WO1986002561A1

WO1986002561A1 - Plastic object containing chlorhexidine and a process for producing the object

Info

Publication number: WO1986002561A1
Application number: PCT/SE1985/000430
Authority: WO
Inventors: Johan Brohult; Per Edenroth; Björn WERNER
Original assignee: Johan Brohult; Per Edenroth; Werner Bjoern
Priority date: 1984-11-02
Filing date: 1985-11-01
Publication date: 1986-05-09
Also published as: SE8405504D0; AU5015585A; SE8405504L; EP0199792A1

Abstract

Plastic object intended for extended contact with living tissue, for example catheters, mainly consisting of a hydrophobic plastic, whereby it contains at least in connection with the surface chlorhexidine in a bactericidally effective amount; and process for the manufacture of such plastic objects using extrusion of a thermoplastic.

Description

Plastic object containing chlorhexidine and a , process for producing the object

The present invention relates to plastic objects which in practical use are in extended contact with living tissue. The in- ^ S vention also relates to a process for the manufacture of such plas tic object. Plastic objects are known which are intended for im¬ plantation in the body or insertion in different parts of the bo¬ dy. Examples of such plastic objects are catheters, plastic pro- stheses of different types etc. One problem in using such plastic

10 objects consists in the extended contact with surrounding tissue causing undesirable infections. Such problems arise for example nearly always in connection with urinarytract catheters resulting, in addition to the inconveniencies for the patient that the infec¬ tion causes, that the catheter has to be replaced at relatively

15 short intervals.

Different attempts to solve the problem have been made, mainly by trying to attach to the surface of the catheters anti- biotically or germicidally acting substances. However, hitherto no satisfactory solution to the problem has been found.

20 The present invention thus has for its object to provide a plastic object of the above-described type whereby the problem indicated is eliminated or at any rate substantially reduced. The invention also has for an object to provide a process for the manu facture of such plastic objects.

25 The present invention is based on the use of the bacteri¬ cidally active substance chlorhexidine known per se the system¬ atic chemical name of which is 1 , 1 '-hexamethylenebis[5-(4-chloro- pheπyDbiguanide] having the following structural formula:

30 Cl - - NH-C-NH-C-NH- (CH₂) ₆-NH-C- H-C-NH ^■ V Cl

\— —. / «ι tt it it \ / ffl NH H NH

This substance of the trivial name chlorhexidine is an active antiseptic with bactericidal effect against gram-posi- 35 tiveas well as gram-negativebacteria. In connection with the pre¬ sent invention it has now been surprisingly found that the substan ce chlorhexidine can be introduced in hydrofobic plastics, so that these, at least in connection with the surface of the plastic ob¬ ject, contain the substance chlorhexidine • Thereby, the plastic object in use causing extended contact with living tissue ob¬ tains a substantially reduced infection risk in that bacterial growth in connection with the plastic object is avoided or at any rate strongly inhibited. It is surprising- that the bacteri- cidal properties of the chlorhexidine are maintained in spite of the fixation i the hydrofobic plastic, and even if the in¬ vention is not limited to any specific theory concerning the mechanism of fixation it is conceivable that the chlorhexidine molecule is folded double in some manner so that the hydrofobic hydrocarbon chain in the middle is fixed in the plastic, where¬ as the bactericidally active terminal parts are externally acce¬ ssible.

The chlorhexidine may be baked into the plastic mainly only in the surface layer of the plastic object but may alter- natively be distributed across the whole mass of the plastic^' object.

In view of the process for the manufacture of the plastic objects according to the invention which will be described in detail below suitable plastics foτ the manufacture of the plast- ic objects are hydrofobic plastics of a thermoplastic nature.

The character of the plastic or polymer in other respects is not chritical, since the ichlorhexidine seems to be fixed by some sort of mechanical anchorage whereby the exact chemical compo¬ sition of the plastic is not critical. Particularly preferred plastics or polymers are thermoplastic products prepared by a addition polymerisation from vinyl monomers, such as ethylene, vinyl chloride, styrene or propylene. Also other polyolefins are useful, for example polybutenes. Particularly preferred are polyethylene, polypropylene and polyvinyl chloride. A bactericidally effective amount of the chlorhexidine is suitably at least about 0.1 by weight based on the part of the plastic material containing chlorhexidine . A preferred quant ity range with regard to chlorhexidine is about 0.5 to about λ % by weight. The invention provides, as previously indicated, also the process for the manufacture of the plastic object, and this process comprises extrusion of a thermoplastic in a manner known per se, the thermoplastic in connection with the extrusion but before cooling or self-cooling of the thermoplastic after leaving the nozzle being supplied with chlorhexidine in solid form in the desired quantity. For the manufacture of plastic objects wherein the chlorhexidine is substantially evenly distributed in the whole mass of the plastic object the chlorhexidine is added to the thermoplastic before feeding into the extruder and is suitably admixed with the plastic granules used before transferring same to the place of feeding the extruder.

Alternatively, the ichlorhexidine can be supplied to the thermoplastic in connection with the extrusion nozzle, and in this alternative procedure the chlorhexidine is found mainly only in the surface layer of the plastic object. This latter alternative does, of course, result in a lesser consumption of chlorhexidine - , since the other parts of the plastic object will not contain the substance in question.

The manufacturing technique is wholly conventional and can be carried out using a plastic extruder, for example equip¬ ped with a feeding funnel, a feeder screw surrounded by a temp¬ erature controlling mantle, heating means and a suitable nozzle. In this case the chlorhexidine may thus be supplied either to the plastic material and admixed therein before feeding into the feeding funnel or may be supplied at a later stage in the extrusion process, either before or in connection with the nozz¬ le by spraying the chlorhexidine in pulverulent form. The present invention will in the following be described in connection with non-limiting examples. The plastics used in these examples are polyethylene and polyvinylchloride of the types shown. The area of use of the plastic object according to the invention is of such nature that the material used should, of course, possess medicinal tolerability.

In the following examples test catheters are manufactured by extrusion in a conventional extruder having a feeding funnel, a feeder screw surrounded by a temperature controlling mantle, for a heat-transfer medium and the usual means in connection with the extrusion nozzle. The chlorhexidine is supplied in pulveru¬ lent form either by spraying of the plastic material in the area immediately ahead of the extrusion nozzle or by admixture in the plastic material used before feeding into the feeding funnel. In the former case no exact knowledge will be obtained about the contents of chlorhexidine in the surface of the catheter prepared, whereas in this later case the content can be calcu¬ lated starting from the quantity of chlorhexidine admixed with the plastic. EXAMPLE 1

In the present example there is used as a starting ma¬ terial for the manufacture of catheters a PVC-plastic obtained from Thevinyl AB, Sweden, which is stated to be of the type GFM, i.e. PVC of suspension type. This plastic is medicinally tolerab¬ le and accepted by FDA, USA. The chlorhexidine. is supplied by spraying of powder into the extruder immediately before entering of the material into the extrusion nozzle.

For investigating the bactericidal properties of the ca- theters made tests were performed using a number of different test bacteria. The test strains were taken from positive urina¬ ry cultures showing significant growth. As nutrient media there were used nutrient broth (Bidife, Milano, Italy) prepared accord¬ ing to the instructions of the manufacturer and transferred in quantities of 5 mis in test tubes before sterilization. As a so¬ lid medium there was used test agar (PDM antibiotic sensitivity medium, AB Biodisk) prepared according to the instructions and transferred into \ 9 cms sterile petridishes.

For the manufacture of inoculate there was used (a) coli- form bacteria. Suspension of 5 colonies in 1 ml sterile 0.9% sa¬ line. While using a graded plastic loop 1 ,ul of suspension was transferred into 1 ml of saline.

(b) staphylococci, enterococci, streptococci Group B. 5 colonies are suspended in 5 is 0.91 saline; (c) beta- and alphastreptocci. 10 colonies are suspended in 1 ml 0.9 saline.

A tube containing 5 mis of broth was inoculated with one drop CO.025 ml) of bacterial suspension. A 4 cm piece of the ca¬ theter is placed in tubes and incubation is performed over night at 37 C. The growth is visually controlled. Each series consists of treated catheters and controls with untreated catheters and only inoculated tubes. The results of the experiments as carried out are shown in following Table 1. In all cases growth of the test strain was observed both in tubes with treated catheters and with untreated catheters.

TABLE 1

Bacterial strain Number of Number show¬ No growth tests ing growth

Esh. coli 31 0 31

Klebsiella spp 13 10 3

Proteus mirabilis 15 5 10

Proteus vulgaris 2 2 0

Ps auriginosa 12 4 8

Enterococcus 13 3 10

Staph.saprophyticus 5 0 5

Staph.aureus 8 0 8

Staph.epidermidis 18 6 12

&-strep, group B 8 0 8

As is clear from the table in the majority of cases no growth of the respective bacterial strains was obtained. EXAMPLE 2

Catheters were made from the same plastic material as in Example 1 but this time while adding the chlorhexidine in the starting material by admixing therein before transfer to the fee¬ der funnel. The following quantities chlorhexidine were added: est catheter A1 0.5 g chlorhexidine per kg of plastic

11 II A2 1.0 g " ^{It fl M}

It It A3 2.0 g " ^{it ι}ι ι^ι " It " It A A44 5.0 g " " " "

It II A5 10.0 g .. .. ^M All catheters were tested against 22 different strains of E.coli, the growth being made submersive to ensure that the test strain grew and not a contaminant. The results of these tests are presented in Table 2. TABLE 2

Catheter Strain A1 A2 A3 A4 A5 ε. coli 6 0 7 0 8 o o 9 o 0 0 10 + + o o 11 + + + o 12 + + o o 13 o 0 o o 14 o 0 0 o 15 + + o 0 16 0 0 o 17 + + o 18 o o 0 19 o 0 20 o 21 o o. 22 o 0 23 + o 24 o o 25 o o 26 o 0 27 o 0

Mote + = growth of test strain o = no growth The table speaks its clear language and shows that a quantity of chlorhexidine of about 0.05 does not give any effect on growth, whereas at increasing concentration the chlor- hexidine inhibition of the growth increases. Even if in many cases a concentration of 0.2°s of chlorhexidine gives an effect it is clear from the table that it is preferred to use a quanti¬ ty of hexidine of at least about 0.5 by weight, whereas for eco¬ nomical reasons it does not seem to be necessary to increase the concentration over about 1 % by weight. EXAMPLE 3

Catheters were manufactured in accordance with the tech¬ nique according to Example 2 but instead of polyvinylchloride there was used a highmolecular polyethylene of low density of

® the type Lupolen 1810D from BASF, DDR. Experiments were carried out with 12 different E.coli-strains while adding (chlorhexidine to the plastic starting material in a quantity of 2 and 5 gs per kg, respectively. The results of the experiments are shown in

Table 3.

TABLE 5 _ Polyethylenecatheter

Bacterial strain 2 gs/kg 5 gs/kg

E. .COli 1 +

2 +

3 +

4 +

5 + O)

^■6 +

7 +

8 +

9 O)

10 +

11 +

12

Note. +=growth and -= no growth Further experiments have been made which verify the fact that autoclaving or washing of the plastic catheters con¬ taining _'chlorhexidine does not have any significant effect with regard to the bactericidal activity. Thus, the chlor - hexidine is strongly anchored in the plastic, whereby the bactericidal effect can be maintained for a long period of time. In using the plastic objects according to the present invention thus for example catheters made in accordance with the invention can be left in position for longer periods of time without non-desirable infections arising.

Claims

1. A plastic object intended for extended contact with living tissue, for example catheters , mainly consisting of a hydrophobic plastic, characterized thereby that it at least in connection with the surface contains •chlorhexidine in a bactericidally effective amount.

2. A plastic object according to claim 1, characterized thereby that the chlorhexidine is baked into the plastic at least in the surface layer of the plastic object.

3. A plastic object according to claim 1 or 2, charac¬ terized thereby that the chlorhexidine is distributed in the whole plastic object.

4. A plastic object according to any preceding claim, characterized thereby that the hydrophobic plastic is poly- vinylchloride.

5. A plastic object according to any of the claims 1-3, characterized thereby that the hydrophobic plastic is a polyolefin . f°^r example polyethylene or polypropylene.

6. A plastic object according to any preceding claim, characterized thereby that the chlorhexidine is present in an amount of at least about 0.1% by weight based upon the part of the plastic containing same.

7. A plastic object according to claims 3 and 6, characterized thereby that the chlorhexidine is present in an amount within the range about 0.5 - about 1 % by weight.

^'8. A process for the manufacture of a plastic object according to claim 1 , containing extrusion of a thermoplastic in a manner known per se, characterized thereby that the ther¬ moplastic in connection with the extrusion and before the cool¬ ing or self-cooling of the thermoplastic after leaving the nozzle is supplied with chlorhexidine in solid form in the desired quantity.

9. A process according to claim 8, characterized the¬ reby that the chlorhexidine is added to the thermoplastic before feeding into the extruder thereby being distributed mainly evenly in the plastic object.

10. A process according to claim 8, characterized thereby that the chlorhexidine is added to the thermoplas¬ tic in connection with the nozzle, whereby it is found main¬ ly only in the surface layer of the plastic object.