EP1067974A1

EP1067974A1 - Moulded bodies made of thermoplastic polyurethane containing an active substance

Info

Publication number: EP1067974A1
Application number: EP99914501A
Authority: EP
Inventors: Reinhard Albers; Ralf Dujardin; Heinz Pudleiner; Joachim Simon; Günther EBERZ; Wolfgang Kreiss; Christina Krasemann-Sharma
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1998-03-20
Filing date: 1999-03-10
Publication date: 2001-01-17
Also published as: US6723333B1; JP2002507457A; NZ506969A; PL342952A1; WO1999048542A1; AU3329899A; DE19812160C1; KR20010042020A; IL137896A0; PL193574B1; HK1036599A1; AU737881B2; CA2324365C; CN1293579A; CN1191868C; CA2324365A1

Abstract

The invention relates to thermoplastic polyurethane (TPU) moulded bodies, especially medical articles such as central venous catheters, containing evenly distributed antibiotic active substances. The invention also relates to a method for the production thereof and the production of TPU containing active substances.

Description

- 1 -

Molded body made of active ingredient-containing thermoplastic polyurethanes

The invention relates to molded articles made of thermoplastic polyurethanes (TPU), in particular medical articles such as central venous catheters, which have antibiotic activity

Contain substances in a homogeneous distribution, process for their production and the production of the active ingredient-containing TPU.

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 / polymer-associated infections.

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

Numerous studies have shown that coagulase-negative staphylococci, the transient germ Staphylococcus aureus and various Candida species

The main causes of catheter-associated infections are. These ubiquitous microorganisms on the skin penetrate the physiological skin barrier when the catheter is applied and thus reach the subcutaneous area and ultimately the bloodstream. The adhesion of the bacteria to the plastic surface is regarded as an essential step in the pathogenesis of foreign body infections. After the skin germs have adhered to the polymer surface, the metabolically active proliferation of the bacteria begins to colonize the polymer. This goes hand in hand with the production of a biofilm through bacterial excretion of extracellular glycocalix. The biofilm supports the adhesion of the pathogen and protects it from the attack of certain cells of the immune system. The film also forms a barrier that is impenetrable to many antibiotics. After increased proliferation - 2 -

of pathogenic germs on the polymer surface, septic bacteremia can eventually occur. Removal of the infected catheter is necessary to treat such infections, since chemotherapy with antibiotics would require unphysiologically high doses.

The frequency of bacterially induced infections in central venous catheters is on average around 5%. In total, central venous catheters are responsible for approx. 90% of all sepsis cases in intensive care medicine. The use of central venous catheters therefore not only poses a high risk of infection for the patient, but also causes enormously high therapeutic follow-up costs (follow-up treatment, extended hospital stays).

Pre-, peri- or post-operative measures (e.g. hygienic measures etc.) can only partially solve this problem. A rational strategy for the prevention of polymer-associated infections is to modify the polymeric materials used. The aim of this modification must be to inhibit bacterial adhesion or the proliferation of already adhered bacteria, in order to avoid causal foreign body infections. This can e.g. by incorporating a suitable chemotherapeutic agent into the polymer matrix (e.g. antibiotics), provided that the incorporated active ingredient also comes from the

Can diffuse out polymer matrix. In this case, the release of the antibiotic can be extended over a longer period of time, so that bacterial adhesion or proliferation on the polymer is prevented for a correspondingly longer period of time.

Methods for producing antibacterial polymers for medical applications are already known. In the numerous processes described, the active ingredient is added using the following techniques:

a) Adsorption on the polymer surface (passive or via surfactants) - 3 -

b) Introduction into a polymer coating that is applied to the surface of a molded body

c) incorporation into the bulk phase of the polymeric carrier material

d) Covalent bond on the polymer top

DE-A-41 43 239, for example, shows a method for introducing active substances into the outer layer of medical articles (impregnation). The implantable device made of polymeric material is swollen in a suitable solvent. The polymer matrix is changed so that a pharmaceutical active ingredient or combination of active ingredients can penetrate into the polymeric material of the implant. After removing the solvent, the active ingredient is included in the polymer matrix. After contact with the physiological medium, the active ingredient contained in the implantable device is passed through

Diffusion released again. The release profile can be adjusted by the choice of solvent and by varying the experimental conditions.

Polymer materials for medical applications which have coatings containing active ingredients are mentioned, for example, in EP-A 328 421. Processes for the production of the antimicrobial coatings and methods for application to the surfaces of medical devices are described. 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.

All of the above-mentioned processes have in common that equipping the medical working agent with an antibiotic substance requires an additional working step, namely either a pretreatment of the polymer material - 4 -

before processing or post-treatment of the molded articles produced. This causes additional costs and increases the time required for production. Another problem with the processes is the use of organic solvents, which usually cannot be completely removed from the material.

The object of the invention was to provide antibiotic moldings, in particular medical articles such as catheters, which efficiently prevent surface colonization by germs for a relatively long period (2 to 4 weeks).

It has now been found that this can be achieved if moldings are used which release a concentration of an antibiotic active substance on the surface which prevents the colonization with germs and which have a low surface roughness depth.

The invention thus relates to moldings made of an antibiotic substance in a homogeneous distribution containing thermoplastic polyurethane, which have a roughness depth <5 μm, preferably <2 μm, particularly preferably <1 μm.

In principle, all active substances which have a broad spectrum of activity against the pathogenic microorganisms involved in polymer-associated infections, in particular against coagulase-negative staphylococci, staphylococcus aureus and Candida species, are suitable as antibiotic substances. According to the invention, the antibiotically active substances can also be used as combinations of active substances in the shaped bodies, provided that their effects do not antagonize.

The active ingredient used must have sufficient (chemical) stability in the polymer matrix. In addition, the microbiological activity of the active ingredient in the polymeric matrix and under the process conditions of incorporation must not be impaired. - 5 -

Working of the polymeric material required temperatures of 150 to 200 ° C and residence times of 2 to 5 minutes to be sufficiently stable.

The incorporation of the pharmaceutically active substance should neither impair the biocompatibility of the polymer compartments nor other desirable polymer-specific properties of the polymer material (elasticity, tear strength, etc.).

Suitable antibiotic substances are, for example, nalixidic acid and nalixidic acid derivatives, such as e.g. Ciprofloxacin, norfloxacin, ofloxacin, pefloxacin,

Enoxacin, preferably ciprofloxacin, aminoglycosides, e.g. Gentamycin, kanamycin, amikacin, sisomycin, preferably gentamycin and kanamycin, macorcyclic antibiotics such as e.g. Rifampicin or erythromycin, preferably rifampicin, bacitracin, mupirocin, thyrothricins such as e.g. Gramicidin, tyrocidin, lincomycin, clindamycin or fusidic acid.

The active ingredients are preferably incorporated in a concentration corresponding to their antibiotic activity. The active compounds are particularly preferably used in a concentration range from 0.1 to 5.0% by weight.

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

A) organic diisocyanate,

B) linear hydroxyl-terminated polyol with a molecular weight of 500 to 10,000,

C) chain extenders with a molecular weight of 60 to 500, - 6 -

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, such as those in Justus

Liebigs Annalen der Chemie, 562, pp.75-136. Aliphatic and cycloaliphatic diisocyanates are preferred.

Examples include: aliphatic diisocyanates such as hexamethylene diisocyanate, cycloaliphatic diisocyanates such as isophorone diisocyanate, 1,4-cyclohexane diisocyanate, l-methyl-2,4-cyclohexane diisocyanate and l-methyl-2,6- cyclohexane diisocyanate and the corresponding isomer mixtures, 4,4'-dicyclohexyl methane diisocyanate, 2,4'-dicyclohexyl methane diisocyanate and 2,2'-dicyclohexyl methane diisocyanate as well as the corresponding isomer mixtures, aromatic diisocyanates, such as 2,4-tolylene diisocyanate, mixtures of 2,4-tolylene diisocyanate and 2,6-

Toluene 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'-diisocyanatodiphenylethane (1,2) and 1,5-naphthylene diisocyanate. Preferably used

1, 6-hexamethylene diisocyanate, isophorone diisocyanate, dicyclohexylmethane diisocyanate, diphenylmethane diisocyanate isomer mixtures with a 4,4'-diphenylmethane diisocyanate content of> 96% by weight 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 can also be used together with up to 15% by weight (based on the total amount of diisocyanate) of a polyisocyanate, for example triphenylmethane 4,4 ', 4 "triisocyanate or polyphenyl polymethylene polyisocyanates.

As component B) are linear hydroxyl-terminated polyols with a medium

Molecular weight M _n from 500 to 10,000, preferably 500 to 5000, particularly preferably 600 to 2000 used. Due to production, these often contain small amounts of branched compounds. One therefore often speaks of "essentially linear polyols". Polyether diols, polycarbonate diols, sterically hindered polyester diols, hydroxyl-terminated polybutadienes or mixtures thereof are preferred.

Polysiloxane diols of the formula (I) can also be used as soft segments, alone or in a mixture with the diols mentioned above.

R ¹ R ¹ ^{HO ^} H ^ (I)

R ¹

in which

m has a value of 1 to 30, preferably 10 to 25 and particularly preferably 15 to 25,

n has a value from 1 to 4, and

R ^{1 is} an alkyl group with 1 to 6 C atoms or a phenyl group,

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)

R ¹ R '

^H X f ° yc »

A ^{1 m}

in a ratio of 1: 2 with an unsaturated, aliphatic or cycloaliphatic alcohol such as allyl alcohol, butene- (1) -ol or pentene- (1) -ol in the presence of a catalyst, for example hexachloroplatinic acid. Suitable polyether diols can be prepared by reacting one or more alkylene oxides with 2 to 4 carbon atoms in the alkylene radical with a starter molecule which contains two active hydrogen atoms bonded. Examples of alkylene oxides are: ethylene oxide, 1,2-propylene oxide, epichlorohydrin and

1,2-butylene oxide and 2,3-butylene oxide. Ethylene oxide, propylene oxide and mixtures of 1,2-propylene oxide and ethylene oxide are preferably used. The alkylene oxides can be used individually, alternately in succession or as mixtures. Examples of suitable starter molecules are: 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. If appropriate, mixtures of starter molecules can also be used. Suitable polyether diols are also the hydroxyl-containing polymerization products of tetrahydrofuran. Trifunctional polyethers can also be used in proportions of 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 essentially 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. Examples of suitable dicarboxylic acids are: 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, for example in the form of a mixture of succinic, glutaric and adipic acids. For the preparation of the polyester diols it may be advantageous to use the corresponding dicarboxylic acid derivatives, such as carboxylic acid diesters having 1 to 4 carbon atoms in the alcohol residue, carboxylic acid anhydrides or carboxylic acid chlorides, instead of the dicarboxylic acids. Examples of polyhydric alcohols are sterically hindered glycols with 2 to 10, preferably 2 - 9 -

up to 6 carbon atoms which bear at least one alkyl radical in the β-position relative to the hydroxyl group, such as 2,2-dimethyl-1,3-propanediol, 2-methyl-2-propyl-1,3-propanediol, 2,2-diethyl-1 , 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 can be used alone or, if appropriate, as a mixture with one another. Also suitable are esters of carbonic acid with the diols mentioned, in particular those with 3 to 6 carbon atoms, such as 2,2-dimethyl-1,3-propanediol or 1,6-hexanediol, condensation products of hydroxycarboxylic acids, for example hydroxycaproic acid and polymerization products of lactones , for example optionally substituted caprolactones. The polyester diols used are preferably neopentyl glycol polyadipate 1,6-hexanediol neopentyl glycol polyadipate. The polyester diols can be used individually or in the form of mixtures with one another.

Chain extenders C) used are diols, diamines or amino alcohols with a molecular weight of 60 to 500, preferably aliphatic diols with 2 to 14 carbon atoms, such as, for example, ethanediol, 1,6-hexanediol, diethylene glycol, dipropylene glycol and in particular 1,4-butanediol. However, diesters of terephthalic acid with glycols having 2 to 4 carbon atoms, such as, for example, terephthalic acid bis-ethylene glycol or terephthalic acid bis-1, 4-butanediol, hydroxyalkylene ether of hydroquinone, such as, for example, 1,4-di (-hydroxyethyl), are also suitable. -hydroquinone, ethoxylated bisphenols, (cyclo) aliphatic diamines, such as isophoronediamine, ethylenediamine, 1,2-propylene-diamine, 1,3-propylene-diamine, N-methyl-propylene-1,3-diamine, 1,6- Hexamethylenediamine, 1,4-diaminocyclohexane, 1,3-diaminocyclohexane, N, N'-dimethyl-ethylenediamine and 4,4'-dicyclohexylmethane diamine and aromatic diamines, such as, for example, 2,4-tolylene diamine and 2,6-tolylene diamine , 3,5-diethyl-2,4-toluenediamine and 3,5-diethyl-2,6-toluenediamine and primary mono-, di-, tri- or tetraalkyl-substituted 4,4'-diaminodiphenylmethanes or amino alcohols such as ethanol - amine, 1-aminopropanol, 2-aminopropanol. Mixtures of the above - 10 -

called chain extender can be used. Smaller amounts of trifunctional or higher functional crosslinking agents can also be added, e.g. Glycerin, trimethylolpropane, pentaerythritol, sorbitol. 1,4-Butanediol, 1,6-hexanediol, isophoronediamine and mixtures thereof are particularly preferably used.

Conventional monofunctional compounds can also be used in small amounts, e.g. as a chain terminator or mold release. Examples include alcohols such as octanol and stearyl alcohol or amines such as butylamine and stearylamine.

The molar ratios of the structural components can be varied over a wide range, as a result of which the properties of the product can be adjusted. Molar ratios of polyols to chain extenders from 1: 1 to 1:12 have proven successful. The molar ratio of diisocyanates and polyols is preferably 1.2: 1 to 30: 1. Ratios of 2: 1 to 12: 1 are particularly preferred. The structural components, if appropriate in the presence of catalysts, auxiliaries and additives, can be used to prepare the TPU amounts are reacted 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 the polyols 0.9: 1 to 1.2: 1, is preferably 0.98: 1 to 1.05: 1, particularly preferably 1.005: 1 to 1.01: 1.

The polyurethanes which can be used according to the invention can be prepared without catalysts; in some cases, however, the use of catalysts may be appropriate. In general, the catalysts are used in amounts of up to 100 ppm, based on the total amount of starting materials. Suitable catalysts according to the invention are the tertiary amines known and customary in the prior art, such as e.g. Triethylamine, dimethylcyclohexylamine, N-methylmorpholine, N, N'-dimethyl-piperazine, 2- (dimethylamino-ethoxy) -ethanol, diazabicyclo- (2,2,2) -octane and similar and in particular organic metal compounds such as titanium acid esters,

Iron compounds, tin compounds, for example tin diacetate, tin dioctoate, tin dilaurate - 11 -

or the tin dialkyl salts of aliphatic carboxylic acids. Dibutyltin diacetate and dibutyltin dilaurate are preferred; amounts of 1 to 10 ppm are sufficient to catalyze the reaction.

In addition to the TPU components and the catalysts, other auxiliaries and additives can also be added. Examples include lubricants such as fatty acid esters, their metal soaps, fatty acid amides and silicone compounds, antiblocking agents, inhibitors, stabilizers against hydrolysis, 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 supplied with a size. More detailed information on the auxiliaries and additives mentioned can be found in the specialist literature, for example J.H. Saunders, K.C. Frisch: "High Polymers", Volume XVI, Polyurethane, Parts 1 and 2, Interscience Publishers 1962 and 1964, R.Gächter, H.Müller (Ed.): Taschenbuch der

Plastic additives, 3rd edition, Hanser Verlag, Munich 1989, or DE-A 29 01 774.

The build-up of the thermoplastically processable polyurethane elastomers is preferably carried out step by step 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 with the chain extender in a second step. The TPU can be manufactured continuously or discontinuously. The best known technical manufacturing processes are the belt process and the extruder process.

Systematic investigations have shown that a homogeneous distribution of the pharmaceutically active substance in the polymer matrix is necessary in order to be able to use the active ingredient diffusion as an adjustable release mechanism. The antibiotic substance and the polymeric carrier material used should therefore have a high level of physico-chemical compatibility. The interfacial energy that occurs in the system is a measure of the compatibility of the active ingredient and the matrix.

If this is high, the active ingredient and matrix are not very compatible and the active ingredient - 12 -

is delivered quickly; the concentration of the active ingredient on the polymer surface drops below the action threshold after a short time. If the interfacial energy is very low, the active ingredient is strongly bound by the polymer matrix; there is no release of effective amounts on the surface. With good physical-chemical compatibility of the active substance and matrix, a high diffusion coefficient of the active substance in the polymer is achieved. In this case, the amount of the release rate of the antibiotic substance can be regulated by varying the amount of active ingredient incorporated, since the amount of active ingredient released is then proportional to the concentration in the matrix.

Combinations of matrix and active substance which have an interfacial energy of 3 to 30 mN / m, particularly preferably 8 to 15 mN / m, very particularly preferably 10 to 13 mN / m are preferably selected for the production of the moldings according to the invention. A combination erfϊndungsgemäß preferred is ciprofloxacin in a matrix of from polytetrahydrofuran, isophorone diisocyanate, iso- phrondiamin and 1, 6-hexanediol produced TPU, which is sold under the trade name Texin ^® 5590 (Bayer Corp., Pittsburgh, PA 15205-9741) . Active substance concentrations between 0.1 and 1.0% by weight of ciprofloxacin are sufficient to efficiently prevent bacterial surface colonization of the polymer surface. In vivo and in vitro experiments have shown that the invention

Catheters made from Texin ^® 5590, containing ciprofloxacin, reduce bacterial colonization by up to 75% over a period of at least 7 days compared to the active ingredient-free reference material.

The shaped bodies according to the invention are distinguished by the fact that they have a molecularly disperse distribution of the antibiotic substance in the polymer matrix. The high morphological homogeneity of the extruded plastics containing the active ingredient could be demonstrated by means of light and scanning electron microscope images. In addition, it was possible to demonstrate with the aid of scanning microscopic images that the polymer had a smooth surface before and after the release of the incorporated active ingredient, ie the biocompatibility of the - 13 -

Polymer surface is not affected by the addition or release of the active ingredient. The surface of the moldings according to the invention has a roughness depth <5 μm, preferably <2 μm, particularly preferably <1 μm. This is an essential factor for the good biocompatibility of the shaped bodies according to the invention and additionally complicates the settlement of germs and adherence of cellular blood components on the surface.

Comparable active substance-containing samples, which were produced by means of the casting film method (solvent casting), on the other hand, are significantly more inhomogeneous. Scanning electron microscopic studies show that the active ingredients incorporated in the

Polymer matrix and partly on the surface are in the form of crystal structures. The crystal formations cause the mechanical properties of the polymer to deteriorate drastically. In addition, the extracted crystal dressings leave a rough surface, which leads to reduced biocompatibility.

Contrary to expectations, it was also found that the mechanical properties of the polymer are markedly improved by the addition of the antibiotic substances in amounts of 0.01 to 10% by weight, preferably 0.1 to 5% by weight.

The active substances introduced change the surface tension of the soft phase of the TPU formed essentially from components (B), thus increasing the phase separation of the block copolymer and thus improving the morphology of the polymer. As a result of the improved morphology, the active substances introduced bring about a significant improvement in the mechanical properties in addition to the improved biocompatibility. The tensile strengths of the active ingredient-containing TPU increase significantly compared to the active ingredient-free TPU and the permanent strains are measurably reduced. The elongations at break are reduced only slightly, which also indicates an improved elastomeric structure of the TPU. - 14 -

The moldings according to the invention can be produced by extruding a melt consisting of the polymer and active ingredient. The melt can contain 0.01 to 10% by weight, preferably 0.1 to 5% by weight, of active ingredient. The components can be mixed in any manner using known techniques. The active ingredient can, for example, be introduced directly into the polymer melt in solid form. A masterbatch containing active ingredient can also be melted directly with the polymer or mixed with the polymer melt already present. The active ingredient can also be applied to the polymer using known techniques (by tumbling, spraying, etc.) before the polymer is melted.

In addition, the mixing / homogenization of the components can be carried out according to known techniques using kneaders or screw machines, preferably in single or twin screw extruders in a temperature range between 150 and 200 ° 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 additional work steps being necessary.

The granules containing the active ingredient obtained in this way can be further processed by the known techniques of thermoplastic processing (injection molding, extrusion, etc.). The moldings are speck-free, flexible, do not stick and can be sterilized without any problems using the usual methods. - 15 -

Examples

Example 1 (comparison)

700 parts by weight of Terathane ^® 2000 (DuPont) and 74.5 parts by weight of 1, 6-hexanediol were charged into a flange flask fitted with stirrer and internal thermometer and long 20 mbar dried for 1 hour at 110 ° C /. Then 320.6 parts by weight of isophorone diisocyanate were added and the reaction mixture was stirred at 120 ° C. until the theoretical NCO value of 3.5% by weight was reached. Then 11.8 parts by weight of Höchstwachs C (Hoechst AG) and 7.5 parts by weight of di-n-butylamine were added. The prepolymer was dissolved in toluene and added dropwise with stirring at room temperature to a solution of 71.6 parts by weight of isophoronediamine in 2456 parts by weight of a mixture of toluene and isopropanol (70/30). A colorless, transparent and homogeneous solution was obtained. After removing the solvent at 65 ° C./15 mbar, colorless, transparent polymer plates were obtained, which were comminuted using a chopper. The chopped granules were finally extruded on a ZSK1 twin-screw extruder and strand-granulated. A colorless, clear and non-sticky cylindrical granulate was obtained.

Part of the cylinder granulate was injection molded into test specimens for microbiological in vitro investigations and for the determination of the release profile of the incorporated active ingredient (control tests).

Another part was extruded for microbiological in vivo studies (animal model) to tubes with an inner diameter of 3 mm.

Example 2

700 parts by weight of Terathane ^® 2000 (DuPont) and 74.5 parts by weight of 1, 6-hexanediol were charged into a flange flask fitted with stirrer and internal thermometer and - 16 -

Dried at 110 ° C / 20 mbar for 1 hour. Then 320.6 parts by weight of isophorone diisocyanate were added and the reaction mixture was stirred at 120 ° C. until the theoretical NCO value of 3.5% by weight was reached. Then 11.8 parts by weight of maximum wax C and 7.5 parts by weight of di-n-butylamine were added. The prepolymer was dissolved in 616 parts by weight of toluene and added with stirring

Dropped room temperature into a solution of 71.6 parts by weight of isophoronediamine in 2456 parts by weight of a mixture of toluene and isopropanol (70/30). 11.74 g of ciprofloxacin betaine (1.0% by weight, based on the polymer mass) were then stirred in. A colorless, transparent and homogeneous solution was obtained. After removal of the solvent at 65 ° C./15 mbar, colorless, transparent polymer plates were obtained, which were comminuted using a chopper. The active ingredient-containing chopped granules were finally extruded on a ZSK1 twin-screw extruder and strand-granulated. A colorless, clear and non-sticky cylindrical granulate was obtained.

A part of the cylinder granulate was processed into test specimens (plates) for microbiological in vitro investigations as well as for the determination of the release professional of the incorporated active substance in injection molding.

Another part of the cylinder granulate was extruded for hoses with an inner diameter of mm for in vivo microbiological studies (animal model).

Example 3 (comparison)

Commercial aliphatic polyether urethane: Tecoflex ^® EG 85 A (from Thermedics, Woburn MA 01888-1799) - 17 -

Example 4

5 g of bacitracin were applied in an intensive mixer to 995 g of active ingredient-free Tecoflex ^® EG 85 A. The active ingredient-containing cylinder granulate was extruded on a ZSKl twin-screw extruder. A clear melt was obtained, which after

Cooling in water / air bath and strand granulation gave colorless, clear cylindrical granules.

The granules became test specimens for microbiological in vitro investigations and for determining the release profile of the incorporated active ingredient

Injection molded.

Example 5

5 g of gramicidin were mixed in an intensive mixer to 995 g of Tecoflex ^® free of active ingredient

EG 85 A applied. The active ingredient-containing cylinder granulate was extruded on a ZSKl twin-screw extruder. A clear melt was obtained which, after cooling in a water / air bath and strand pelletization, gave colorless, clear cylindrical pellets.

The granules were injection molded into test specimens (plates) for in vitro microbiological investigations and for determining the release profile of the incorporated active ingredient.

Example 6

S2 tensile bars were punched from the test specimen sheets of the materials produced in Examples 3 to 5 and the strength values were determined in accordance with DIN 53 455. The tensile deformation residues of the test specimens were determined in accordance with DIN 53 518. - 18 -

The results of the tests are summarized in Table 1. They document that the active ingredients contained in the polymers significantly improve the mechanical properties.

Table 1

Measured values Tecoflex ^® EG 85 A Tecoflex ^® EG 85 + Tecoflex ^® EG 85 + (example 3) 0.5% by weight 0.5% by weight bacitracin gramicidin (example 4) (example 5)

Tensile strength 20.3 MPa 29.2 MPa 25 MPa

Elongation at break 750% 630% 700%

Permanent 29% 25% 27% stretch at 200% stretch

Permanent 74% 66% 72% elongation 400% stretch

Example 7

To prepare a masterbatch containing active ingredients, 749 g were free of active ingredients

Cylinder granules made of thermoplastic polyurethane (Texin® 5590, Bayer Corp.) dissolved in chloroform and mixed with 27.16 g of ciprofloxacin betaine. The mixture was heated (approx. 70 ° C) until a colorless, homogeneous solution was obtained. After removal of the solvent at 65 ° C./15 mbar, colorless, slightly opaque polymer plates were obtained, which were comminuted using a chopping machine.

The 3.5% by weight masterbatch was mixed with 1664 g of active ingredient-free cylindrical granulate and extruded on a ZSKl twin-screw extruder. A clear melt was obtained which, after cooling in a water / air bath and strand pelletization, gave colorless, clear cylindrical pellets. - 19 -

For microbiological in vitro investigations, the granules were injection molded into test specimens (plates).

Example 8

10 g of ciprofloxacin betaine were applied in an intensive mixer to 990 g of the active ingredient-free cylindrical granulate (from example 1). The active ingredient-containing cylinder granulate was extruded on a ZSKl twin-screw extruder. A clear melt was obtained which, after cooling in a water / air bath and strand granulation, gave colorless, clear cylindrical granules.

Example 9

The release profiles of ciprofloxacin-containing polymer samples were determined by elution in Millipore water (0.1% NaN ₃ ). In a typical experiment, 5 g of tubing containing Texin ^® 5590 (length: approx.

1 cm) at 37 ° C with 20 ml Millipore water and stirred at constant speed. The eluent was replaced with fresh Millipore water at regular intervals of 24 hours. The released ciprofloxacin in the corresponding solutions was quantified via HPLC analysis.

The release profiles were determined for different concentrations of the incorporated active ingredient. Sample 1 contained no ciprofloxacin and was used as a negative control, sample 2 contained 0.1% by weight and sample 3 1.0% by weight ciprofloxacin. The results of the investigations are summarized in Table 2. They document that the active ingredient diffusion from the polymer can be used as an adjustable release mechanism: the higher the incorporated one - 20 -

The amount of active substance, the greater the active substance concentration released from the polymer matrix in the elution medium.

- 21 -

Table 2

Release profiles of tube samples containing ciprofloxacin, released amount of ciprofloxacin [mg / 1]

Time [h] 0 24 48 72 91 168 192 216 240

Sample 1 0 0 0 0 0 0 0 0 0

Sample 2 0 1.01 1.61 2.22 - 2.95 3.59 4.21 4.85

Sample 3 0 22.58 29.01 34.12 37.84 49.53 53.4 57.08 60.79

Example 10

The microbiological evaluation and the quantification of the active ingredient release was carried out using a new bioimaging technique. The method uses the selective effect-dependent bioluminescence of sensor bacteria (E. coli test strain) to visualize the biological activity of the active ingredient released by the polymer. In the inventive system Texin ^® 5590 / ciprofloxacin gyrase, the inhibitory effect is exploited ciprofloxacin.

For the imaging of the antibacterial effect, approximately 1 cm ² large samples of the active substance-containing material were placed in a petri dish and covered with a suspension of sensor bacteria in agarose. After an incubation period of approx. 30 minutes, the effect-dependent bioluminescence is evaluated with a video imaging system (eg EG&G Berthold, Luminograph LB 980). Antibiotic active samples emerge as luminescent surfaces.

With the help of the method it could be demonstrated, inter alia, that the microbiological effectiveness of the ciprofloxacin released from the polymer matrix is retained even after the high temperatures of approximately 200 ° C. required for the thermoplastic processing of polymers have been applied. In addition, local - 22 -

Differences in tration (e.g. surface defects, fresh cut edges) that are characterized by different intensities of luminescence are shown.

FIG. 1 shows bioluminescence images of ciprofloxacin-containing polymer patterns:

Samples 1 and 2 are injection-molded foils containing ciprofloxacin, sample 3 a cast foil containing ciprofloxacin, sample 4 a polymer sample free of active ingredient (negative control). The left picture of the figure shows the cross section of the 1 cm ² large sample plates, the right one the top view. The luminescence images show that the cast film (3) releases higher doses of ciprofloxacin than the injection molded films (1 + 2). As expected, the negative control (4) shows no luminescence.

Example 11

Evaluation of the in vivo microbiological activity of ciprofloxacin-containing

Catheters were made by qualitative comparison with drug-free control catheters on a pig model developed at RWTH Aachen University (KLOSTERHALFEN). Pigs were used in the model whose immune system was suppressed by infusion of sublethal doses of a lipopolysaccharide (LPS). In this way, a septic shock corresponding to humans is said to be

Stage in the experimental animals.

For the study, the test animals (n = 10) were each implanted with a ciprofloxacin-containing test catheter and a drug-free control catheter in the right and left external jugular vein under sterile conditions. After a week, the catheters were removed under sterile conditions, divided into 5 segments and examined microbiologically.

The results of the microbiological examinations of the individual catheter segments can be summarized as follows: 23

Coagulase-negative staphylococci play the most important role in the

Germination of the catheter.

The analysis of different catheter segments after an implantation period of 7 days shows a descending, extraluminal germ colonization with a maximum in the catheter part, which lies subcutaneously in the skin. The

Germ density or colonization progressively decreases towards the tip of the catheter

(see Table 3).

The bacterial colonization of the test catheter containing ciprofloxacin is significantly lower compared to the control catheter free of active substance, except for the area of the catheter tip (see Table 3).

Table 3

Germination of the different catheter segments after 7 days of implantation. Statistical evaluation of 10 catheters per group (t-test).

Group skin middle V prox * dist endol

Control 99.8 ± 107.7 195 + 139.7 7.7 + 13.03 2.2 ± 6.9 0 + 0

Test 5.9 + 12.6 48.5 + 71.6 0 + 0 0.1 0.32 0 ± 0

P <0.014 0.009 0.078 0.353 0

Values given in CFU, p = level of significance

V _dist = catheter tip, V _prox = 5 cm, middle = 10 cm, skin = 15 cm,

Claims

- 24 patent claims

1. Shaped body made of an antibiotic substance in a homogeneous distribution containing thermoplastically processable polyurethane, which have a roughness depth <5 microns.

2. Moldings made of an antibiotic active substance in a homogeneous distribution containing thermoplastically processable polyurethane, which have higher tensile strengths than molded articles made of the corresponding active ingredient-free polyurethane.

3. A process for the production of the molded article according to claim 1 or 2 by extrusion or injection molding of a thermoplastically processable polyurethane containing an antibiotic active substance in homogeneous distribution.

4. A process for the production of the molded article according to claim 1 or 2 by joint extrusion of an antibiotic substance and a thermoplastically processable polyurethane.

5. A process for the production of a thermoplastically processable polyurethane containing an antibiotic substance in homogeneous distribution by mixing the antibiotic substance with the polyurethane.

6. Thermoplastic processable polyurethane obtainable by reaction of polytetrahydrofuran, isophorone diisocyanate, isophrone diamine and 1,6-hexanediol, which contains ciprofloxacin in a homogeneous distribution.

7. Use of the polyurethane according to claim 6 in medical articles.