WO2016079538A1

WO2016079538A1 - Dressing system

Info

Publication number: WO2016079538A1
Application number: PCT/GB2015/053549
Authority: WO
Inventors: Hugh Semple Munro; Nicholas David Boote
Original assignee: Edixomed Limited; First Water Limited
Priority date: 2014-11-21
Filing date: 2015-11-20
Publication date: 2016-05-26
Also published as: GB201420761D0

Abstract

The present invention relates to skin dressings that are useful in the treatment of conditions associated with tissue ischaemia and skin lesions such as diabetic foot ulcers, burns and surgical wounds. The skin dressings are also useful to effect transdermal delivery of pharmaceutically active agents.

Description

DRESSING SYSTEM

Field of the invention

Background to the invention

Nitric oxide (NO) is a potent vasodilator, synthesised and released by vascular endothelial cells and plays an important role in regulating local vascular resistance and blood flow. Biologically, nitric oxide (NO) is generated from L-arginine via NO synthase enzymes and performs a variety of functions, including vasodilatation and host defence. NO is also manufactured on epithelial surfaces (such as in the mouth and stomach, and on the skin surface) in humans by sequential reduction of nitrate and nitrite. This relies on the synthesis of nitrite by the bacterial reduction of inorganic nitrate present in saliva, mucosal secretions or sweat. Nitrite is further reduced to NO in an acidic environment.

The combination of acid and nitrite is effective in killing a wide variety of pathogens by the generation of NO and oxides of nitrogen such as nitrogen dioxide (N0₂). It is likely that NO generated in this way has a significant role in host defence against microbial pathogens, many of which are known to be susceptible to this agent.

A system has previously been devised that mimics this endogenous mechanism of NO generation, using inorganic nitrite and an organic acid to produce NO on the skin surface. This method relies on keeping the components separate until applied directly to the skin. Individually, these components elicit no significant effects.

WO 2000/053193 relates to the use of acidified nitrite as an agent to cause local production of nitric oxide at the skin surface for the treatment of peripheral ischaemia and associated conditions such as Raynaud's phenomenon and wounds such as post- operative wounds and burns. In some embodiments, a barrier consisting of a membrane allows diffusion of the nitrite ions while preventing direct contact of the acidifying agent with the skin. It has also previously been discovered that a system using inorganic nitrite and an organic acid to produce NO on the skin surface can be used for the transdermal delivery of pharmaceutically active agents. WO 02/17881 discloses a transdermal delivery system comprising a pharmaceutically active agent and acidified nitrite as an agent to cause local production of nitric oxide at the skin surface. Also disclosed is the use of a barrier consisting of a membrane to allow diffusion of the pharmaceutically active agent and nitrite ions while preventing direct contact of the acidifying agent with the skin.

Summary of the invention

The present inventors have developed an improved dressing system that is useful in the treatment of conditions associated with tissue ischaemia and skin lesions such as diabetic foot ulcers, burns and surgical wounds, and can also be used as a transdermal delivery system. The dressing makes use of a hydrogel to provide the acidifying effect on a nitrite for the production of NO. The use of a hydrogel is advantageous as it can be placed directly in contact with the skin and can absorb exudates from wounds. The inventors have now surprisingly found that the use of a hydrogel which comprises sulphonic acid in such a dressing system is advantageous since it results in a reduced amount of the N0₂ by-product of the reaction to produce NO, whilst producing NO at therapeutic levels.

Accordingly, in a first embodiment the present invention provides a system comprising:

(i) a layer containing a nitrite; and

(ii) a hydrogel comprising a sulphonic acid.

Detailed description of the invention

The system of the invention is a dressing system. A "dressing", as will be well known to a person of skill in the art, is something that is applied to the skin of a human or animal to cover, protect and/or treat a lesion on the skin of the human or animal. A dressing is suitable for use in relation to any breakage or interruption in the skin barrier, which can be caused, for example, by ulcers, surgery, burns, cuts, lacerations, trauma and/or abrasions.

The system of the invention is a two component system, comprising a first component which comprises a layer containing a nitrite and a second component comprising a hydrogel comprising a sulphonic acid. The hydrogel contains hydrogen (H⁺) ions and therefore has an acidic pH. The two components can in fact be considered as two separate dressings. When the two components are placed in contact with each other, a chemical reaction takes place to produce nitric oxide (NO). The two components will now be described in detail.

The first component of the system of the invention comprises or is a layer containing a nitrite. The layer is permeable (fully permeable or at least semi-permeable) to the diffusion of nitric oxide, which forms when the first and second components of the dressing are placed in contact with each other. The first component of the system of the invention is typically placed in direct contact with the skin (i.e. on a wound or ulcer) during use, and should not adhere to the skin and/or cause damage to the wound bed or friable wound tissue. The layer can therefore be described as a wound contact layer. The layer can therefore be made of any material that is suitable for this purpose and which can be impregnated with, imbibed with or otherwise contain a nitrite. The layer is typically, but not limited to, a mesh, non-woven bat, film, foam, alginate, amorphous hydrogel, crosslinked hydrogel or a membrane.

In one embodiment, the layer is a mesh. A mesh consists of connected strands of solid, typically flexible material, that form a lattice with holes or gaps through which certain substances can pass. The mesh can be woven or non-woven, but is typically non-woven.

The mesh is typically made of a polymeric material. Any polymeric material is suitable, for example viscose, polyamide, polyester, polypropylene or blends of these, but a preferred polymeric material is polypropylene.

In another embodiment, the layer is a dissolvable film. The term "dissolvable film" includes polymers with solubility in water. Examples include polyvinyl alcohols or polyvinylpyrrolidones and cellulose-based polymers for example hydroxypropylcellulose or carboxymethylcellulose.

Such a film can be made of any suitable material, for example cellulose.

In some embodiments, the system of the invention comprises a plurality of (i.e. more than one) layers containing a nitrite. For example, the system of the invention can comprise 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more layers containing a nitrite. For example, the system of the invention can comprise a plurality of meshes imbibed with a nitrite, for example as a nitrite solution. Typically, when a plurality of layers is used, each of the layers is formed of the same material, for example a mesh or a dissolvable film.

In one embodiment, the layer is not a membrane and/or a gel, for example a hydrogel.

The layer contains a nitrite salt in solid or solution form. Typically, the nitrite is in the form of a nitrite solution. The layer is typically imbibed or impregnated with the nitrite, for example by soaking the layer in a solution of the nitrite. The nitrite is typically a pharmacologically acceptable source of nitrite ions or a nitrite precursor thereof.

The layer (such as a mesh) functions to retain the nitrite solution essentially within a region defined by the area of the layer (such as a mesh). This provides for ease of application of the dressing to the skin and/or wound. The pharmacologically acceptable source of nitrite ions may be an alkaline metal nitrite or an alkaline earth metal nitrite. For example, LiN0₂, NaN0₂, KN0₂, RbN0₂, CsN0₂, FrN0₂, Be(N0₂)₂, Mg(N0₂)₂, Ca(N0₂)₂, Sr(N0₂)₂, Ba(N0₂)₂, or Ra(N0₂)₂. In a preferred embodiment the nitrite is sodium nitrite (NaN0₂), potassium nitrite (KN0₂) or calcium nitrite (Ca(N0₂)₂).

Alternatively, a nitrite precursor may be used as the source of the nitrite ions in the composition. Other sources of nitrite ions are nitrate ions derived from alkali metal or alkaline earth metal salts capable of enzymic conversion to nitrite. For example, LiN0₃, NaN0₃, KN0₃, RbN0₃, CsNOs, FrN0₃, Be(N0₃)₂, Mg(N0₃)₂, Ca(N0₃)₂, Sr(N0₃)₂, Ba(N0₃)₂, or Ra(N0₃)₂.

The concentration of the nitrate/nitrite ion source in the layer containing a nitrite may be up to 20% w/w, suitably 0.25 to 15%, suitably 2 to 12%, suitably 4 to 10%, for example 5 to 8%. A particularly preferred concentration is 6% to 7% w/w.

Suitably, the final nitrite ion concentration present in the layer containing a nitrite is up to 20% w/w, generally in the range of from 0.25% to 15% w/w, for example 0.5% to 14% w/w, 1 % to 13% w/w, suitably 2% to 12% w/w, suitably 3% to 1 1 % w/w, suitably 4 to 10% w/w or 5 to 8% w/w. A particularly preferred nitrite ion concentration is 6% to 7% w/w. If a solution of nitrite ions is being used, the molarity of the solution is typically from 0.01 M to 2M, for example from 0.1 M to 2M, for example from 0.2M to 1.8M, from 0.3M to 1.7M, from 0.4M to 1.6M, from 0.5M to 1.5M, for example around 0.7M, 0.8M, 0.9M, 1 M, 1.1 M, 1.2M or 1.3M.

In one specific embodiment, the first component of the dressing system is a polypropylene mesh or a plurality of polypropylene meshes impregnated with sodium nitrite, typically as a sodium nitrite solution. In certain embodiments of the invention, which can optionally comprise a reductant, the amount (weight or volume) of nitrite solution can be used to control the amount of nitric oxide produced over time. Preferred amounts of sodium nitrite solution are from 5mg to 100mg per cm² of the area of nitrate containing layer (for example mesh) in contact with the hydrogel, for example from 10mg to 85mg per cm², from 20mg to 75mg per cm², from 30mg to 60mg per cm² or from 10mg to 85mg per cm².

The second component of the dressing system of the invention is a hydrogel comprising a sulphonic acid. It will be appreciated that there are alternative spellings of "sulphonic acid" and "sulphonate". Accordingly, references herein to "sulphonic acid" are interchangeable with "sulfonic acid" and references herein to "sulphonate" are interchangeable with "sulfonate".

The hydrogel contains hydrogen (H⁺) ions as a result of the presence of sulphonic acid and is therefore acidic. Hydrogen (H⁺) ions can alternatively be referred to as protons. By virtue of the presence of hydrogen ions, the hydrogel reduces the pH at the site of application.

When the hydrogel is placed in contact with the layer containing a nitrite, the acidic environment created by the hydrogel allows the chemical reaction that produces nitric oxide from nitrite to take place. Thus, when the hydrogel is placed in contact with the layer containing a nitrite, nitric oxide is produced which diffuses through the layer containing a nitrite and onto or into the skin or wound bed of the patient. It can therefore be seen that the two components of the system of the invention are typically kept apart until use, to prevent nitric oxide from being generated prematurely. In accordance with the present invention, a minimal amount of nitrogen dioxide is produced as a by-product of the reaction. Without wishing to be bound by theory, when the hydrogel comprising sulphonic acid is placed on top of the first component of the system (the layer or layers containing a nitrite), hydrogen ions (which are normally bound within the gel) are released and diffuse down a concentration gradient through the hydrogel and into the layer containing a nitrite, where they react with the nitrite to produce nitric oxide. A second process occurs where the hydrogel absorbs the nitrite solution or layer containing the nitrite and the reaction takes place at the surface of or within the hydrogel; the nitric oxide is released from the hydrogel through the layer containing the nitrite into the tissue.

Hydrogels suitable for use in wound dressings or for transdermal delivery are typically three-dimensional networks of cross-linked hydrophilic polymers that are insoluble in water and interact with aqueous solutions by swelling. They are highly conformable and permeable and can absorb varying amounts of fluid depending on their composition. In some embodiments, the hydrogel of the invention belongs to the category of materials described as super-absorbent. In the present invention the counter-ion to the hydrogen ion is typically bound into the three-dimensional polymer network of the hydrogel and is not released into the wound. In one embodiment, the hydrogel for use in the invention is cross-linked.

The hydrogel for use in the present invention comprises sulphonic acid.

In some embodiments, the sulphonic acid is a pendant functional group of a polymerisable monomer. Suitable monomers are 2-acrylamido-2-methylpropane sulfonic acid (AMPS™, Lubrizol Corporation), 4-styrenesulfonic acid and vinylsulfonic acid.

In some embodiments, the hydrogel is a co-polymer, i.e. a polymer made up of two or more different monomer components, at least one of which comprises a sulphonic acid moiety. In one embodiment, the hydrogel is a co-polymer of a sulphonic acid and an alkali metal salt of a sulphonic acid. Suitable alkali metal salts of a sulphonic acid include (3- sulphopropyl)-acrylate potassium salt and the alkali metal salts of 2-acrylamido-2- methylpropane sulphonic acid, 4-styrenesulfonic acid and vinylsulphonic acid, where the alkali metal is, for example, sodium, potassium or calcium. In some embodiments, the sulphonic acid from which the alkali metal salt is derived is the same as the sulphonic acid moiety that is present in one of the monomers in the copolymer. The hydrogel typically comprises from 0.03 to 2% (weight/weight), for example from 0.05 to 1.75%, from 0.1 to 1.5%, from 0.2 to 1.25%, from 0.3 to 1 %, from 0.4 to 0.9%, from 0.5 to 0.8% or from 0.6 to 0.7% (weight/weight) of sulphonic acid. The pH of the hydrogel is typically from pH2 to pH6, for example from pH2.5 to pH5.9, from pH2.6 to pH5.8, from pH2.7 to pH5.7, from pH2.8 to pH5.6, from pH2.9 to pH5.5, from pH3 to pH5.4, from pH3.1 to pH5.3, from pH3.2 to pH5.2, from pH3.3 to pH5.1 , from pH3.4 to pH5, from pH3.5 to pH4.9, from pH3.6 to pH4.8, from pH3.7 to pH4.7, from pH3.8 to pH4.6, from pH3.9 to pH4.5, for example around pH4, pH4.1 , pH4.2, pH4.3 or pH4.4.

The present inventors have previously devised a dressing system in which it is preferable for the pK_a of the monomer or one of the monomers in the hydrogel to be within 1 unit of the pH of the hydrogel. Such a dressing system is described in International Application No. PCT/GB2014/051543 (published as WO/2014/188174) and International Application No. PCT/GB2014/051544 (published as WO/2014/188175), which are incorporated herein by reference in their entirety.

However, in the present invention, this is not necessary and indeed it is desirable for the pK_a of the monomer or one of the monomers in the hydrogel to be lower than the pH of the hydrogel.

In one embodiment, the hydrogel is partially hydrated, i.e. it contains some water. This means that the hydrogel provides a moist environment that assists the healing of a wound or ulcer. In certain embodiments, the hydrogel contains from 5% to 50%, for example from 10% to 40%, for example from 15% to 35%, for example from 20% to 30% or around 30% water by weight of the hydrogel.

The hydrogel typically contains the polymer as its major component. For example, the hydrogel can contain from 10% to 60%, for example from 20% to 50%, for example from 30% to 45%, for example around 40% of the polymer by weight of the hydrogel.

In some embodiments, the hydrogel contains no other components, i.e. it consists of a monomer or a co-polymer comprising sulphonic acid.

In other embodiments, the hydrogel may contain other components in addition to the monomer or monomers of which its polymeric structure is composed. Additional components such as glycerol may be present. Such additional components may make up a substantial amount of the hydrogel. For example, the hydrogel can contain from 5% to 50%, for example from 10% to 40%, for example from 15% to 35%, for example from 20% to 30% or around 30% of glycerol by weight of the hydrogel.

The hydrogel may contain a pH buffer to maintain the pH in the range 2-4.5. However, the addition of a pH buffer is typically not required.

The thickness of the hydrogel is typically up to 4mm, typically 0.5-2mm, more typically 1- 2mm, even more typically 1-1.6mm.

In one embodiment, the hydrogel contains a solid layer within it to provide mechanical strength, for example for processing purposes. The solid layer can be made of any suitable material and in one embodiment is a mesh, suitably made of a polymer, suitably a polypropylene mesh. The solid layer is suitably provided in the middle of the hydrogel, for example in the form of a "sandwich" wherein the solid layer is sandwiched in between two layers of hydrogel.

In one embodiment, the hydrogel has a barrier layer, for example a film such as a polyurethane film or an adhesive coated polyurethane film, on one of its external surfaces, typically on the surface that will be exposed to the air when in use. This layer typically provides a bacterial barrier.

In one embodiment, the system of the first aspect of the invention further contains a pharmaceutically active agent. In this embodiment, the NO produced by the system is used to deliver the pharmaceutically active agent transdermally. The pharmaceutically active agent may be present either in the layer containing a nitrite or in the hydrogel comprising a sulphonic acid. If the pharmaceutically active agent is present in the layer containing the nitrite, the layer is typically imbibed or impregnated with the pharmaceutically active agent, for example by soaking the layer in a solution of the pharmaceutically active agent. This can be done at the same time as imbibing or impregnating the layer with the nitrite. For example, the layer can be soaked in a solution comprising a mixture of a nitrite and the pharmaceutically active agent for this purpose. If the pharmaceutically active agent is present in the hydrogel, the pharmaceutically active agent is typically incorporated into the hydrogel, or is present on the surface of the hydrogel, in any suitable format. When it contains a pharmaceutically active agent, the system of the invention can be used for the transdermal delivery of any pharmaceutically active agent.

The pharmaceutically active agent may comprise any suitable drug or combination of drugs to treat a disease in a patient. The agent may be immediately active in the form administered or may become active in the body of the patient following administration, such as for example through hydrolysis or by the action of an endogenous enzyme.

Therapeutically, the system of the invention can facilitate the delivery of a wide number of systemically active substances. Active substances include, but are not limited to, antibiotics, hormones, proteins, peptides, proteoglycans, nucleotides, oligonucleotides (such as DNA, RNA, etc.), vitamins, minerals, growth factors, non-steroidal antiinflammatory drugs (NSAIDs) and vaccines. In a preferred embodiment, the delivery system of the present invention can be used to deliver anaesthetic, analgesic, hormone, immunosuppressant or steroid formulations. Other pharmaceutical agents include, but are not limited to, analgesic agents such as ibuprofen, indomethacin, diclofenac, acetylsalicylic acid, paracetamol, propranolol, metoprolol, oxycodone, thyroid releasing hormone, sex hormones such as oestrogen, progesterone and testosterone, insulin, verapamil, vasopressin, hydrocortisone, scopolamine, nitroglycerine, isosorbide dinitrate, anti-histamines (such as terfenadine), clonidine and nicotine, non-steroidal immunosuppressant drugs (such as cyclosporin, methotrexate, azathioprine, mycophenylate, cyclophosphamide, TNF antagonists), anticonvulsants and other drugs for dementia/Alzheimer's/Parkinson's disease such as apamorphone and rivastigmine, and steroids. Typically, the pharmaceutically active agent is an anaesthetic. The anaesthetic can be any appropriate anaesthetic for local anaesthesia and can be provided in aqueous or powdered form, for example, lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine or ***e, or a mixture thereof, preferably in the hydrochloride form.

The general concentration range is around 1 to 4%, up to 10% w/w, although greater or lesser amounts can be empirically determined by a physician. Suitably preferred concentrations are tetracaine (0.01 to 10% w/w, suitably 1 to 8% w/w, preferably 2% w/w), lidocaine (0.01 to 10% w/w, suitably 1 to 8% w/w, preferably 5% or 10% w/w) and ***e (1 to 4% w/w). Generally accepted safe dosages of such compounds for topical anaesthesia in a healthy 70 kg-adult are 750 mg for lidocaine, 200 mg for ***e, and 50 mg for tetracaine. Other suitable anaesthetics are within the competence of the medical practitioner and can also be used in the system of the present invention at the relevant concentrations.

Prior art methods of improving local anaesthesia have suggested the use of low concentrations of vasoconstrictors, such as phenylephrine (0.005%). However, the compositions of the present invention utilise a previously unknown property of an acidified nitrite composition to produce NO, a vasodilator, which accelerates the transfer of anaesthetic into the dermis. The combination of the NO-generating system and anaesthetic will promote patient compliance of venepuncture and bloodletting techniques by reducing the pain experienced during the procedure and reducing associated infection.

The choice of pharmaceutically active agent may be determined by its suitability for the treatment regimen of the disease or medical condition concerned and reference can be made to standard reference works such as Martindale, the Merck Index, Goodman & Gilman's "The Pharmacological Basis of Therapeutics", 10th edition (2001), McGraw Hill and the British National Formulary (http://www.bnf.org/bnf/index.htm).

It should be emphasised that when it contains a pharmaceutically active agent the system of the invention is typically used to deliver a pharmaceutically active agent other than nitric oxide, i.e. the pharmaceutically active agent is not nitric oxide.

In use, the second component of the dressing system (the hydrogel) is placed on top of the first component of the dressing system (the layer containing a nitrite). The second component has a number of functions. Firstly, by virtue of the presence of hydrogen ions that are released from the sulphonic acid component of the hydrogel, the second component creates an acid environment for the conversion of nitrite to nitric oxide. Also, the second component of the dressing system is typically larger than the first component, and is of a suitable size and shape that when it overlays the first component it entirely covers the first component, such that there is an area on one or more of its edges, and typically all the way round the first component, that is in contact with the skin of the patient (although typically not in contact with a wound; the first component of the dressing system is typically in contact with a wound when the dressing system is a wound dressing system). The second component is adhesive and so, in this configuration, the second component retains the first component in place on the skin of a patient, typically over an ulcer or wound, in a manner analagous to that of a plaster (or BandAid™). Since the system of the invention is a dressing useful, for example, for the treatment of ulcers and wounds, it is adapted for transdermal administration. The components of the system of the invention may be prepared by any method known in the art of pharmacy, and are typically prepared under sterile conditions. The system of the invention is a two component system, comprising a first component which comprises a layer or a plurality of layers containing a nitrite and a second component comprising a hydrogel comprising a sulphonic acid. In one embodiment, the system of the invention does not contain any other components. In this embodiment, the system consists of or consists essentially of a first component which comprises a layer or a plurality of layers containing a nitrite and a second component comprising a hydrogel comprising a sulphonic acid. In one embodiment, the first component consists of or consists essentially of a (typically permeable) layer or plurality of layers containing a nitrite. In another embodiment, the second component consists of or consists essentially of a hydrogel comprising a sulphonic acid.

The system of the invention typically does not contain certain other substances. In particular, the system itself or one or both of its components typically does not contain a thiol and/or a reductant, typically a non-thiol reductant, or only contains these substances in trace amounts, i.e. less than 0.05%, typically less than 0.01 %, more typically less than 0.005% by weight of the sytem, or one or both components thereof. Thiols include glutatione (typically L-glutathione), 1-thioglycerol, 1- thioglucose, cysteine, and methyl- or ethyl-ester of cysteine, N-acetylcysteine, mercaptoethylamine and 3-mercaptopropanoic acid. Non-thiol reductants include iodide anion, butylated hydroquinone, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene and beta-carotene, erythrobate or a- tocopherol, ascorbic acid (vitamin C). In some embodiments, the system itself or one or both of its components does not contain a source of Cu²⁺ Zn²⁺ and/or Fe²⁺ ions.

In one embodiment, the first component does not contain a thiol and/or a reductant, typically a non-thiol reductant. In another embodiment, the second component does not contain a thiol and/or a reductant, typically a non-thiol reductant. In another embodiment, both the first component and the second component do not contain a thiol and/or a reductant, typically a non-thiol reductant.

In one embodiment, the first component does not contain a source of Cu²⁺ Zn²⁺ and/or Fe²⁺ ions. In another embodiment, the second component does not contain a source of Cu²⁺ Zn²⁺ and/or Fe²⁺ ions. In another embodiment, both the first component and the second component do not contain a source of Cu²⁺ Zn²⁺ and/or Fe²⁺ ions.

The dressing system of the invention has either (a) two active components: the hydrogel which comprises a sulphonic acid and the layer containing a nitrite; or (b) three active components: the hydrogel which comprises a sulphonic acid, the layer containing a nitrite and a pharmaceutically active agent. No other active components are necessary for the functioning of the dressing system of the present invention. The dressing system of the present invention has a number of advantages over those known in the art. Firstly, the use of the hydrogel to provide the acidifying component for production of the nitric oxide has the advantage that it can be placed in direct contact with the skin, in contrast with the prior art systems where the acidifying agent is typically not suitable for direct contact with the skin and therefore it is often suggested to provide a membrane to prevent contact of the acidifying agent with the skin. In contrast, the system of the present invention can be kept in contact with the skin for prolonged periods of time, which represents a significant advantage. This feature of the hydrogel and also its physical properties means that it can be used to secure, trap or fix the underlying nitrite- imbibed layer in place on the skin of a patient, in a manner analagous to that of a sticking plaster (or BandAid™), thus allowing the correct positioning of the nitrite-containing layer. This also has the advantage that the amount of nitric oxide produced can be controlled by changing the volume of nitrite solution imbibed by the layer or layers containing the nitrite, which is/are then held in place by the hydrogel. This is an advantage of the use of a nitrite solution together with a hydrogel. Another advantage of the use of the hydrogel is that it is useful for absorbing exudate (i.e. blood, plasma and other fluids) from wounds and thus can be used to maintain an environment suitable for healing. The hydrogel maintains a suitable level of moisture on the wound surface (whilst not allowing it to become "wet"), which further promotes healing. A further advantage of the dressing system of the invention is that bubbles are not produced, thus creating a more aesthetically pleasing dressing. The dressing system of the present invention thus provides a system that is easy to apply, well tolerated by patients and provides a controlled environment for the chemical reaction in which NO is produced. These advantages are all described in International Application No. PCT/GB2014/051543 (published as WO/2014/188174) and International Application No. PCT/GB2014/051544 (published as WO/2014/188175), which are incorporated herein by reference in their entirety. The present inventors have now surprisingly found that the use of a sulphonic acid in the hydrogel component of the dressing system of the invention is advantageous as it limits the amount of N0₂ by-product in the reaction that occurs to produce NO. This is demonstrated in the Examples of the present application. In a second aspect, the present invention provides the system of the first aspect of the invention for use in medicine.

In a third aspect, the present invention provides the system of the first aspect of the invention for use in the treatment of a condition associated with tissue ischaemia or a wound. This aspect of the invention also extends to the use of a layer containing a nitrite and a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of a condition associated with tissue ischaemia or a wound.

This aspect of the invention also extends to:

A layer containing a nitrite for use in the treatment of a condition associated with tissue ischaemia or a wound, wherein said layer is administered simultaneously, separately or sequentially with a hydrogel comprising a sulphonic acid. A hydrogel comprising a sulphonic acid for use in the treatment of a condition associated with tissue ischaemia or a wound, wherein said hydrogel is administered simultaneously, separately or sequentially with a layer containing a nitrite.

Use of a layer containing a nitrite in the manufacture of a medicament for the treatment of a condition associated with tissue ischaemia or a wound, wherein said layer is administered simultaneously, separately or sequentially with a hydrogel comprising a sulphonic acid.

Use of a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of a condition associated with tissue ischaemia or a wound, wherein said hydrogel is administered simultaneously, separately or sequentially with a layer containing a nitrite. A system comprising a layer containing a nitrite and a hydrogel comprising a sulphonic acid as a combined preparation for simultaneous, separate or sequential use in treating a condition associated with tissue ischaemia or a wound.

This aspect of the invention also extends to a method of treatment of a condition associated with tissue ischaemia or a wound comprising administering a system of the first aspect of the invention to a subject in need thereof. The subject is a patient having a condition associated with tissue ischaemia or a wound, as described herein. The method typically comprises administering to the patient the first component described herein and then subsequently administering the second component described herein, on top of the first component. Tissue ischaemia is a restriction of the blood supply to tissues. In some embodiments, the tissue ischaemia is peripheral ischaemia, i.e. where peripheral circulation is restricted, for example skin ischaemia.

In some circumstances, damage to the skin leads to tissue ischaemia as the blood supply is reduced or prevented by the body's own repair or defence mechanisms.

Conditions associated with tissue ischaemia include Raynaud's syndrome, severe primary vasospasm and tissue ischaemia caused by septic shock or irradiation or a peripheral vascular disease (for example caused by diabetes and other chronic/systemic diseases), as well as post-surgical tissue ischaemia.

The present invention is also useful in the treatment of wounds. Wounds include ulcers, skin donor sites, surgical wounds (post-operative), burns (for example scalds, superficial, partial thickness and full thickness burns), lacerations and abrasions, and can be chronic or acute. Some burns (for example full thickness and some partial thickness burns) are also associated with tissue ischaemia. Ulcers can be of various origin, for example of venous or arterial origin, and include leg ulcers, pressure ulcers, venous ulcers and ulcers associated with diabetes such as diabetic foot ulcers.

Dosages of nitric oxide, which is the active substance produced by the system of the present invention when it does not contain an additional pharmaceutically active agent, can vary between wide limits, and can be tailored depending upon the disease or disorder to be treated, the severity of the condition, and the age and health of the individual to be treated, etc. A physician will ultimately determine appropriate dosages to be used. The system is configured so as to deliver nitric oxide in a therapeutically active amount, which is an amount that ameliorates or eliminates the symptoms of the condition (such as an ulcer or wound) that is being treated. As described herein, the system of the present invention can be used to control the amount and duration of nitric oxide release. This dosage may be repeated as often as appropriate. If side effects develop the amount and/or frequency of the dosage can be reduced or otherwise altered or modified, in accordance with normal clinical practice.

The system of the invention may be formulated for use in human or for veterinary medicine. The present application should be interpreted as applying equally to humans as well as to animals, unless the context clearly implies otherwise.

In a fourth aspect, the present invention provides a kit comprising a layer containing a nitrite and a hydrogel comprising a sulphonic acid as a combined preparation for simultaneous, separate or sequential use in treating a condition associated with tissue ischaemia or a wound. The kit is suitably provided with instructions for use in the treatment of a condition associated with tissue ischaemia or a wound.

When the system of the first aspect of the invention also comprises a pharmaceutically active agent, the invention also extends to the use of such a system for the treatment of a disease or condition other than a condition associated with tissue ischaemia or a wound.

Accordingly, in a fifth aspect, the present invention provides the system of the first aspect of the invention comprising a pharmaceutically active agent for use in the treatment of a disease or medical condition. Medical conditions that can be treated using the system of the present invention comprising a pharmaceutically active agent include pain, wherein the system of the invention is used to provide local anaesthesia, and transplant rejection, wherein the system of the invention is used to provide the effect of immunosuppression. Pain includes chronic and acute pain, post-operative pain and neuropathic pain. Diseases suitable for treatment using the system of the present invention comprising a pharmaceutically active agent include but are not limited to cardio-vascular diseases, neurological diseases or disease of the central nervous system, (e.g. multiple sclerosis, Parkinsons' Disease), epilepsy, psychiatric disorders (e.g. schizophrenia), inflammation (e.g. rheumatoid arthritis, osteoarthritis, asthma, gout), in particular topical inflammation, hypertension, arrhythmia, hyperlipoproteinemias, gastrointestinal disorders (e.g. peptic ulcers), kidney disease, parasite infections (e.g. protozoal infection, helminthiasis, amebiasis, giardiasis, thichomoniasis, leishmaniasis, trypanosomiasis, malaria), microbial infection (e.g. yeast, fungus, bacteria), viral infection, cancer, immunosuppression, blood disorders (blood clots etc.), endocrine (e.g. hormonal) disorders (e.g. thyroid condition, hypoglycaemia), diabetes, dermatological disorders (e.g. psoriasis). It will be understood that the disease to be treated using the system of the invention will depend on the nature of the pharmaceutically active agent that to be delivered transdermal^ using the system of the present invention.

In one embodiment, the present invention provides the system of the first aspect of the invention for use in the treatment of pain, wherein the pharmaceutically active agent is an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof. In this embodiment, the treatment of pain is typically local anaesthesia. This aspect of the invention also extends to the use of a layer containing a nitrite and a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of a disease or medical condition, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent. In particular, this aspect of the invention extends to the use of a layer containing a nitrite and a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of pain, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent and wherein the pharmaceutically active agent is an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof.

This aspect of the invention also extends to:

A layer containing a nitrite for use in the treatment of a disease or condition, wherein said layer is administered simultaneously, separately or sequentially with a hydrogel comprising a sulphonic acid, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent.

A hydrogel comprising a sulphonic acid for use in the treatment of a disease or condition, wherein said hydrogel is administered simultaneously, separately or sequentially with a layer containing a nitrite, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent. Use of a layer containing a nitrite in the manufacture of a medicament for the treatment of a disease or condition, wherein said layer is administered simultaneously, separately or sequentially with a hydrogel comprising a sulphonic acid, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent.

Use of a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of a disease or condition, wherein said hydrogel is administered simultaneously, separately or sequentially with a layer containing a nitrite, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent.

A system comprising (i) a layer containing a nitrite and (ii) a hydrogel comprising a sulphonic acid as a combined preparation for simultaneous, separate or sequential use in treating a disease or condition, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent.

In this aspect of the invention, the disease or condition is typically pain and the pharmaceutically active agent is an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof.

This aspect of the invention also extends to a method of treatment of a disease or condition comprising administering a system of the first aspect of the invention comprising a pharmaceutically active agent to a subject in need thereof. The method typically comprises administering to the patient the first component described herein and then subsequently administering the second component described herein, on top of the first component. The subject is typically a patient suffering from pain. In this embodiment, the pharmaceutically active agent is typically an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof.

Dosages of the pharmaceutically active agent that is delivered by in this embodiment of the system of the present invention can vary between wide limits, depending upon the disease or disorder to be treated, the severity of the condition, and the age and health of the individual to be treated, etc. and a physician will ultimately determine appropriate dosages to be used. The system is configured so as to deliver the pharmaceutically active agent in a therapeutically active amount, which is an amount that ameliorates or eliminates the symptoms of the disease or disorder that is being treated. In a sixth aspect, the present invention provides a kit comprising (i) a layer containing a nitrite, and (ii) a hydrogel comprising a sulphonic acid as a combined preparation for simultaneous, separate or sequential use in treating a disease or condition wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent. The disease or condition is typically pain and the pharmaceutically active agent is typically an anaesthetic selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof. The kit is suitably provided with instructions for use in the treatment of the disease or condition.

The present inventors have also previously found that when applied as a pre-treatment, a dressing system of the invention functions to increase the effectiveness of a topically applied aqueous-soluble anaesthetic. The system of the invention can therefore also be used in combination with an aqueous-soluble drug such as an anaesthetic when the dressing system is administered simultaneously with the drug (such as an anaesthetic) or before or after the drug (such as an anaesthetic). In this aspect of the invention, the dressing system of the first aspect of the invention does not include a pharmaceutically active agent; the aqueous-soluble drug is administered separately from the dressing system.

Accordingly, in a seventh aspect, the present invention provides the system of the first aspect of the invention in combination with an aqueous-soluble drug for use in medicine. By "aqueous-soluble drug" is meant one that for each part of the drug will require 1000 parts or less of an aqueous solvent to solubilise it. In other words, the drug is at least slightly soluble in accordance with the definition given in The United States Pharmacopeia, USP 30-NF 25, 2007 and British Pharmacopoeia, 2009. For example, lidocaine hydrochloride is soluble on this scale requiring 20 parts water to 1 part lidocaine.

Examples of aqueous-soluble drugs for use in accordance with this aspect of the invention include the anti-hypertensive, Atenolol, the water soluble antibiotics, Ampicillin, Streptomycin, Penicillin and the naturally water-soluble vitamins, specifically B and C. In an eighth aspect, the present invention provides the system of the first aspect of the invention in combination with an anaesthetic for use in the treatment or prevention of pain. The anaesthetic can be any appropriate anaesthetic for local anaesthesia and is typically selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof. The anaesthetic is typically provided in aqueous or powdered form. For example, anaesthetics such as lidocaine hydrochloride can be provided in the form of a spray of the drug in aqueous form.

The treatment or prevention of pain is typically local anaesthesia but can be the treatment or prevention of any kind of pain. Pain includes chronic and acute pain, post-operative pain and neuropathic pain. Treatment includes both amelioration and prevention (prophylaxis) of pain.

This aspect of the invention also extends to: A system of the first aspect of the invention for use in the treatment or prevention of pain, wherein said system is administered simultaneously, separately or sequentially with an anaesthetic.

Use of a system of the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of pain, wherein said system is administered simultaneously, separately or sequentially with an anaesthetic.

This aspect of the invention also extends to a method of treatment or prevention of pain comprising administering a system of the first aspect of the invention and an anaesthetic to a subject in need thereof. The subject is a patient suffering from pain, or one who is likely to suffer from pain in the future (and therefore is in need of anaesthetic). The method typically comprises either administering to the patient the system of the first aspect of the invention (as a pre- treatment) and then subsequently administering an aqueous-soluble drug such as an anaesthetic, or administering to the patient an aqueous-soluble drug such as an anaesthetic and then subsequently administering the patient the system of the first aspect of the invention. Alternatively, the system of the first aspect of the invention and the aqueous-soluble drug such as an anaesthetic are administered simultaneously. Preferred features for the second and subsequent aspects of the invention are as for the first aspect mutatis mutandis.

The present invention will now be described by way of illustration only with reference to the following Examples:

Example 1 - Production of dressing system using hydrogel compositions of the invention

Primary Layer: Wound Contact Mesh (containing 1M Sodium Nitrite)

The Mesh is a polypropylene mesh (RKW-Group), imbibed with 1 M Sodium Nitrite solution, from Sodium Nitrite Extra Pure ph Eur, USP Merck and deionised water.

Description of Manufacturing Process

Sodium nitrite is weighed into a suitably sized vessel and then transferred carefully into a known volume of deionised water, which is then stirred until dissolution is complete to make a solution of appropriate concentration. In this embodiment the sodium nitrite solution is dispensed onto the mesh and then is placed into each petri dish for a minimum time to imbibe the mesh with the sodium nitrite solution. The finished products are sterilised by irradiation.

Secondary Layer: Hydrogel Top Layer

The hydrogel chosen for this study has high capability for absorption and facilitates a moist wound-healing environment. The hydrogel comprises a cross-linked anionic copolymer, circa 30% water and circa 30% glycerol. It has an outer polyurethane film that provides a bacterial barrier and aesthetically pleasing outer surface to the dressing. The gels have an acidic surface pH circa 2-5 arising from the presence of some sulfonic acid groups. These groups provide the acidity for the conversion of Sodium Nitrite to Nitric Oxide. As the sulfonic acid groups are covalently bound to the hydrogel network they are not released into the wound.

Description of Manufacturing Process

The hydrogel is manufactured from the list of ingredients set out below. The process of manufacture is as according to patents EP1100555B1 and EP1 10556B1 , which are incorporated by reference in their entirety herein.

The ingredients are dispensed into a suitable mixing vessel (dispensing is controlled by weight) and stirred overnight. Once mixed, a portion of the liquid solution is dispensed onto a moving substrate (clear polyurethane film, Inspire 2304) at the required coat weight. Then a mesh made of polypropylene (RKW 20 g/m²) is laid onto the top of the liquid formulation, which is then exposed to UV light and cured. A second layer is coated on top of the first at the required coat weight and exposed to UV light, thus making a "sandwich" with the mesh in the middle.

The hydrogel is cut to the required size and pouched, sealed and sterilised. The finished products are sterilised by gamma irradiation. The components of the hydrogels are:

Monomer, Sodium AMPS 2405A (58% solution in water) (Lubrizol)

Monomer, 2-acrylamido-2-methylpropane sulfonic acid (Sigma-Aldrich)(AMPS Acid)

Monomer, Acrylic Acid (BASF)

Glycerine BP, EP (H. Fosters)

Darocur 1173, 2-hydroxy-2-methylpropiophenone (BASF) (D1 173)

SR 344, poly (ethylene glycol) diacrylate (Sartomer) (PEG diacylate)

Mesh, Carded non-woven 20gsm (RKW-Group)

Inspire 2304, polyurethane film (Coveris)

70 micron, low density polyethylene, siliconised (Adcoat)

'NeoCarta,' peelable laminate (Safta)

The components of the nitrite layer are:

Mesh, Carded non-woven 20gsm (RKW-Group)

'NeoCarta,' peelable laminate (Safta)

Sodium Nitrite, extra pure, Ph Eur, USP (Merck)

De-ionised water (First Water Ltd) Example Hydrogel Compositions

Samples 1 , 2 and 3 are example compositions of the invention. Example 2 Extent of colour change of the hydrogel layer when contacted with agueous sodium nitrite

A 40mm x 25mm piece of hydrogel from Example 1 was contacted with a 25mm x 15mm piece of mesh imbibed with sodium nitrite (Example 1) and then covered with a polyethylene film and left for 16 hours. After 16 hours hydrogel samples 1 , 2 and 3 had essentially not changed colour whereas sample 4 (comprising carboxylic acid) had a distinct yellow/brown colour indicative of the presence of nitrogen dioxide.

These results indicate that the hydrogel compositions comprising sulphonic acid are advantageous compared to the hydrogel compositions comprising carboxylic acid as a reduced amount of nitrogen dioxide by-product is produced.

Example 3 Change in skin colour

Pieces 25mm x 15mm of mesh imbibed with sodium nitrite were placed on the underside of a healthy male forearm and then covered with a hydrogel secondary layer to form a dressing. The composition of the hydrogel was as described in Example 1 , i.e. samples 1 , 2 and 3. After 15 minutes the hydrogel and mesh were removed and the colour of the skin under was visually assessed and compared to the colour of the skin surrounding the dressings. The dressing with hydrogel composition Sample 1 gave rise to the greatest distinct red colouration. The dressing with hydrogel composition Sample 3 gave rise to a very low level of discolouration and the dressing with hydrogel composition Sample 2 gave rise to a red colouration of the skin intermediate between Sample 1 and 3. The increase in the red colouration of the skin is indicative of vasodilation arising from the production of nitric oxide from the dressing.

When the hydrogel compositions (Samples 1 , 2 and 3) were applied to the skin for 15 minutes in the absence of the nitrite mesh no discernible change in skin colouration was observed.

Claims

1. A system comprising:

(i) a layer containing a nitrite; and

(ii) a hydrogel comprising a sulphonic acid.

2. The system according to claim 1 , wherein the layer is a mesh.

3. The system according to claim 2, wherein the mesh is formed of a polymer.

4. The system according to claim 3, wherein the polymer is polypropylene.

5. The system according to claim 1 , wherein the layer is a dissolvable film.

6. The system according to claim 5, wherein the dissolvable film is formed of a polyvinyl alcohol, polyvinylpyrrolidone, a cellulose-based polymer or cellulose.

7. The system according to any one of the preceding claims, wherein the nitrite is an alkaline metal nitrite or an alkaline earth metal nitrite.

8. The system according to claim 7, wherein the nitrite is sodium nitrite.

9. The system according to any one of the preceding claims, wherein the system comprises a plurality of layers containing a nitrite.

10. The system according to any one of the preceding claims, wherein the nitrite is present as a nitrite solution.

11. The system according to any one of the preceding claims, wherein the hydrogel is partially hydrated.

12. The system according to any one of the preceding claims, wherein the hydrogel is cross-linked.

13. The system according to any one of the preceding claims, wherein the sulphonic acid is a pendant functional group of a polymerisable monomer.

14. The system according to claim 13, wherein the monomer is selected from the group consisting of 2-acrylamido-2-methylpropane sulfonic acid, 4-styrenesulfonic acid and vinylsulfonic acid.

15. The system according to any one of the preceding claims, wherein the hydrogel is a co-polymer.

16. The system according to claim 15, wherein the hydrogel is a co-polymer of a sulphonic acid and an alkali metal salt of a sulphonic acid.

17. The system according to claim 16, wherein the alkali metal salt of a sulphonic acid is selected from the group consisting of (3-su!phopropy!)-acry!a†e potassium salt and the alkali metal salts of 2-acrylamido-2-methylpropane sulphonic acid, 4- styrenesulfonic acid and vinylsulphonic acid.

18. The system according to claim 17, wherein the alkali metal is selected from the group consisting of sodium, potassium and calcium.

19. The system according to any one of claims 16 to 18, wherein the sulphonic acid from which the alkali metal salt is derived is the same as the sulphonic acid.

20. The system according to any one of the preceding claims, wherein the hydrogel comprises from 0.05 to 2% (weight/weight) of sulphonic acid.

21. The system according to any one of the preceding claims, wherein the pH of the hydrogel is from 2 to 4.5.

22. The system according to any one of the preceding claims, wherein the system does not contain a thiol or a reductant.

23. The system according to any one of the preceding claims, further comprising a pharmaceutically active agent.

24. The system according to any one of the preceding claims for use in medicine.

25. The system according to any one of the preceding claims for use in the treatment of a condition associated with tissue ischaemia or a wound.

26. The system according to claim 25, wherein the wound is an ulcer.

27. The system according to claim 26, wherein the ulcer is a leg ulcer, pressure ulcer or diabetic ulcer.

28. The system according to claim 25, wherein the wound is a skin donor site, a surgical wound, a burn, a laceration or an abrasion.

29. The system according to claim 25, wherein the condition associated with tissue ischaemia is Raynaud's syndrome or tissue ischaemia caused by septic shock, irradiation or a peripheral vascular disease.

30. Use of a layer containing a nitrite and a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of a condition associated with tissue ischaemia or a wound.

31. A method for the treatment of a condition associated with tissue ischaemia or a wound, comprising administering the system according to any one of claims 1 to 24 to a subject in need thereof.

32. The method according to claim 31 , comprising:

(i) administering a layer containing a nitrite; and then

(ii) administering a hydrogel comprising a sulphonic acid

to a subject in need thereof.

33. A kit comprising a layer containing a nitrite and a hydrogel comprising a sulphonic acid as a combined preparation for simultaneous, separate or sequential use in treating a condition associated with tissue ischaemia or a wound.

34. The system according to claim 23 for use in the treatment of a disease or medical condition.

35. Use of a layer containing a nitrite and a hydrogel comprising a sulphonic acid in the manufacture of a medicament for the treatment of a disease or medical condition, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent.

36. A method for the treatment of a disease or medical condition, comprising administering the system according to claim 23 to a subject in need thereof.

37. A kit comprising (i) a layer containing a nitrite, and (ii) a hydrogel comprising a sulphonic acid as a combined preparation for simultaneous, separate or sequential use in treating a disease or condition, wherein the layer containing a nitrite and/or the hydrogel comprises a pharmaceutically active agent.

38. The system according to any one of claims 1 to 22 in combination with an aqueous-soluble drug for use in medicine.

39. A system comprising:

(i) a layer containing a nitrite; and

(ii) a hydrogel comprising a sulphonic acid

in combination with an anaesthetic for use in the treatment or prevention of pain.

40. The system for use according to claim 39, wherein the system is administered simultaneously, separately or sequentially with said anaesthetic.

41. The system for use according to claim 39 or 40, wherein the anaesthetic is selected from the group consisting of lignocaine (lidocaine), amethocaine (tetracaine), xylocaine, bupivacaine, prilocaine, ropivacaine, benzocaine, mepivocaine, ***e or a mixture thereof.

42. Use of a system comprising:

(i) a layer containing a nitrite; and

(ii) a hydrogel comprising a sulphonic acid

in the manufacture of a medicament for the treatment or prevention of pain, wherein said system is administered simultaneously, separately or sequentially with an anaesthetic.

43. A method of treatment or prevention of pain comprising administering a system comprising:

(i) a layer containing a nitrite; and

(ii) a hydrogel comprising a sulphonic acid

and an anaesthetic to a subject in need thereof.