean particle size d₅₀ from 0.5 to 15 microns, preferably between 1 and 10 microns, and a particle size distribution between 0.1 to 30 microns, preferably 0.5 to 20 microns has.

p0025The invention further the use of suspensions for interference of the antiseptic in the silicone rubber formulation in a preferred variant, the suspension medium is incorporated chemically into the silicone elastomer.

p0026The invention further relates to moldings that are produced by crosslinking the konkautschukformulierungen SiIi- invention. The invention also provides the use of the silicone elastomers according to the invention for the production of medical tubes, urinary catheter (Foley catheters, intermittent catheters, suprapubic and transurethral catheter), hemodialysis catheters, single and multi-lumen central venous catheter Peripheral catheter, thermodilution, balloon catheter for percutaneous transluminal coronary angioplasty (PTCA).

p0027Another object of the present invention are medical devices, especially catheters, can be prepared from the silicone elastomers of the invention.

p0028Another object of the present invention is a process for preparing the silicone rubbers according to the invention comprising providing a subsequently described silicone rubber formulation and the polymerization of said silicone rubber formulation. The silicone rubber formulation is a further object of the present invention.

p0029The silicone rubber formulation according to the invention comprises the following components:

p0030A) at least one polysiloxane of the formula (I)

p0031^ ^ R'R SiCMSiRVO- SiR'R ^ (I),

p0032wherein the radicals

p0033R¹ and R² each may be the same or different, and each represents <img id="imgf000006_0001" he="5" wi="23" file="imgf000006_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" /> Ci-Cπ-fluoroalkyl, and optionally substituted phenyl or naphthyl,

p0034R³ and R⁴ each may be identical or different, expressly including each repeating unit, and each represents C Cπ-alkyl, Ci-C_l2Fluoroalkyl and optionally substituted phenyl or naphthyl, in addition also for --OSiR²R³R, wherein R symbolizes the continuation of the siloxane chain analogue of formula (I) in the branching, so that the polymer molecular branching units of the formula SiO_4Z2 and R³SiO_3Z2 may include

p0035R¹ and R³ In addition, independently of one another stand for Ci-Cn alkenyl, wherein the polymer comprises from 0.0002 to 3 wt .-% of vinyl groups, and the molecule has at least two olefinically unsaturated multiple bonds has,

p0036x is an integer from 2 to 15,000 stands and is varied so that the viscosity of the polymer from 0.1 to 1000 Pas at 25 ° C ranges, B) optionally at least one filler having a specific surface area between 50 and 500 m²/ G by BET,

p0037C) optionally at least one filler having a specific surface area below 50 m²/ G by BET,

p0038D) optionally at least one further auxiliary material,

p0039E) optionally at least one saturated water repellents from the group consisting of disilazane, siloxanediols, alkoxysilanes silylamines, silanols Acetoxysiloxanen, acetoxy, chlorosilanes, chlorosiloxanes and alkoxysiloxanes

p0040F) optionally at least one unsaturated hydrophobicizing agent from the group consisting of multiply vinyl-substituted Methyldisilazanen, and methylsilanols and

p0041Alkoxysilanes each having unsaturated radicals from the group consisting of alkenyl, alkenyl aryl, acrylic and methacrylic,

p0042G) optionally at least one non-functional polysiloxane,

p0043H) optionally at least one inhibitor for the hydrosilylation reaction,

p0044I) at least one polyhydrogensiloxane of formula (E)

p0045R ^ R ^ SiO ^ SiR ^ R ^ O KSiR²¹! *²^ (II),

p0046wherein the substituents

p0047R²¹ and R²² each may be identical or different, and each represents C Cπ-alkyl, Ci-Cπ-fluoroalkyl, and optionally are substituted phenyl or naphthyl,

p0048R²³ each specifically is independently in each repeating unit is hydrogen, Ci-Cn-alkyl, CPCN-fluoroalkyl and optionally substituted phenyl or naphthyl, in addition also for --OSiR²³R²⁴R, wherein R is the continuation of the siloxane chain analogue of formula (IT) symbolized in the branching, so that the polymer molecular branching units of the formula SiO ^ and R²³SiO_3/2 may comprise, where R²³ this Silyldioxyleinheiten is in at least 4 represents hydrogen, so that disposes a molecule at least 4 cross-linking sites,

p0049R²⁴ case expressly including each repeating unit independently represents C)₂Alkyl, Ci-Cn-fluoroalkyl, and optionally substituted phenyl or Naphthyl, in addition also for --OSiR²³R²⁴R, wherein R symbolizes the continuation of the siloxane chain analogue of formula (D) in the branching, so that the polymer molecular branching units of the formula SiO_4/2 and R²³SiO_3Z2 may include

p0050x is an integer from 4 to 10,000, and is available is varied so that the viscosity of the polymer ranges from 0.0005 to 0.1 Pas at 25 ° C,

p0051J) at least one catalyst containing an element of the platinum group,

p0052wherein up to 3 parts by weight of metal compounds such as oxides and / or carbonates and other salts and complex compounds of Fe, Al, Zn, Ti, Zr, Ce or other lanthanides based on 100 parts by weight of component A) are present,

p0053K) at least one suspension, the suspension medium polysiloxanes of the formula (I) and / or (II) and / or non-functional siloxanes G) and at least one antiseptic in particular those selected from the group of bispyridinium-alkanes, the poly- meric Amidobiguanide , the quaternary ammonium compounds, in particular benzalkonium chloride and chlorhexidine, taurolidine and triclosan contains.

p0054Bispyridinium alkanes

p0055Active compounds in principle all defined in the DE 27 08 331 C2 in the claims 1 to 4 on page 28 substances in question. (L, 10-decanediyl) bis [- preferably its hydrochloride, the dihydrochloride l, l ', the compounds from Examples 1-82 (p 5 to page 18 line 19), more preferably is octenidine, or very particularly preferably 4- (octylamino) pyridine- ium] dichloride used.

p0056These as bis [4- (substituted-amino) -l-pyridinium] alkanes designated active substances are defined by the general formulas (III) and (FV)

p0057<img id="imgf000008_0001" he="53" wi="92" file="imgf000008_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" /> in which

p0058Y is an alkylene group having 4 to 18 carbon atoms,

p0059R is C₆-C] 8 alkyl, C₅-C₇Cycloalkyl or is phenyl substituted by a halogen atom and

p0060A two monovalent or one divalent anion.

p0061Y stands preferably for 1,10-decylene or 1,12-dodecylene, more preferably 1,12-dodecylene.

p0062R is preferably n-hexyl, n-heptyl or n-octyl, particularly preferably represents n-octyl.

p0063A is, for example a sulfate, 2 each fluoride, chloride, bromide, iodide, or methane sulfonate ion, preferably for 2 fluoride, chloride, bromide, more preferably 2

p0064Chloride ions.

p0065The formula (IV) refers to the corresponding free bases, which can be prepared by neutralization of the salts of formula (HI) according to standard methods of organic chemistry. The salts of formula (III) are in the literature often also in the form of the formula (V)

p0066Formula (IV) x H₂A (V),

p0067where "formula (IV)" and A are defined as stated above. Naturally is a chemical formula tautomers only a simplified representation of reality. In this case there are dew, for which there is no evidence that this under customary conditions and temperatures are distinguishable. For octenidine dihydrochloride there are still depending 2 Chemical Abstracts registry numbers and 2 numbers in the European existing chemicals. For the invention it is not relevant whether the compounds of formula (U) or the formula (V) are used or salts of formula (III) or (V). Preferably, the form in which they are present in the polymer composition.

p0068polymers Amidobiguanid

p0069The erfϊndungsgemäss to be used Aminopropylbiguanide have in particular the formula VI, <img id="imgf000010_0001" he="25" wi="141" file="imgf000010_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="yes" />

p0070wherein n is an integer between 1 and 500, as well as salts of compounds of formula VI can be used, in particular the salts thereof.

p0071The compounds of formula VI are known. Their preparation is described for example in GB 702.268 and GB 1,152,243. Moreover, these compounds are also commercially available, eg as Vantocil ™, Cosmocil ™ or Arlagard ™ E from ICI Chemicals.

p0072The compounds of formula VI can, depending on their method of production comprise certain proportions of a by-product of the formula VII,

p0073<img id="imgf000010_0002" he="23" wi="152" file="imgf000010_0002.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" /> (VII)

p0074or salts thereof, wherein n is a whole also means number between 1 and 500th Mixtures of compounds of formula VI with those of the formula VE erfϊndungsgemäss can also be used. The proportion of compounds of the formula VII, based on the total amount of compounds of formula VI and compounds of formula VE, is preferably less than 20 weight percent, more preferably less than 2 to 10 weight percent, and is more preferably zero percent by weight.

p0075The subscript n in formulas VI respectively VE is preferably 1 to 200, particularly 2 to 100, particularly preferably 2 to 50 and most preferably 3 to 12. Depending on the importance of the index n in the formulas VI or VII, the molecular weight of the usable aminopropyl biguanide as low as that molecular weight of the monomers of formula VI (n = 1), or in the range of about 600 to 1,600, if the oligomers are used, that is, when n is, for example 3 to 8, or even in the range of about 50 000 to about 90 000, if n is significantly higher values, for example for about 270 to 500th

p0076Suitable salts are those with inorganic or organic acids, for example hydrochlorides, hydrobromides, borates, acetates, gluconates, sulfonates, maleates, ascorbates, tartrates or citrates. The antiseptics are preferably incorporated in a concentration corresponding to their antimicrobial activity in the silicone rubber formulations of the invention. The antiseptics are usually used in a concentration range of 0.01 to 10.0 wt .-%, preferably 0.05 to 5 wt .-%, particularly preferably 0.1 to 5 wt .-% in the silicone elastomers used.

p0077In the present invention, component A) by at least one linear or branched polysiloxane of the of the general formula given above (I) is defined.

p0078<img id="imgf000011_0001" he="7" wi="91" file="imgf000011_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0079R¹ and R² each may be the same or different, and are each preferably CJ Cπ-alkyl, Ci-Ci₂Fluoroalkyl, and optionally one or more times by F, Cl, CF₃, Cj-Cβ- alkyl, C_rC₆Alkoxy, C₃-C₇Cycloalkyl, C₂-C₆Alkenyl or phenyl substituted phenyl or naphthyl.

p0080R³ and R⁴ may each be identical or different, expressly including each repeating unit, and each preferably represents Ci-Cπ-alkyl, Ci-C₁₂Fluoroalkyl, and optionally one or more times by F, Cl, CF₃, C₆-alkyl, C₆Alkoxy, C₃-C₇- Cycloalkyl, C₂-C₆Alkenyl or phenyl substituted substituted phenyl or naphthyl.

p0081R¹ and R³ are preferred in addition independently for Ci-C]₂Alkenyl, wherein the polymer comprises from 0.0002 to 3 wt .-% of vinyl groups, and each molecule has at least two olefinically unsaturated multiple bonds has.

p0082x is preferably an integer from 2 to 15,000, and is varied so that the

p0083Viscosity of the polymer from 0.1 to 1000 Pas at 25 ° C is sufficient.

p0084R² to R⁴ more preferably are Ci-Ci₂Alkyl.

p0085R¹ particularly preferably represents vinyl.

p0086R² to R⁴ very particularly preferably methyl.

p0087The viscosity of component A) is preferably 0.1 to 30,000 Pa s.

p0088In the present invention, the component B) has the meaning of a filler having a specific surface between 50 and 500 m²/ G according to BET. It is expedient to reinforcing fillers. Reinforcing means that the mechanical Improved strength properties, particularly the tensile strength, tear strength, etc. can be improved. The reinforcing fillers are advantageously added in a form which affects the electrical properties of the cured inventive mixtures positive or at least not deteriorated. This is for example the addition of precipitated or pyrogenic, preferably pyrogenic, silica having a BET surface area of ​​50 to 500 m²/ G achieved (The BET surface area is determined according to S. Brunauer, P H. Emmett, E. Teller, J. Am. Soc. 60.309 (1938)).

p0089The fillers may be hydrophobic or hydrophilic fillers. The fillers B) can oberflächenmodifϊziert, ie hydrophobic, to be, for example with organosilicon compounds. The modification may take place before or during the compounding of the silicone rubber formulation of the invention.

p0090Preferably, the hydrophobicization is carried out with the components e) and / or F) if appropriate with addition of water. Preferably, the hydrophobic treatment with saturated or unsaturated disilazane and methylsilanols that can be generated from the disilazane if necessary, in accordance with the definition of components E) or F) is carried out.

p0091Preferred ranges of BET surface area of ​​the filler B) are from 50 to 400, more preferably 150 to 300 m²/G. The amount of component B) is suitably 0-75 parts by weight per 100 parts by weight of component A), preferably 20 to 50 parts by weight.

p0092In the present invention, the component C) is a filler having a specific surface area below 50, preferably below 40 more preferably below 30 m²/ G according to BET. Suitably it concerns so-called "non-reinforcing fillers" that does not improve the mechanical properties, especially tensile strength, tear resistance, etc.. It is preferable to diatomaceous earths, finely divided quartz or. Cristobalite, other amorphous silicas or silicates. The amount the component C) is suitably between 0 and 300 parts by weight per 100 parts by weight of component A), preferably 0 to 50 parts by weight.

p0093In the present invention the term "excipient suitably includes' according to component D), pigments, release agents, extrusion aids, and hot-air stabilizers, stabilizers against hot air aging ie a. Conveniently, the release agent from the group of mold release agents such as stearyl derivatives or waxes, metal salts of fatty acids are selected. Extrusion agents are boric acid or PTFE pastes. Hot stabilizers are for example, metal compounds such as oxides and / or carbonates as well as further salts and complex compounds of Fe, Al, Zn, Ti, Zr, Ce or other lanthanides and antioxidant. The amount of component D) is suitably between 0 and 10 parts by weight per 100 parts by weight of component A), wherein the presence of more than 3 parts by weight, preferably more than 2 parts by weight of metal compounds such as oxides and / or carbonates and other salts and complex compounds of Fe, Al, Zn, Ti, Zr, Ce or other lanthanides with exception of.

p0094Preferably, the Silikonkautsehukformulierung invention contains no metal compounds such as oxides and / or carbonates as well as no weitereren salts and complex compounds of Fe, Al, Zn, Ti, Zr, Ce or other lanthanides.

p0095In the present invention, the component E) is a saturated water repellents from the group consisting of disilazane, siloxanediols, alkoxysilanes silylamines, silanols Acetoxysiloxanen, acetoxy, chlorosilanes, chlorosiloxanes and alkoxysiloxanes. The component E) serves to hydrophobilize the fillers C) and preferably B). The hydrophobicization can be carried out separately before the compounding or during compounding in situ. The amount of component E) is suitably based on 100 parts by weight of B), 0 to 30 parts by weight, preferably 2 to 25th

p0096In the present invention, the component F) is an unsaturated hydrophobicizing agent from the group consisting of multiply vinyl-substituted Methyldisilazanen, and methylsilanols and alkoxysilanes each having unsaturated radicals from the group consisting of alkenyl, alkenylaryl, acryl and methacryl. The component F) also serves hydrophobicizing the fillers B) and C). The amount of component F) is appropriately based on 100 parts by weight of A), 0 to 2 parts by weight, preferably 0.01 to first

p0097The total amount of components E) and F) based on the total amount of components B) and C), preferably based on B), is preferably from 5-25 wt .-%.

p0098As part of the present invention is meant by the term "non-functional polysiloxanes" according to component G) suitably low molecular weight, in terms of hydrosilylation lierungsreaktion, not functional, not curable, preferably trimethylsilyl-end-capped polysiloxanes with dimethyl, diphenyl or Phenylsilyloxy groups having degrees of polymerisation of 4-1000 leading to the molded body, the surface of the insulators reliably hydrophobize after crosslinking, for example as described in EP A 0,057,098. the amount of component G) is advantageously based on 100 parts by weight of A), 0 to 15, preferably 1 to 3 parts by weight.

p0099In the present invention, the term "addition reaction inhibitor for the hydrosilylation" in accordance with the H) component, all known from the prior art inhibitors for the hydrosilation reaction with metals of the Pt group, such as maleic acid and its Derivatives, amines, azoles, Alkylisocyanurate phosphines, phosphites and acetylenically unsaturated alcohols in which the OH group at a CC triple bond adjacent carbon atom is bonded, such as are described in more detail in US 3,445,420. Preferably, when G) component to 2-methyl-3-butyn-2-ol or 1- ethynylcyclohexanol or (±) 3-phenyl-l-butyn-3-ol. The component H) is preferably used in an amount ranging from 0 to 1 parts by weight based on 100 parts by weight of the sum of A) to I). Preferably, the H) component in an amount ranging from 0.0001% to 2% by weight, more preferably, 0.01% by weight to 2% by weight and most preferably 0.05 wt% to 0 5% by weight, each based on the total weight of the mixture.

p0100In the present invention, the component I) with at least one poly is polymethyl hydrogen that has at least two directly bonded to different silicon atoms are hydrogen atoms, defined as indicated above general formula (II). In it are the following radical definitions:

p0101R ^ R ^ R ^ ^ SiCMSiR O kSiR²¹! *²^ (II),

p0102R²¹ and R²² may each be the same or different and preferably each represents Q- Cπ-alkyl, C_]-C₂fluoroalkyl, _U.N(j optionally substituted phenyl or naphthyl.

p0103R²³ preferably each expressly also in each repeat unit are independently hydrogen, alkyl CpCπ, CPCN-fluoroalkyl, and optionally substituted phenyl or naphthyl, where R²³ this Silyldioxyleinheiten is in at least 4 represents hydrogen, so that disposes a molecule at least 4 cross-linking sites.

p0104R²⁴ preferably each case expressly including each repeating unit independently Ci-Cπ-alkyl, Ci-Cn-fluoroalkyl and optionally substituted phenyl or naphthyl.

p0105x is preferably an integer from 4 to 10,000, and is varied so that the viscosity of the polymer 0.0005 to 0.1 Pas at 25 ° C is sufficient.

p0106In component I) preferably is the molar fraction of bonded directly to a silicon atom of hydrogen atoms between 0.01 and 10 mmol / g, more preferably between 0.5 and 9 mmol / g and very particularly preferably between 1 and 7 mmol / g.

p0107The amount of component I) is preferably 0.2 to 30, preferably 0.2 to 20 parts by weight based on 100 parts by weight of component A). Component J) is a catalyst comprising at least one element of the platinum group.

p0108Preferably, the component J) is a catalyst which catalyses the hydrosilylation reaction and is selected from metals of the platinum group such as Pt, Rh, Ni, Ru, and compounds of platinum group metals, such as salts or complex compounds thereof. Furthermore, the component J) is preferably a catalyst containing an element from the platinum group selected from platinum and platinum compounds which can be coated on a support, where appropriate, as well as other compounds of elements of the platinum group. Platinum and platinum compounds are most preferred. Thus, preferably Pt salts, Pt complex compounds with nitrogen used, phosphorus and / or alkene compounds or Pt metal on carriers. Preference is given to all Pt (O) - and Pt (g) compounds, preferably Pt-olefin complexes and platinum vinylsiloxane are complex. Particularly preferred are Pt-vinylsiloxane complexes, Pt-vinyldi- and tetrasiloxan- complexes which have preferably in the siloxane of at least 2 or 4 olefinically unsaturated double bonds (see for example US 3,715,334). The term siloxane fall in this connection polysiloxanes or polyvinylsiloxanes.

p0109In addition, can also be a reaction product of reactive platinum compounds with the inhibitors H) component J).

p0110The amount of component J) in the formulation according to the invention is preferably, based on the total amount of components A) to I), 10 to 100 ppm, preferably 15 to 80 ppm and very particularly preferably 20 to 50 ppm calculated on the metal of the platinum group in of component J). Preferably, the silicone rubber formulations containing 20 to 100 ppm Pt, based on the amount of components A) to J), in the form of Pt salts, Pt complex compounds with nitrogen, phosphorus and / or alkene compounds or Pt metal on carriers.

p0111The active substance suspension K) is on the one preferred from polysiloxanes of the formula given above (I) as suspension agent. In it are the following radical definitions

p0112R¹R²₂SiO- (SiR³R⁴O-)_xSiR¹R²2 (I),

p0113R¹ to R⁴ independently of one another particularly preferably each represent methyl, and vinyl, wherein said polymer comprises from 0.0002 to 3 wt .-% of vinyl groups, and each molecule has at least two olefinically unsaturated multiple bonds.

p0114x is particularly preferably varied so that the viscosity of the polymer from 0.1 to 1,000

p0115Pas at 25 ° C is sufficient. The suspension K) for the other at least one antiseptic selected from the group of bispyridinium-alkanes, the polymeric Amidobiguanide, the quaternary ammonium compounds, in particular benzalkonium chloride and chlorhexidine, taurolidine and triclosan is dispersed in an average particle size d₅₀ from 0.5 to 15 microns, preferably between 1 and 10 microns, and a particle size distribution between 0.1 to 30 microns, preferably 0.5 to 20 microns.

p0116The powdery antiseptics are typically supplied in a micronized form. In order to interfere in the silicone rubbers, they are previously brought into a suspension in a suitable medium. It is important to ensure that the medium has good solubility in the silicone elastomer. For this purpose, commercially available silicone oils in one embodiment of the invention (R 'and R "is alkyl), vinyl-terminated polydimethylsiloxanes (R¹ is vinyl; R¹ is methyl) or Polyhydrogensiloxane (R¹ is H; R 'is methyl) in question, the viscosities from 100 to 1,000,000 mPas, preferably 100 to 500,000 mPas at 25 ° C, have. For the fitness is crucial that the drug / medium mixture can be sufficiently finely homogenized in the bead mill.

p0117In a preferred variant, at least one vinyl group-terminated silicone polymer is used as a suspension medium that is chemically incorporated in the subsequent cross-linking reaction in the silicone elastomer. This can not be leached into the surrounding body tissue or a body fluid, the suspension medium with the use of the silicone elastomer. For example vinylgruppenterminierte silicone polymers as polymer VS 200 (η (25 ° C) = 200 mPas; vinyl group content 0.25 mmol / g), Polymer VS 1000 (η (25 ° C) = 1000 mPas; Vinyl groups content 0.11 mmol / g), or polymer VS 165,000 (η (25 ° C) = 165.000 mPas; vinyl group content 0.015 mmol / g), obtainable from Hanse-Chemie.. From other vendors such as Dow Corning (Syl-Off^® 7673: η (25 ° C) = 425 mPas) or Wacker Silicones (Dehesive^® 920: η (25 ° C) = 500 mPas) or (Dehesive^® 924: η (25⁰C) = 200 mPas), offered similar products.

p0118"Expressly including each repeating unit" means that deviation from the exact definition of the corresponding formula, for example, at the indicated repeating units of the polymer of formula (I) employed in this invention in one molecule each individual x times occurring R³ or R⁴ may be each independently selected from the specified definitions and their areas of preference, ie the radicals occurring in one molecule may be the same or different.

p0119Ci-Ci₂Alkyl in the present invention, aliphatic hydrocarbon radicals having 1 to 12 carbon atoms which may be straight or branched. Example- which may be mentioned methyl, ethyl, propyl, n-butyl, pentyl, hexyl, heptyl, nonyl, decyl, iso-propyl, neopentyl, and 1,2,3-trimethylhexyl.

p0120Ci-Ci₂Fluoroalkyl means aliphatic hydrocarbon radicals having 1 to 12 carbon atoms which may be straight or branched and are substituted with at least one fluorine atom in the context of the present invention.

p0121Examples include perfluoroalkyl ethylene, 1, 1, 1-trifluoropropyl, 1,1,1-trifluorobutyl listed, preference is trifluoropropyl.

p0122Substituted phenyl in the present invention, unsubstituted or mono- or polysubstituted by F, Cl, CF₃, C_rC₆Alkyl, C_rC₆Alkoxy, C₃-C₇Cycloalkyl, C₂-C₆Alkenyl or phenyl substituted phenyl, preferably phenyl.

p0123The polymerization of the silicone rubber formulations according to the silicone rubbers according to the invention can in principle be at any temperature customary for this purpose. Preferably, the polymerization takes place at or in the vicinity of room temperature (20 to 25⁰C).

p0124From the literature, for example the product brochure "The platinum catalyzed addition crosslinking with Elastosil® R plus" of Messrs. Wacker, it is known that inter alia amines affect platinum catalyst in its activity in the crosslinking.

p0125Surprisingly it has been found, however, that in the platinum-catalyzed cross-linking of the silicone rubber formulations according to the invention despite the presence of amine groups of the platinum catalyst retains its activity. On the silicone rubber formulations made from the silicone rubber according to the invention the same mechanical properties as on the antiseptikafreien comparative samples were detected.

p0126In principle, formulations can contribute to the preparation of the silicone rubbers according to the invention except the above-described platinum-catalyzed at room temperature crosslinking silicone rubber formulations also thermosetting (HV) are used, the catalysts based curing such as benzoyl peroxide or di-p-chlorobenzoyl peroxide at temperatures of about 200⁰C be cured and a heat treatment need. Such silicone elastomers can be prepared 2,541,137 or 3,002,951 according to the US-patents.

p0127In addition, so-called one-component silicone rubber formulations can be used to prepare the silicone rubbers according to the invention which cure at room temperature under exposure to atmospheric humidity without any further addition. This one-component formulations comprise mainly organopolysiloxanes having two terminal acyloxy, such as acetoxy groups which hydrolyze to form trifunctional siloxane units in the presence of moisture and act in the polymer as a crosslinking agent with formation of elastomers.

p0128The platinum-catalyzed cross-linking at room temperature silicone rubber, however, are preferred in the context of the present invention, since in the case of HV-silicone rubber systems, the active substances used could be chemically modified in the required high curing temperature and the use of peroxide catalysts. Moreover, in the case of HV silicone rubber systems remaining in the elastomer catalyst residues may be responsible for toxic reactions in the body.

p0129The conventional moisture-curing silicone rubber formulations columns at room temperature under the influence of atmospheric moisture as a byproduct of the vulcanization acetic acid from the unwanted side reactions can form the active ingredient employed.

p0130In a preferred Ausftihrungsform the invention further relates to the silicone rubber formulations described above, wherein

p0131the polysiloxane A) is a polysiloxane of formula (I)

p0132R'R ^ ^ O SiCMSiR kSiR'R²! (I)

p0133wherein the radicals

p0134R¹ and R² each may be identical or different, and each represents C Cπ-alkyl, Ci-Cπ-fluoroalkyl, and optionally are substituted phenyl or naphthyl,

p0135R³ and R⁴ each may be identical or different, expressly including each repeating unit, and each Cj-Cπ-alkyl, Ci-Ci₂Fluoroalkyl and optionally substituted phenyl or naphthyl,

p0136R¹ and R³ In addition, independently of one another stand for CpCπ-alkenyl, wherein the polymer comprises from 0.0002 to 3 wt .-% of vinyl groups, and the molecule has at least two olefinically unsaturated multiple bonds has,

p0137x is an integer from 2 to 15,000 stands and is varied so that the viscosity of the polymer from 0.1 to 1000 Pas at 25⁰C ranges,

p0138a filler B) having a specific surface between 50 and 400 m²/ G is used according to BET,

p0139the polyhydrogensiloxane I) of the formula (II) R²¹R²²₂SiO- (SiR²³R²⁴O -), SiR^2IR²²₂ (II)

p0140wherein the substituents

p0141R²¹ and R²² each may be the same or different, and are each Ci-C₁₂Alkyl, Ci-Ci₂Fluoroalkyl, and optionally substituted phenyl or naphthyl,

p0142R²³ case expressly including each repeating unit is independently hydrogen, Ci-Ci₂Alkyl, CPCN-fluoroalkyl, and optionally substituted phenyl or naphthyl, where R²³ this Silyldioxyleinheiten is in at least 4 hydrogen so that a molecule has at least 4 crosslinking sites has,

p0143R²⁴ each specifically is independently in each repeating unit for Ci-Cn-alkyl, Ci-Cπ-fluoroalkyl and optionally substituted phenyl or naphthyl,

p0144x is an integer from 4 to 10,000, and is available is varied so that the viscosity of the polymer ranges from 0.0005 to 0.1 Pas at 25 ° C,

p0145the catalyst from the platinum group J) is a catalyst which catalyses the hydrosilylation reaction and is selected from metals of the platinum group such as Pt, Rh, Ni, Ru, and compounds of platinum group metals, such as salts or complex compounds thereof,

p0146is used for the suspension K), at least one polysiloxane of the formula (I) according to A) as a suspension medium, wherein the substituents R¹ to R⁴ each methyl and vinyl radicals, so that the polymer contains from 0.0002 to 3 wt% of vinyl groups, and the molecule has at least two olefinically unsaturated multiple bonds grouted, and x varies so that the viscosity of the polymer from 0.1 to 1,000 Pas at 25 ° C ranges,

p0147and the suspension K) at least one antiseptic selected from the group of Bispy- ridinium-alkanes, the polymeric Amidobiguanide, the quaternary ammonium compounds, in particular benzalkonium chloride and chlorhexidine, taurolidine and triclosan, which contains, which in each case an average particle size dso of 0 , from 5 to 15 microns, preferably between 1 and 10 microns, and a particle size distribution between 0.1 to 30 microns, preferably 0.5 to 20 microns contains. Preferred, particularly preferred or very particularly preferred embodiments, which make use of under preferred, particularly preferred or very particularly preferably mentioned parameters, compounds, definitions and explanations.

p0148The general or in preferred ranges Defϊ- listed in the description definitions, parameters, compounds and explanations can, however, also with one another, ie between the respective ranges and preferred ranges are combined arbitrarily.

p0149Polymeric additives such as polyvinylpyrrolidone or polyethylene glycol may be silicone rubbers up to a concentration of 5 wt .-% admixed in principle. In a preferred embodiment of such release to the surface influencing additives will be omitted.

p0150For the preparation of the suspension K) customary dissolvers are used, which are used as a bead mill. Ingredient, suspending medium and beads are placed in the tempering vessel. In the total volume of 1/3 glass beads are additionally added. Instead of glass beads, other grinding media can be used, for example, from zirconium oxide.

p0151The concentration of the active ingredient in the suspension K) is 10 to 40 wt .-%, preferably 15 to 35 wt .-%. The ground material can to 100⁰C be heated to adjust the appropriate viscosity for grinding. However, in principle, the lowest possible temperature to favor the processing of the drug to perform as gently as possible.

p0152The suspensions K) are used for example on a roll mill into the silicone rubber matrix works. For this purpose, they must not be too low, since they flow away too easily. For highly viscous pastes there is a risk that they can no longer be homogeneously incorporated into the silicone rubber.

p0153Therefore, the inventive suspensions K) should have at room temperature viscosities of 10,000 mPas to 2,000,000 mPas. Such thereof are suitable for use for the method according to the invention preferably adapted to the viscosities at 25 ° C from 20 thousand to 1 million mPas, particularly preferably from 50,000 to 500,000 mPas.

p0154In the inventive suspension K), the active ingredients typically have a mean particle size d₅₀ from 0.5 to 15 microns, preferably between 1 and 10 microns, and a particle size distribution between 0.1 to 30 microns, preferably 0.5 to 20 microns. Furthermore, the suspensions produced K) several weeks remain stable in this range of viscosity and do not sediment. In additional dispersing aid can be dispensed with.

p0155In the drug-containing silicone rubber mixtures according to the invention preferably should the components A) + B) + K) and I) are present in a proportion such that the molar ratio of directly to a silicon atom bonded hydrogen (SiH) in the component I) to unsaturated groups in the components A), F) and K) between 0.1 and 20, preferably between 0.8 and 10 and very particularly preferably 1 to 5

p0156The silicone rubber formulations of the invention comprise the components A) to K), wherein the components B) to H) are optionally present. Preferably, the erfϊndungs- according silicone rubber formulation contains, in addition to the necessary components A), I), J) and K), the component G).

p0157In the case of rubber formulations according to the invention, the components A), polysiloxanes of the formula (I) can, and I), Polyhydrogensiloxane of formula (II), partially or completely in the component K), the suspension may be contained as a suspension medium. This also separate formulations without further components A) and / or I) are detected in accordance with the invention.

p0158The invention further relates to a process for the preparation of the inventive silicone rubber formulations, which is characterized in that initially the components A) to J) were combined and mixed, and K) is then added and incorporated.

p0159The suspension K) is added to the silicone rubber compositions on the roll mill, in a kneader or in an extruder. In a preferred embodiment, the two components are premixed and then added the active ingredient suspension in 2-component systems composted.

p0160Preferably, the preparation of the silicone rubber formulations according to the invention, in which adding the hydrophobicizing agent optionally used E) and F) and optionally water to component A) and at temperatures of 20 to 160 is carried out⁰C under nitrogen atmosphere, the D) component (filler) interferes, thus causing the hydrophobicization of the filler D) under reaction with the components E) and F). Subsequently, excess reaction products E) and F), and volatile reaction products thereof (such as silanols, alcohols and water) is removed (preferably by heating at 150 to 170⁰C optionally under vacuum). In the resulting, preferably cooled mixture is metered in the case of a two-component formulation either the h) and i) component or, alternatively, J). If the components C), D) and G) is carried out requires the dosage thereof after removal of the volatile components E) and F). In the case of one-component H), I) and J) are metered in, first the inhibitor H) is added.

p0161The customary mixer used, such as internal mixers, screw mixers, kneaders, preferably kneaders.

p0162The inventive curable silicone rubber compounds can thereby be 1-, 2-or even multi-component systems. Multi-component systems include those which H), I) and J) separately contained.

p0163The following examples serve to illustrate the invention without any limiting effect,

p0164Examples

p0165Raw materials:

p0166Silicone solid rubbers for urinary catheter

p0167Door the silicone Foley catheter shaft production was a 50:50 A / B 2K platinum-catalyzed solid silicone rubber system 3097 / PA Fa. Degania used.

p0168A component: Vinyl group terminated polydimethylsiloxane; contains the components A), B) and J).

p0169Component B: polyhydrogensiloxane; contains the components B), G) and I).

p0170The quantity ratios of components A), B); G), I) and J) are set in the A / B-component so that the silicone elastomer has a Shore A hardness of 65th

p0171Silicone solid rubbers for pattern plates

p0172For the laboratory tests for the preparation of sample boards an IK platinum-catalyzed addition-solid silicone rubber Addisil 160 Fa. GE Bayer Silicones was used.

p0173suspension medium

p0174Polymer VS 1000: vinyl group terminated polydimethylsiloxane of the company Hanse-Chemie;. Viscosity / 25 ° C) = 1000 mPas; Vinyl content: 0.11 mmol / g

p0175agents

p0176Octenidine dihydrochloride was obtained as white powder having an average Patikeldurchmesser of 15 microns in a purity of> 98.5% of the Fa. PCAS, Turku, Finland, based.

p0177Vantocil hydrochloride (PHMB) was obtained as a light yellow crystalline powder of the Fa. Avecia. Before use, it was ground to give a colorless powder having an average particle size of 16 .mu.m was produced. Examples 1-2

p0178Preparation of drug suspension in Polymer VS 1000:

p0179For the preparation of the suspension of the Dispermat F was 105 of Fa. VMA Getzmann used. When grinding tool a plastic disc was used. The tempering Gefaß was heated with a thermostat of the Fa. Julabo HC.

p0180In a 250 ml tempering Gefaß 45 g vinyl-silicone polymer VS 1000 15 g of active ingredient (see table) and 20 ml of zirconium oxide weighed with a diameter of about 2.8 mm. The vessel is heated to 25 ° C and retracted the dissolver. The ground material is mixed for 20 minutes at 8000 / min. Thereafter, the zirconia beads are separated. There is obtained a white creamy paste. The average particle diameter was determined.

p0181<img id="imgf000024_0002" he="30" wi="149" file="imgf000024_0002.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0182<img id="imgf000024_0001" he="75" wi="128" file="imgf000024_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0183Particle size distribution of PHMB suspension of Example 2 by ultracentrifuge <img id="imgf000025_0001" he="80" wi="136" file="imgf000025_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0184Particle size distribution of the octenidine dihydrochloride suspension from Example 1 by ultracentrifuge

p0185example 3

p0186The thermal stability of Ocetnidindihydrochloridsuspension of Example 1 was determined by thermogravimetric analysis (TGA).

p0187<img id="imgf000025_0002" he="81" wi="134" file="imgf000025_0002.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0188TGA curve of the suspension from Example 1

p0189The suspension is up to at least 200⁰C thermally stable so that when incorporated into the silicone rubber at 17O⁰C performed crosslinking reaction can take place without problems of stability of the active ingredient or the suspending medium. Examples 4-7

p0190In a mixing mill of the company Vogt. (2 rolls; roll diameter 80 mm, roll width 280 mm; Working width 200 mm) were the solid silicone rubber Addisil 160 applied while cooling at room temperature. The front rotating drum was 16.5 min^'1, The rear roller with 20 min^'1 operated. For the interference of the active compounds then the amounts of the active ingredient suspension indicated in the table were added in the example 1 or 2 and as long as mixing continues until the suspension was incorporated homogeneously in the nip. Subsequently, the active substance-containing Silicone rubber was removed as a 2 mm thick skin from the roller.

p0191<img id="imgf000026_0001" he="37" wi="161" file="imgf000026_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0192<img id="imgf000026_0002" he="37" wi="161" file="imgf000026_0002.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0193Thereafter, the respective plates to cure (cross-linking) were added 2 hours at 170⁰C..

p0194example 8

p0195drug distribution

p0196By scanning electron micrographs with EDX coupling only the drug particles in the silicone elastomer matrix can be made visible by specific chloro-detection. Figures 1 and 2 show scanning electron micrographs of the silicone elastomer sample plates of Example 6 (1 wt .-% PHMB) and Example 7 (2 wt .-% PFMB) (PHMB agent particles shown in light). The images show that the active ingredient is homogeneously and very finely divided, about 1 to 5 microns sized particles dispersed in the silicone elastomer matrix. example 9

p0197Continuity of the surface protection of PHMB-containing silicone elastomer plates

p0198The elution was carried out with the active substance-containing Silicone elastomer plates from Examples 6 and 7, in the 1 cm² Large pieces were zerschnnitten The specimens weighed about 2.1 g and had a surface area of ​​about 22 or 25 cm², As elution 16 ml of demineralized water were used. After 1 h, 4 h, 8 h, 24 h, 48 h, 120 h and 360 h (15 days), the elution water was exchanged each against new and the drug determined content in the solutions.

p0199<img id="imgf000027_0001" he="72" wi="67" file="imgf000027_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0200Over the study period takes a diffusion of the active ingredient instead of the specimen surface, thereby ensuring a continuous surface protection against colonization by bacteria and yeasts.

p0201example 10

p0202Continuity of the surface protection of the octenidine dihydrochloride-containing silicone elastomer plates

p0203The elution experiments were performed with the plates in Examples 4 and 5, in the 1 cm² Large pieces were zerschnnitten. The specimens weighed about 2.0 g and had a surface area of ​​about 35 cm², As elution 16 ml of demineralized water were used. After 1 h, 4 h, 8 h, 24 h, 48 h, 120 h and 360 h (15 days), the elution water was exchanged each against new and the active ingredient content determined in the solutions. <img id="imgf000028_0001" he="72" wi="68" file="imgf000028_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0204Over the study period takes a diffusion of the active ingredient instead of the specimen surface, thereby ensuring a continuous surface protection against colonization by bacteria and yeasts.

p0205The samples give more than 15 days from small amounts of active ingredient, wherein the amount is far from a pharmacologically effective dose.

p0206example 11

p0207Microbiological evaluation of the samples from Examples 4-5

p0208Plaques were punched with about 5 mm in diameter from the drug-containing silicone elastomer boards of Examples 4 and 5, and sterilized by gamma radiation .. These sterile plaques were carried out the following microbiological tests.

p02091. method

p0210The study on the antibacterial activity was carried out using the Agardifrusionstestes.

p02111.1. test plates

p0212Petri dishes of 9 cm in diameter were cast with 18 ml Mueller-Hinton agar according to NCCLS (Merck KGaA Darmstadt / Lot ZC217935 430). 1.2. bacterial suspension

p0213From an overnight culture of test strain on Columbia blood agar, a suspension with density corresponding to McFarland 0.5 in NaCl solution. 0.85% hergestellt.Für the suspension was a "colony - pool" used from 3 to 4 by spotting the Impfbse colonies.

p02141.3. assay

p0215In the suspension, a sterile swab is dipped. The excess liquid is expressed at the glass edge. Using the pad, the Mueller-Hinton agar plate is inoculated evenly in three directions at angles of 60 °. Thereafter, the material samples are placed on the test plate. The test plates were incubated at 37 ° C for 24 hours. The antibacterial activity of the samples was evaluated at zones of inhibition.

p02162.2 Test strains

p0217As test strains was representative gram-negative rods, an MRSA (Staphylococcus aureus MRSA 1150-93) and a Candida species (Candida albicans ATCC 14053) selected.

p02183. results

p0219In the samples of Examples 4 and 5, a zone of inhibition could be detected. The active ingredient in the silicone material, thereby preventing bacterial growth.

p0220Particularly striking is the effect with respect to the sprouting Candida albicans.

p0221Figures 3 and 4 document the test result. Here, Figure 3 shows the inhibition zones of the samples of Example 4 (5217) and 5 (5219) against Candida albicans ATCC 14053, Figure 4 shows the inhibition zones of the samples of Example 4 (5217) and 5 (5219) against Staphylococcus aureus MRSA 1150-93

p0222example 12

p0223Microbiological evaluation of the samples from Examples 6-7

p0224From the drug-containing silicone elastomer boards of Examples 6 and 7 plaques were punched with about 5 mm in diameter and sterilized by gamma radiation .. These sterile plaques were carried out the following microbiological tests.

p02251. method

p0226The study on the antibacterial activity was carried out using the agar diffusion test. 1.1. test plates

p0227Petri dishes of 9 cm in diameter were cast with 18 ml Mueller-Hinton agar according to NCCLS (Merck KGaA Darmstadt / Lot ZC217935 430).

p02281.2. bacterial suspension

p0229From an overnight culture of test strain on Columbia blood agar, a suspension with density corresponding to McFarland 0.5 in NaCl solution. 0.85% hergestellt.Für the suspension was a "colony - pool" used from 3 to 4 by spotting the Impfbse colonies.

p02301.3. assay

p0231In the suspension, a sterile swab is dipped. The excess liquid is expressed at the glass edge. Using the pad, the Mueller-Hinton agar plate is inoculated evenly in three directions at angles of 6oo. Then samples of material are placed on the test plate. The test plates were incubated at 37o C for 24 hours. The antibacterial activity of the samples was evaluated at zones of inhibition.

p02322.2. test strains

p0233As test strains ATCC strains of three gram-negative rods, a Staphylococcus aureus, an MRSA strain and a Candida species were selected representative.

p02343. results

p0235<img id="imgf000030_0001" he="38" wi="131" file="imgf000030_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0236The antibacterial activity of the samples could be detected on the basis of the inhibition zones. Figures 5 to 8 document the results. Figure 5 shows the inhibition zones of the samples of Example 6 (5289) and 7 (5291) against Escherichia coli ATCC 35218th Figure 6 shows the inhibition zones of the samples of Example 6 (5289) and 7 (5291) against Staphylococcus aureus MRSA 0134-93. Figure 7 shows the inhibition zones of the samples of Example 6 (5289) and 7 (5291) against Candida albicans ATCC 14,053th Figure 8 shows the inhibition zones of the samples of Example 6 (5289) and 7 (5291) against Staphylococcus aureus ATCC 29213th example 13

p0237The active substance suspension from Example 1 was mixed on a calender kneader In the A / B 2 K platinum-catalyzed addition-silicone rubber system of Fa. Degania and octenidine dihydrochloride-containing silicone rubber anschleißend to Foley catheter shafts with 1 wt .-% octenidine processed.

p0238example 14

p0239Continuity of the surface protection of the octenidine dihydrochloride-containing silicone elastomer Foley catheter shafts

p0240The elution was carried out with the shafts of Example 13, which were zerschnnitten in 2 cm long pieces ge. The specimens weighed about 2.0 g and had a surface area of ​​about 33 cm², As elution 16 ml of artificial urine having the following composition were used

p0241Urea 1.94%

p0242NaCl 0.84% ​​MgSO₄, Heptahydrate 0.11% to

p0243CaCl₂ 0.06% to

p0244After 1 h, 4 h, 8 h, 24 h, 48 h, 120 h and 360 h (15 days), the elution medium was exchanged each against new and the active ingredient content determined in the solutions.

p0245<img id="imgf000032_0001" he="117" wi="91" file="imgf000032_0001.tif" img-format="tif" img-content="table" orientation="portrait" inline="no" />

p0246Over the study period takes a diffusion of the active ingredient instead of the specimen surface, thereby ensuring continuous protection of surface colonization by bacteria and yeasts.

p0247The samples give more than 15 days from small amounts of active ingredient, wherein the amount is far from a pharmacologically effective dose.

p0248example 15

p0249Biocompatibility tests according to DIN ISO 10993-5 (1999), EN 30993-5 (1994)

p0250The catheter shafts from Example 13 were at 37 to 24 h insteril⁰C and 5% pCO₂ in extraction medium (DMEM including antibiotics without FCS) extracted. The surface to volume ratio was Icm²/ Ml extraction medium. After the extraction, the extraction medium was sterile and sterile FCS supplemented (Endkonzentrdation: 10% FCS in the extraction medium). The FCS supplumentierte extraction medium was added to sterile precultured L 929 mouse fibroblast cells and 48 h at 37 ° C, 5% pCO₂ incubated. The extract was tested four times in parallel. As toxic positive control Triton X 100 was used, which was added to the used L929 cells (final concentration 1%). As non-toxic negative control was cell culture medium.

p0251After the 48 hour incubation, the release of lactate dehydrogenase (LDH) was measured in the cell culture supernatant by means of a photometric method. The cells were then lysed alkaline and determined the protein content by the Bradford method.

p0252The cells were fixed to determine cell number and stained with methylene blue. After acid extraction of the methylene blue dye content was recorded by means of photometry, and the absorbance compared with a standard curve to determine the number of cells based on the dye concentration.

p0253Cell count:

p0254Cytotoxicity: cell count after 48 h incubation

p0255<img id="imgf000033_0001" he="57" wi="112" file="imgf000033_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0256Triton 1% medium extract

p0257The value of the positive control is 0.5% of the negative control value in the valid range below 35% relative to the culture medium control.

p0258Cell numbers of extracts that fall below the cell count value of the negative control by more than 19% are evaluated as cytotoxic. This is not the case in the present extract of the sample of Example thirteenth The material extract possesses no cytotoxic potential.

p0259Protein content: Cytotoxicity protein content after 48 h incubation

p0260<img id="imgf000034_0002" he="62" wi="126" file="imgf000034_0002.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0261Triton 1% medium extract <img id="imgf000034_0001" he="87" wi="8" file="imgf000034_0001.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0262The value of the positive control is 6.8% of the negative control value in the valid range below 35% relative to the culture medium control.

p0263Protein values ​​of extracts that fall below the protein content value of the negative control by more than 19% are evaluated as cytotoxic. This is not the case in the present extract of the sample of Example thirteenth The material extract possesses no cytotoxic potential.

p0264LDH Freisetzune:

p0265r

p0266Cytotoxicity: LDH release / mg protein after 48 h incubation

p0267<img id="imgf000034_0003" he="75" wi="2" file="imgf000034_0003.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" /><img id="imgf000034_0004" he="62" wi="128" file="imgf000034_0004.tif" img-format="tif" img-content="drawing" orientation="portrait" inline="no" />

p0268Triton 1% medium extract Unlike of Triton X 100 in cell culture medium the spzeifische LDH activity compared to the negative control (medium) is increased more than 31 fold.

p0269The sample from Example 13 acts not cytotoxic.