WO2001091681A1

WO2001091681A1 - Wound dressing

Info

Publication number: WO2001091681A1
Application number: PCT/EP2001/006194
Authority: WO
Inventors: Colin Marshall; Volker Fritz Achterberg; Klaus Alfred Ruhnau; Andreas Matthias Von Der Weth
Original assignee: Ucb S.A.
Priority date: 2000-06-01
Filing date: 2001-05-31
Publication date: 2001-12-06
Also published as: GB0013186D0; CA2411240A1; AU2001277498A1; EP1289457A1

Abstract

Wound dressings consisting of a self supporting cellulosic films having two substantially parallel and opposed surfaces made by a non-microbiological (preferably regenerative) method with a wet flatness less than about 35 seconds. Preferably average thicknesses are up to about 2 mm, and water permeabilities are at least about 100 g/m2.d. They preferably have a molecular weight cut off such that micro-organisms are substantially prevented from crossing them, (film-pore size preferably less than about 1 µm), have haze values of at least about 10 %, and an average surface roughnesses of at least about 10 ml/min. The films can include particles in amounts of from about 0.5 % to about 25 % of the total film weight, the particles preferably being substantially on or near at least one film surface. The mean dimension of the particles along their longest axis is preferably from about 5 mµ to about 5 mm. The particles are preferably cellulose fibers from a wood source.

Description

WOUND DRESSINGS

The present invention relates to the field of cellulosic films which are optionally useful in the preparation of wound dressings.

A wound can be considered any damage to the epidermis and/or dermis of the human or animal body however caused (for example any abscess, abrasion, blister, boil, blotch, burn, carbuncle, cosmetic affliction, cut, dermatological pathology, furuncle, graft donor site, incision, injury, lesion, pimple, pustule, skin graft [e.g. autogeneous, allogeneic and/or donor], sore, trauma, ulcer and/or wound). For example a wound may be caused by any external insult, disorder, disease, injury, surgery, treatment and/or underlying condition.

Therefore the field of wound dressing relates to means for locating adjacent a wound on a human or animal body any device or composition (for example a cataplasm, cream, dressing, emulsion, film, granulate, gauze, liquid, medicament, patch, plaster, poultice, powder, protecting material and/or sheet) as part of a local, non-systemic, topical method for the diagnosis, prophylaxis, surgery, therapy and/or treatment of a wound.

Skin wounds have always been a grave problem to be confronted by medicine, particularly those caused by burns. In these cases, the patient suffers extensive hydro-electrolitic losses, these losses being greater as the extent of the burned area increases. There is a critical period of approximately 36 hours in which substantial loss of blood fluids occurs in the burned region. After this period, this fluid loss is interrupted by the closure of the tissues, and the opposite effect is noted, i.e. a fluid retention which causes swelling. In cases where the area affected is great, the consequences can be fatal.

These extreme symptoms provoked by loss of skin through burns from heat radiation or , chemical products also occur to a lesser extent in cases where skin loss is occasioned by abrasion or other mechanical causes. The conventional treatment, which is long and painful, consists in the continued application of medications, such as ointment, lubricated gauze, and bandages for retaining the gauze in place. The affected region is kept covered, and the patient receives large doses of antibiotics to prevent infection. For many years the above described problems have been tackled by applying skin substitutes to the affected area. The incessant search for solutions to these problems is illustrated by a vast bibliography of more than 120 studies published in the last ten years throughout the world, concentrating on attempts to find a skin substitute having the same properties and characteristics as human skin. A material for protecting an externally wounded or burnt skin at an accident or disaster, to promoting regrowth of the epidermis and healing of the wound is also known as vulnerary cover, artificial skin and/or wound dressing. A wide variety of products are currently available in the medical field for such uses.

The FDA currently define five categories of wound dressing in their regulatory framework (which are defined below) and the field of wound dressing includes but is not limited to dressings which fall into any of these categories, i) Nonresorbable gauze/sponge dressings for external use These are sterile or non-sterile devices intended for medical purposes, such as to be placed directly on a patient's wound to absorb exudate. They comprise a strip, piece or pad made from open woven or non-woven mesh cotton, cellulose or a simple chemical derivative of cellulose, ii) Hydrophilic wound dressings Available in sterile or non-sterile form, hydrophilic wound dressings are intended to cover a wound and to absorb exudate. They comprise non-resorbable materials with hydrophilic properties that are capable of absorbing exudate (e.g. cotton, cotton derivatives, alginates, dextran and/or rayon), iii) Occlusive wound dressings Occlusive dressings are non-resorbable, sterile or non-sterile devices intended to cover a wound, to provide or support a moist wound environment, and to allow the exchange of gases such as oxygen and water vapor through the device. They comprise a piece of synthetic polymeric material, such as polyurethane, with or without an adhesive backing, iv) Hydrogel wound and burn dressings These dressings, available in sterile or non-sterile form, are intended to cover a wound, to absorb wound exudate, to control bleeding or fluid loss, and to protect against abrasion, friction, desiccation and/or contamination. They comprise a non-resorbable matrix made of hydrophilic polymers and/or other material in combination with at least 50% water and are capable of absorbing exudate. v) Interactive wound and burn dressings

These products contain added drugs such as antimicrobial agents or added biologies such as growth factors and/or comprise materials derived from animal sources.

Plain and medicated gauze-type dressings are widely employed in hospitals after major surgery and also in the home for minor accidental injuries. Gauze pads wetted with physiologically acceptable fluids such as glycerol have been suggested for use as tissue drapes to prevent exposed organs from surface drying during extended surgical procedures. Gauze pads impregnated with antibacterial agents may be used as wipes to clean and disinfect or otherwise treat skin areas. Wide-mesh gauze impregnated with hydrophobic ointments such as paraffin is widely used as a non-adherent dressing to cover large surface wounds.

However, in spite of their wide acceptance, the gauze-type dressings are not without their disadvantages. For instance, frequent changes of such dressings are necessary in order to observe the healing process and to apply medication. Such changes are often accompanied by discomfort to the patient since some adherence to the wound or wound exudate normally occurs. Moreover, the gauze-type dressings do not protect the wound from extraneous bacteria nor do they control the proper moisture balance favourable to healing. Gauze is not lint-free and the deposition of lint on wound surfaces is considered undesirable.

To date, the following human skin substitutes exist. Autologous grafting, in which skin is taken from another location on the patients body and heterogeneous grafting, which may be of two types. The first type is where either human skin from donors or cadavers, or amniotic membrane from donors may be used. The second type is where skin from pigs or bovine embryos, or artificial skins such as silicon, collagen, mixtures of collagen and silicon, or polytetrafluoroethylene polyurethane are used.

Autologous grafting involves a surgical operation, extracting an area of the patients own skin from an selected donor region, to be immediately applied over the wound. Since this causes a trauma equivalent to a second degree burn, this is only justifiable in patients who have third degree burns.

The first method of allogeneic grafting uses human skin from donors, and this method is extremely rarely used since as well as requiring donors to submit themselves to extensive traumas, the benefits of this type of grafting are transitory as the graft only lasts for a maximum of two weeks. Grafting human skin from cadavers is almost never used, due to the inherent difficulties in obtaining cadavers at the appropriate time, together with their entire medical histories. There also exist ethical and legal difficulties, as well as objections from the family of the deceased. Use of an amniotic membrane requires a careful choice of donor, and the total absence of risk of contamination. The membrane must be prepared by a specialised team in a medical centre, and must be done within twelve hours. Like artificial skin substitutes, amniotic membranes are not durable lasting no more than a week.

Among the various animal skins exhaustively tested for use as human skin substitutes, pigskin can give good results as with the correct preparation can give this skin anatomic characteristics similar to human skin. Recently, lyophilised pig skin (LPS) has been used. LPS is soft and has a good adhesion to a wound and is superior in that it promotes regrowth of the skin. However, the care required in the choice of animal and the preparation of a piece of skin make this option extremely laborious and complex. For example pigskin must be stored under refrigeration (maximum temperature 4°C) in physiological serum with antibiotics. This skin once applied to the patient has a limited durability of two weeks.

Various studies have been carried out over the years in attempts to use synthetic products as skin substitutes for lesions where skin loss has occurred. One type of a completely synthetic skin is prepared totally from synthetic substances such as silicon, polyurethane, but these have not yet passed through the investigative stage and no product has been placed on the market.

The second type of synthetic film is of an organic material prepared from derivatives of animal blood such as for example collagen and is prepared from two integral layers (for example a non-woven fabric or film comprising collagen complexed with a silicone film). Such films have no antigenic properties and can be sterilised. The layer which enters into contact with the lesion is formed from dried organic material (preferably derived from animal blood, in which case the film has excellent absorbing properties and is not irritating to the human body, but since the starting material is expensive, such film is not easily available). The other layer is silicon, polyurethane, or the like and functions as a support, this layer being exposed. The organic part is absorbed by the organism, and the support is then rejected.

However vulnerary covers formed from LPS or collagen are readily decomposed by a protease and fuse causing contamination. Accordingly, it is necessary to frequently renew such dressings.

Various other polymeric materials have been investigated for use in the treatment of wounds, burns, and other skin disorders. Thus polyvinyl alcohol, gelatin, and a wide variety of polymeric materials have been disclosed in the literature as being useful in the treatment of accidental and surgical wounds. For example a complex of a polyamino acid film and a synthetic polymer film has been proposed as a wound dressing. Although such films are not decomposed by protease, they must be supported by an appropriate support such as a silicone film and thus the manufacturing process is complicated.

Hydrophilic polymer gels of polyethylene oxide and their use as wound dressings are described in U.S. 3,419,006 and suggested to be particularly useful in the treatment of bums, surgical and accidental injuries to the skin and eyes, and in a variety of dermatological applications. These gel dressings are alleged to provide a barrier to bacteria and viruses, to be permeable to vapors and gases while being impermeable to fluids, and to control the moisture environment of the wound.

Burns (1991 ), 17(3), 239-242, Dr Vartak et aj describes the use of conventional untreated regenerated plain cellulose film (Cellophane ®) as a dressing for burn graft donor sites. However the wound dressing properties of conventional cellulose film are less than satisfactory. Dr Vatak selected such plain cellulose film as much for its cheapness as for any optimal wound dressings properties.

US 5,558,861 (assignee Ajinomoto Co., Inc.) describes a gel of microbially-produced cellulose, characterised in that the microbially-produced cellulose is modified by physically or chemically bonding an animal cell adhesive protein to the cellulose, and/or substituting hydrogen atoms of at least part of the hydroxyl groups of the cellulose with a positively or negatively charged organic group. This gel is used as a carrier for mass culture of animal cells or as a medical vulnerary cover. However it is complicated and expensive to produce as it requires chemical treatment of a microbial cellulose film.

EP 0197969 (Bio. Fill. Prod. Biotech. SA) = US 4,912,049 describes a process for the preparation of cellulose film, comprising the steps of preparing a culture medium having as nutrients sources of nitrogen and of carbohydrate, seeding this medium with a culture of acetobacter, species Xylinium; incubating the culture at temperatures which permit bacterial activity for a time suitable to the final intended use of the film, and removing the formed film from the culture medium for dehydration in a distended state. The film thus prepared is suitable for use as an artificial skin graft, a separating membrane, or artificial leather. This produces the cellulose film by a microbiologic method.

GB 2131701 (Johnson & Johnson) = EP 0114481 describes liquid loaded pads useful as wound and burn dressings are prepared from pellicles of microbially-produced cellulose gel obtained, for example, by culturing Acetobacter xylinum. A pellicle having a thickness from about 0.1 to 15 mm or greater is processed to replace the culture medium with water or other physiologically compatible liquid. The liquid-loaded pellicle is sterilised prior to its use as a dressing or in other medical applications. These gel-like films have poor adhesion to epidermal cells, are readily peeled from the wound causing contamination, and do not promote regrowth of the skin. They are also porous to micro-organisms and so do not satisfactorily protect the wound from infection. The term microbially-produced cellulose denotes cellulose produced by a microbe. A microbial cellulose gel denotes a solid colloidal solution of microbially-produced cellulose in a physiologically-acceptable liquid such as deionised water, saline or glycerol.

It can be seen that previous methods for dressing wounds are unsatisfactory in some respects for example because of performance, cost and/or complexity. Previous cellulose wound dressings are unsatisfactory. The prior art teaches that for use in wound dressings cellulose films must be made by microbial methods, but these are expensive methods and cannot be readily scaled up to produce large dressings or large volumes.

Various other cellulosic films have been described in the prior art which are used in fields unrelated to wound dressing.

WO 00/05310 (University of Minnesota) describes a method of making edible films to pack food using as a raw material non-wood sources of cellulose fibers. Such films are formed from entangled micro-fibers of cellulose optionally dispersed within lipids and thus have a woven or entangled discontinuous structure of cellulose unlike a conventional cellulose sheet.

JP 09-A-195194 (OJI Paper Ltd) describes a paper comprising 1 to 30 % by dry weight of non-wood pulp cellulose fibers used to make tea bags.

Neither of the preceding documents suggest that the film or paper disclosed therein could be used in the very different field of wound dressings. Even in the unlikely event that a reader of either document attempted to use the sheets therein as a dressing, such a dressing would not be particularly effective as it would not have the specific optimised properties described herein for the films of the invention.

The present invention resolves some or all of the problems described above with methods for wound dressing and devices for achieving the same, in a simple but effective way by providing a novel cellulosic film which optionally has improved wound dressing properties.

Therefore broadly in accordance with the present invention there is provided a self supporting cellulosic film having two substantially parallel and opposed surfaces characterised in that the cellulosic film is made by a non microbiological method and has a wet flatness less than about 35 seconds. Preferably the film comprises at least one cellulose layer which is substantially continuous, more preferably non-woven and/or entangled, in structure.

Wet flatness is a measure of the absorption and dimensional stability i.e. wrinkleability of the film. Low wrinkleability leads to less blood pockets being formed and hence less pain. Wet flatness herein was measured in units of time (seconds) in the following quantitative "blue spot test" where 0.2 mis of a 0.1 % Methylene Blue dye solution in water was spotted onto a glass plate using a micro pipette. A 5cm square sample of film was placed centrally over the drop of dye solution. The time taken for the drop to be absorbed was measured, the faster the better. Preferably the wet flatness of the film is less than about 30 seconds, more preferably less than about 20 seconds, most preferably less than about 15 seconds. Optionally it may be desirable for the wet flatness absorption time not to be so rapid so there is insufficient time to position the dressing and correctly locate it adjacent the wound. However the most rapid absorption time possible may still be desirable for certain applications.

The desired wet flatness may be achieved by any suitable means, which may for example suitably modify the physiochemical properties at the surface of the cellulose film. For example the cellulose film surface may be modified by suitable mechanical treatment, chemical treatment and/or additives. Suitable techniques may include embossing; printing; patterning, chemical etching, drawing the cellulose film web over a suitably prepared surface (e.g. a surface roughened and/or chemically etched roller); and/or incorporation of particulate materials such as fibers to the film surface. The preferred technique is incorporation of particles.

Preferably the non-microbial cellulose of the present invention is cellulose regenerated from a cellulosic dispersion in a non-solvating fluid (such as but not limited to NMMO, LiCI / DMP, LiCI/DemAc). One specific example of a cellulose in a solvating fluid is "viscose" which is sodium cellulose xanthate in caustic soda. Cellulose from a dispersion can be cast into film by regenerating the cellulose jn situ by a suitable treatment (e.g. addition of suitable reagent which for viscose can be dilute sulfuric acid) and optionally extruding the cellulose thus formed. Such cellulose is known herein as regenerated cellulose and preferred films of the present invention comprise regenerated cellulose.

More preferred films of the present invention substantially comprise cellulose from a wood source, most preferably at least 90% of the cellulosic material is from a wood source.

Preferably the cellulose film of the present invention comprises particulate material: the particles being present in an amount of from about 0.5% to about 25 % by weight of the total film; the particles being substantially located on or substantially near at least one of the film surfaces; and the mean linear dimension of the particles along their longest axis is from about 5 microns to about 5 mm.

In an optional aspect of the invention it is believed that optimal film properties may be achieved with an amount of the particulate material being from about 5% to about 20% by weight of the film, conveniently from about 10% to about 15% by weight, more conveniently from about 12% to about 15% by weight.

Preferably the celulosic film of the present invention further exhibits at least one of the following properties; has an average thickness of up to about 45 microns; has a water permeability of at least about 100 g/m².d; has a selective permeability with a molecular weight cut off such that micro-organisms are substantially prevented from crossing the film, (preferably having a film-pore size of less than about 1 micron); has a wet flatness as measured by the blue spot test of from less than about 35 seconds; has a haze value of at least about 10%; has an average surface roughness of at least about 10ml min^"1; has some kind of stiffness when dry and yet becomes pliable and/or elastic after uptake of water; has good mechanical stability in the dry state but also after wetting; has a water vapor transmission rate (denoted herein by WVTR) of at least about 1 ,500 g/m².d; and/or has at least about a 5 fold higher WVTR value when wet than when dry (intelligent water vapor handling).

Water permeability herein may be measured in standard test ASTM E 96 at 38°C and 90% relative humidity (RH). Preferably the water permeability of the film is from about 200 to about 10,000 g/m².d, more preferably from about 400 to about 2,000 g/m².d, most preferably from about 600 to about 1 ,600 g/m².d, and especially about 1 ,500 g/m².d.

Alternatively or as well the as water permeability, the water vapor transmission rate (WVTR) of the films herein may be measured in standard test ASTM E 96 at 37°C and 30% relative humidity (RH) using the water method for the dry film and the inverted water method for the wet film. Preferably the WVTR of the dry film is from about 2000 to about 4,000 g/m².d, more preferably from about 2,500 to about 3,000 g /m².d. When measured the wet film may show from about 5 to about 15 fold, preferably from about 5 to about 8 fold higher WVTR than the same film when dry.

The average surface roughness of the film herein was measured using a Bendtsen Gauge as described in the DIN EN 53108 method. Preferably the average surface roughness of the film is from about 10 to about 80 ml min^"1, more preferably from about 20 to about 70 ml min^"1, most preferably from about 30 to about 60 ml min^"1.

The haze value of the films herein were measured using a spherical hazemeter as described in ASTM D 1003. Preferably the haze value of the film is from about 10% to about 100%, more preferably from about 20% to about 80%, most preferably from about 30% to about 70%.

Oxygen permeability herein may be measured in standard test ASTM D 3985 at 23°C and 0 to 5% RH. Preferably the oxygen permeability of the film is from about 0.1 to about 30 cm³ / m².d.bar, more preferably from about 1 to about 20 cm³ / m².d.bar, most preferably from about 2 to about 10 cm³ / m².d.bar, and especially about 8 cm³ / m².d.bar.

Preferably the film further includes a plasticiser, more preferably in an amount from about 10% to about 30%, most preferably about 20% by weight of the cellulose film. The plasticiser may be any suitable material which is compatible with wound dressings for example substantially non-toxic in the amounts used. For example the plastcisier may be selected from sorbitol, glycerol or mixtures thereof such as a mixture of sorbitol and glyercol in the respective weight ratio of 60:40 by weight of solids.

It has been found that the films of the present invention may have one or more of the following benefits as wound dressings. The films have a reduced tendency to wrinkle which leads to less blood pockets being formed under the skin and therefore a reduction in the pain felt by the patient. The films are sufficiently porous to water (and optionally oxygen) yet may maintain a moist wound environment and/or allow exudate to evaporate from the wound in a controlled way to aid wound healing, whilst excluding substantially all micro-organisms from the wound. The film is able to adapt its WVTR to the amount of fluid present underneath the dressing. Due to this intelligent water vapor handling property a substantially ideal moist wound environment is maintained and cell growth can be at a maximal rate. The films have a reduced tendency to slip on a moist wound and therefore are easier to locate adjacent the wound.

The micro-rough surface of the film is also believed to assist in cell adhesion which may promote skin re-growth and/or wound healing. An increase in the rate of wound healing leads to a reduced hospitalisation with resultant benefits to patients and cost reductions to the health care provider. Wounds can heal with substantially less scarring.

As the film is made by a non-microbiological method (for example regenerated cellulose film ) standard equipment used to produce such cellulose can be used to readily prepare the film in large volumes.

The film is easy to handle because it is relatively stiff when dry and yet becomes pliable and/or elastic after wetting which enables easy draping on the wound. Furthermore handling is also good because of the mechanical stability of the material.

Other advantages are apparent with cellulose films, such as:

The film is inert, lint free and may be readily sterilised.

The film can be applied as a one piece film obviating the need for a more complicated dressing.

The physical properties of the film allow it better to conform to the body surface. The film is easily stored and has a long shelf life.

The strong adhesion of the film to the wound reduces the proliferation of germs, and leaves the wound hermetically sealed.

The film can be made with good optical properties (i.e. transparent) which allows visual inspection of the wound without removal of the dressing and thus the pain to the patient and risk of infection of the wound is reduced.

The film can be applied once and the dressing does not need to be changed.

The film can be applied delicately over the injured region and because of the optimised surface roughness it can be readily but rapidly positioned adjacent the wound with a much reduced tendency to form air bubbles or blood secretions between the wound and the film. Once the film covers the wound completely, the film quickly absorbs exudate from the wound and this process is enhanced because of the increased film surface area due to the roughened surface. The film allows the exudate to coagulate within the film and thus form a bridge between the film and the wound. Coagulation can also occur before the exudate has penetrated the film, for example both in the microscopic spaces existing between the particles on the film and on the wound surface. Thus this improved adhesion prevents hydro-electrolytic losses and substantially reduces the risk of infection. Additionally, since the nerve endings are isolated, the pain of the injury is immediately reduced. The film, therefore, makes it possible for the epithelial tissues to regrow since the wound is isolated and contamination is avoided. There is no necessity to change dressings, since the adhesion of the film to the wound will only cease gradually, as the tissue regenerates. Preferably if the particulate material is cellulose (such as cellulose fibers and/or ground cellulose) then the film may be formed totally from inert cellulose which does not have any undesired medicinal action on the wound. Once the wound heals under these optimum conditions, the film ceases to adhere to the patient, and leaves no residue on the regenerated area.

Since the cellulose film is strong and inert, it can be sterilised in any convenient way. It may be stored at any temperature, and does not require special conditions. The film has determined permeability to liquids and air, a characteristic molecular weight and structure, a predictable thickness when dehydrated, in addition to other specific physical characteristics.

Preferably the cellulosic film may be produced by any conventional non-microbiological means. A preferred cellulosic film is produced by regeneration of natural cellulose from any source using the well known viscose process. More preferably the cellulose source comprises mostly or substantially wood, such as a wood pulp.

As well as particulate additives the cellulosic film may include other conventional film additives and/or coatings well known in the art of film making and which are compatible with wound dressing, such as softeners, anti-static agents, adhesive coatings and/or may be tinted or otherwise treated, for example impregnated with one or more pharmaceutically active ingredients. The film may also comprise other layers and/or be a laminate.

Preferably the particulate material is itself any natural fiber (such as cellulosic fiber, wool pulp, cotton linters, vegetable fiber, hemp and/or sisial), synthetic fiber (such as viscose, polyester, and/or nylon) and/or particles of any shape such as spherical and/or amorphous particles (e.g. ground cellulose, cellulose spheres, amorphous polysaccharides, starch, chitin, super absorbent polyacrylate powder and/or silver zinc zeolite particles). Most preferably the particulate material comprises cellulosic particles, such as cellulose fibers. The cellulose fibers may be substantially from a wood source, for example at least 90% from a wood source. The cellulose fibers may also have a lignin content of at least 1 % by weight. Optionally the particulate material does not comprise non-wood cellulose fibers less than 2 mm in length.. The particulate material may also comprise one or more of the following; cross-linked gelatin beads (such as those available commercially from KC Biological Co., USA. under the trade name Gell-Beads); charged group-added polyacrylamide beads (such as those available commercially from Bio-Rad Co., USA. under the trade name Biocarrier); polystyrene beads (such as those available commercially from Nunc Co., Denmark under the trade name Biosilon); dextran beads (such as those available commercially from Flow Labs Co., USA under the trade name Superbeads); cellulose granules (such as those available commercially from Whatman Co., UK under the trade designation DE-52) ; collagen-coated dextran beads (such as those available commercially from Pharmacia Upjohn, Sweden under the trade name Cytodex); and/or cellulose acetate hollow fibers (such as those available commercially from Amicon Co., USA).

If the particles comprise fibers, the mean linear dimensions of the fibers are preferably from about 5 μm to about 5 mm, more preferably from about 15 μm to about 3 mm, most preferably from about 20 μm to about 1000 μm, for example from about 20 μm to about 100 μm, e.g. from about 20 μm to about 50 μm along a major axis (such as length), and from about 0.1 μm to about 100 μm, more preferably from about 5 μm to about 80 μm, most preferably from about 10 μm to about 50 μm, for example from about 10 μm to about 30 μm, e.g. from about 10 μm to about 20 μm, along a minor axis (such as fiber diameter or thickness) preferably orthogonal to the major axis.

The average thickness of a film of the present invention may be up to about 2 mm (e.g. if a foamed film is used), preferably up to about 45 μm, before incorporation of the particulate additives. More preferably the average thickness of a film of the present invention is from about 20 to about 30 μm as this has been found to conform better with the contours of a wound.

Preferably the film of the invention is provided in a form directly suitable for use in wound dressing, more preferably as a sterile and packaged form capable and effective for such a use, most preferably in a form which has obtained the necessary regulatory approval for use in such an application.

Preferably the film of the present invention comprises a sheet-like substrate comprising cellulosic film modified with cellulosic beads and/or fibers and optionally may further comprise one or more pharmaceutically-effective active ingredients. More preferably the film of the present invention includes as a component thereof a regenerated cellulose membrane film which substantially excludes microbiological organisms when it is applied topically to a wound. In a still further aspect of the present invention there is provided a preferably sterile wound dressing comprising a cellulosic film of the present invention as described herein preferably the film being sealed inside a sterilised tamper evident pack and/or being associated with instructions for use of said film as a wound dressing.

A wound dressing film of the present invention may act as a partial or complete substitute for and/or an aid to any of the following in wound dressing: aminotic membrane, animal skin (e.g. pig skin), artificial skin, conventional wound dressings [e.g. bandages, gauze, plasters and the like], human skin [e.g. normal healthy skin jn situ or that obtained from cadaver]; protecting material, skin graft [e.g. autogeneous, allogeneic and/or donor], synthetic skin and/or vulnerary cover. Such a product may promote regrowth of the epidermis and/or dermis and/or healing of the wound.

In a further aspect of the present invention, broadly there comprises a method for preparing a cellulosic film, the method comprising the steps of:-

(a) dispersing a cellulosic material in a substantially non-solvating fluid;

(b) incorporating particulate material into said fluid, the particles being present in an amount of from about 0.5% to about 30% by weight of the fluid; and the mean linear dimension of the particles along their longest axis is from about 5 microns to about 5 mm; and

(c) extruding the cellulose thus formed; to form a self supporting cellulosic film having two substantially parallel and opposed surfaces in which the particulate material is substantially located on or substantially near at least one of the surfaces of the film.

Preferred amounts of particles which can be incorporated into the fluid are those ranges given herein for the amounts of particles in the film. However it will also be appreciated that to achieve a given amount of particles in a film of the invention, it may be necessary to add a greater amount of the particles to the fluid in the above process to compensate for loss of particles during the process.

Any suitable methods of incorporation can be used such as injection or stirring of the particulate additives which can be incorporated into any cellulose film made by any regenerated method. A preferred method is the well known viscose method for preparing cellulose film in which case the particles are added to the viscose. The cellulose film of the invention may also be used as a surgical suture, given the necessary preparation, and presents a high knot strength but preferably such films are used to prepare a sterile dressing in a form suitable for application to a wound. The dressings of the present invention which comprise a film of the present invention are permeable and biologically inert.

Dressings of the present invention may optionally be impregnated with one or more active ingredients, such as chemotherapeutic agents, medicinal agents and/or additives which may be fluid, preferably powder, cream or liquid. For instance, the dressings can contain topical anaesthetics such as butamben picrate, lidocaine hydrochloride, piperocaine hydrochloride and the like; bacteriostatic agents such as silver zinc zeolite particles, silver nitrate (0.5% solution), sulfa drugs, for example, 10% suspension of p-aminomethyl- benzene sulfonamide in a water dispersible cream, benzalkonium chloride and the like; antibiotics such as bacitracin, neomycin, aureomycin, tetracycline, penicillin, polymyxin, streptomycin, signemycin, erthromycin, oleandomycin, and the like; topical steroids such as prednisone, dexamethasone, hydrocortisone, and the like; enzymes such as collagenase, fibrinolysin, desoxyribonuclease and the like; coagulants and anticoagulants; antifungal agents, such as isopropanol, nystatin, miconazole, ketoconazole, tolnaftate and the like. Nonwater soluble medicaments such as silver sulfadiazine are preferably dispersed in nonaqueous ointment bases which may be liquefied to impregnate the film.

The quantity of the aforementioned medicinal agents, chemotherapeutic agents or additives which can be incorporated into the dressings of the present invention will, of course, be dependent upon the particular agent, its solubility, and the presence of other additives. In general, however, the agents will be employed in a therapeutic amount. This can range from about, 0.0001% and lower, upwards to about 40% and higher by weight of the film.

Additional or different chemotherapeutic agents and/or medicaments can be added to the dressing which can be transported to the site of the wound by diffusion through the material.

Hence, it is possible to provide controlled supply of medication to the wound site.

The dressings of the present invention may be used as wet or dry dressings in combination with an occlusive film backing for some applications. For example, in the case of an ulcer dressing which is required to provide a wound environment conducive to the growth of new tissue, the dressing may provide a source of moisture over an extended period of time and ensure an antibacterial environment. A dressing of the present invention which is also impregnated with an aqueous solution containing an antimicrobial agent, may be applied to such an ulcer and covered with an occlusive film backing to prevent evaporation of moisture from the dressing. A wide variety of films are suitable for use as optional backings for a wound dressing of the present invention include, for example, polyvinylidene chloride, polyethylene, polypropylene, polyethylene terephthalate, polyamides, polyvinyl chloride, cellulose acetate and derivatives thereof, polydimethyl butadiene, polyurethanes, polyvinyl alcohol, silicone rubbers, polyacrylic acid, and the like. The backing film may be attached to the film of the invention through the use of adhesives, mechanical fastening and/or (e.g. if the film is impregnated with liquid) by surface tension of liquid. In one embodiment of the invention, the backing film may extend beyond the area of the dressing and be adhesive coated to form an island dressing which may be secured directly to the skin of the patient.

If the dressings of the present invention have absorbed liquid such liquids may be intended specifically for use with burns to provide for evaporation from the dressing to provide a cooling effect over the wound area. Such dressings may comprise an evaporative liquid which may be water, saline or a water/glycerol or water/polyethylene glycol solution and are not covered with an occlusive backing film during use. The products of this invention may also be produced in long lengths for use as burn bandages, and in large sheets, i.e. 3 by 5 feet or greater, for use as burn blankets.

Cold packs for burns, as distinguished from burn dressings, may be provided with a removable insulating backing for an optionally liquid impregnated cellulosic film of the invention. Cold packs are chilled prior to application and do not initially depend upon evaporative cooling. The cooling effect of the cold pack may be extended by removing the backing and allowing evaporative cooling to take place. Cold packs additionally may utilise thicker or multiple layers of film of the invention optionally impregnated with liquid to increase their heat capacity.

Dressings according to the present invention may also be used as long-term coverings for severe burns and certain other wounds. In this application, a thin dressing of this invention from about 0.1 μm to about 5 mm thick is placed immediately over the wound and a second dressing containing medicaments or other wound treating agents may be placed over the primary dressing. Since the medicaments will migrate through the primary dressing to the wound surface, the secondary dressing may be changed from time to time to renew the medicament treatment while the healing process of the wound is observed through the primary dressing which is not disturbed.

While the dressings of the present invention may comprise a single sheet of the cellulosic film prepared as described herein which may or may not be impregnated with liquid, such films may also contain other optionally reinforcing sterile materials such as random or carded fibers, plastic net, reticulated plastic film, open weave fabrics and fabric mesh which may be incorporated in the dressing if desired. For example, nylon gauze, rayon net, Dacron or cellulose mesh or reticulated polyethylene can be laminated with the cellulosic film.

An additional optional feature of the dressings of the present invention is their ability to absorb fluid from the wound site when the dressing is applied. In the case of burn dressings, moisture evaporating from the dressing will tend to be replaced by fluids exuding from the burn site. Preferably, such a dressing is covered with an occlusive film to prevent the dressing from drying out while in place over the wound.

The dressings of the present invention may be sterilised prior to use by any appropriate method such as auto-claving, irradiation with cobalt-60 and/or electron beam and/or ethylene oxide treatment. The dressings may be packaged in sterile hermetically sealed moisture-proof containers. For example, the dressings may be heat sealed in packages constructed of aluminum foil laminated with a heat sealable polymeric film such as polyethylene. The contents of the package may be sterilised by irradiation in accordance with conventional methods for packaging surgical products. Sterile materials may be stored for extended periods of time with no adverse effect.

The dressings of the present invention may be constructed in a variety of shapes, sizes, and thicknesses and be impregnated with a variety of physiologically-acceptable liquids and medicaments to accommodate the requirements of any particular application. Additionally, the films of the present invention materials may be used in combination with internal reinforcements or external backing films and may be used as the pad portion of island dressings which include adhesive attachment means.

A sterile wound dressing of the present invention may comprise a cellulosic film of the present invention sealed inside a sterilised tamper evident pack and being associated with instructions for use of said film as a wound dressing.

Many other variations and the details of construction and composition will be apparent to those skilled in the art and such variations are contemplated within the broad scope of the present invention.

One aspect of the invention is the use of a dressing of the present invention in a method of protecting a wound.

Another aspect of the invention is the use of a cellulosic film of the present invention, in a method of preparing a dressing of the present invention. Another aspect of the invention is a method of preparing a dressing of the present invention, comprising the steps of sterilising a cellulosic film of the present invention, and packing said film under sterile conditions.

It will be appreciated that although the films of the present invention are primarily designed for use in the field of wound dressings they could be used in other applications where similar film properties are desired.

The present invention will now be described in detail with reference to the following non limiting examples which are by way of illustration only.

Example 1

A production machine was set up in a conventional manner to produce regenerated cellulose film from the well known xanthate viscose method. The viscose used had a cellulose content of 9.3% and the resultant film had a substance of 30 gm^"2.

A 15% dispersion of highly pure cellulose fibers in water was prepared. These fibers were from a beech wood source and were milled to an average length of 23 μm with an average thickness of 17 μm. This dispersion was injected into the viscose stream just prior to the extrusion die and homogenised through a static (labyrinth) mixer before casting into a film. The flow rate of the dispersion was adjusted to produce a level of 5% by weight of fibers (as a percentage of the regenerated cellulose content) in the final film, which had a substance of 30 gm^"2.

The film was plasticised with a mixture of sorbitol and glycerol (60:40 by weight solids) at a level of 20% of the regenerated cellulose content, dried and wound into reels.

Examples 2 to 4 and Comp. A

The above injection of fibers into the viscose was repeated, flow rates being adjusted to produce films with fiber contents of 7.5%, 10% and 12.5% (Examples 2 to 4 respectively). A comparative Example (Comp A) was prepared as above without the injection of fibers.

The exemplified films were each tested in the following ways:

To establish a quality control test to determine the level of injected fiber in production, the films were tested for haze value using a Spherical Hazemeter model ASTM D 1003. The results exhibited a straight line relationship when plotted against fiber percentage, indicating that a suitable control method was possible. To measure surface roughness, a Bendtsen Gauge was employed as described in the DIN EN 53108 method.

To measure absorption and dimensional stability the following test was devised: 0.2 mis of a 0.1% Methylene Blue dye solution in water was spotted onto a glass plate using a micro pipette. A 5cm square sample of film was placed centrally over the drop of dye solution. The time taken for the drop to be absorbed was noted and any evidence of "pooling" or wrinkling was reported. The results obtained are given in Table 1 below:

Table 1

The following observations were made:

Comp. A had many severe wrinkles and pools. Example 1 had many wrinkles and pools.

Example 2 had some wrinkles and pools, some curling.

Example 3 had curling which straightened, no pools.

Example 4 had no wrinkles or pools.

Thus all of Examples 1 to 4 would be improved wound dressings compared to the unroughened film Comp A.

Wound dressings

Films prepared in accordance with the Examples 1 to 4 described herein are of particular use in preparing dressings for application to a wound formed by an autograft on a burns patient. A dressing of the present invention comprising a film exemplified in Examples 1 to 4 can be applied, after bleeding has stopped, directly to the donor site such that no air bubbles or blood secretions are formed between the dressing and the wound. Due to its good wettability the dressing adheres very rapidly and firmly to the moist wound surface. The rough surface of the dressing ensures that it is not displaced. Once the dressing is applied to and completely covers the wound, it completely seals the wound, forming a mechanically stable protective layer. This protects nerve endings thus eliminating pain. It also promotes an ideal moist environment under the dressing which leads to a maximum rate of re-epithelisation, so the dressing spontaneously lifts from the graft site after only a few days. The newly formed epithelial tissue is of good quality, which makes re-harvesting possible shortly after the dressing has been removed.

Claims

1 A wound dressing comprising a self supporting cellulosic film having two substantially parallel and opposed surfaces characterised in that the cellulosic film is made by a non microbiological method and has a wet flatness less than about 35 seconds.

2 A dressing according to claim 1 , packed in a suitable sealed pack and sterilised by any conventional method.

3 A dressing according to either preceding claim, packed in a suitable tamper evident bag and being associated with instructions for use of said film as a wound dressing.

3. A dressing according to any preceding claim, further comprising particulate material: the particles being present in an amount of from about 0.5% to about 25% by weight of the total film; the particles being substantially located on or substantially near at least one of the film surfaces; and the mean linear dimension of the particles along their longest axis is from about 5 μm to about 5 mm.

4. A dressing according to any preceding claim, in which the particles are present in an amount of from about 10% to about 15% by weight of the total film.

5. A film according to any preceding claim, in which the particles substantially comprise cellulose fibres from a wood source.

6. A dressing according to any preceding claim, which comprises regenerated cellulose.

7. A dressing according to any preceding claim, which has an average film thickness of up to about 2 mm.

8. A dressing according to any preceding claim, which has a water vapor transmission rate of at least about 1 ,500 g/m².d.

9. A dressing according to any preceding claim, which has a water vapor transmission rate of from about 5 to about 15 fold higher in the wet state than in the dry state.

10. A dressing according to any preceding claim, which has a water permeability of at least about 100 g/m².d.

11. A dressing according to any preceding claim, which has a selective permeability with a molecular weight cut off such that micro-organisms are substantially prevented from crossing the dressing.

12. A dressing according to any preceding claim, which has a haze value of at least about 10%.

13. A dressing according to any preceding claim, with an average surface roughness of at least about 10 ml/min.

14. A dressing comprising a cellulosic film obtained and/or obtainable by method comprising the steps of

(a) dispersing a cellulosic material in a substantially non-solvating fluid;

15. Use of a dressing as claimed in any preceding claim, in a method of protecting a wound.

16. Use of a cellulosic film as described in any of claims 1 to 14, in a method of preparing a dressing as claimed in any of claims 1 to 14.

17. A method of preparing a dressing in any of claims 1 to 14, comprising the steps of sterilising a cellulosic film as described in any of claims 1 to 14 and packing said film under sterile conditions.