EXOTHERMIC TOPICAL DEVICES FOR DELIVERING PHARMACEUTICALS AND COSMETICS TO THE SKIN

Abstract

Devices and systems for delivering an agent to the skin of a subject comprise an anhydrous agent (e.g. a pharmaceutical agent or a cosmetic agent), and an anhydrous heating component and a reservoir containing a solvent. When in use solvent released from the reservoir hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution. The devices and systems enable the transdermal delivery of pharmaceutical and cosmetic agents.

Claims

1.-52. (canceled)

53. A device for delivering an agent to the skin of a subject comprising: a. an anhydrous agent, wherein the agent is a pharmaceutical agent or a cosmetic agent, b. an anhydrous heating component, and c. a reservoir containing a first solvent and a second solvent, wherein the first solvent and the second solvent are different and wherein the second solvent is water; wherein in use the first and second solvents are released from the reservoir and the second solvent hydrates the anhydrous agent to produce a solution comprising the first solvent, the second solvent and the agent, and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and wherein the device further comprises: (i) a backing layer, wherein the backing layer is permeable to vapour of the first solvent, (ii) a solid substrate, wherein in use a portion of the first solvent is removed from the solution by adsorption onto the solid substrate, or (iii) a copolymer, wherein in use a portion of the first solvent is separated from the solution by selective absorption by the copolymer.

54. A system comprising: a. a device for delivering an agent to the skin of a subject comprising i. an anhydrous agent, wherein the agent is a pharmaceutical agent or a cosmetic agent, and ii. an anhydrous heating component; and b. a reservoir containing a first solvent and a second solvent, wherein the first solvent and the second solvent are different and wherein the second solvent is water; wherein in use the first and second solvents are released from the reservoir and the second solvent hydrates the anhydrous agent to produce a solution comprising the first solvent, the second solvent and the agent, and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and wherein the device further comprises: (i) a backing layer, wherein the backing layer is permeable to vapour of the first solvent, (ii) a solid substrate, wherein in use a portion of the first solvent is removed from the solution by adsorption onto the solid substrate, or (iii) a copolymer, wherein in use a portion of the first solvent is separated from the solution by selective absorption by the copolymer.

55. The system of claim 54, wherein the device further comprises: a. (i) a backing layer, wherein the backing layer is permeable to vapour of the first solvent, and (ii) a solid substrate, wherein in use a portion of the first solvent is removed from the solution by adsorption onto the solid substrate; b. (i) a backing layer, wherein the backing layer is permeable to vapour of the first solvent, and (ii) a copolymer, wherein in use a portion of the first solvent is separated from the solution by selective absorption by the copolymer; c. (i) a solid substrate, wherein in use a portion of the first solvent is removed from the solution by adsorption onto the solid substrate, and (ii) a copolymer, wherein in use a portion of the first solvent is separated from the solution by selective absorption by the copolymer; or d. (i) a backing layer, wherein the backing layer is permeable to vapour of the first solvent, (ii) a solid substrate, wherein in use a portion of the first solvent is removed from the solution by adsorption onto the solid substrate, and (iii) a copolymer, wherein in use a portion of the first solvent is separated from the solution by selective absorption by the copolymer.

56. The system of claim 54, wherein in use the first solvent is removed from the solution by evaporation.

57. The system of claim 54, wherein the solid substrate is activated carbon.

58. The system of claim 54, wherein (i) the first solvent is a solvent with a lower boiling point than water, (ii) the first solvent is stronger solvent for the anhydrous agent than water, (iii) the first solvent is a co-solvent, (iv) the first solvent is a water-miscible organic solvent, or (v) wherein the first solvent is ethanol.

59. The system of claim 54, wherein the anhydrous agent has a higher solubility in the first solvent than in the second solvent.

60. The system of claim 54, wherein the reservoir contains the first solvent and the second solvent as a mixed solvent.

61. The system of claim 54, wherein the reservoir containing the first and second solvent is pressurised, optionally wherein a gas is dissolved in the first and/or second solvent, optionally wherein the gas is carbon dioxide.

62. The system of claim 54, wherein the anhydrous agent is provided in fibres and/or granules.

63. The system of claim 54, wherein the anhydrous agent is formulated with a carrier polymer and/or a plasticiser, optionally wherein the carrier polymer is a soluble polymer; and optionally wherein the device comprises the anhydrous agent in an anhydrous agent composite and wherein the anhydrous agent composite further comprises a carrier polymer.

64. The system of claim 54, wherein the anhydrous agent is a hydrophilic agent, a lipophilic agent or an amphiphilic agent.

65. The system of claim 54, wherein the anhydrous heating component comprises an anhydrous salt capable of reacting exothermically with the solvent; optionally wherein the anhydrous salt is calcium chloride, magnesium sulphate, magnesium chloride, calcium oxide, barium oxide, magnesium sulphate, ferric chloride, ferrous chloride, aluminium sulphate hexahydrate and/or aluminium chloride.

66. The system of claim 54, wherein the anhydrous heating component forms a gel on hydration, optionally wherein the gel is a hydrogel.

67. The system of claim 54, wherein the device further comprises a phase change material (PCM); optionally wherein the PCM is a fatty acid, paraffin wax and/or a salt hydrate.

68. The system of claim 54, wherein the device comprises: c. an anhydrous agent composite comprising the anhydrous agent and a carrier polymer, d. the anhydrous heating component, and e. a backing layer, optionally wherein the backing layer is permeable to the vapour of the first solvent; optionally wherein the anhydrous heating component forms a gel on hydration; and/or optionally wherein the anhydrous agent composite and the anhydrous heating component are interwoven.

69. The system of claim 54, wherein the device comprises in sequence: f. a first layer comprising the anhydrous agent, g. a second layer comprising the anhydrous heating component, and h. a third layer, wherein the third layer is a backing layer, optionally wherein the second and third layers are permeable to vapour of the first solvent.

70. The system of claim 54, wherein the device is a patch, optionally wherein the device is a transdermal patch.

71. A method of treating a subject using a device or system as defined in claim 54, or a method of delivering a cosmetic agent to the skin of a subject using a device or system as defined in claim 54, comprising: a. releasing the first and second solvents from the reservoir, wherein the second solvent released from the reservoir hydrates the anhydrous agent to produce a solution comprising the first solvent, the second solvent and the agent, and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject; optionally wherein after step (a) the first solvent is removed from the solution over time thereby concentrating the pharmaceutical agent or cosmetic agent in the solution; optionally wherein the first solvent is removed from the solution by evaporation; optionally wherein the device comprises a backing layer and wherein the first solvent is removed from the solution by evaporation through the backing layer; optionally wherein the first solvent is removed from the solution by adsorption onto a solid substrate; and/or optionally wherein after step (b) the pharmaceutical agent or cosmetic agent becomes supersaturated in the solution on the skin.

72. A method of manufacturing the system as defined in claim 54 comprising: i. formulating the anhydrous agent with a carrier polymer by spinning or extrusion to produce an anhydrous agent composite, and j. preparing the anhydrous heating component; optionally wherein the method further comprises the step of (c) attaching the anhydrous agent composite and the anhydrous heating component to a backing layer; optionally wherein steps (a) and (b) are performed under anhydrous conditions, optionally wherein steps (a), (b) and (c) are performed under anhydrous conditions; optionally wherein the method further comprises the step of adding a reservoir containing a solvent to the device; and/or optionally wherein the method further comprises the step of sealing the device in a packing system under anhydrous conditions.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0133] The present disclosure will now be described, by way of example only, with reference to the accompanying drawings in which:

[0134] FIG. 1 illustrates a device (a patch) of the invention.

[0135] FIG. 2 illustrates a system of the invention.

[0136] FIG. 3 illustrates the structure of the different layers of a device of the invention in use.

DETAILED DESCRIPTION

[0137] FIG. 1 illustrates a device (a patch) of the invention. The patch has a textile vapour permeable backing layer (001); optionally a layer (002) that promotes loss of ethanol from the heated solution e.g. an ethanol pervaporation membrane, an activated carbon layer which may be in the form of activated carbon fibres or a gel with high ethanol affinity; an anhydrous bed of water-soluble polymer matrix carrier material (003) capable of rapidly wicking up a volume of solvent and within which a pharmaceutical agent(s) or cosmetic agent(s) is/are entrained in one component of the anhydrous bed and within another component exothermic hydration materials and phase change materials are entrained; optionally an adhesive perimeter to adhere the patch to the skin (004)

[0138] The outer visible layer (001) could be an attractive fabric that has a sensorial feel and allows escape of ethanol vapour. The loss of the latter creates the supersaturated solution of the drug/cosmetic agent pushing that substance deeper into the skin. An optional middle layer (002) could be ethanol absorbing or adsorbing such as activated carbon so preventing the need for loss of ethanol vapour from the outer surface. An adhesive perimeter (004) holds the patch in place.

[0139] Different anhydrous morphologies of the soluble polymer (003) containing the pharmaceutical/cosmetic agent and the water absorbing heating component may be manufactured (see (005) to (011)). Both components need to be able to wick up the added solvent (including water). The two components may be provided interwoven as fibres, threads or strands (005). Alternatively, one component may be present as a fibre, thread or strand and the second component may be present as solid particles interspersed with amongst the fibres (006). The two components may be present as solid particles mixed together to form a granular bed (007). One component may be present as solid particles positioned between the layers of the second component present as a solid mesh (008). The two components may be present as alternating mesh layers (009). The two components may be present as alternating layers of a film or sheet similar to that manufactured as oral dissolving film whereby a degree of porosity is provided by channels through the films (010). The two components may be present, one as a permeable film/sheet and the other as a mesh (011).

[0140] FIG. 2 illustrates a system of the invention. The figure shows the spatially separated solvent reservoir (012) connected via pre-formed channel (013) which has been mechanically sealed with a frangible seal (014) that can be ruptured via firm finger pressure applied to the solvent reservoir (012). The solvent is then forced through the channel (013) into the patch compartment (015).

[0141] FIG. 3 illustrates the structure of the different layers of a device of the invention in use. Starting with the layer proximal to the skin, there is shown a drug-loaded soluble polymer layer (i.e. produced from anhydrous agent composite on hydration) (016), an exothermic layer (produced from anhydrous heating component on hydration) (017) and an outer vapour permeable backing layer (018). Arrows show the loss of ethanol vapour when the device is in use, the ethanol vapour passing through the open weave of the exothermic layer (017) and the backing layer (018) as it is removed from the solution in the device.

[0142] The invention is further defined in the following set of numbered clauses: [0143] 1. A device for delivering an agent to the skin of a subject comprising: [0144] a. an anhydrous agent, wherein the agent is a pharmaceutical agent or a cosmetic agent, [0145] b. an anhydrous heating component, and [0146] c. a reservoir containing a first solvent and a second solvent, [0147] wherein in use solvent released from the reservoir hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution. [0148] 2. A system comprising: [0149] a. a device for delivering an agent to the skin of a subject comprising [0150] i. an anhydrous agent, wherein the agent is a pharmaceutical agent or a cosmetic agent, and [0151] ii. an anhydrous heating component; and [0152] b. a reservoir containing a first solvent and a second solvent; [0153] wherein in use solvent released from the reservoir hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution. [0154] 3. The device or system of clause 1 or clause 2, wherein in use the first solvent is removed from the solution over time thereby concentrating the agent in the solution. [0155] 4. The device or system of clause 3, wherein in use the first solvent is removed from the solution by evaporation. [0156] 5. The device or system of clause 3 or clause 4, wherein the device or system further comprises a solid substrate, and wherein in use the first solvent is removed from the solution by adsorption onto the solid substrate. [0157] 6. The device or system of clause 5, wherein the solid substrate is activated carbon. [0158] 7. The device or system of any one of clauses 1 to 6, wherein the first solvent is a solvent with a lower boiling point than water and wherein the second solvent is water. [0159] 8. The device or system of any one of clauses 1 to 7, wherein the first solvent is stronger solvent for the anhydrous agent than water. [0160] 9. The device or system of clause 7 or clause 8, wherein the first solvent is a co-solvent. [0161] 10. The device or system of clause 7 or clause 8, wherein the first solvent is a water-miscible organic solvent. [0162] 11. The device or system of clause 7 or clause 8, wherein the first solvent is ethanol, acetal (e.g. methylal and/or butylal), benzyl alcohol, dimethyl sulfoxide, ether, glycerol, glycol ether, mannitol, methanol, isopropyl alcohol, 1,3-propanediol, 1-propanol, propylene glycol and/or urea. [0163] 12. The device or system of any one of clauses 1 to 11, wherein the anhydrous agent has a higher solubility in the first solvent than in the second solvent. [0164] 13. The device or system of any one of clauses 1 to 12, wherein the reservoir contains the first solvent and the second solvent as a mixed solvent. [0165] 14. The device or system of any one of clauses 1 to 13, wherein the reservoir further contains a skin penetration enhancer. [0166] 15. The device or system of any one of clauses 1 to 14, wherein the reservoir containing the first and second solvent is pressurised. [0167] 16. The device or system of clause 15, wherein a gas is dissolved in the first and/or second solvent, optionally wherein the gas is carbon dioxide. [0168] 17. The device or system of any one of clauses 1 to 16, wherein the anhydrous agent is provided in fibres and/or granules. [0169] 18. The device or system of any one of clauses 1 to 17, wherein the anhydrous agent is formulated by spinning or extrusion. [0170] 19. The device or system of clause 18, wherein the spinning is melt spinning, wet spinning, or electrospinning. [0171] 20. The device or system of clause 18, wherein the extrusion is hot melt extrusion. [0172] 21. The device or system of any one of clauses 1 to 20, wherein the anhydrous agent is formulated with a carrier polymer and/or a plasticiser, optionally wherein the carrier polymer is a soluble polymer. [0173] 22. The device or system of clause 21, wherein the carrier polymer is polyethylene oxide, polyethylene glycol, hyaluronic acid, hydroxypropyl methylcellulose, methyl cellulose, carboxymethylcellulose, hydroxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polymethylacrylate, polyvinylpyrollidone, cyclodextrins, chitosan, polyvinyl alcohol, pullulan, gelatin, sodium alginate, maltodextrins, and silicone gel, gellan gum, iota carrageenan, kappa carrageenan, starch, modified starch, starch derivative (e.g. amylose and/or dextrin), polyacrylic acid (PAA), xanthan gum, pectin and/or guar gum. [0174] 23. The device or system of clause 21 or clause 22, wherein the plasticiser is polyethylene oxide, mannitol, glycerol, polyoxime, polyoxyethylated oil (caster oil), polyethylene glycol and/or vitamin E. [0175] 24. The device or system of any one of clauses 21 to 23, wherein the device comprises the anhydrous agent in an anhydrous agent composite, and wherein the anhydrous agent composite further comprises a carrier polymer. [0176] 25. The device or system of any one of clauses 1 to 24, wherein the anhydrous agent is a hydrophilic agent, a lipophilic agent or an amphiphilic agent. [0177] 26. The device or system of any one of clauses 1 to 25, wherein the pharmaceutical agent is an analgesic agent, an anaesthetic agent (e.g. a local anaesthetic), an anti-acne agent, an anti-allergy agent, an anti-arthritis agent, an anti-cancer agent, an anti-depressant, an anti-diabetic agent, an anti-infectant agent, an anti-inflammatory agent (e.g. a non-steroidal anti-inflammatory agent), an anti-hypertensive agent, anti-migraine agent, an anti-obesity agent, an antibiotic, an antiemetic, an antimicrobial, an antiviral agent (e.g. an antiretroviral agent), an appetite suppressant, a contraceptive agent, a cardiovascularly active agent, a dermatological therapeutic (e.g. an eczema therapeutic, a psoriasis therapeutic and/or an Ichthyosis therapeutic), a scar tissue reducing agent, a drug cessation agent, a fungal control agent, a hormone, an immunizing antigen, a sedative, a smoke cessation agent, a steroid (e.g. an androgen and/or an estrogen), a stimulant (e.g. caffeine and/or taurine) and/or a vaccine. [0178] 27. The device or system of any one of clauses 1 to 26, wherein the cosmetic agent is an antioxidant, an amino acid, a peptide, a polysaccharide, an oligosaccharide, a glycosaminoglycan, a proteoglycan, a non-digestible sugar, uronic acid, an anti-glycation agent, a fatty acid, a ceramide, a glycoglycerolipid, a skin lightening agent, a film-forming agent, a retinoid, a humectant, an anti-cellulite agent, cell proliferation agent, an extracellular matrix expression stimulating agent, a vasodilatory agent, a CoQ10 quinone, a retro-photo damage compound, a fat lipolysis agent, a prebiotic, a probiotic, a stimulant (e.g. caffeine and/or taurine), an organic UV protection compound, a firming and lifting agent (e.g. Botox or botulinum toxin), a scar tissue reducing agent and/or a collagen enhancer (e.g. matrixyl), a palmitoyl-peptide, a palmitoyl-oligopeptide or a palmitoyl-tripeptide), [0179] 28. The device or system of any one of clauses 1 to 27, wherein the anhydrous heating component comprises an anhydrous salt capable of reacting exothermically with the solvent. [0180] 29. The device or system of clause 28, wherein the anhydrous salt is calcium chloride, magnesium sulphate, magnesium chloride, calcium oxide, barium oxide, magnesium sulphate, ferric chloride, ferrous chloride, aluminium sulphate hexahydrate and/or aluminium chloride. [0181] 30. The device or system of clause 29, wherein the anhydrous salt is calcium chloride and/or magnesium sulphate. [0182] 31. The device or system of any one of clauses 1 to 30, wherein the anhydrous heating component forms a gel on hydration. [0183] 32. The device or system of clause 31, wherein the gel is a hydrogel. [0184] 33. The device or system of clause 32, wherein the hydrogel comprises a polyacrylate, an alginate (e.g. sodium alginate), polyethylene oxide, polyethylene glycol, hyaluronic acid, hydroxypropyl methylcellulose, methyl cellulose, carboxymethylcellulose, hydroxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyly cellulose, sodium carboxymethyl cellulose, polymethacrylate, polyvinylpyrollidone, cyclodextrin, chitosan, polyvinyl alcohol, pullulan, gelatin, maltodextrin, silicone gel, gellan gum, iota carrageenan, kappa carrageenan, starch, modified starch, starch derivative (e.g. amylose and/or dextrin), polyacrylic acid (PAA), xanthan gum, pectin and/or guar gum. [0185] 34. The device or system of any one of clauses 28 to 33, wherein on hydration the anhydrous salt is retained within the heating component. [0186] 35. The device or system of any one of clauses 1 to 34, wherein the device further comprises a phase change material (PCM), optionally wherein the PCM is a blend of two or more PCMs. [0187] 36. The device or system of clause 35, wherein the PCM has a melting point of 30-60 C. [0188] 37. The device or system of clause 36, wherein the PCM has a melting point of 40-50 C. [0189] 38. The device or system of any one of clauses 35 to 37, wherein the PCM is a fatty acid, paraffin wax and/or a salt hydrate. [0190] 39. The device or system of clause 38, wherein the PCM is lauric acid, stearic acid, capric acid, palmitic acid and/or myristic acid. [0191] 40. The device or system of clause 39, wherein the PCM is lauric acid and/or myristic acid. [0192] 41. The device or system of clause 38, wherein the PCM is a paraffin wax comprising hydrocarbon molecules containing 21-27 carbon atoms. [0193] 42. The device or system of any one of clauses 1 to 41, wherein the device further comprises a crystalline material capable of releasing gas on contact with the solvent. [0194] 43. The device or system of any one of clauses 1 to 42, wherein the device further comprises an anti-nucleation agent. [0195] 44. The device or system of any one of clauses 1 to 43, wherein the device comprises a backing layer. [0196] 45. The device or system of clause 44, wherein the backing layer is permeable to vapour of the solvent. [0197] 46. The device or system of any one of clauses 1 to 45, wherein the device comprises: [0198] a. an anhydrous agent composite comprising the anhydrous agent and a carrier polymer, [0199] b. the anhydrous heating component, and [0200] c. a backing layer, optionally wherein the backing layer is permeable to the vapour of the solvent. [0201] 47. The device or system of clause 46, wherein the anhydrous heating component forms a gel on hydration. [0202] 48. The device or system of clause 46 or clause 47, wherein the anhydrous agent composite and the anhydrous heating component are interwoven. [0203] 49. The device or system of clauses 1 to 47, wherein the device comprises in sequence: [0204] a. a first layer comprising the anhydrous agent, [0205] b. a second layer comprising the anhydrous heating component, and [0206] c. a third layer, wherein the third layer is a backing layer, optionally wherein the second and third layers are permeable to vapour of the first solvent. [0207] 50. The device or system of any one of clauses 1 to 49, wherein the device comprises an adhesive perimeter, by means of which the device is, in use, secured to the skin. [0208] 51. The device or system of any one of clauses 1 to 50, wherein the device is a patch. [0209] 52. The device or system of clause 51, wherein the device is a transdermal patch. [0210] 53. The system of any one of clauses 1 to 52, wherein the device is provided in a first sealed compartment of a packaging system and the reservoir is provided by a second spatially separated sealed compartment of the packaging system. [0211] 54. The system of clause 53, wherein the first and second compartments of the packaging system are connected by a frangible seal, and wherein in use the frangible seal is broken releasing the solvent onto the device. [0212] 55. The device or system of any one of clauses 1 to 54, wherein in use the solution reaches a temperature of 30-60 C. [0213] 56. The device or system of clause 55, wherein in use the solution reaches a temperature of 40-50 C. [0214] 57. A kit comprising: [0215] a) an abrasive pad and [0216] b) a device or system as defined in any one of clauses 1 to 56. [0217] 58. The kit of clause 57, wherein the abrasive pad comprises a penetration enhancer, optionally wherein the penetration enhancer is menthol, linalool, ethanol, propylene glycol and/or deionised water. [0218] 59. The kit of clause 57 or clause 58, wherein the kit further comprises a skin cream. [0219] 60. A method of treating a subject comprising: [0220] a. contacting a device with a solvent comprising a first solvent and a second solvent, wherein the device comprises [0221] i. an anhydrous pharmaceutical agent, and [0222] ii. an anhydrous heating component; [0223] wherein the solvent hydrates the anhydrous pharmaceutical agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and [0224] b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject. [0225] 61. A method of treating a subject using a device or system as defined in any one of clauses 1 to 56 comprising: [0226] a. releasing the solvent from the reservoir, wherein solvent released from the reservoir hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and [0227] b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject. [0228] 62. A method of delivering a cosmetic agent to the skin of a subject comprising: [0229] a. contacting a device with a solvent comprising a first solvent and a second solvent, wherein the device comprises [0230] i. an anhydrous cosmetic agent, and [0231] ii. an anhydrous heating component; [0232] wherein the solvent hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and [0233] b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject. [0234] 63. A method of delivering a cosmetic agent to the skin of a subject using a device or system as defined in any one of clauses 1 to 56 comprising: [0235] a. releasing the solvent from the reservoir, wherein solvent released from the reservoir hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and [0236] b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject. [0237] 64. The method of any one of clauses 60 to 63, wherein after step (a) the first solvent is removed from the solution over time thereby concentrating the pharmaceutical agent or cosmetic agent in the solution. [0238] 65. The method of clause 64, wherein the first solvent is removed from the solution by evaporation. [0239] 66. The method of clause 65, wherein the device comprises a backing layer and wherein the first solvent is removed from the solution by evaporation through the backing layer. [0240] 67. The method of any one of clauses 64 to 66, wherein the first solvent is removed from the solution by adsorption onto a solid substrate. [0241] 68. The device or system of clause 67, wherein the solid substrate is activated carbon. [0242] 69. The method of any one of clauses 60 to 68, wherein after step (b) the pharmaceutical agent or cosmetic agent becomes supersaturated in the solution on the skin. [0243] 70. The method of any one of clauses 60 to 69, wherein after step (b) the solution on the skin reaches a temperature of 30-60 C. [0244] 71. The method of clause 70, wherein after step (b) the solution on the skin reaches a temperature of 40-50 C. [0245] 72. The method of clause 70 or clause 71, wherein the temperature is reached in less than 20 minutes, less than 15 minutes, less than 10 minutes or less than 5 minutes after step (a). [0246] 73. The method of any one of clauses 70 to 72, wherein the temperature is maintained for 10 to 60 minutes, optionally wherein the temperature is maintained for 15 to 45 minutes. [0247] 74. The method of any one of clauses 60 to 73, wherein the pharmaceutical agent or cosmetic agent is delivered transdermally. [0248] 75. The method of any one of clauses 60 to 74, wherein the device is as defined in any one of clauses 1 to 56. [0249] 76. An anhydrous pharmaceutical agent for use in the treatment of a subject, wherein the agent is administered to the subject by a therapeutic method comprising: [0250] a. contacting a device with a solvent comprising a first solvent and a second solvent, wherein the device comprises [0251] i. an anhydrous pharmaceutical agent, and [0252] ii. an anhydrous heating component; [0253] wherein the solvent hydrates the anhydrous pharmaceutical agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and [0254] b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject. [0255] 77. An anhydrous pharmaceutical agent for use in the treatment of a subject, wherein the agent is administered to the subject using a device or system as defined in any one of clauses 1 to 56, and wherein the agent is administered to the subject by a therapeutic method comprising: [0256] a. releasing the solvent from the reservoir, wherein solvent released from the reservoir hydrates the anhydrous agent to produce a solution and hydrates the anhydrous heating component which reacts exothermically thereby heating the solution, and [0257] b. contacting the skin of the subject with the device thereby delivering the agent to the skin of the subject. [0258] 78. The anhydrous pharmaceutical agent for use of clause 76 or clause 77, wherein after step (a) the first solvent is removed from the solution over time thereby concentrating the pharmaceutical agent in the solution. [0259] 79. The anhydrous pharmaceutical agent for use of clause 78, wherein the first solvent is removed from the solution by evaporation. [0260] 80. The anhydrous pharmaceutical agent for use of clause 79, wherein the device comprises a backing layer and wherein the first solvent is removed from the solution by evaporation through the backing layer. [0261] 81. The anhydrous pharmaceutical agent for use of any one of clauses 78 to 80, wherein the first solvent is removed from the solution by adsorption onto a solid substrate. [0262] 82. The anhydrous pharmaceutical agent for use of clause 81, wherein the solid substrate is activated carbon. [0263] 83. The anhydrous pharmaceutical agent for use of any one of clauses 76 to 82, wherein after step (b) the pharmaceutical agent or cosmetic agent becomes supersaturated in the solution on the skin. [0264] 84. The anhydrous pharmaceutical agent for use of any one of clauses 76 to 83, wherein after step (b) the solution on the skin reaches a temperature of 30-60 C. [0265] 85. The anhydrous pharmaceutical agent for use of clause 84, wherein after step (b) the solution on the skin reaches a temperature of 40-50 C. [0266] 86. The anhydrous pharmaceutical agent for use of clause 84 or clause 85, wherein the temperature is reached in less than 20 minutes, less than 15 minutes, less than 10 minutes or less than 5 minutes after step (a). [0267] 87. The anhydrous pharmaceutical agent for use of any one of clauses 84 to 86, wherein the temperature is maintained for 10 to 60 minutes, optionally wherein the temperature is maintained for 15 to 45 minutes. [0268] 88. The anhydrous pharmaceutical agent for use of clauses 76 to 87, wherein the pharmaceutical agent is delivered transdermally. [0269] 89. The anhydrous pharmaceutical agent for use of any one of clauses 76 to 88, wherein the device is as defined in any one of clauses 1 to 56. [0270] 90. A method of manufacturing the device or system as defined in any one of clauses 1 to 56 comprising: [0271] a. formulating the anhydrous agent with a carrier polymer by spinning or extrusion to produce an anhydrous agent composite, and [0272] b. preparing the anhydrous heating component. [0273] 91. The method of clause 90, wherein the spinning is melt spinning, wet spinning, or electrospinning. [0274] 92. The method of clause 90 or clause 91, wherein the extrusion is hot melt extrusion. [0275] 93. The method of any one of clauses 90 to 92, wherein the method further comprises the step of (c) attaching the anhydrous agent composite and the anhydrous heating component to a backing layer. [0276] 94. The method of any one of clauses 90 to 93, wherein steps (a) and (b) are performed under anhydrous conditions, optionally wherein steps (a), (b) and (c) are performed under anhydrous conditions. [0277] 95. The method of any one of clauses 90 to 94, wherein the method further comprises the step of adding a reservoir containing a solvent to the device. [0278] 96. The method of any one of clauses 90 to 95, wherein the method further comprises the step of sealing the device in a packing system under anhydrous conditions. [0279] 97. A device or system substantially as described herein with reference to FIGS. 1, 2 and 3.

EXAMPLES

Example 1

[0280] Tetracaine (amethocaine) is formulated with soluble polymer polyethylene glycol, vitamin E TPGS and Pluronic Lecithin organogel and hot melt extruded as fine anhydrous fibres. Separately anhydrous calcium chloride and lauric acid phase change material are blended with sodium alginate and melt extruded into fine anhydrous fibres. The fibres are combined into a non-woven mat. The mat is adhered to a tactile soft but ethanol vapour permeable fabric that forms the outer layer of the patch. An outer perimeter of skin-safe pressure sensitive adhesive such as Durotak enables the patch to adhere to the skin. The anhydrous patch is hermetically sealed within a dedicated section of a blister pack spatially separated from a hermetically sealed measured volume of an aqueous volume of deionised water, ethanol, propylene glycol, glycerol, non-ionic surfactant Pluronic F-127 (BASF) and penetration enhancer Transcutol P (Gattefosse). The volume of liquid can be added to the anhydrous patch by manually squeezing the liquid compartment which forces the liquid passed a frangible barrier and through a pre-engineered channel into the patch compartment. The anhydrous fibre network wicks up the liquid. In the following seconds the active-containing fibres starts to dissolve forming a solution and the shape-retaining heating fibre network will absorb the liquid triggering an exothermic heating reaction. The patch is applied to the target area of skin promptly upon addition of the liquid.

Example 2

[0281] A pair of patches are formed from an anhydrous composite of L-ascorbic acid co-formulated with hydroxypropyl methylcellulose and a range of molecular weights of hyaluronic acid including very low molecular weight oligomers such as tetramers as well as the monomers of hyaluronic acid, D-glucuronic acid and D-N-acetyl glucosamine. Also formulated are anti-glycation actives carnosine and arginine. The composite is melt cast into thin flexible water soluble permeable films via melt-cast manufacturing processes used in oral dissolving films with soluble polymer polyvinylpyrolidone (T.sub.m=150-180 C.) whose melting point is below the thermal decomposition temperature of the entrained actives such as L-ascorbic acid (200-225 C.) also blended with an anti-nucleation agent such as hydroxypropyl methylcellulose (HPMC) to prevent crystallisation of the actives during formation of the supersaturated solution. The films are manufactured to have some degree of through-film porosity to allow the activating fluid to travel between layers and be wicked-up into the material. In parallel, the separate anhydrous heating element is manufactured as melt-extruded fibres formed into a porous water-wickable non-woven mat positioned as consecutive layers of which will be located between the cosmetic active containing flexible films. The fibres are formed from water-absorbing sodium polyacrylate blended with the exothermically hydrating material anhydrous magnesium sulphate and phase change eutectic mixture of lauric and capric acids. Between both the cosmetic active and heating components and the outer fabric layer is an ethanol vapour permeable layer of activated carbon that can adsorb the ethanol vapour formed due to the heating of the aqueous activating fluid. A textile outer backing material is adhered to the activated carbon layer with an attractive design of patterns and colours. The patches are housed within a hermetically sealed blister pack. A separately contained volume of an aqueous solution of deionised water, ethanol, propylene glycol and glycerol is contained within a physically separate ampoule that can be undone and added to the film/fibre composite patches. No perimeter of adhesive is used in this example; however, the patch is held in place on the skin due to the lightweight nature of the patch combined with the adhesion/tackiness created due to the formation of the gels in situ.

Example 3

[0282] N-acetyl salicylic acid (aspirin) is co-formulated with water soluble polymer polyethylene glycol and vitamin E to lower the glass transition temperature of the PEG. The anhydrous mixture is blended and formed into a coarse grain powder of particle size in the range of 500-1000 m. Optionally, crospovidone (PVPP) may be co-formulated to cause rapid disintegration of the aspirin-containing solid particles. A separate and anhydrous heating component is similarly blended and melt-extruded to form fibres that comprise anhydrous calcium chloride, sodium alginate and lauric acid. The two anhydrous components are mixed and an aggregate of fibres and solid particles and produced which are adhered firstly to a vapour permeable activated carbon fabric layer to adsorb ethanol which in turn is attached to an outer fabric layer that can be patterned with thermochromic inks to show, by way of a colour change, an underlying temperature change as the patch heats and then cools. The fibre and granular particle material is held against the activated carbon and fabric backing by an insoluble mesh or gauze that has inter-thread gap sizes which allow liquid flow to the skin but holds in the fibres and particles in place until the time of use. An outer perimeter (5 mm width) of dermatologically-benign adhesive holds the patch in place and prevents escape of aspirin aqueous gel formed through the hydration of each of the anhydrous components. In a separate section of the packaging a measured volume of the activating aqueous solution of deionised water, ethanol, propylene glycol, Transcutol-P is contained that can be directed to the anhydrous fabric-backed patch with a simple motion of the user such as compressing the liquid section.

Example 4

[0283] Nicotine is co-formulated with water soluble polyvinyl alcohol polymer into a porous dissolving and liquid-wicking mesh that is positioned innermost on the skin contact side of the patch. Optionally there may be an open weave fabric layer whose thread spacing is of the order of 0.5-1.0 mm to allow maximum flow of solution and maintenance of the concentration gradient adjacent to the skin. Adjacent to the nicotine loaded mesh and on the opposite side of the nicotine mesh to the skin contact side within the patch is the exothermic heating component that is also formed into a porous liquid-wicking mesh from a blend of sodium polyacrylate, anhydrous calcium chloride and lauric acid. Still further from the skin, and forming the outermost layer, is a patterned fabric that has a soft and tactile feel that also allows loss of ethanol vapour as the patch heats and after this time over the duration of use of the patch whilst in position on the skin. The anhydrous two-part mesh system is hydrated by the addition of a precise volume of an aqueous solution of deionised water, ethanol, propylene glycol, glycerol and menthol. The aqueous solution is contained adjacent to the nicotine patch in a blister pack such that simple rupturing of a thin impermeable membrane between the patch and the solution allows flow into the patch. The liquid is then wicked up by the patch in its entirety dissolving the nicotine mesh into a solution and hydrating the heating mesh to initiate the exothermic hydration reaction. The user promptly applies the patch to the skin once wetted by the solution by simple removal from its compartment of the blister pack and applying to the skin so that the patterned fabric layer is outermost. After a period of use, the user simply removes the patch which is structurally intact due to the mechanical strength conferred by the outer fabric layer and the inner skin contacting open weave retaining layer.

Example 5

[0284] Lidocaine is formulated with polyethylene glycol, vitamin E, vitamin E TPGS and solvent electrospun into nanofibers. Similarly, anhydrous calcium chloride and lauric acid is blended with sodium polyacrylate and solvent electrospun into nanofibers. The two fibres and interspersed to form an evenly mixed non-woven mat. The mat is backed with a layer of activated carbon fibre matting and then a patterned textile layer if adhered to the carbon fibre layer providing the outer air-facing side of the patch. A thermochromic dye is added to this outer layer to show temperature changes within the patch to the user. A 5 mm width outer perimeter of hypoallergenic adhesive is located around the patch to secure it to the skin. An activating liquid comprising deionised water, ethanol, propylene glycol and Transcutol-P is hermetically sealed and adjacently located close to the lidocaine patch within the same blister packaging. Upon addition of the activating fluid to the patch the clinician removes the patch and applies it to the site where the skin procedure such as cannulation, mole removal or skin graft is about to be conducted. After approximately 15-20 minutes the patch has heated, shown by the change in colour of thermochromic ink, and then cooled shown by a reversion of colour to the original colour, the clinician can remove the patch in readiness for conducting the procedure.

Example 6

[0285] Retinoic acid is co-formulated with polyethylene glycol, pluronic lecitihin organogel and vitamin E TPGS into melt extruded fibres of the order of 10's or 100's microns diameter. Co-located and interwoven into a non-woven mat are melt-extruded fibres of sodium alginate, anhydrous magnesium sulphate and a phase change eutectic mixture of lauric (m.pt 42.6 C.) and myristic acid (m.pt. 52.2 C.). The mat is backed by an ethanol vapour permeable textile layer that is patterned with thermochromic ink. Separately and adjacently located in a hermetically sealed compartment is a measured volume of the aqueous activating fluid comprising deionised water, ethanol and Zemea propanediol and urea. The barrier between the fluid and the patches is easily rupturable by concerted applied pressure to the fluid chamber and the fluid flows into the patch-containing compartment. No perimeter of adhesive is needed as the patch is lightweight and the addition of the aqueous activating fluid creates a tacky gel that adheres to the skin. The patches may be left in position even after cooling which enhances the level of saturation and may even be left on overnight to allow time-dependent diffusion into the skin.

[0286] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Moreover, all aspects and embodiments of the invention described herein are considered to be broadly applicable and combinable with any and all other consistent embodiments, including those taken from other aspects of the invention (including in isolation) as appropriate. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

REFERENCES

[0287] .sup.1Comparative Safety of Testosterone Dosage Forms, JAMA Intern Med. May 11, 2015. [0288] .sup.2Gordon, R. D. & Peterson, T. A., 2003, Four myths about transdermal drug delivery, Drug Deliv. Technol., 3, 1-7. [0289] .sup.3Patrono C, Garcia Rodriguez L A, Landolfi R, Baigent C: Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005, 353:2373-2383 [0290] .sup.4Sakamoto C, Sugano K, Ota S, Sakaki N, Takahashi S, Yoshida Y, Tsukui T, Osawa H, Sakurai Y, Yoshino J, Mizokami Y, Mine T, Arakawa T, Kuwayama H, Saigenji K, Yakabi K, Chiba T, Shimosegawa T, Sheehan J E, Perez-Gutthann S, Yamaguchi T, Kaufman D W, Sato T, Kubota K, Terano A: Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan. Eur J Clin Pharmacol 2006, 62:765-772 [0291] .sup.5Shishido T, Oka S, Tanaka S, Aoyama T, Watari I, Imagawa H, Yoshida S, Chayama K: Diagnostic yield of capsule endoscopy vs. double-balloon endoscopy for patients who have undergone total enteroscopy with obscure gastrointestinal bleeding. Hepatogastroenterology 2012, 59:955-959. [0292] .sup.6McCafferty D F, Woolfson A D. New patch delivery system for percutaneous local anaesthesia. Br J Anaesth 1993; 71:370-4. [0293] .sup.7CosmeticsDesign.com, Louise Prance, 3 Apr. 2007 (Related topics: Skin Care, Market Trends) [0294] .sup.8Polla, Penetration of Cosmetics through the stratum corneum, Cosmetics & Toiletries Magazine, 128(2), February 2013. [0295] .sup.9Lee et al, 2001, Lasers and microdermabrasion enhance and control topical delivery of vitamin C, J. Invest. Dermatol., 121, 1118. [0296] .sup.10Mikszta, J. A., Britingham, J. M., Alarcon, J., Pettis, R. J. and Dekker, J. P. (2001) Applicator having abraded surface coated with substance to be applied, Patent (Serial Number WO 01/89622 A1). [0297] .sup.11Sintov et al, 2003, radiofrequency driven skin microchanneling as a new way for electrically assited transdermal delivery of hydrophilic drugs, J Cotrol Rel, 89, 311-320.