Use of polymeric or oligomeric active ingredients for medical articles

Abstract

The invention relates to the use of polymeric or oligomeric active ingredients having a biocidal effect as additives in the composition of medical articles. The invention further relates to medical articles that comprise such additives.

Claims

1. A process for preparing a medical article, comprising the following steps: a) combining and admixing a polymeric or oligomeric active ingredient having biocidal activity that is obtainable by the polycondensation of a guanidine acid addition salt with a mixture of amines containing at least one diamine and/or triamine, wherein at least one amine is selected from the group consisting of i) a diamine having at least one cycloaliphatic residue; and ii) dialkylene triamine with at least one plastic material to form a composition, wherein the at least one plastic material includes thermoplastic polyurethane, wherein the polymeric or oligomeric active ingredient is present in the composition in an amount ranging from 1% by weight to 4% by weight, wherein the polymeric or oligomeric active ingredient is incorporated into the plastic material, and; b) subjecting the composition obtained under a) to one or more shaping methods to form a medical article, wherein the polymeric or oligomeric active ingredient has a structure selected from the group comprising ##STR00011## wherein HCl* means that the HCl is not covalently bonded, n is a natural number from 1 to 20, p, q and r are integers defining the preferred molar ratio of the structural fragments in the formulas, wherein the medical article exhibits a surface roughness that is lower than a surface roughness of a medical article comprising a composition that excludes the polymeric or oligomeric active ingredient.

2. The process according to claim 1, characterized in that said polymeric or oligomeric active ingredient is subjected to the shaping method in step b) as pellets or as a master batch.

3. The process according to claim 1, characterized in that said admixing in step a) is performed in an extruder.

4. The process according to claim 1, characterized in that said shaping method is an extrusion.

5. A medical article comprising a composition, wherein the composition comprises, as a first component, a polymeric or oligomeric active ingredient having biocidal activity that is obtained by the polycondensation of a guanidine acid addition salt with a mixture of amines containing at least one diamine and/or triamine, wherein at least one amine is selected from the group consisting of i) a diamine having at least one cycloaliphatic residue; and ii) dialkylene triamine, and at least one plastic material, wherein the at least one plastic material includes thermoplastic polyurethane, wherein the polymeric or oligomeric active ingredient and the at least one plastic material are admixed together, wherein the polymeric or oligomeric active ingredient is incorporated into the plastic material, and wherein the medical article exhibits a surface roughness that is lower than a surface roughness of a medical article comprising a composition that excludes the polymeric or oligomeric active ingredient, wherein the polymeric or oligomeric active ingredient has a structure selected from the group comprising ##STR00012## wherein HCl* means that the HCl is not covalently bonded, n is a natural number from 1 to 20, p, q and r are integers defining the preferred molar ratio of the structural fragments in the formulas, wherein the polymeric or oligomeric active ingredient is present in the composition in an amount ranging from 1% by weight to 4% by weight.

6. The medical article according to claim 5, characterized by being a tubular medical article.

7. The medical article according to claim 5, characterized in that said guanidine acid addition salt is guanidine hydrochloride.

8. The medical article according to claim 5, characterized in that said polymeric or oligomeric active ingredient has an average molecular weight within a range of 500 to 7000 Da.

9. The medical article according to claim 5, characterized in that said medical article is selected from the group consisting of central venous catheters; peripheral venous catheters; breathing tubes, stents; products for application in regional anesthesia; products of formulation, mixing sets; urological products, urine measuring and collecting devices; wound drains; wound dressing; surgical suture materials; implantation auxiliaries as well as implants; disposable surgical instruments; thoracic drains; probes; catheters; housings of medical devices; artificial dentures; and containers for liquids.

10. The medical article according to claim 5, characterized in that said medical article is selected from the group consisting of catheters, couplings, filters, containers, ports, conduit systems, connectors, spikes, valves, three-way stopcocks, syringes, conduits, and injection ports.

Description

Example 1

Synthesis of poly(4,4-methylenebis(cyclohexylamine)guanidine hydrochloride) (PMBCG)

(1) In an argon countercurrent, 1 equivalent (8.12 g, 85 mmol) of guanidine hydrochloride is added to a 100 ml three-necked flask that had been baked out three times. Subsequently, 1 equivalent (17.88 g, 85 mmol) of 4,4-methylenebis(cyclohexylamine) was added in a glove box.

(2) The flask is equipped with an internal thermometer and a reflux condenser with a non-return valve according to Stutz (referred to as Stutz condenser in the following) that had been baked out three times.

(3) The reaction mixture is heated in an oil bath, a slow evolution of gas starting from a temperature of 100 C. When the temperature is increased further, the gas evolution only slowly becomes stronger. After a total of 85 minutes, a temperature of 170 C. is reached.

(4) This temperature is maintained for nine hours until the evolution of gas is complete according to visual inspection.

(5) Under ice cooling and in an oil-pump vacuum, the melt is cooled down to room temperature.

(6) Under the conditions mentioned above, the starting amounts employed yield 24.48 g of a transparent, colorless and brittle solid.

(7) The structure of the polymer obtained can be shown according to formula (I).

(8) ##STR00002##
where n=1 to 8, predominantly 1 to 3.

(9) The residues R1 and R2 may be derived from either the monomer employed or the guanidine hydrochloride employed, and they are therefore defined as follows:

(10) R1 is selected from H or

(11) ##STR00003##
and R2 is selected from NH.sub.2 or

(12) ##STR00004##

(13) The mixture of products obtained thus contains polymeric compounds corresponding to formulas (II), (III) and (IV):

(14) ##STR00005##
wherein n is defined as in formula (I).

Example 2

Synthesis of a Homopolymer Based on Diethylene Triamine

(15) In a 100 ml three-necked flask with an internal thermometer, Stutz condenser and suction piece with cock that had been baked out three times and filled with argon, 1 equivalent (8.12 g, 85 mmol) of guanidine hydrochloride and 1 equivalent (8.77 g, 85 mmol) of diethylene triamine are heated to a temperature of 150 C. within 50 minutes by means of an oil bath.

(16) From the time when a temperature of 95 C. is reached, an evolution of gas can be observed, which rapidly increases when the temperature is increased further.

(17) The melt is maintained at 150 C. for five hours with stirring until the evolution of gas is complete.

(18) Under ice cooling and in an oil-pump vacuum, the melt is cooled down to room temperature.

(19) Under the conditions mentioned above, the starting amounts employed yield 11.96 g of a white and brittle solid.

(20) Surprisingly, the repeating monomer unit of the polymeric active ingredient obtained shows the cyclic structure according to formula (V):

(21) ##STR00006##
where n=1 to 12, predominantly 2 to 8.

(22) R3 is either NH.sub.2 or

(23) ##STR00007##
and

(24) R4 is selected from

(25) ##STR00008##

(26) Thus, the product mixture obtained contains polymeric compounds corresponding to formulas (VI), (VII) and (VIII):

(27) ##STR00009##

(28) It is conceivable that about 90% of the rings in formulas (VI), (VII) and (VIII) carry a positive charge. It is also conceivable that the positive charge is not localized on one of the nitrogen atoms in the ring, but is rather delocalized. Thus, an alternative form of representing formula (VIII) is the following formula (VIII):

(29) ##STR00010##

(30) Formulas (I) to (IV) of Example 2 also can be represented analogously, wherein the positive charge is distributed to all three nitrogen atoms of the guanidine unit in a tautomeric way.

Example 3

Synthesis of Guanidine Copolymers

(31) In a reaction flask prepared in accordance with the above described Examples, 1 equivalent (8.12 g, 85 mmol) of guanidine hydrochloride and 1 equivalent of the comonomers, which are present in a mixing ratio according to Table 1, are commonly heated to a temperature of 170 C. within 30 minutes by means of an oil bath.

(32) The melt is maintained at this temperature for five hours with stirring. Under ice cooling and in an oil-pump vacuum, the melt is cooled down to room temperature.

(33) TABLE-US-00001 TABLE 1 Mixing ratios of the di- and triamines employed in the amine mixture for preparing guanidine copolymers Amount of Amount of monomer 1 monomer 2 No. Monomer 1 Monomer 2 employed employed C1 4,4-methylenebis- diethylene 14.30 g 2.21 g (cyclohexylamine) triamine 68 mmol 17 mmol 0.80 eq 0.2 eq C2 4,4-methylenebis- diethylene 13.41 g 2.77 g (cyclohexylamine) triamine 63.75 mmol 21.25 mmol 0.75 eq 0.25 eq C3 4,4-methylenebis- diethylene 11.92 g 3.69 g (cyclohexylamine) triamine 56.67 mmol 28.33 mmol 0.67 eq 0.33 eq C4 4,4-methylenebis- diethylene 8.94 g 5.53 g (cyclohexylamine) triamine 42.50 mmol 42.50 mmol 0.50 eq 0.50 eq C5 4,4-methylenebis- hexamethylene 3.58 g 7.90 g (cyclohexylamine) diamine 17.00 mmol 68.00 mmol 0.20 eq 0.80 eq C6 4,4-methylenebis- hexamethylene 4.47 g 7.41 g (cyclohexylamine) diamine 21.25 mmol 63.75 mmol 0.25 eq 0.75 eq C7 4,4-methylenebis- hexamethylene 5.96 g 6.59 g (cyclohexylamine) diamine 28.33 mmol 56.67 mmol 0.33 eq 0.67 eq C8 4,4-methylenebis- hexamethylene 8.94 g 4.94 g (cyclohexylamine) diamine 42.50 mmol 42.50 mmol 0.50 eq 0.50 eq C9 4,4-methylenebis- hexamethylene 11.92 g 3.29 g (cyclohexylamine) diamine 56.67 mmol 28.33 mmol 0.67 eq 0.33 eq C10 4,4-methylenebis- hexamethylene 13.41 g 2.47 g (cyclohexylamine) diamine 63.75 mmol 21.25 mmol 0.75 eq 0.25 eq C11 4,4-methylenebis- hexamethylene 14.30 g 1.98 g (cyclohexylamine) diamine 68.00 mmol 17.00 mmol 0.80 eq 0.20 eq C12 4,4-methylenebis- triethylene 13.41 g 3.15 g (cyclohexylamine) glycol diamine 63.75 mmol 21.25 mmol 0.75 eq 0.25 eq C13 4,4-methylenebis- triethylene 11.92 g 4.20 g (cyclohexylamine) glycol diamine 56.67 mmol 28.33 mmol 0.67 eq 0.33 eq C14 4,4-methylenebis- triethylene 8.94 g 6.30 g (cyclohexylamine) glycol diamine 42.50 mmol 42.50 mmol 0.50 eq 0.50 eq C15 4,4-methylenebis- triethylene 5.96 g 8.40 g (cyclohexylamine) glycol diamine 28.33 mmol 56.67 mmol 0.33 eq 0.67 eq C16 4,4-methylenebis- triethylene 4.47 g 9.45 g (cyclohexylamine) glycol diamine 21.25 mmol 63.75 mmol 0.25 eq 0.75 eq C17 diethylene triamine hexamethylene 1.75 g 7.90 g diamine 17.00 mmol 68.00 mmol 0.20 eq 0.80 eq C18 diethylene triamine hexamethylene 2.19 g 7.41 g diamine 21.25 mmol 63.75 mmol 0.25 eq 0.75 eq C19 diethylene triamine hexamethylene 3.69 g 6.59 g diamine 28.33 mmol 56.67 mmol 0.33 eq 0.67 eq C20 diethylene triamine hexamethylene 5.53 g 4.94 g diamine 42.50 mmol 42.50 mmol 0.50 eq 0.50 eq C21 diethylene triamine triethylene 8.30 g 3.15 g glycol diamine 63.75 mmol 21.35 mmol 0.75 eq 0.25 eq C22 diethylene triamine triethylene 7.38 g 4.20 g glycol diamine 56.67 mmol 28.33 mmol 0.67 eq 0.33 eq C23 diethylene triamine triethylene 5.53 g 6.30 g glycol diamine 42.50 mmol 42.50 mmol 0.50 eq 0.50 eq (eq = equivalent)

Example 4

Determination of the Minimum Inhibition Concentration of the Polymeric Guanidine Derivatives Used According to the Invention

(34) For testing the biocidal activity of the polymeric guanidine derivatives used according to the invention, the compounds prepared in accordance with one of the previous Examples are added to a bacterial nutrient medium, preferably tryptic soy broth, and diluted to different concentrations.

(35) These solutions of different concentrations are inoculated with a suspension of Escherichia coli and incubated at 37 C. for 24 hours.

(36) The minimum inhibition concentration (MIC) is the lowest concentration of the biocide to be tested in the solution that still inhibits the growth of the bacteria. In the corresponding solution, turbidity from the growth of the bacteria cannot be observed.

(37) For the homopolymers prepared in Example 1 and Example 2, corresponding to formula (I) and formula (V), and for the copolymers obtained from the comonomer mixtures C1 to C23 mentioned in Example 3, the minimum inhibition concentrations (MICs) as shown in Table 2 are obtained.

(38) TABLE-US-00002 TABLE 2 Determination of the minimum inhibition concentration of polymeric guanidine derivatives used according to the invention (MIC = minimum inhibition concentration). Compound MIC [g/ml] Control polymer 5 corresponding to 5 formula (I) corresponding to >250 formula (V) C1 7.5 C2 22.5 C3 25 C4 50 C5 1.5 C6 4.7 C7 4.25 C8 2.5 C9 3.5 C10 2.5 C11 9.75 C12 5.5 C13 8.5 C14 10 C15 10 C16 10 C17 3 C18 10 C19 10 C20 40 C21 >50 C22 >50 C23 >50

(39) A control polymer whose biocidal activity is known and whose minimum inhibition concentration is usually 5 g/ml was employed as a control.

(40) It is seen that all the polymeric guanidine derivatives used according to the invention, especially the copolymers used according to the invention, have a biocidal effect. In particular, copolymers having hexamethylene diamine as the second monomer show a minimum inhibition concentration that is even below 5 g/ml:

(41) TABLE-US-00003 TABLE 3 Selected copolymers used according to the invention having a particularly low minimum inhibition concentration (MIC). Monomer Monomer Reaction Copolymer 1 2 Mixing ratio conditions MIC C5 MBC HMD 1:4 5 h, 170 C. 1.5 C6 MBC HMD 1:3 5 h, 170 C. 4.7 C7 MBC HMD 1:2 5 h, 170 C. 4.25 C8 MBC HMD 1:1 5 h, 170 C. 2.5 C9 MBC HMD 2:1 5 h, 170 C. 3.5 C10 MBC HMD 3:1 5 h, 170 C. 2.5 C17 DETA HMD 1:4 5 h, 170 C. 3 (MBC = 4,4-methylenebis(cyclohexylamine), HMD = hexamethylene diamine, DETA = diethylene triamine).

(42) In the polymeric or oligomeric active ingredients having a biocidal activity, used according to the invention, wherein the active ingredient is a product of a polycondensation of a guanidine acid addition salt with a mixture of amines that contains at least one diamine and/or triamine, it is seen that it is particularly favorable if at least one amine is selected from 4,4-methylenebis(cyclohexylamine) and diethylene triamine. Conveniently, the guanidine acid addition salt is guanidine hydrochloride.

(43) It is further seen that the polymeric or oligomeric active ingredient can be a homopolymer. In this case, it is favorable if the mixture of amines consists of the triamine diethylene triamine, or if the mixture of amines consists of the diamine 4,4-methylenebis(cyclohexylamine).

(44) It is also seen that the mixture of amines can contain a first component and at least one second component, wherein the first component is a diamine or triamine selected from the group of 4,4-methylenebis(cyclohexylamine), diethylene triamine, and wherein the second component is a diamine or triamine selected from the group of 4,4-methylenebis(cyclohexylamine), diethylene triamine, hexamethylene diamine, triethylene glycol diamine, and wherein the first component is different from the second component.

(45) More preferably, the first component is 4,4-methylenebis(cyclohexylamine), and the second component is selected from diethylene triamine, hexamethylene diamine, triethylene glycol diamine. It is also favorable if the first component is diethylene triamine, and the second component is selected from hexamethylene diamine and triethylene glycol diamine.

(46) The first component and the second component are preferably in a mixing ratio of 4:1 to 1:4. The mixture of amines and the guanidine salt are preferably employed in approximately equimolar amounts.

(47) In the polymeric or oligomeric active ingredients used according to the invention, wherein the active ingredient is a product of a polycondensation of a guanidine acid addition salt with a mixture of amines that contains at least one diamine and/or triamine, it is seen that it is particularly advantageous if they are prepared by a process comprising the steps of providing about one equivalent of guanidine hydrochloride, adding about one equivalent of a mixture of amines containing one or two of the compounds of the group comprising a diamine having at least one cycloaliphatic residue, and dialkylene triamine, heating at 150 to 170 C., and stirring the melt at 150 to 170 C. until the evolution of gas is complete, but at least for 5 hours.

Example 5

General Protocol for Producing a Polyurethane-Based Catheter Tube from TPU Granules Treated with the Polymeric or Oligomeric Active Ingredient to be Employed According to the Invention

(48) An aliphatic thermoplastic polyurethane (based on a polytetramethylene glycol ether) is mixed with 10 to 35% by weight, based on the total mixture, of barium sulfate having an average particle size of 0.01 m to 10 m and 0.5 to 10% by weight of a polymeric or oligomeric active ingredient to be used according to the invention, and the mixture was extruded. The extrusion was performed using extruders as usual for catheter production, for example, the extruder Maillefer type ED45-30D.

Example 6

Production of a Catheter Tube

(49) The thermoplastic polyurethane Pellethane 2363-90A (Lubrizol Advanced Materials; U.S.A.) is mixed with 25% by weight barium sulfate having an average grain size of 0.7 m and 3% by weight of the active ingredient C20, and the mixture was extruded. The extrusion was performed using the extruder Maillefer type ED4530D at temperatures above 160 C.

Example 7

Comparative Example

(50) A piece of catheter tube according to Example 6 is prepared, but without adding a polyguanidine. The pieces of catheter tube prepared according to Examples 6 and 7 were examined by scanning electron micrographs. By optical microscopy, it could already be detected that the pieces of catheter tube according to the invention had a substantially smoother shape as compared to the pieces of catheter tube according to Comparative Example 7.

(51) In addition, the surface roughness R.sub.z [m] was measured. A surface roughness R.sub.z of 2.91 m was detected for Comparative Example 7, and a surface roughness R.sub.z of only 2.32 m was detected for the inventive piece of catheter tube according to Example 6.

Example 8

Comparative Example

(52) A piece of catheter tube according to Example 6 is prepared, but poly[2-(2-ethoxy)ethoxyethyl)guanidinium chloride] is employed in an amount of 3% by weight instead of the polyguanidine to be employed according to the invention.

(53) The pieces of catheter tube according to Example 6 (according to the invention) and according to Comparative Example 8 were subjected to a proliferation test.

(54) The proliferation test is based on the publication Nature Medicine, vol. 6, No. 8, 1053-1056; 2000. Thus, the pieces of catheter tube to be tested are contaminated with different germs, and then the germ growth is observed in comparison with a sample that has not been antimicrobially treated. The time required by the germ growth to reach a predefined value (0.2 onset OD) as compared to a sample that has not been antimicrobially treated is measured. The longer the time, the higher is the antimicrobial effectiveness of the sample against the individual germs.

(55) Table 4 shows the results of the proliferation test using different germs.

(56) TABLE-US-00004 TABLE 4 Germ Example 8 [h] Example 6 [h] MRSA 21.0 48.0 Staphylococcus 35.5 48.0 epidermidis Staphylococcus 26.8 48.0 aureus Pseudomonas 0.1 48.0 aeruginosa Enterococcus 0.3 48.0 faecalis Klebsiella 48.0 pneumoniae

(57) From the results in Table 4, it is clear that the pieces of catheter tube treated according to the invention are significantly more efficient against MRSA, Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa and Enterococcus faecalis.