WO2002009676A1 - Adhesive dressings for the treatment and prophylaxis of scars - Google Patents

Abstract

Adhesive dressings for the treatment or prophylaxis of scars and incipient scars comprise a backing and an adhesive layer, a substance effective in the prophylaxis and/or treatment of scarring being borne in the adhesive, the adhesive consisting essentially of a block copolymer having soft and hard segments and wherein there is chemical cross-linking between the soft segments, the adhesive further comprising at least 10 % by weight of a plasticiser, such dressings having good adhesion, cohesion and high drug loading and being removable without pain or danger to sutures.

Description

ADHESIVE DRESSINGS FOR THE TREATMENT AND PROPHYLAXIS OF SCARS

The present invention relates to corticosteroid-containing dressings for the prevention and treatment of scars.

Surgical incisions and traumatic injury to the skin elicit a normal wound healing response, accompanied by the deposition of a collagen-rich, fibrous matrix which contributes to the formation of a scar. In certain cases, the response may be excessive, and lead to the formation of a hypertrophic scar, in which the tissue can become red and raised, or even to a keloid, in which the scar extends beyond the confines of the original injury, and may continue to extend, indefinitely. Such scars are cosmetically poor, especially after cosmetic surgery, and may be associated with considerable psychological and physical morbidity, including restricted function, pruritus, dysaesthesia and pain.

As noted above, keloids are firm, raised scars extending beyond an original wound or surgical incision. They may also occur after other trauma such as, for example, vaccinations, acne, traumatic wounds, insect bites, skin piercings, burns, and chicken pox. Keloids, or keloid scars, may have a size ranging from that of a small insect bite to that of an area covering the whole of the chest, for example, and may itch, cause pain or be tender to touch and, if large or inconveniently positioned, may interfere with and/or restrict movement.

The biology of scar formation is incompletely understood, despite an extensive body of evidence describing several pre-dispositions to scarring, including; ethnicity, age, wound tension, anatomical site, surgical technique, suture materials, the type of injury sustained, as well as other local and systemic factors relating to wound healing. In particular, recent advances in molecular biology have focused attention on the interrelationship between the chemical and cellular response associated with wound healing.

Clinically, the management of hypertrophic and keloid scars has proven challenging. A wide range of treatments has been described, including compression

WPP82443 using pressure garments, occlusive dressings, cryosurgery, laser therapy, radiation, surgical excision and intra-lesional corticosteroid injections. More recently, experimental therapies have targeted angiogenesis and the down-regulation of collagen synthesis. In particular, surgical excision of hypertrophic scars and keloids has limited success and is associated with significant recurrence rates.

The commonest and most successful treatment for (non-burn) hypertrophic scarring is the use of intra-lesional injections of corticosteroids. The aim of this therapy is to reduce the thickness of the scar, and to encourage softening and colour changes secondary to a direct effect on the ground substance. Such intra-lesional therapy results in down-regulation of collagen and glycosaminoglycan synthesis, a decrease in fibroblast proliferation, and a reduction in the inflammatory process.

Although encouraging results with response rates of 65-100% have been documented, intra-lesional injection of potent steroids, such as triamcinolone acetonide (the steroid of choice) causes severe pain, often necessitating general anaesthesia in children, for example. This treatment generally requires the steroid to be administered by a physician, typically every 3 to 4 weeks, and is, therefore, inconvenient in that it requires the patient to repeatedly visit a surgery for periodic injections into the scar tissue.

The mechanism of the anti-inflammatory effect of topical corticosteroids is not completely understood, but corticosteroids with anti-inflammatory activity may stabilise cellular and lysosomal membranes. The effect on the membranes of lysosomes may prevent the release of proteolytic enzymes and, thus, play a part in reducing inflammation. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids.

Steroid creams or gels have also been used to treat hypertrophic scars and keloids by topical application to an affected area. Steroids which have been used for this purpose include betamethasone, methylprednisolone and triamcinolone. A problem with topical application of steroid creams to hypertrophic scars and keloids, in practice, is that, in spreading the steroid cream on the scar tissue, the steroid may inadvertently be applied also to healthy skin immediately adjacent, or peripheral to, the area of scarring. Unnecessary steroid treatment on healthy skin is undesirable and the skin- thinning effect of the steroids, which is intended to reduce the level of the raised keloid tissue relative to the adjacent skin, may cause atrophy of healthy tissue skin. Topical application of steroids to keloids using creams or ointments is also prone to over- or under-application, making it difficult to administer the correct dose. Thus, topical steroid creams are difficult to administer correctly without careful supervision.

Ladenheim, D. J. [Pharm. Pharmacol. (1996), 48 (8), 806-811] and Martin, G. P.

[Drug Dev. Ind. Pharm., (2000), 26 (1), 35-43] disclose studies relating to the effect of using hydrocolloid occlusive patches on in vitro penetration of triamcinolone acetonide in human skin. Fisher, L. B. [Archg. Dermatol., (1978) 114 (5), 727-9] discloses hydrocortisone tapes. However, neither of these documents teaches the prevention or treatment of hypertrophic and keloid scars .

Cordran® (USA) or Haelan® (Eur) tape is applied as an occlusive topical steroid dressing and comprises flurandrenolone at 4μg/cm². These tapes are indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid- responsive dermatoses, particularly dry, scaling, localised lesions. The adhesive is a synthetic copolymer of acrylate ester and acrylic acid, and serves as a vehicle for the steroid. Daily application of Haelan tape for 28 days following removal of skin sutures was shown to minimise keloid formation following surgery [British Journal of Sexual Medicine, (1981), Vol/155/Pg. 8/68 (10-12)]. The problem with Haelan tape is that the adhesive is powerful, and cannot be removed without both pain and the risk of tearing the sutures. In addition, the drug loading capacity of the adhesive is low. Established scars tend to be sensitive, so that treatment with Haelan tape is still painful.

Thus, there is still a need for an effective treatment for scarring that overcomes the above problems . We have now found, surprisingly, that dressings comprising a drug-loaded, cross-linked adhesive containing plasticiser not only carries effective amounts of drug, but can be removed with minimal pain.

Accordingly, in a first aspect, the present invention provides an adhesive dressing comprising a backing and an adhesive layer, a substance effective in the prophylaxis and/or treatment of scarring being borne at least partially in the adhesive, characterised in that the adhesive consists essentially of a block copolymer having soft and hard segments and wherein there is chemical cross-linking between the soft segments, the adhesive further comprising at least 10% by weight of a plasticiser.

The present invention further provides the use of such a dressing in the prophylaxis and/or treatment of scarring, as well as a method for the prophylaxis and/or treatment of scarring comprising application of such a dressing to the skin of a patient in need thereof.

In an alternative aspect, the present invention provides a bioadhesive drug delivery system, preferably a patch or tape, for the topical prevention or treatment of scar tissue, by the delivery of a suitable drug thereto, wherein the adhesive material has drug retention properties and comprising a cross-linked block copolymer, the block copolymer having hard and soft segments wherein there is chemical cross-linking between the soft segments.

The dressings of the present invention may take any suitable form. In general, it is preferred that they be in the form of tapes or patches that may be cut to fit the contours or shape of the area to be treated. Reference to "tapes" or "patches" herein will be understood also to incorporate reference to any other style of dressing, unless otherwise apparent, or indicated. It will be appreciated that, in general, suitable backings incorporate a level of flexibility, so that it is not necessary to cut the dressings precisely. Tapes and patches may be made from similar materials, and will generally comprise a layer of flexible backing material carrying a layer of the adhesive. In order to maintain cleanliness, the adhesive will generally be protected, before use, by a release layer, or web, of any suitable material, as well known in the art. The adhesive may be impregnated with drug over its entire surface area or, if desired, only selected areas, such as a strip down the centre, may be impregnated. In the case of a patch, this may comprise a central area, such as a square or circle. In the event that the whole adhesive area is not treated with drug, then it is preferred to mark the adhesive or backing, or both, in such a way as to indicate the drug-loading area. This may be effected by the use of dye, or in some other appropriate manner.

Separate adhesives may be used in areas with and without drug, although this is not generally necessary. It may also be preferable to provide a barrier to diffusion of drug away from the loading area, and this may be provided by any suitable means, such as a gap between adhesive areas, for example. In general, it is preferred to provide an area of the dressing extending beyond the drug-impregnated area that is suitable to secure to the skin without delivering drug.

A preferred form of dressing involves a first tape carrying a layer of adhesive impregnated with corticosteroids, for example, and which may be cut to fit an area of skin. A second tape of greater width than the first and carrying an adhesive of the invention but without drug can then be cut to cover the first and secure the first by attachment to skin beyond the boundaries of the area to be treated. The advantages of this embodiment of the invention are several: the active strip can be cut precisely; the adhesive area is usefully broad, even where the treatment area is narrow; effects of the drug on adhesion are minimised; and the area of the dressing containing drag is tailored precisely, whereas loading specific areas of a single tape may be subject to diffusion effects.

It will also be appreciated that the distinction between tapes and patches may be somewhat artificial, the only real difference generally being that tapes will be provided in endless form that needs cutting prior to use, and may be provided on a spool, for example, while patches may be provided as sheets which can be further cut, if desired.

Suitable conditions for which dressings of the present invention may be indicated include skin traumas, such as wounds and any post surgical trauma. Particularly included are the disciplines of corrective and augmentative plastic surgery (including burns treatment), cardiothoracic surgery, gastrointestinal surgery, obstetric and gynaecological surgery, breast reduction, breast enhancement, mastectomy, urology, orthopaedic surgery and maxillofacial surgery.

In general, dressings of the invention are useful in any post trauma use, i.e. in the prevention or treatment of hypertrophic scarring and keloids that result from injury or surgery. It will also be appreciated that other conditions, such as plaque psoriasis, burns and general dermatoses are suitable for treatment with dressings of the present invention. Scarring from burns can be quite significant, and the treatment and/or prophylaxis of scarring resulting from burns is a preferred objective of the present invention.

Adhesive dressings of the present invention are suitable to be removably secured onto or in the region of skin to be treated. The adhesives of the present invention have the advantage of providing good levels of adhesion so that patches or tapes will not come off before desired, but that, on removal, there is minimal pain and substantially no exfoliation. The patches may be adhered anywhere appropriate for the treatment of scars or incipient scars, and it is particularly preferred that drug-loaded adhesive contact the tissue to be treated, while drug-free adhesive serve to secure the dressing to surrounding tissue, or skin.

By "drug-free" is meant that the adhesive has not intentionally been loaded with drug, but it will be appreciated that, in some formulations, it is possible for drug to pass from a drug-loaded region to a drug-free region in small quantities. It is preferred to minimise this effect, as described herein. When it does happen, it is generally in such small amounts that surrounding, healthy tissue is not affected to any appreciable degree. Suitable backings are described hereinbelow. They may take any suitable form, and may be in the form of films or materials, for example. Films may be selected for breathability and/or their occlusive properties, occlusive films being preferred. It is possible to use metallised films, but it is generally preferred to use plastics, such as polyethylene terephthalate (PET). Materials may be selected from woven and non- woven, with non-wovens generally providing a greater degree of flexibility. Such materials are generally highly porous, and it is preferred to impregnate them with a water-proofing substance, as well known in the art, to provide a degree of occlusivity.

The adhesive layer is preferably layered directly onto the backing, although the backing itself may be multilaminate. The adhesive is suitable to directly adhere to most backings, but it may be necessary, or desirable, in some instances, to provide further means for the adhesive to be secured to the backing, such as by a cross-linking layer.

Substances effective in the prophylaxis and/or treatment of scarring are manifold, and have been described above, and are described in more detail below. However, they are generally selected from steroids and especially corticosteroids, and are any substance that is recognised in the art as being effective in the management of scarring. In general, such drugs are effective in both the prophylaxis and the treatment of scarring, but it will be appreciated that the present invention envisages substances which are more effective in one aspect than the other. In addition, some drugs may be more appropriate to the treatment of hypertrophic scars than keloids, and it is generally preferred that more powerful corticosteroids, such as triamcinolone and its associated family, be used in the management of keloids, particularly for the initial treatment of an existing keloid.

The drug is borne at least partially in the adhesive, by which is meant that the adhesive is impregnated with, or otherwise carries, at least some of the drug. It is not necessary to saturate the adhesive with the drug and, conversely, it is also possible to provide a reservoir patch, wherein the drug is contained in a reservoir located between the adhesive and the backing. This is not generally preferred, and it is preferred for substantially all of the drug of the patch to be borne in the adhesive, such patches generally being termed matrix patches, in the art.

Suitable adhesives are described in detail below, and are block copolymers having both soft and hard segments. Chemical cross-linking between the soft segments provides a large drug-loading capacity and remarkable cohesion in the adhesive. Such adhesives are also strong, and this is tempered by the addition of 10% or more plasticiser. Such levels of plasticiser have not previously been described in effective adhesives, and it is the unique structure of the adhesives of the invention that permit such levels of plasticiser to be used. The resulting adhesive can then be removed without pain, but remains in place until removed, under conditions of reasonable care.

Levels of plasticiser are described in more detail below, but will generally be between 10 and 30% in adhesives not characterised by any further cross-linking (infra). Levels of plasticiser of between 10 and 20% are more preferred, especially 15 and 20%.

In a further aspect, the present invention provides a bioadhesive patch for the topical prevention or treatment of hypertrophic and keloid scars, comprising a flexible adhesive material for attachment to skin, and a treatment drug for delivery to the scar or its potential site of development, the adhesive material having drug retention properties and comprising a cross-linked block copolymer, the block copolymer having hard and soft segments wherein there is chemical cross-linking between the soft segments.

In a preferred embodiment, tapes of the present invention comprise a first, active tape and a second occlusive tape serving to further secure the active tape to healthy skin or tissue. It will be appreciated that the active tape need not be occlusive, although it is generally preferred that the backings used herein are impermeable to the drags used. If desired, the second, occlusive tape need not actually be occlusive, the term "occlusive" being one of convenience, as this is the preferred embodiment. The adhesive of the occlusive strip need not necessarily be the same as for the active strip although, for comfort and convenience, it is generally preferred that the same or substantially the same adhesive be used as for the active strip, but without drug. The two tapes may be provided separately or integrally, each having advantages. In the former, the active strip can be cut to precisely the size desired, there being no such requirement for the second tape while, in the latter, there is the convenience of having the two provided and dispensed together, possibly in the form of plasters or on a roll. Separate strips may be used for established scars which it is desired to treat precisely, while integral strips may be useful in the prevention of hypertrophic scars after surgery.

The widths of the strips may be any that is suitable, and will vary according to the application to which it is desired to put the dressing. Typically, the active strip will be from about 5 mm up to about 80 mm wide, depending on intended use. For preventative use, a preferred range is about 10 to 30 mm, preferably about 10 to 20 mm. A preferred strip is 10 mm wide. The occlusive strip has an overlap which may be about 5 to about 20 mm over the active strip, more preferably about 8 to 15 mm. A preferred occlusive strip has an overlap of 10 mm. Such overlap applies generally to any dressing involving an area of unmedicated adhesive, and not just to two tape or patch systems.

The present invention also provides a dispenser into which is loaded each type of strip and which associates the tapes and, if necessary, strips the release layer(s) on dispensing the tapes. This avoids any possibility of drug leaking from the active tape to the occlusive tape, prior to their combination.

It is generally preferred that the tapes should be thin and flexible to allow the strips to mould to the contours of the scar. It is also preferred that at least the occlusive strip should be translucent or transparent in order to facilitate location of the active strip.

It is also generally preferred that the dressings of the present invention be used in the prophylaxis or early treatment of scars. Patients with existing hypertrophic or keloid scars in excess of 12 months old may be less susceptible to the benefits of the dressings of the present invention. Dressings of the present invention are significantly more effective at preventing hypertrophic and keloid scar formation than routine post-operative or post-trauma wound care. Significant reduction of hypertrophic and keloid scarring is seen in patients, especially with daily application for a period of about 12 weeks. Tapes of the present invention generally leave a more cosmetically acceptable scar than routine postoperative wound care, where a scar is left but, in general, there is no occurrence of hypertrophic/keloid scarring, post-treatment.

It is an advantage of the present invention that it is generally painless to remove the dressings when needed, and that there is no, or only low grade skin irritation. Further, it is relatively easy to ensure that there is no/minimal thinning of surrounding healthy skin, and there is no, or only minimal, systemic absorption, so that there are no systemic steroid-related adverse-effects. In addition, dressings of the present invention are relatively stable, and may generally be kept under standard conditions for up to two years, or more, at room temperature.

Any drug that is effective in the prevention or treatment of scars may be used in accordance with the present invention. Suitable drugs are biologically active compounds or mixtures of compounds that have therapeutic, prophylactic or other beneficial pharmacological or physiological effects in the prevention or treatment of scars. It will be appreciated that the term 'drug', as used herein, refers to any such substance or compound suitable for topical administration from an adhesive patch, when located over a scar or its potential site of development and/or surrounding skin.

Preferred are steroid drugs, in particular beclomethasone dipropionate, betamethasone, betamethasone valerate, clobetasol propionate, diflucortolone valerate, fluocinolone acetonide, fluocinonide, fluticasone propionate, halcinonide, methylprednisolone, mometasone furoate, triamcinolone, methylprednisolone, flurandrenolone, and other derivatives of such compounds, such as the acetonide, hexacetonide and diacetate, especially of triamcinolone, and mixtures thereof, as well as pharmaceutically acceptable equivalents thereof and pharmaceutically acceptable esters and the salts of such compounds with pharmaceutically acceptable acids and bases as appropriate. Preferred steroids include; triamcinolone hexacetonide, betamethasone and methylprednisolone, as well as triamcinolone hexacetonide and triamcinolone diacetate, and particularly preferred, at present, are betamethasone valerate and triamcinolone acetonide, individually.

In order to provide a sufficiently strong attachment to the scar and/or surrounding skin, we prefer that the adhesive material is bioadhesive, and in particular that it has an adhesive strength of about 30g/inch (~1.2g/mm) to about 300 g/incli (~12g/mm), preferably, about 40g/inch (~1.6g/mm) to about 200 g/inch (~8g/mm), although the skilled person will recognise appropriate strengths. Materials with an adhesive strength greater than about 300 g/inch (~12g/mm) are likely to cause skin irritation when the patch is removed, as the outer skin layer is concomitantly removed (exfoliation), and should therefore be avoided for any part of the patch to be adhered to skin. The adhesive surface for attachment to the skin may be continuous or discontinuous, as desired, but it is generally preferred that it be continuous.

The copolymeric adhesive material for use in according to the present invention has drag retention properties to enable the treatment drug to be incorporated into the adhesive material. A substance having drag retention properties is taken herein as being a substance capable of absorbing, adsorbing or otherwise carrying a drag. In order to be able to deliver the drug to the area of skin to be treated, it will be appreciated that the uptake of drag needs to be at least partially reversible when in situ, although it is preferred that the drug not weep or otherwise exude from the tape or patch until applied to the skin. In general, levels of delivery of drug over 48 hours are between about 1 and 5% of the total load of the patch in contact with the skin and, more usually, between 2 and 4% for steroid delivery systems, thus making the high loading ability of the present invention particularly useful.

As noted above, patches of the invention preferably comprise a drug- impermeable backing layer. Suitable examples of drug-impermeable backing layers which may be used for the patches include films or sheets of polyolefins, polyesters, polyurethanes, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chloride, polyamides, ethylene- vinyl acetate copolymer (EVA), ethylene-ethylacrylate copolymer (EEA), vinyl acetate-vinyl chloride copolymer, cellulose acetate, ethyl cellulose, metal vapour deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, non-woven fabrics, fabrics, knitted fabrics, paper and foils. One preferred drug-impermeable backing material is non-woven polyethylene terephthalate (PET). This and other woven and especially non-woven backings are advantageous in that they are also able to stretch, in order to compensate for any skin movement, while the patch or tape is in place. Another particularly preferred backing is a thin, occlusive, polyester layer. Other backings will be readily apparent to those skilled in the art. Preferably, the backing is a semi-occlusive or occlusive backing, in order to maintain hydration of the tissue.

Patches of the present invention used for the prevention or treatment of small, discrete scars or larger, extensive scars, will generally be shaped or cut accordingly.

For example, for the prevention or treatment of extensive scarring, the patch can be provided in the form of flexible matrix strips and sheets that contain the drug throughout their extent, for daily or, more preferably, night-time, application to the scar. It will be appreciated that, in the case of keloids, the strips can be provided in any appropriate width, suitably a width in the range from 1 to 10 cm, for example a width of 1 cm, 2 cm or 5 cm. If necessary, several strips can be combined so as to cover the scar by abutting one strip with the next, or one or more sheets or strips can be cut so as to cover and fit over an extensive scar. Once in place, the sheets or strips can then be secured more firmly, if desired, by application of a further, non-medicated tape over them and adjacent skin areas.

Accordingly, in one embodiment, the patch is in the form of a strip or sheet in which the drug is present throughout the extent of the patch.

For the prevention or treatment of discrete scars, it may preferable if, instead of the drug being present throughout the extent of the patch, the drug is only present in a central area of the patch, so that there is a peripheral area around it that is bioadhesive but free of drug. In this form, prevention or treatment of a discrete scar can be conducted by adhering the central, medicated, area onto the scar, whilst the surrounding peripheral area is adhered to the healthy skin adjacent to the scar. Thus, the drag- containing portion of the patch may be firmly secured over and around the surface of the scar by benefiting from the adhesion between the peripheral portion and healthy skin. At the same time, the peripheral portion, being free of the drag, advantageously prevents the underlying healthy skin from being exposed to the drug, thereby effectively masking the healthy skin from contact with the drag. The drug may therefore be accurately targeted to the scar or incipient scar, leaving the surrounding healthy skin unaffected.

For example, tape strips approximately 3.0 cm wide containing a scar prophylaxis or treatment drug only within a central area approximately 0.5-1.0 cm in diameter may conveniently be used for the prevention or treatment of small surgical scars. The dimensions and shapes of the central and peripheral areas can of course be varied according to choice, depending on the particular dimensions of the healing wound or scar to be treated with the patch.

Accordingly, in another embodiment, the patch comprises a central portion and a peripheral portion, and the drug is present substantially only in the central portion.

The adhesive strength of the central and peripheral areas can be the same, for example, if the patch is formed from one adhesive material. Alternatively, the patch may be formed such that the central and peripheral areas have differing adhesive strengths, degrees of flexibility, elasticities, or other properties. This maybe achieved, for example, by forming the central and peripheral areas of different adhesive materials, each tailored to provide the desired properties. Alternatively, the patch may be formed using one adhesive material and subsequently modified to provide different properties for a central or peripheral area. Other means of producing a patch in which a central area has different properties from the peripheral area will be apparent to those skilled in the art. In one embodiment, therefore, the adhesive strength of the peripheral portion is different from that of the central portion.

In a preferred embodiment, drug from the central area is unable to diffuse, to any substantial extent, into the peripheral area. This may be achieved by selection of the peripheral adhesive, or by use of an appropriate barrier.

For example, scar sites are often sensitive, so that a strongly adhering patch would cause irritation. In such cases, it may be desirable for the adhesive strength of the peripheral portion to be greater than that of the central portion. On the other hand, if the scar surface is relatively insensitive, or less sensitive than the surrounding skin, then it may be desirable for the adhesive strength of the peripheral portion to be less than that of the central portion. In any case, we prefer that the adhesive material of the peripheral portion has an adhesive strength of about 40g/inch (~1.6g/mm) to about 200 g/inch (~8g/mm).

It will be appreciated that the central portion of the patch, and preferably the patch as a whole, should be sufficiently thin and flexible for it to be moulded around and to the contours of a scar. Advantageously, the use of a cross-linked block copolymer, having hard and soft segments in which there is chemical cross-linking between the soft segments, permits such a thin, flexible patch to be formed, having the required adhesion, cohesion and drug-loading capabilities.

In another embodiment, the patch comprises a peripheral portion that is adhered to healthy skin surrounding a scar, and that does not contain a drug but provides a scaffold or support for a drag-containing portion to be applied over the scaffold and keloid. Thus, healthy skin is masked from contact with the drag, whilst the scar is in contact with the drag-containing portion of the patch.

It will be appreciated that the patch according to this embodiment may be applied in two or more parts: first the peripheral scaffold portion is adhered to the skin surrounding the scar to be treated. Optionally, a scar treatment cream or ointment containing a drag is applied to the keloid, whilst the healthy skin is advantageously protected by the peripheral portion from inadvertent application with the drag- containing cream or ointment. Next, a drag-containing portion is applied over the peripheral scaffold portion and the scar. Preferably, the drag-containing portion is adhered to the scaffold portion, so as to be supported and held in place over the scar for treatment. Alternatively, or additionally, the parts of the patch can be held in place by additional drag-free tape adhered over the patch and to adjacent skin.

Optionally, a treatment cream or ointment containing drag is applied to the scar, whilst the healthy skin is advantageously protected by the peripheral portion from inadvertent application with the drag-containing cream or ointment. When a treatment cream or ointment containing a suitable drag is applied to the scar, the portion applied over the peripheral scaffold portion and the scar may optionally contain no drug, but be used simply to occlude the cream or ointment. It will also be appreciated that the scaffold portion need only serve as a masking or barrier area sufficient to prevent access of drag to healthy skin.

The term 'block copolymer', as used herein, refers to a macromolecule comprised of two or more chemically dissimilar polymer structures, terminally connected together (Block Copolymers: Overview and Critical Survey, Noshay and McGrath, 1977). These dissimilar polymer structures, sections or segments, represent the 'blocks' of the block copolymer. The blocks may generally be arranged in an A-B structure, an A-B-A structure, or a multi-block -(A-B)_n- system, wherein A and B are the chemically distinct polymer segments of the block copolymer, the A blocks generally being the hard and the B blocks generally being the soft segments.

It is generally preferred that the block copolymer is of an A-B-A structure, especially wherein one of A and B is an acrylic-type polymeric unit. It will be appreciated that the present invention is also applicable using block copolymers which possess three or more different blocks, such as an A-B-C block copolymer. However, for convenience, reference hereinafter to block copolymers will assume that there are only A and B sub-units, but it will be appreciated that such reference also encompasses block copolymers having more than two different sub-units, unless otherwise specified.

It will be appreciated that the properties of block copolymers are very largely determined by the nature of the A and B blocks. Block copolymers commonly possess both 'hard' and 'soft' segments. A 'hard' segment is a polymer that has a glass transition temperature (T_g) and/or a melting temperature (T_M) that is above room temperature, while a 'soft' segment is a polymer that has a T_g (and possibly a T_M) below room temperature. The different segments are thought to impart different properties to the block copolymer. Without being constrained by theory, it is thought that association of the hard segments of separate block copolymer units result in physical cross-links within the block copolymer, thereby promoting cohesive properties of the block copolymer. It is particularly preferred that the hard segments of the block copolymers form such physical close associations.

The block copolymers useful in the present invention are preferably acrylic block copolymers. In acrylic block copolymers, at least one of the blocks of the block copolymer is an acrylic acid polymer, or a polymer of an acrylic acid derivative. The polymer may be composed of just one repeated monomer species. However, it will be appreciated that a mixture of monomeric species may be used to form each of the blocks, so that a block may, in itself, be a copolymer. The use of a combination of different monomers can affect various properties of the resulting block copolymer. In particular, variation in the ratio or nature βf the monomers used allows properties such as adhesion, tack and cohesion to be modulated, so that it is generally advantageous for the soft segments of the block copolymer to be composed of more than one monomer species.

It is preferred that alkyl acrylates and alkyl methacrylates are polymerised to form the soft portion of the block copolymer. Alkyl acrylates and alkyl methacrylates are thought to provide properties of tack and adhesion. Suitable alkyl acrylates and alkyl methacrylates include n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2- ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate, although other suitable acrylates and methacrylates will be readily apparent to those skilled in the art. It is preferred that the acrylic block copolymer comprises at least 50% by weight of alkyl acrylate or alkyl methacrylate (co)polymer.

A polar monomer is advantageously copolymerised with the alkyl acrylate or alkyl methacrylate, in order to enhance the drag solubility of certain, especially hydrophilic, drugs. Suitable polar monomers which can be copolymerised with alkyl acrylates or alkyl methacrylates include hydroxyethyl acrylate, hydroxypropyl acrylate, vinyl pyrrolidone, acrylamide, dimethylacrylamide, acrylonitrile, diacetone acrylamide and vinyl acetate, although others will be apparent to those skilled in the art. Diacetone acrylamide, or a combination of diacetone acrylamide and vinyl acetate, is useful as polar monomer if a drug is incorporated in the adhesive. The diacetone acrylamide component enables more advantageous drag loading capabilities than vinyl acetate, but vinyl acetate enhances the rate of polymerisation, which is of commercial importance. In such a case, where two polar monomers are used in an adhesive, it will be appreciated that the levels of each monomer may be manipulated in such a way as to provide optimum drug retention and delivery.

As stated above, variation in the components of the soft segment affects the overall properties of the block copolymer, although the essential feature remains the cross-linking of the soft segments. For example, soft segments essentially consisting of diacetone acrylamide with either butyl acrylate and/or 2-ethylhexyl acrylate, in approximately equal proportions, work well, and a ratio by weight of about 3 : 4 : 4 provides good results. It is preferred that diacetone acrylamide, or other polar monomer, such as hydroxyethyl methacrylate or vinyl acetate, be present in no more than 50% w/w of the monomeric mix of the soft segment, as this can lead to reduced adhesion, for example. The acrylate component may generally be varied more freely, with good results observed with both 2-ethylhexyl acrylate and butyl acrylate together or individually. As noted above, ratios of the various monomers are generally preferred to be approximately equal. For adhesives, this is preferred to be with a polar component of 50% or less of the soft segment, with the apolar portion forming up to about 85% w/w, but preferably between about 50 and 70% w/w. In the example above, this is about 72% (4+4) apolar to about 18% (3) polar.

As discussed above, polymers suitable for use as the hard portion of the block copolymer possess glass transition temperatures above room temperature. Suitable monomers for use in forming the hard segment polymer include styrene, α-methylstyrene, methyl methacrylate and vinyl pyrrolidone, although other suitable monomers will be readily apparent to those skilled in the art. Styrene and polymethyl methacrylate have been found to be suitable for use in the formation of the hard segment of the block copolymers. It is preferred that the hard portion of the block copolymer forms from 3-30% w/w of the total block copolymer, particularly preferably

The block copolymer is further characterised in that the soft portions contain a degree of chemical cross-linking. Such cross-linking may be effected by any suitable cross-linking agent. It is particularly preferable that the cross-linking agent be in the form of a monomer suitable for incorporation into the soft segment during polymerisation. Preferably the cross-linking agent has two, or more, radically polymerisable groups, such as a vinyl group, per molecule of the monomer, at least one tending to remain unchanged during the initial polymerisation, thereby to permit cross- linking of the resulting block copolymer.

Suitable cross-linking agents for use in the present invention include divinylbenzene, methylene bis-acrylamide, ethylene glycol di(meth)acrylate, ethylene glycol tetra(meth)acrylate, propylene glycol di(meth)acrylate, butylene glycol di(meth)acrylate, or trimethylolpropane tri(meth)acrylate, although other suitable cross- linking agents will be readily apparent to those skilled in the art. A preferred cross- linking agent is tetraethylene glycol dimethacrylate. It is preferred that the cross-linking agent comprises about 0.01-0.6% by weight of the block copolymer, with 0.1-0.4% by weight being particularly preferred.

Methods for the production of block copolymers from their monomeric constituents are well known. The block copolymer portions of the present invention may be produced by any suitable method, such as step growth, anionic, cationic and free radical methods (Block Copolymers, supra). Free radical methods are generally preferred over other methods, such as anionic polymerisation, as the solvent and the monomer do not have to be purified.

Suitable initiators for polymerisation include polymeric peroxides with more than one peroxide moiety per molecule. One suitable initiator has been found to be 'Perhexa MC (l,l'-di-tertbutyl-peroxy-2-methyl cyclohexane, Nihon Yusi C.C.). This compound contains two tertiary butyl peroxy groups which allow stepwise polymerisation of the hard and soft segments of the block copolymer. The initiator 'CH-50-AL' (Peroxid-Chemie GmbH) has also been found to be suitable in the manufacture of copolymers suitable for the present invention. An appropriate choice of reaction conditions is well within the skill of one in the art, once a suitable initiator has been chosen.

The initiator is preferably used in an amount of 0.005-0.1% by weight of the block copolymer, with 0.01-0.05% by weight being particularly preferred, although it will be appreciated that the amount chosen is, again, well within the skill of one in the art. In particular, it is preferred that the amount should not be so much as to cause instant gelling of the mix, nor so low as to slow down polymerisation and to leave excess residual monomers. A preferred level of residual monomers is below 2000 ppm. It will also be appreciated that the amount of initiator will vary substantially, depending on such considerations as the initiator itself and the nature of the monomers.

The block copolymeric adhesives of the present invention are, typically, pressure sensitive adhesives. Pressure sensitive adhesives can be applied to a surface by hand pressure and require no activation by heat, water or solvent. As such, they are particularly suitable for use in accordance with the present invention.

The block copolymers may be used without tackifiers and, as such, are particularly advantageous. However, it will be appreciated that the block copolymers may also be used in combination with a tackifier, to provide improved tack, should one be required or desired. Suitable tackifiers are well known and will be readily apparent to those skilled in the art.

Without being constrained by theory, it is thought that the combination of chemical cross-links between the soft segments of the copolymer combined with the, generally, hydrophobic interaction, or physical cross-linking, between the hard portions results in a 'matrix-like' stracture. Copolymers having only physical cross-linking of the hard segments are less able to form such a matrix. It is believed that the combination of both forms of cross-linking of the block copolymers provides good internal strength (cohesion) and also, if needed, high drag storage capacity.

More particularly, it is believed that the hard segments associate to form 'islands', or nodes, with the soft segments radiating from and between these nodes. There is a defined physical structure in the 'sea' between the islands, where the soft segments are cross-linked, so that there is no necessity for extensive intermingling of the soft segments. This results in a greater cohesion of the whole block copolymer while, at the same time, allowing shortened soft segment length and still having as great, or greater, distances between the islands, thereby permitting good drug storage capacity.

The block copolymer preferably cross-links as the solvent is removed, so that cross-linking can be timed to occur after coating, this being the preferred method. Accordingly, not only can the block copolymer easily be coated onto a surface, but the complete solution can also be stored for a period before coating. Accordingly, in the manufacturing process of the patches, the process preferably comprises polymerising the monomeric constituents of each soft segment in solution, then adding the constituents of the hard segment to each resulting solution and polymerising the resulting mix, followed by cross-linking by removal of any solvent or solvent system, such as by evaporation. If the solution is to be stored for any length of time, it may be necessary to keep the polymer from precipitating out, and this may be achieved by known means, such as by suspending agents or shaking. It may also be necessary to select the type of polymers that will be subject to substantially no cross-linking until the solvent is evaporated.

In general, it is preferred that the adhesive possesses a minimum number of functionalities having active hydrogen, in order to avoid undesirable reactions/ interactions, such as with any drug that it is desired to incorporate into the adhesive material. It will be appreciated that this is only a preferred restriction, and that any adhesive may be tailored by one skilled in the art to suit individual requirements. For example, it may be desirable to incorporate certain active groups into the adhesive in order to encourage uptake of a given compound, such as a drag. It is also the case that, where the adhesive is not intended for medical use, restrictions on any medically undesirable function are not so severe. Where the adhesive is used as an adhesive in its own right, without carrying a drag, then it is also less of a requirement to limit active functionalities, although limiting such functionalities generally helps to reduce irritation and, so, is preferred.

Limiting active functionalities, especially those with active hydrogen, is generally preferred, in order to permit wide use of any given formulation of adhesive without having to take into account how it is likely to interact, chemically, with its environment. However, as stated above, an adhesive required for any individual purpose may be tailored as seen fit by one skilled in the art. Thus, a generally chemically inert adhesive is preferred, in the absence of requirements to the contrary.

It is established in the prior art that strong adhesives can be tempered with plasticisers. These generally take the form of oily substances introduced into the adhesive polymer. The effect of the introduction of such oily substances is to soften the physical stracture of the adhesive whilst, at the same time, acting at the interface between the adhesive and the skin, thereby helping to somewhat weaken the adhesive, and to prevent exfoliation. Such a beneficial type of adhesive was first noted in certain types of electrical insulating tape.

A problem with such softened, or plasticised, adhesives is that, once they are weak enough to be medically acceptable, their cohesive strength is poor. Thus, such adhesives, when used in patches or surgical tape, for example, have insufficient integrity, and tend to tear, leaving bits of adhesive behind on the skin.

For example, EP-A-450986 discloses an acrylic adhesive plasticised with isopropyl yristate (IPM) and which also contains nitroglycerine, which can further serve as a plasticiser. In order to improve cohesion of this adhesive, cross-linking was effected with aerosil silica. However such cross-linking presents a technical difficulty in sufficiently finely dividing the aerosil silica and incorporating it uniformly throughout the adhesive, and would therefore not be generally practical.

US-A-5298258 discloses acrylic adhesives containing substantial amounts of plasticisers. Various methods for cross-linking the adhesive are mentioned, including irradiation and exposure to UV, but chemical cross-linking with a metal alcoholate, metal chelate or trifunctional isocyanate is preferred. The cross-linking of such an adhesive requires the presence of active hydrogen, generally in the form of a carboxyl or hydroxyl group, typically provided by a co-monomer having the required functionality. A problem with such a system is with regard to the nature of the cross- linking, where there is necessarily involved an active chemical reagent, either on the adhesive (carboxyl groups, for example) or in the cross-linker (such as aluminium in aluminium alcoholate). Many drugs can react or interact with such groups, which can lead to problems, such as breakdown of the drag, or simple blocking of the cross- linking. For example, where a drag is weakly basic, then this can interact with the carboxyl groups present on the adhesive, thereby competing with the cross-linker.

Our WO 99/02141, incorporated herein by reference, discloses block copolymers wherein the soft segments are cross-linked, these copolymers being suitable for use as drug-retaining bioadhesives in transdermal patches. The adhesive is strong, however. Use of any significant level of plasticiser with these adhesives is not suggested or taught.

We have found, however, that it is possible to incorporate between about 10 and

20%, even up to 30%, plasticiser in the adhesives of WO 99/02141, and that the resulting adhesive has good adhesive properties, but also has good release qualities. In these adhesives, we have found that incorporation of a plasticiser in the copolymer still provides sufficiently good cohesion and adhesion properties and low irritation for a scar treatment patch, as long as the amount of plasticiser is less than about 20% w/w, preferably less than about 10% w/w, of the adhesive. Accordingly, in one embodiment, the adhesive material comprises a plasticiser in an amount of less than 20% w/w, preferably less than 10% w/w, of the adhesive.

Suitable plasticisers may be selected by those skilled in the art. The only requirement for the plasticiser is that it be appropriate to the adhesive. For example, using the preferred adhesive noted above, naturally occurring castor oil has been found not to be appropriate, for example, as it leaks out of the adhesive, thereby preventing adhesion. However, appropriate plasticisers are readily established by those skilled in the art. In particular, a simple mixture of a plasticiser with the adhesive should provide a bioadhesive material, or material suitable for use as a bioadhesive (which expressions are used interchangeably herein), which does not separate, and which is adhesive, within the broad general ranges that have generally been noted.

The plasticiser may be used in an amount less than 20%, preferably less than

10%, of the adhesive, unless the adhesive copolymer comprises ketone groups cross- linked by a polyamine cross-linking agent in which case the plasticiser. may also be used in an amount generally between about 10 and 300%, preferably between 20 and 200% of the adhesive, more specifically between about 40% and 160%, preferably between about 60 and 120%, with about 100% generally providing good results. It will be appreciated, however, that different plasticisers will have different optima for different adhesives. Thus, in one embodiment, the plasticiser comprises between about 17% and 71% w/w, preferably between about 37% and 62% w/w, of the adhesive.

Plasticisers are generally liquids having high boiling points, and suitable examples include glycols, such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol; fats and oils such as olive oil, jojoba oil, squalene and lanolin; organic solvents such as dimethyl decyl sulphoxide, methyl octyl sulphoxide, dimethyl sulphoxide, dimethylformamide, dimethylacetamide, dimethyllaurylamide, dodecyl pyrrolidone and isosorbitol; liquid surfactants; specific plasticisers such as diisopropyl adipate, phthalates and diethyl sebacate; hydrocarbons such as liquid paraffin; ethoxylated stearyl alcohol, glycerol esters, isopropyl myristate, isotridecyl myristate, ethyl laureate, N-methylpyrrolidone, ethyl oleate, oleic acid, isopropyl adipate, isopropyl pahnitate, octyl pahnitate and 1,3-butanediol. Of the above, phthalates, isopropyl myristate, isotridecyl myristate and octyl pahnitate are currently preferred. These substances can be used either alone or as a mixture or mixtures thereof.

In co-pending WO 00/44846, incorporated herein by reference, we show that it is possible to provide a satisfactory medical adhesive with good cohesion and adhesive properties, together with low irritation, and which comprises an adhesive polymer and a plasticiser, wherein the polymer is cross-linked by a polyamine reacting with ketone groups present in the adhesive. The adhesive used is preferably as disclosed in WO 99/02141, so that there is cross-linking between soft segments and further cross- linking effected by reacting a polyamine with keto groups contained in the adhesive.

The adhesives of WO 00/44846 are particularly useful in the present invention. Accordingly, in a preferred embodiment, the copolymer of the adhesive comprises ketone groups cross-linked by a polyamine cross-linking agent.

Preferably, the adhesive material has an adhesive strength such that the patch can be applied to the skin and then removed without removing the stratum corneum layer of the skin surface. For example, preferred adhesives are those which, in tests, can be applied to newspaper and readily removed therefrom without tearing the paper. Particularly preferred are those adhesives which can be removed from, and reapplied to, newspaper repeatedly, without losing adhesion or damaging the paper.

Furthermore, if the patch comprises a central, drag-containing portion and a peripheral, drag-free portion, one of the central and peripheral portions maybe formed of an adhesive material that comprises a plasticiser and in which the copolymer comprises ketone groups cross-linked by a polyamine cross-linking agent. Thus, in one embodiment, only the central portion is formed of an adhesive material that comprises a plasticiser and in which the copolymer comprises ketone groups cross-linked by a polyamine cross-linking agent. In another embodiment, only the peripheral portion is formed of an adhesive material that comprises a plasticiser and in which the copolymer comprises ketone groups cross-linked by a polyamine cross-linking agent.

In the embodiments above in which the copolymer comprises ketone groups cross-linked by a polyamine cross-linking agent, the copolymer constituents thereof are cross-linked, wherein at least a portion of the cross links comprise a moiety:

>C=N-(X)-N=C<

in which the carbon atoms are each a part of the copolymer constituents and each X is the same or different, preferably the same, and is directly equivalent to any group that would serve to carry the necessary amine groups of a polyamine cross-linking agent.

Accordingly, it will be appreciated that -(X)-, at its simplest, need only represent a direct bond, in the instance of hydrazine, for example. It will also be appreciated that more than two suitable amine groups may be attached to X, although X may often be of the form X^!-N<, or of the form X²(NA-)₂, wherein X¹ and X² represent the kernel of X, and the groups -N< and NA represent the links with -N=C< groups, with each A representing a hydrogen or a direct bond with X². The polyamine cross-linked adhesive materials have been found to possess good water vapour permeabilities, which may allow the skin to breathe when the patch is in place. In addition, the lack of any necessary reactive groups is useful for drug stability, •and are generally susceptible to very little interaction with other materials. These adhesive copolymers, or a substantial component thereof, have at least one ketone group which is able to react with a polyamine.

Ketone groups are capable of tautomerisation, where there is an equilibrium between the ketone and the corresponding enol compound. This equilibrium is generally in favour of the ketone. In the present invention, it is strongly preferred that the ketone-containing polymer should have at least one ketone group with little or substantially no tendency to enolisation. Hence, it is preferred that the ketone group should not be part of a larger functionality, and it is particularly the case that the ketone group should not be part of a carboxyl group or any derivative thereof, such as an esteric linkage or amide group, although it may be linked to or adjacent such a group. It is also strongly preferred that the ketone group should not be part of an aldehyde group.

It appears that the cross-linking reaction takes place between the keto form of the carbonyl group and the amine group of the cross-linking agent. It has been found that, if the ketone group is not stable in the keto form, then it reacts only poorly, if at all, with the cross-linking agent. Preferred compounds are those in which the keto form is at least 100 fold more stable than the enol form, preferably more stable by a factor of 10⁴, most preferably more stable by a factor of 10⁶ or greater. Preferably the equilibrium constant K (enol/keto), when measured in water, is less than 10^"2, more preferably less than 10^"4, and most preferably less than 10^"6, or even smaller. In this way, the equilibrium is strongly biased in favour of the keto form. Other factors aside, the more strongly biased the equilibrium toward the ketone group, the better.

Given the preference for the ketone group to not readily be able to form an enol group, then it will be appreciated that functionalities in the proximity of the reactive ketone group are preferred which do not encourage the keto group to enolise. In fact, such functionalities are preferred where stabilisation of the keto group is encouraged. Where the adhesive does not already possess a suitable ketone group, this can readily be provided by the incorporation of a suitable monomer when preparing the polymer. The adhesives of WO 99/02141 already possess good cohesion and adhesion, but addition of large amounts of plasticiser compromises cohesion. Cross-linking with a polyamine cross-linker that reacts with ketone groups enables the use of these adhesives, retaining their superior drag retention properties and allowing control of the level of adhesion, while allowing painless and irritation-free removal of the patch.

Examples of suitable ketone-providing monomers include aliphatic, olefinically unsaturated keto, preferably monoketo, compounds such as vinyl esters or allyl esters of aliphatic monobasic or dibasic acids containing a keto group and having a suitable number of carbon atoms, such as three to eight. Suitable such acids include pyruvic acid, acetoacetic acid and levulinic acid, a suitable ester of such being the vinyl alcohol ester. For example, one suitable compound, pyruvic acid vinyl alcohol ester, has the formula H₂C=CH-O-CO-CO-CH₃.

Other suitable compounds include aliphatic amides substituted at the nitrogen by a vinyl or allyl group and other suitable monomers are the olefinically unsaturated ketones, such as vinylmethyl ketone and vinylethyl ketone. However, the currently preferred monomer is diacetone acrylamide, which is readily commercially available and which has the structure CH₂=CH-CONH-C(CH₃)₂-CH₂-COCH₃. A particularly preferred adhesive uses a combination of butyl acrylate, 2-ethylhexyl acrylate and diacetone acrylamide, preferably in a ratio of about 4 : 4 : 3, either as the adhesive, or as the soft segment of the block copolymer, although other suitable preparations will be apparent to those skilled in the art. In general, unless otherwise specified, ratios and percentages, as given herein, are by weight.

Suitable plasticisers are as described above, with isopropyl myristate currently being preferred, although other plasticisers suitable for use in the present invention will be readily apparent to those skilled in the art. Suitable polyamines for use as cross-linking agents should have two or more free amine groups to react with the ketone moiety of the adhesive. By "free" amine groups is meant that there is at least one hydrogen substituent on the nitrogen. In the simplest embodiment, hydrazine, or hydrazine hydrate, may be used as the polyamine. However, we have established that it is highly preferable that the reactive amine should be bound directly to another nitrogen, or to another group providing the same or generally equivalent electronegativity as another nitrogen. Thus, dihydrazine compounds and linked amine compounds are particularly preferred. Examples of the latter include dialkylene triamines, such as di-C_2-6 alkylene triamines wherein the alkylene groups are preferably the same length as each other, especially diethylene triamine [2-(2-aminoethylamine)ethylamine] or bishexamethylene triamine, but other suitable triamine and polyamine compounds will be readily apparent to those skilled in the art.

Dihydrazine compounds are especially preferably dihydrazides of polybasic organic acids, especially dicarboxylic acids. Examples of aromatic dicarboxylic acids include phthalic acid, isophthalic acid and terephthalic acid, although others will be readily apparent to those skilled in the art. Particularly preferred dihydrazides are those of aliphatic saturated dicarboxylic acids, especially those having 2-10 carbon atoms, and dihydrazides of oxalic acid, adipic acid, and sebacic acids are suitable examples, while the diamino derivatives of medium chain alkanes are useful (Cs_-12), especially the straight chain alkanes, of which the hexane and dodecane derivatives are currently preferred, especially 1,6-diaminohexane and 1,12-diaminododecane. It will be apparent that polyhydrazides, as well as the dihydrazides, may also be employed.

We prefer that the polyamines be used in an amount generally between about 0.05% and 2% of the adhesive, more specifically between about 0.3% and 1%, although individual polyamines will have different optima for different adhesives. In addition, it will be appreciated that the quantity of the polyamine that is required may vary depending upon the amount of plasticiser that is used. We prefer that the amount of cross-linker that is added results in gelation of the adhesive, and is such that the adhesive cannot be subsequently dissolved by a solvent after cross-linking. The polyamine cross-linking agent used in plasticised copolymer adhesives is preferably used only after partial cross-linking of the soft segments of the copolymer has been effected using an initial cross-linking agent. Suitable initial cross-linking agents include divinylbenzene, methylene bis-acrylamide, ethylene glycol di(meth)acrylate, ethylene glycol tetra(meth)acrylate, propylene glycol di(meth)acrylate, butylene glycol di(meth)acrylate, or trimethylolpropane tri(meth)acrylate, as previously described.

The polyamine cross-linked copolymer may be prepared in any suitable manner as known in the art. This will generally comprise the adhesive being prepared in a solvent and, prior to removal of the solvent, it is preferable to involve, as a final step, the polyamine. This is mixed with the prepared adhesive solution and then applied, for example, to a flat mould surface or drug-impermeable backing for the patch. The solvent can be removed as known in the art. In a preferred process, a copolymeric material comprising substantially non-enolisable ketone groups is blended with a suitable plasticiser therefor and, at the same time, or thereafter, further blended with a polyamine cross-linking agent, and the mixture allowed to complete the cross-linking reaction. The adhesive material will normally be prepared in solution, prior to the addition of plasticiser and polyamine. Cross-linking will normally be done under conditions of heat.

It will be appreciated that there is no particular restriction on further substances being used in association with the adhesive. For example, suitable agents may be used to inhibit crystallisation of the drug in the adhesive. Many agents will be apparent to those skilled in the art, and polyethylene glycol is generally particularly effective.

Permeation enhancers, which allow greater permeation of drug into the skin, may also be used in the adhesive. Compounds suitable for use as permeation enhancing agents include compounds containing at least one amide bond, esters of lactic acid, lactic acid, salts of lactic acid, dicarboxylic acids, salts of dicarboxylic acids, citric acid and salts of citric acid, O-alkyl (polyoxyethyl)phosphates and esters of higher fatty acids, carboxylic acids of glycerine and ethers of polyoxyethylene and monoalcohols. Suitable enhancers include lauryl di-methanol amide, glycerine monolaurate, glycerine triacetate and polyoxyethylene lauryl ether. Other specific examples of permeation enhancers include PEG (polyethylene glycol), liquid paraffin, Azone, Transcutol, propylene glycol and vitamin E, which also has plasticiser qualities. In addition, such enhancers may improve the adhesive qualities of the block copolymer and, where used, it may be desirable to select an adhesive with lower adhesive properties. Alternatively, such enhancers may be used to supplement a block copolymer having low adhesive qualities.

The preferred drug concentration in the medicated section of the patch is between 0.001% and 25%. Preferred concentrations are between 0.1 and 1% with 0.5% being especially preferred for the prophylaxis and/or treatment of hypertrophic scarring for example. In the case of keloids, higher concentrations may be desirable, and a range of 1 to 10%, preferably 2 to 5%, is useful.

The patches according to the invention, in the form of strips or sheets, allow self-application by the patient of a fixed dose of a potent steroid, or other treatment drug, to a particular area of skin. An advantage is convenience to the patient, as the patches may allow the patient to treat the target areas without the levels of supervision required for topical application of steroid creams or gels, or with intra-lesional injections. Moreover, the patches can be sized and shaped so as to ensure that only the target areas are contacted with the drag, thus reducing the likelihood that healthy skin is inadvertently treated.

The present invention will now be illustrated by the accompanying, non-limiting Examples. All ratios are by weight, unless otherwise specified. EXAMPLE 1

Example formulations for the medicated (0.1% and 0.25% triamcinolone acetonide) and unmedicated patch sections are given in Table 1. Adipic acid dihydrazide was used as the cross linker. The in vitro rat skin permeation of triamcinolone acetonide from the patches in Table 1 was compared with that from two 0.1% commercial formulations (applied at a dose of 5 mg/cm²). The results are shown in Figure 1, which shows the effect of the delivery system on the permeation (μg/cm²±SE) of triamcinolone acetonide across a human epidermal sheet.

Table 1

Triamcinolone Acetonide (TA) Patches

^a40 mg of TA was dissolved in 10 ml ethanol. ^b0.1 g adipic acid dihydrazide was dissolved in 20 ml of mixture solution of methanol and water (15:5).

It can be seen from Figure 1 that there is a clear concentration effect on permeation from the patches in that the flux from the 0.25% patch is approximately 2.5 times greater than that from the 0.1% patch.

The in vitro human skin penetration of triamcinolone acetonide from the two patches containing 0.1 and 0.25% (w/w) steroid triamcinolone acetonide was compared with that from a currently marketed 0.1% cream over a 48 hour application period. The results are shown in Figure 2. All the formulations delivered a similar percentage of their respective loadings through the skin (approximately 2 to 4 % over 48 hours). This degree of triamcinolone acetonide permeation approximates that reported for creams through rat skin, 1.9 - 2.3 % (H-Y. Yu and H-M. Liao, Int. J. Pharm. 127, 1-7, 1996) and human skin, 2.9 -3.3 % [Ladenheim et al., J. Pharm. Pharmacol., 48, 806-811 (1996)].

There was a plateau in permeation from all the formulations after 24 hours of application. Although possibly related to changes in the cream formulation after application (evaporation of volatile excipients, for example), it is unlikely that such changes would occur in the case of the occlusive patches. This shape (sigmoidal) of permeation profile is often observed in the case of steroids (C. F. H. Vickers, Arch. Derm. 88, 20-24, 1963; R. C. Wester and H. I. Maibach, Drag Metab. Rev., 14, 169- 205, 1983) and may be related to drag deposit formation in the skin rather than vehicle effects, probably as a result of the binding of triamcinolone acetonide to the skin fibroblasts (M. Ponec, A. Kempenaar and E. R. de Kloet. J. Invest. Derm., 75, 293-296, 1980).

The absolute amount of triamcinolone acetonide permeated over 48 hours is shown in Figures 3 and 4, and amounted to 319±29 ng/cm² from the 0.25% patch and 219±28 ng/cm² from the 0.1% patch. Hence, there was a degree of concentration related control on the skin penetration of triamcinolone acetonide. Permeation from the marketed cream amounted to 114±11 ng/cm² after 48 hours. Accordingly, it can be seen that the patches of the invention are actually better than creams at delivering corticosteroids.

Current therapy for hypertrophic scars is based upon intra-lesional injection of 0.2

- 0.6 ml of a 10 mg/ml triamcinolone acetonide solution every 6-10 weeks until efficacious (Adcortyl SmPC, UK marketing authorisation No PL 0034/5002R; B. Berman and F. Flores, Eur. J. Derm. 8, 591-596, 1998). Administration of such an injection equates to a triamcinolone acetonide dose of 2-6 mg every 6-10 weeks. Consideration of a scar 1 cm by 20 cm (20 cm² in area) covered by a 0.25% triamcinolone acetonide patch for 24 hours, indicates a daily exposure of 260 ±40 ng/cm², equating to a total daily exposure of 5.2 μg or approximately 0.2 mg per 6 weeks. On the basis of the foregoing experiments, a patch is prepared having a concentration of triamcinolone acetonide in the patch of 2.5% i.e. a 10-fold increase. The resultant flux, by extrapolation from the data obtained, increases by the same factor to 2.6 μg/cm /24hr, so that the exposure from a 20 cm patch over 6 weeks is raised to approximately 2 mg. Such delivery is equivalent to that of an injection, is readily prepared and poses no problems in terms of systemic exposure.

EXAMPLE 2

Non-medicated strips made with 1,6-diaminohexane

Prior to cross-linking with 1,6-diaminohexane, an adhesive corresponding to those of WO 99/02141 was first prepared in a two step synthesis, the first step providing the soft segment of the block copolymer, with the second step completing formation of the block copolymer.

Step 1:

A mixture of 115g of 2-ethylhexyl acrylate, 84g of diacetone acrylamide, 115g of butyl acrylate and 0.72g tetraethylene glycol dimethacrylate was made, and a homogeneous solution obtained. The solution was placed in a flask, and 200 ml of ethyl acetate along with 200 ml of toluene were added. The solution was heated to 80°C under nitrogen, then 0.05 g of 1,1 '-di-tert-butylperoxy-2 -methyl cyclohexane dissolved in 10 ml of ethyl acetate were added. Polymerisation was allowed to proceed for 24 hours at this temperature. This step produced the soft segments.

Step 2:

After 24 hours, 45g methyl methacrylate and 300 ml of toluene were added to the mix of Step 1. The solution was then heated to 99°C in order to initiate the second stage polymerisation step, which was continued for 12 hours at 99°C. After this time, the polymer was transferred to a bottle for cooling. The resulting solution contains the pre-crosslinked polymer, and can be stored for substantial periods. The average molecular weight of the polymer produced in this way was estimated to be 358,000 Da by gel permeation chromatography. This solution can be used, per se, but the solids content of the solution generally varies between about 30 and 50%. Accordingly, it is preferred to dry the solution, with heating, in order to obtain a first stage adhesive. This adhesive generally corresponds to that of WO 99/02141, and, after the evaporation stage, already possesses a degree of cross-linking between the soft segments of the block copolymer. This adhesive is then dissolved at a rate of 1.0 gper 2.0 g of a 2 : 5 v/v mixture of ethyl acetate and toluene, which solution can then be used for further cross-linking. In the present Example, the dried first stage adhesive was employed in the next stage.

Step 3:

A solution of 80 mg 1,6-diaminohexane in 50 ml of methanol was prepared, and 22.22 g (28.13 ml) of this solution were added to 19.80 g of isopropylmyristate and 64.10 g of the dried adhesive of step 2. This mixture was then combined with 12.05 g of water and stirred (using a large head, UltraTurrax T25, IKA, Germany) at 13,500 m for 5 min without heating. A white opaque liquid was formed, which was stable at a viscosity of approx. 5 Pas both straightaway and during the lamination period.

The nominal composition of the resulting adhesive is given in Table 2:

Table 2

A hand coating machine was used to coat the adhesive solution onto the release liner (FL2000, Rexam, the Netherlands). The slit width was set to 200 μm and the liner was pulled through at a constant speed to laminate the adhesive solution thereon j through the slit. The resulting laminate having approximate dimensions of 0.18 m x 0.50 m was then put into a drying chamber at 85°C for approximate one hour. Finally, the laminate was covered with the backing liner (Hostaphan 15 μm, Mitsubishi Foil, Germany). The laminates were cut to strips of 10 cm x 3 cm, which were stored in heat- sealed polyethylene covered aluminium-pouches.

Incorporation of Steroid

Steroid containing strips were prepared in a manner similar to that of the non- medicated strips prepared above. The crosslinkers chosen were adipic acid dihydrazide (AADH) and 1,6-diaminohexane, and these were dissolved in a solvent (water and methanol, respectively). Triamcinolone acetonide was dissolved in methanol, for combination with AADH, or in the methanolic crosslinker solution, to either 8 mg/ml or 1.6 mg/ml, to provide a final adhesive with a 0.5% or 0.1% loading. 1 lg of isopropylmyristate and 34.7g of step 2 adhesive are weighed into a container. Then, either a) 12.34 g of the methanolic solution containing just triamcinolone acetonide or b) both triamcinolone acetonide and 1,6-diaminohexane were added. This was followed by the addition of 6.7 g of pure water, in the case of b), or by the addition of 6.7 g of the aqueous solution of the AADH. Laminated adhesive strips were then prepared as before, but cut to dimensions of 10 cm x 1 cm, and stored in heat-sealed polyethylene covered aluminium-pouches.

AADH and 0.5 % Triamcinolone acetonide

The nominal composition of the adhesive containing 0.5% triamcinolone acetonide was as follows:

AADH and 0.1 % Triamcinolone acetonide

The nominal composition was as follows:

1,6-hexandiamine and 0.5% Triamcinolone acetonide

The nominal composition was as follows:

1,6-hexandiamine and 0.1% Triamcinolone acetonide

The nominal composition was as follows:

Claims

CLAIMS:

1. An adhesive dressing comprising a backing and an adhesive layer, a substance, or drug, effective in the prophylaxis and/or treatment of scarring being at least partially borne in the adhesive, characterised in that the adhesive consists essentially of a block copolymer having soft and hard segments and wherein there is chemical cross-linking between the soft segments, the adhesive further comprising at least 10% by weight of a plasticiser.

2. A dressing according to claim 1, which is in the form of a tape.

3. A dressing according to claim 1 , which is in the form of a patch.

4. A dressing according to any preceding claim, wherein the backing is flexible.

5. A dressing according to any preceding claim, having a first drug-impregnated area and a second, substantially drug-free area extending beyond the first drag- impregnated area that is suitable to secure to skin without delivering drag.

6. A dressing according to claim 5, wherein the first area is located on a first tape or patch, and the second area is located on a second tape or patch.

7. A dressing according to claim 5 or 6, wherein at least that area of the dressing corresponding to the said second area is transparent or translucent.

8. A dressing according to claim 6, wherein the tape or patch comprising the second area forms a peripheral scaffold over which the tape or patch comprising the first area is overlaid.

9. A dressing according to any preceding claim, which is a matrix dressing suitable for transdermal drag delivery, the drug being borne substantially completely in the adhesive.

10. A dressing according to any of claims 1 to 8, which is a reservoir dressing suitable for transdermal drag delivery.

11. A dressing according to any preceding claim, wherein the amount of plasticiser is between 10 and 30% by weight.

12. A dressing according to any preceding claim, wherein the drug is a corticosteroid.

13. A dressing according to claim 12, wherein the drag is selected from beclomethasone dipropionate, betamethasone, betamethasone valerate, clobetasol propionate, diflucortolone valerate, fluocinolone acetonide, fluocinonide, fluticasone propionate, halcinonide, methylprednisolone, mometasone furoate, triamcinolone, methylprednisolone, flurandrenolone, derivatives thereof, and mixtures thereof.

14. A dressing according to claim 12, wherein the drag is triamcinolone acetonide.

15. A dressing according to any preceding claim, wherein the adhesive is capable of topically delivering the drag at a rate of greater than 1 % of the total load of the patch in contact with the skin over 48 hours.

16. A dressing according to any preceding claim, having one or more backing layers, and wherein at least the external backing layer is semi-occlusive.

17. A dressing according to any of claims 1 to 15, having one or more backing layers, and wherein at least the external backing layer is occlusive

18. A dressing according to any preceding claim, having one or more backing layers, and wherein at least the external backing layer is non-woven polyethylene terephthalate.

19. A dressing according to any preceding claim, having one or more backing layers, and wherein at least the external backing layer is occlusive polyester.

20. A dressing according to any preceding claim, wherein the soft segments of the block copolymer comprise monomeric units selected from alkyl acrylates and alkyl methacrylates.

21. A dressing according to claim 20, wherein the monomeric units are selected from n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and tridecyl methacrylate, and mixtures thereof.

22. A dressing according to claim 20 or claim 21, wherein the acrylic block copolymer comprises at least 50% by weight of alkyl acrylate or alkyl methacrylate (co)polymer.

23. A dressing according to any preceding claim, wherein the hard segment polymer is formed from styrene, α-methylstyrene, methyl methacrylate, vinyl pyrrolidone or a mixture thereof.

24. A dressing according to claim 23, wherein the hard segment polymer is formed from styrene and/or polymethyl methacrylate. ,

25. A dressing according to any preceding claim, wherein the hard segments of the block copolymer form from 3-30% w/w, preferably from 5-15% w/w, of the total block copolymer.

26. A dressing according to any preceding claim, wherein the adhesive comprises ketone groups cross-linked by a polyamine cross-linking agent.

27. A dressing according to claim 26, wherein the amount of plasticiser is between 20 and 200% by weight of the adhesive.

28. A dressing according to claim 26 or claim 27, wherein the cross-linked ketone groups, prior to cross-linking, have substantially no tendency to enolisation.

29. A dressing according to any of claims 26 to 28, wherein, prior to cross-linking, the keto form is at least more stable, than the enol form by a factor of 10⁴, preferably by a factor of 10⁶.

30. A dressing according to any of claims 26 to 29, wherein one or more ketone groups are provided by aliphatic, olefinically unsaturated keto monomer residues.

31. A dressing according to claim 30, wherein said residues are residues of vinyl esters or allyl esters of aliphatic monobasic or dibasic acids containing a keto group.

32. A dressing according to claim 31 , comprising a combination of butyl acrylate, 2-ethylhexyl acrylate and diacetone acrylamide residues.

33. A dressing according to claim 32, wherein said butyl acrylate, 2-ethylhexyl acrylate and diacetone acrylamide residues are in a ratio of about 4 : 4 : 3.

34. A dressing according to any of claims 26 to 33, wherein the polyamine is a dialkyl triamine.

35. A dressing according to any of claims 26 to 33, wherein the polyamine is selected from diethylene triamine, 1,6-diaminohexane, 1,12-diaminododecane, adipic acid dihydrazide and bishexamethylene triamine.

36. A dressing according to any preceding claim, wherein the plasticiser is isopropyl myristate or methyl oleate.

37. Use of a dressing according to any preceding claim for the prophylaxis and/or treatment of scarring.

38. Use according to claim 37, wherein the scarring is selected from hypertrophic, keloid, psoriatic, dermatotic and burn scarring.

39. A method for the prophylaxis and/or treatment of scarring comprising application of a dressing according to any of claims 1 to 36 to the skin of a patient in need thereof.

40. The method of claim 39, wherein the scarring is selected from hypertrophic, keloid, psoriatic and dermatotic scarring.

41. A dispenser into which can be loaded first and second tapes according to claim 6, said dispenser associating the tapes and, optionally, removing any release layers, on dispensing the tapes.