NL8703116A - METHOD FOR MANUFACTURING A POROUS POLYETHERURETHANE FILM; WOUND COVERAGE MATERIAL. - Google Patents

Description

%% *> VO 9478

Titles Method of manufacturing a porous polyether urethane film; wound dressing material

The invention relates to a method of manufacturing a porous polyether urethane film, as well as to a wound dressing material comprising a porous polyether urethane film.

It is known that partial epithelial formation of partial-thickness wounds can be accelerated by covering the wound with a wound dressing material that keeps the wound moist, prevents wound drying. Most known wound dressing materials therefore have a relatively low water vapor permeability and can be referred to as occlusive wound dressing materials.

Examples include Bioclusive (Johnson & Johnson),

Opraflex (Lohmann), On Site (Smith & Nephew Ltd) and 15 Tegaderm (3M). 2e usually consist of a polyurethane film which is provided with an adhesive layer.

In practice, these occlusive wound dressing materials, sometimes referred to confusingly as water vapor per-meable or semi-permeable, have been found to keep the wound much more moist than is desired for proper healing. During the first days of the healing process under occlusive wound dressing materials, wound exudate accumulates under the wound dressing. The liquid exudate forms liquid-filled vesicles 25 which may leak or be aspirated from under the wound dressing with the associated risk of infection, tissue maceration and inhibited keratin formation.

In addition, these known wound dressing materials have the drawback that their adhesive layer adheres only to the intact skin, and not to the wound. If insufficient skin is present along the circumference of the wound, __ .8703116 ψ * -2-, the wound cannot be closed properly and. the sealing effect of the wound dressing is completely lost, resulting in the wound drying out. When skin is present, it must be depilated to prevent pain 3 due to tensile forces on the attached hair under the wound dressing.

Because of these drawbacks of known wound dressing materials, surgery manuals often recommend traditional methods such as 10-oily gauze (tulle grass) and exposure to the air (no wound dressing).

Therefore, there is still a need for a synthetic wound covering that is able to keep the wound moist, but is also sufficiently permeable to water vapor to allow evaporation of excess exudate. In addition, the wound dressing should preferably also adhere to the wound without an adhesive layer, be elastic and pliable, impermeable to bacteria, easy to apply, non-toxic, and have haemostatic properties.

The need for such a material exists not only for wound dressings, which can be used as a temporary covering of partial-depth wounds such as skin-donor sites (donor sites) or second-degree burns, but also for the topsheet of two or more different layers of built-up artificial skin products that can be used to cover full-depth (burn) wounds. Such multilayer artificial skin products include a biodegradable porous bottom layer, which acts as a temporary matrix for skin regeneration, and a protective non-degradable top layer. The biodegradable porous substrate can be based on a mixture of polyurethane and poly (L-lactide), or more preferably consist of. 87031 16 -3- * a biodegradable polyester-urethane elastomer network, which is hydrolyzed relatively quickly to non-toxic degradation products of the polymer constituents and based on a polyester-urethane from an L-lysine polyisocyanate and a polyester polyol prepolymer, obtained by reaction of a polyhydroxy compound with L-lactide, glycolide and / or one or more lactones. A polyester urethane elastomer network obtained by reacting a cyclic polyhydroxy compound, such as myo-ino-sitol, with L-lactide and / or glycolide as well as with one or more lactones, such as ε-caprolactone and δ-valerolactone, is particularly suitable, and reacting the obtained star-shaped polyester polyol prepolymer with L-lysine-ethyl-15-ter-diisocyanate. Such a polyester urethane elastomer network has the advantage of a relatively rapid degradation and the advantage that no toxic, carcinogenic aromatic diamines such as 4,4'-methylenediamiline are released. For such a polyester urethane elastomer network, rights are claimed in another, simultaneous patent application.

The topsheet of such artificial skin products should meet the aforementioned criteria of sufficient water vapor permeability, adhesion, elasticity and pliability, etc., but no such material has been found to date.

The invention now addresses the existing need by a method of obtaining a porous polyether urethane film having the desired properties.

The method according to the invention is characterized in that a solution of an aliphatic polyether urethane elastomer and a hygroscopic salt in an organic solvent is spread over a substrate after a heat treatment, the substrate together with the ---- - -. 8703116 * -4 thereon. - the applied layer is brought into contact with a water-vapor-containing atmosphere, after the clear layer has turned white, the residual organic solvent is removed by drying, the hygroscopic salt 5 is removed by contacting the substrate with the white film thereon with water, also releasing the film from the substrate and drying the film.

Although a plate of plastic or metal can be used as substrate, a glass plate is preferred as substrate. Various known hygroscopic salts can be used as hygroscopic salt.

However, LiCl is preferred.

The aliphatic polyether urethane elastomer to be used as starting material is preferably a reaction product of 4,4'-methylene bis cyclohexyl diisocyanate, a polytetramethylene ether glycol and 1,4-butanediol.

Such elastomers are described by Szycher et al, J. Elastomers and Plastics 15 (1983) pp. 81-95 and are marketed under the trademark Tecoflex.

The commercial product Tecoflex EG-80A is very suitable.

The organic solvent used according to the invention should be able to dissolve the aliphatic polyether urethane elastomer and the hygroscopic salt and is preferably quite volatile and miscible with the non solvent (water). Tetrahydrofuran is very suitable.

Preferably a solution is used containing 4-6% (w / w), most preferably about 5% (w / w) elastomer and 0.5-2 30% (w / w), most preferably about 1% (w / w) contains hygroscopic salt.

The solution is first subjected to a heat treatment. It preferably consists of a reflux treatment, for example for 2 hours, in an inert gas atmosphere, such as nitrogen. This heat treatment 35 results in a complete dissolution of the physically cross-linked. 87 031 16 ____ · * »-5- polyurethane chains by breaking the existing super-molecular structure in the solution.

The solution is then preferably cooled to room temperature and, for example, stirred at room temperature for 2 hours. The salt present prevents aggregation of the chains on cooling because it complexes at the urethane bonds. This results in a better solubility of the polyurethane and in the formation of a new super molecular structure. 10 Known methods and tools can be used to spread the solution over the substrate. The application with a 500 µm cast iron has proved very suitable. By varying the thickness (recess) of the cast iron, e.g. 250 15 / um, 500 / um or 1000 / um, the thickness of the film can be set to a desired value. The thickness of the film is one of the factors determining the water vapor permeability.

When the substrate with the transparent layer applied thereon is brought into contact with a moist atmosphere, preferably by placing it in an open space above a layer of water, phase inversion takes place due to the attraction of water by the hygroscopic salt, wherein the water diffuses into the polymer solution and at the same time the organic solvent evaporates. As a result, the initially transparent layer turns white, usually after only a few minutes.

The remaining part of the organic solvent can then be removed, eg after half an hour, by drying the non-translucent film under reduced pressure, for example 2 hours at 40-60 ° C, most preferably about 50 ° C.

By contacting the substrate with the film present thereon with water, the film can be detached from the substrate and the existing salt can also be removed from the film. This contact with water can be effected in any way, e.g. by spraying with water or, preferably, by immersion in a water bath.

Finally, the film is dried, preferably under reduced pressure and optionally under elevated temperature.

If desired, the polyether urethane film can also be cross-linked, for which various possibilities are known, eg cross-linking with dicumyl peroxide. For example, cross-linking can prevent creep, which is a very undesirable phenomenon when the film is placed over movable surfaces such as joints and the like: creep leads to stretching of the film, so that it no longer adheres well to the wound surface.

For example, to obtain a cross-linked film, dicumyl peroxide (eg, 10% by weight based on the amount of polyether urethane in the solution) can be added to the refluxed solution. The film obtained after the subsequent drying can then be cross-linked, e.g. under nitrogen at an elevated temperature (e.g. 150 ° C) or by UV exposure. The preliminary drying should be carried out under conditions (not too high temperatures) such that no significant evaporation of the cross-linking agent occurs.

The thickness of the film can be adjusted to a desired value by controlling the layer thickness of the solution applied to the substrate. Preferably, the film has a thickness of 10-30 µm, most preferably about 15 µm. Such a thickness, in combination with the high elasticity and other inherent properties of the obtained material, ensures that the film is very pliable and has a relatively high water vapor permeability.

k. - .8703116 -7- t,

The resulting film contains many micropores / sizes up to about 5 µm, which are substantially non-interconnected. The film has a bottom (i.e., the side intended to face the wound) with a relatively rough surface / and a smoother top (i.e., the side of the film initially facing the substrate). This structure ensures good adhesion of the film to moist surfaces / including wound surfaces.

A separate adhesive layer is not necessary / which is also favorable for the handling of the film.

The film is impermeable to bacteria and has a relatively high water vapor permeability. The water vapor permeability is affected not only by the thickness of the film, but also by the size of the pores. Larger pores can be achieved by using a lower polymer concentration, while a higher concentration of the polymer in the organic solvent leads to smaller pores, expressed as water vapor permeability (WVP), the water vapor permeability is of the order of magnitude of 6-7, preferably about 6.7 g. This water vapor permeability is clearly higher than that of, for example, the skin (WFP * 0.3 gm “2.hours“ ^. KPa_ ^ ·) and of the well-known occlusive wound covering material On Site (WFP - 2.0 gm-2.hr "l .kPa “i), and slightly lower than that of the known water vapor permeable wound dressing material Omiderm (WFP = 7.6 µm ^ .hr ^ .kPa" 1).

The elasticity is considerably higher than that of eg On Site. For example, the film obtained by the process of the invention may have a Young's modulus of about 1.2 N.mu.m. High elasticity and flexibility make it easier to achieve a complete and tightly covering wound, also in bendable places such as joints. However, with aging, the elasticity of the film appears to decrease somewhat; after a few months, the elasticity is noticeably lower (the Young's modulus higher) than immediately after the production of the film. The elongation at break also decreases somewhat with the passage of time.

When the porous polyether urethane film of the invention is used as a wound dressing material, a gel-like fibrin exudate clot appears to form under the wound dressing which promotes wound healing (renewed epithelial and keratin formation). The formation of this clot promoting clot healing is attributed to the combination of optimal wound drainage and good adhesion of the film to the wound surface.

The invention is explained in more detail by means of an example.

Example 20 A 5% (w / w) solution of the cycloaliphatic elastomeric polyether urethane Tecoflex EG-80A (a commercial product of Thermedics Ine.) In tetrahydrofuran, also containing 1 S (w / w) lithium chloride, was stirred for 2 hours a nitrogen atmosphere refluxed and then stirred at room temperature for an additional 2 hours.

The polymer solution was streaked on a glass plate using a 500 µm cast iron as a film. The glass plate was placed in an open space just above a layer of water. After a few minutes, the clear film turned white. After half an hour, when most of the organic solvent had evaporated, the non-translucent film was dried under reduced pressure at 50 ° C for 2 hours and then placed in a water bath to release the film from the glass plate. 87 031 16 o «i -9- and remove the salt. Finally, the whiter elastic film was dried under reduced pressure.

The film had a thickness of 15 µm.

Stress strain measurements were made on 5 5 x 20 mm samples of the dried film. For comparison, the commercially available On Site wound dressing material was taken at a thickness of 28 µm.

The measurements were performed at room temperature with an Instron (4301) tensile tester equipped with an ION 10 load cell, at a drawing speed of 50 mm / min.

The microstructure of the film was examined with an I.S.I.-DS 130 scanning electron microscope.

The latter study (the results of which are not shown) showed that the film according to the invention had a rough and smooth surface and was completely microporous with pores up to about 5 µm. The pores were essentially not interconnected.

Measurements of the water vapor transmission rate at different water vapor pressure differences across the thickness of the film are plotted in Figure 1 for various wound dressing materials. The slope of the empirically found lines is the water vapor transmission capacity WVP. This amounted to 6.7 µm "2h" 1.kPa "1 for the film according to the invention.

Figure 2 shows stress-strain curves of the wound dressing material of the invention a) immediately after manufacture, and b) three months after manufacture, as well as the comparative On Site commercial product.

Use of the film of the invention as a wound dressing material for partial depth wounds has been investigated in rats and guinea pigs. Compared to controls, the wounds of which were either covered with Op Site or exposed to the open air, the wounds covered with the material of the invention appeared to heal better.

.8703116

Claims (18)

A method of manufacturing a porous polyether urethane film, characterized in that a solution of an aliphatic polyether urethane elastomer and a hygroscopic salt in an organic solvent 5 is spread over a substrate after a heat treatment, the substrate together with the layer applied thereon is brought into contact with a water-vapor containing atmosphere, after the clear layer has turned white, the residual organic solvent is removed by drying, the hygroscopic salt is removed by contacting the substrate with the white film thereon with water, also the film is released from the substrate, and the film is dried. 2. Method according to claim 1, wherein a glass plate is used as substrate. A method according to claims 1 or 2, wherein LiCl is used as hygroscopic salt. 4. Process according to one or more of the preceding claims, wherein as aliphatic polyether urethane elastomer a reaction product of 4,4'-methylene bis cyclohexyl diisocyanate, a poly tetramethylene ether glycol and 1,4-butanediol is used. 5. A method according to claim 4, wherein Tecoflex EG-80A 25 is used as the aliphatic polyether urethane elastomer. Process according to one or more of the preceding claims, wherein tetrahydrofuran is used as the organic solvent. A method according to any of the preceding claims, wherein a solution is used containing 4-6% (w / w) elastomer and 0.5-2% (w / w) hygroscopic salt. .6703116 5 S '-11- A method according to any of the preceding claims, wherein the heat treatment of the solution consists of a reflux treatment in an inert gas atmosphere, such as nitrogen gas. A method according to any of the preceding claims, wherein the solution is stirred at room temperature after the heat treatment. 10. Method according to one or more of the preceding claims, in which the solution is spread on a substrate using a 500 µm cast iron. 11. Method according to one or more of the preceding claims, wherein the substrate with the layer applied thereon is placed in an open space above a layer of water. A method according to any of the preceding claims, wherein the remaining organic solvent is removed by drying under reduced pressure. 13. Method according to claim 12, wherein the drying is carried out at a temperature of 40-60 ° C. A method according to any of the preceding claims, wherein the film is released from the substrate and the hygroscopic salt is removed by immersion in a water bath. A method according to any of the preceding claims, wherein the film is dried under reduced pressure. Method according to one or more of the preceding claims, characterized in that the film is cross-linked. Process according to claim 16, characterized in that a cross-linking agent is added to the polymer solution after the heat treatment and the final film obtained is cross-linked in the dry state by heating or irradiation. Wound dressing material, comprising a porous polyether urethane film obtained by the method according to one or more of the preceding claims. .8703116