WO2002100448A1

WO2002100448A1 - Antibacterial material

Info

Publication number: WO2002100448A1
Application number: PCT/AU2002/000772
Authority: WO
Inventors: Barrie David Cooper; Harry Knowles
Original assignee: Barrie David Cooper; Harry Knowles
Priority date: 2001-06-13
Filing date: 2002-06-13
Publication date: 2002-12-19
Also published as: CN1527728A; EP1401509A4; US20050008840A1; AUPR564301A0; JP2005501016A; EP1401509A1

Abstract

An antibacterial material, a method of producing an antibacterial material and a method of inhibiting infection during the treatment of wounds using an antibacterial material. The antibacterial including a fibrous substrate impregnated with a carrier and a controlled release biocide dispersed through the carrier.

Description

TITLE: ANTIBACTERIAL MATERIAL

The present invention relates to antibacterial material and in particular to material suitable as a dressing for wounds such as ulcerated or burned tissue.

The invention has been developed primarily for use in dressing wounds and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use. Background of the Invention

The treatment and dressing of slow healing open wounds has been a long-standing medical problem. Wound healing is an extremely complex biological process and there are many factors to be taken into account when considering the best possible treatment and dressing. Factors such as risk of infection, time of treatment and patient comfort are important considerations.

Ulcers are a particularly painful form of slow healing wound and are often difficult to treat due to underlying circulatory problems and the continuous risk of infection. Ulcers are secreting skin wounds which produce exudates such as blood, pus and other wound fluids. These fluids can accumulate in the wound cavity and form a rich pool of nutrients which promotes bacterial growth. This, in turn, delays or prevents the healing process, or in some cases leads to further tissue damage or even the possibility of systemic life threatening infection. It is would be desirable to allow such wounds to heal in a slightly moist environment provided infection can be controlled and excess wound exudates can be removed to prevent blisters forming under the dressing or the dressing becoming embedded in the woimd. Examples of conventional dressings used to protect open wounds and promote the healing process include traditional cloth, cotton or lint pads, non-adherent latex dressings and synthetic-algin coatings.

However, each of these dressings has drawbacks. Traditional dressings in direct contact with a wound can interfere with the healing process. This is particularly so with chronic ulcerated wounds because of the repeated mechanical impact and interaction of the bandage with the fragile and pressure sensitive tissues within the wound. This problem is amplified by the repeated dressing changes which are often required. In many cases because there is new tissue growth the dressings adhere to the wound. This makes them difficult to remove without disrupting the healing process.

Non-adherent latex dressings have a high rate of allergic reaction. Along with some other types of conventional dressings, they are unable to absorb exuded fluids at a rate commensurate with the rate of fluid production by the wound or alternatively, their fluid holding capacity is not significant to allow long periods of time in contact with the wound. The progressive build up of bacteria then delays healing and may also produce unpleasant odours.

Algin type dressings are designed to avoid adhering to healing wounds and for easy removal. They present the appearance of being coated with jelly-like substance. While these may avoid adhering to a healing wound, they have a propensity to go mouldy when exposed to bacteria filled fluids for extended periods.

There is a need for a wound dressing that can continuously inhibit the growth of bacteria and be easily removed from the wound. Moreover, it would be particularly desirable if the dressing could be left on the wound for a longer period of time than conventional dressings allow, in order to avoid disrupting the wound and thus accelerating the healing process. It is an object of the invention to overcome or ameliorate at least some of the disadvantages of the prior art, or to provide a useful alternative. Disclosure of the Invention

The present invention relates to an antibacterial material, a method of producing an antibacterial material and methods of inhibiting infection during the treatment of wounds using the antibacterial material of the present invention.

According to a first aspect, the present invention provides an antibacterial material including: a fibrous substrate impregnated with a carrier; and a controlled release biocide dispersed through said carrier.

According to a second aspect, the present invention provides a process for making an antibacterial material according to the first aspect, said process including: dispersing a controlled release biocide within a carrier to provide an active carrier mixture; and impregnating a fibrous substrate with said active carrier mixture.

According to a third aspect, the present invention provides a method of inhibiting infection during the treatment of wounds by applying an antibacterial material according to the first aspect to an affected skin area on a patient.

According to a fourth aspect, the present invention provides use of an antibacterial material according to the first- aspect in the manufacture of a dressing for inhibiting infection during the treatment of wounds.

The term "wound" includes tissue injury such as flesh wounds, mechanical injuries, ulcers, burns, open surgical wounds and lesions and also skin conditions such as acne. Preferably, the substrate is paper. The carrier is preferably propylene glycol, although other glycols may be used as carriers. Other suitable carriers include alcohols. Water based carriers may also be used. The biocide is preferably triclosan, mobile within the carrier. Other suitable biocides may also be employed. Detailed Description of the Invention

A preferred embodiment of the invention will now be described, by way of example only, with reference to several examples.

The antibacterial material includes a fibrous substrate impregnated with a carrier having a controlled release biocide dispersed therethrough. Once the controlled release takes place, the biocide is mobile within the carrier so that it can travel to the site of action.

In its preferred embodiment, the substrate is a substantially cotton cellulose fibre blend, most preferably a soft sheet of open weave paper. In other embodiments, the substrate may be creped paper which has a high surface area and increased stretch and flexibility. This enables the material in use to adapt readily to various configurations of the patient.

The preferred paper substrate has sufficient wet strength to be pulled intact from a wound. However, in some embodiments the paper strength may be selected to be disintegrable or dissolvable such that it can be washed out of a wound if necessary. The weight of the substrate may vary. Depending on particular requirements, the weight may be in the range of 50 to 200 gsm, more preferably in the range of 80 to 150 gsm, and most preferably in the range of 100 to 120 gsm.

Importantly, the biocide of the present invention is a controlled release biocide. In its preferred form, the biocide is encapsulated so as to be in a latent state capable of being activated by external stimuli. The encapsulation for example, may be by means of polypropylene microspheres for instance. The external stimuli may include pressure or light, in particular ultraviolet light. The level of antibacterial effect may be varied by increasing or decreasing the amount of biocide.

When the biocide is released from encapsulation, it is taken up in the carrier and dissolves therethrough.

The biocide itself is preferably triclosan. The preferred form of encapsulated

triclosan is that known under the trademark CANSAN^®TCH.

Triclosan is non-toxic and non-allergenic to humans and inhibits the growth of bacteria such as E. coli, Legionella or Staphylococcus and low titre viruses for example HIV. Preferably, the biocide is deactivated by blood serum such that it is effective in killing bacteria but has no effect on humans. Preferably, the biocide is present in an amount of 10 to 10,000 ppm of the carrier, depending upon the intended use.

For instance, use for dressings for non-serious wounds is 10-1,000 ppm biocide, or 10-200 ppm biocide in even less serious cases. For serious wounds, the concentration of biocide in the carrier is anywhere up to about 3,000-6,000ppm.

For other applications, such as handwipes, an amount of 10-100 ppm is found to be appropriate. For air conditioning filters, a concentration of about 100-500ppm biocide in carrier is an appropriate concentration. These concentrations are those which would be used when the carrier is applied at its preferred rate of 100 ml/m , or 1 litre of carrier per 10m². Appropriate adjustments to the concentration and rate of application to the substrate can be made to provide equivalent amounts of active if required.

Surprisingly, when triclosan itself is applied to wounds or dressings in a conventional manner, it is rapidly degraded by serum and becomes ineffective within a fairly short time. The encapsulated biocide is dispersed through a carrier which is preferably a glycol and most preferably propylene glycol. The carrier is applied to the substrate at a rate of between 80 and 120 ml per square metre, and more preferably around 100ml of the carrier is used per square metre of the substrate. As well as acting as a carrier to take the biocide to the necessary site of action, the humectant properties of propylene glycol keep the dressing damp and enable it to be easily removed from the wound.

The preferred method of adjusting the total amount of active in a dressing or other article of the present invention is through varying the concentration of active in the carrier, rather than by the alternative procedure of varying the amount of carrier applied to the substrate.

Preferably, the fibrous substrate further includes strengthening material, such as a nylon resin and most preferably a Kymene resin. Typically, the strengthening resin is present in an amount of around 0.01% to 0.06% by weight of the paper. Most preferably, the amount of Kymene resin is around 0.03%. The higher the amount of Kymene, the harder the paper. For example, air conditioning filters will have an amount of Kymene near the high end of the range as they require high strength.

The antibacterial material of the present invention has a wide range of possible applications in the medical, dental and veterinary fields. In its preferred form, the material is most suitable as a wound dressing. Unlike conventional dressings, which are changed daily, in its preferred form the material of the present invention can be left on the wound for extended periods of time, for example 3 to 4 days in some cases. By minimising the number of dressing changes the wound has a better chance of healing over a shorter period of total treatment time. The controlled release of active biocide kills bacteria or maintains a low bacterial population throughout this time, thus inhibiting infection and reducing odour. It will be appreciated that the material is particularly applicable to the treatment of sensitive skin wounds such as burns and ulcers.

Similarly, the material of the present invention may be adapted for use to inhibit infection during treatment of animal wounds such as injuries to the front forelegs of horses. The skin in this area is particularly thin and prone to injury. Such injuries behave like ulcers in that they are open and slow healing. The antibacterial material of the present invention can be used to accelerate the healing time of such wounds and thus return the horse more quickly to an active state.

The antibacterial material of the present invention has other uses in the field of infection control.

One such alternative use is as a dressing during dental surgery. Gum wounds have a tendency to become ulcerated because of the favourable conditions for bacterial growth. Triclosan can be applied to the buccal mucosa without adverse effects.

Another use is as a surgical barrier, such as a bib for the protection of surgeons, or as a sheet to protect patients. Any disruption to the surgical barrier would result in immediate release of the antibacterial agent from the antibacterial material of the present invention.

The antibacterial material of the present invention may also be used to wrap autoclaved instruments. The controlled release of active biocide ensures sterility for longer periods of time than wrapping with standard plastic material which is susceptible to bacterial infection.

In other embodiments, the material of the present invention may be employed as a wipe, including surface wipe to sterilise surfaces or a hand cleansing wipe to reduce the hand transfer of bacteria. It is well-known that hand to mouth transfer of bacteria is a major cause of bacterial infection. The material of the present invention may also be useful in the treatment of acne. It will be appreciated that the biocidal material of the present invention may be used with, for example, waterproof backing materials or elastic backed sticking plasters.

In still further embodiments, the material of the present invention may be used to combat airborne pathogens. Examples of this include production of medical or other microbiologically protective masks formed from the antibacterial material.

The antibacterial material of the present invention may also be adapted for use as an air conditioning filter to combat Legionella or other bacteria in the recirculated air within air conditioning ducts. Breakdown of the encapsulated biocide is proportional to the air flow velocity through the filter. Thus, when air flow (and consequently bacterial flux through the filter) is high, the amount of triclosan released is also high. When the air flow is off, there is not a significant increase of airborne bacteria, and nor is there significant further release of triclosan. Thus, the biocide is delivered when it is needed, and is not overproduced during times of low demand. The antibacterial material of the present invention can be easily cut to any size, contributing to its wide range of applications.

By its very nature, the preferred material of the present invention is inherently sterile in its packaged form and is not fully activated until placed in use. This avoids the necessity for complex autoclaving procedures. The packaged material of the present invention can be treated with gamma radiation in order to verify that the material is sterile. Should any damage occur to the packaged material the damage itself releases the biocide to inhibit bacterial contamination.

Manufacture of the preferred material includes the step of producing an open weave paper by conventional methods. However, before the final drying stage, the paper is sprayed with the carrier, which may be an aqueous carrier, an alcohol or a glycol, such as propylene glycol containing a dispersion of encapsulated triclosan at the requisite concentration for the intended purpose and then drying the paper with heat.

For preference, roller drying is not used after the encapsulated biocide has been applied.

The mechanical effect of packaging the dressing in a sealed package means that the paper of the present invention is self-sterilising when packaged. The material of the present invention thus avoids the need for expensive and complex autoclaving.

It will be appreciated that reduction in the amount of latex and plastics materials normally used in many of the above-mentioned applications hugely reduces waste levels as well as costs. The following examples illustrate preferred embodiments of the invention adapted for particular applications.

Example 1. Dressing for non-serious wounds:

CANS AN ®TCH 1 ,000ppm available triclosan

Propylene glycol 100ml Open weave paper lm²

Kymene resin 0.03% by weight of paper

Example 2. Dressing for serious wounds:

CANSAN ®TCH 3,000ppm available triclosan

Propylene glycol 100ml Open weave paper lm²

Kymene resin 0.03% by weight of paper

Example 3. Air conditioning filter:

CANSAN ®TCH 500ppm

Propylene glycol 100ml Open weave paper lm² Kymene resin 0.06% by weight of paper

Example 4. Hand wipe:

CANSAN ®TCH 80ppm

Propylene glycol 100ml Open weave paper lm

Kymene resin 0.03% by weight of paper

The following tests demonstrate the effectiveness of the preferred embodiment of the invention against several known forms of bacteria.

Example 5. Determination of the antimicrobial activity of Paper Sheet, treated with CANSAN^® TCH

In Test 1, the antimicrobial activity of the different antibacterial Paper Sheets, treated with Cansan TCH has been determined under agar diffusion test conditions. In Test 2, the remaining antibacterial effect on hands after usage of the Cansan

^®TCH containing Paper Sheets have been tested under in- vivo fingerprint test conditions against gram-positive and gram-negative bacteria.

Example 5. Test 1:

Samples: Paper Sheets

Cansan TCH sprayed on hand Sheets

Microbiological evaluation 1. Determination of the bacteriostatic activity according to the bacterial growth inhibition test.

Principle:

Discs with a diameter of 2cm were punched out from the hand Sheets. The discs were applied on the top layer of the solidified agar containing the bacteria. For the preparation of the top agar layer, from overnight cultures, a 1 : 100 (Staphyloccocus aureus and Micrococcus luteus) and a 1:1000 (Escherichia coli) dilution were made and 3.5 ml of the dilutions were added to 500 ml agar. Test bacteria: Staphylococcus aureus ATCC 9144

Escherichia coli NCTC 8196 Nutrient medium: Casein soy meal pepton agar (two layers of agar: 15 ml bottom layer without germs and 5 ml top layer with bacteria)

Incubation: 18-24 hours at 37°C.

Results

Legend: Zl = zone of inhibition in mm VR = Vinson rating, for growth under the disc

0 = strong growth (no activity) 4 = no growth (good activity) LJ. Vinson et al. J.Pharm. Sci. 50, 827-830, 1961

Example 5. Test 2: Finger print test

In vivo test for determination of the bacteriostatic activity of a product that contains an antimicrobial agent. Samples: Paper Sheets Cansan TCH sprayed on Hand Sheets

Test bacteria: Staphylococcus aureus ATCC 9144

Escherichia coli NCTC 8196

Nutrient medium: Casein soy meal pepton agar

Incubation: 24 hours at 37°C

Principle:

1. The hands were wetted for 15 sec. under running tap water.

2. Hands were washed with a placebo soap, rinsed with tap water and dried.

3. Filter paper discs (2 cm diameter) soaked with ethanol were placed in sterile plates. The fingertips were applied on the filter paper discs for 30 sec. in order to allow a migration of Cansan due to the excellent adsorption of ethanol. After 1 minute contact time, the filter discs were dried in the plates and then placed in the middle of agar plates containing the test germs (placebo sample).

4. The hands were rinsed under running lukewarm tap water and subsequently washed with the placebo soaps for 60 seconds. Subsequently the later was washed off under running lukewarm tap water. The hands have been dried with the test Paper Sheets for 1 minute.

5. Ethanol soaked filter paper disks (2 cm diameter) were placed in sterile plates and the same procedure as described under 3. has been performed. 6. The procedure after application of the test Sheets in order to determine the activity of Cansan ^®TCH on the skin. 7. The plates were incubated under optimal conditions according to the germ's requirements on temperature and media.

Due to the diffusion of the antimicrobial ingredient from the filter into the surrounding agar medium the growth of the test germs is inhibited in the diffusion zone. For the assessment of the bacteriostatic activity, zones of inhibition around the filter discs are measured and given in mm. Example 5 Results

Cansan TCH sprayed on Sheets

Each test was performed twice and both results are given in the table.

Zl = Zone ofinhibition in mm Vr = Vinson rating 0 = strong growth (no activity) 4 = no growth (good activity) Example 5 Conclusions

The Paper Sheets with Cansan ^®TCH showed good antibacterial effects against gram-positive and gram-negative test bacteria under agar diffusion test conditions where the Paper Sheets were in direct contact with the contaminated agar.

In order to show the effects under real in- vivo test conditions, an in- vivo finger print test has been performed. For this test the hands were washed with a placebo soap and dried with Cansan containing Paper Sheets.

It was possible to show clear antibacterial effects on the hands, dried with the "antibacterial Sheets". The results show clearly, that the use of Cansan ^®TCH containing Paper Sheets can help to protect the hands from growth of pathogenic bacteria and increase the hygiene on hands.

Example 6. Preliminary Patient Test A patient with a leg ulcer had the ulcer dressed with the antibacterial material of the present invention. The dressing was changed after 3 days, and the condition of the wound was observed after one week.

The natural healing of the wound was scored by a registered nurse as being 8/10. A normal natural healing score for a leg ulcer dressed with a conventional dressing is expected to be around 4/10. While there is a degree of subjectivity in the scores, the preliminary test result is believed by the present applicants to be significant. The dressing was readily removed, and did not adhere to the wound. Conventional dressings would be expected to adhere to the wound to varying degrees after only about one day, which is the life span of the dressing. The condition of the dressing was also examined and triclosan was determined to be present. It was estimated that the dressing could be used for a further.period, possibly being allowed to remain untouched on the wound for as long as 4-5 days. Example 7. Preliminary Patient Test

A medical practitioner applied a dressing according to the present invention on the skin ulcers of six patients. The dressings of the present invention maintained a high standard of cleanliness of the wounds. After 2-3 weeks, the wounds exhibited accelerated healing relative to comparable ulcers dressed with conventional dressings. Example 8. Preliminary Patient Test

A medical practitioner applied a dressing of the present invention to a minor burn as a result of scalding. The dressing contained lOOppm Cansan TCH in propylene glycol (applied at 100ml per square metre) impregnated onto 120gsm paper. After five days, the bum was almost completely healed, with only slight signs of scarring.

Although the invention has been described with reference to specific tests and examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS :-

I . An antibacterial material including: a fibrous substrate impregnated with a carrier; and a controlled release biocide dispersed through said carrier. 2. An antibacterial material according to claim 1, wherein said biocide is mobile within said carrier.

5. An antibacterial material according to claim 1 or claim 2, wherein said substrate is a substantially cellulose fibre blend.

6. An antibacterial material according to any one of the preceding claims, wherein said substrate is paper.

7. An antibacterial material according to claim 6, wherein said paper has an open weave configuration.

8. An antibacterial material according to any one of the preceding claims, wherein the weight of said substrate is in the range of 50 to 200 gsm. 9. An antibacterial material according to claim 8, wherein the weight of said substrate is in the range of 80 to 150 gsm.

10. An antibacterial material according to claim 9, wherein the ^'weight of said substrate is in the range of 100 to 120 gsm.

I I . An antibacterial material according to any one of the preceding claims, wherein said substrate dissolves in water.

12. An antibacterial material according to any one of the preceding claims, wherein said biocide is in a latent state capable of subsequent activation by external stimulus.

13. An antibacterial material according to claim 12, wherein said external stimulus is pressure.

14. An antibacterial material according to claim 12, wherein said external stimulus is light.

15. An antibacterial material according to claim 14, wherein said light is ultraviolet light. 16. An antibacterial material according to any one of claims 12 to 15, wherein said biocide is encapsulated.

17. An antibacterial material according to claim 16, wherein said encapsulation is adapted to release biocide at a predetermined effective rate in response to said external stimulus. 18. An antibacterial material according to any one of the preceding claims, wherein said biocide is inactivated by blood serum.

19. An antibacterial material according to any one of the preceding claims, wherein said biocide is non-allergenic to humans.

20. An antibacterial material according to any one of the preceding claims, wherein said biocide inhibits the growth of E. coli, Legionella or Staphylococcus.

21. An antibacterial material according to any one of the preceding claims, wherein said biocide is triclosan.

22. An antibacterial material according to claim 21, wherein said triclosan is that

known under the trademark CANSAN ®TCH.

23. An antibacterial material according to any one of the preceding claims, wherein said biocide is present in an amount of 10 to 10,000 ppm.

24. An antibacterial material according to any one of the preceding claims, wherein said carrier transports said biocide to the site of action.

25. An antibacterial material according to any one of the preceding claims, wherein said carrier is a glycol.

26. An antibacterial material according to claim 25, wherein said glycol is propylene glycol.

27. An antibacterial material according to any one of the preceding claims, wherein 100 ml of said carrier is used per m² of said substrate. 28. An antibacterial material according to any one of the preceding claims, wherein said material further includes a nylon resin.

29. An antibacterial material according to claim 28, wherein said nylon is a Kymene resin.

30. An antibacterial material according to any one of claims 1 to 29, wherein said material is adapted for use as a wound dressing.

31. An antibacterial material according to any one of claims 1 to 29, wherein said material is adapted for use as a wiping cloth.

32. An antibacterial material according to any one of claims 1 to 29, wherein said material is adapted for use as an air conditioning filter. 33. A process for making an antibacterial material according to any one of the preceding claims, said process including: dispersing a controlled release biocide within a carrier to provide an active carrier mixture; and impregnating a fibrous substrate with said active carrier mixture. 34. A method of inhibiting infection during the treatment of wounds by applying an antibacterial material according to any one of claims 1 to 30 to an affected skin area on a patient.

35. A method according to claim 34, wherein said wound is an ulcer.

36. A method according to claim 34, wherein said wound is a burn.

37. Use of an antibacterial material according to any one of claims 1 to 30 in the manufacture of a dressing for inhibiting infection during the treatment of wounds.

38. Use according to claim 37, wherein said wound is an ulcer.

39. Use according to claim 37, wherein said wound is a burn. 40. An antibacterial material, substantially as herein described with reference to any one of the examples but excluding comparative examples.

41. A process for making an antibacterial material, substantially as herein described with reference to any one of the examples but excluding comparative examples. 42 A method of inhibiting infection, substantially as herein described with reference to any one of the examples but excluding comparative examples.

43. Use of an antibacterial material in the manufacture of a medicament, substantially as herein described with reference to any one of the examples but excluding comparative examples.