CA2417279C - Treatment of hyperproliferative skin disorders and diseases - Google Patents

Abstract

The invention relates to the use of one or more noble metals selected from silver, gold, platinum, and palladium but most preferably silver, in a nanocrystalline form, for the treatment of a hyperproliferative skin disorder or disease such as psoriasis. Among the noble metals, silver is preferred for such treatment. The nanocrystalline noble metal of choice may be used in the form of a nanocrystalline coating of one or more noble metals, a nanocrystalline powder of one or more noble metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more noble metals.

Description

1 Treatment of Hyperproliferative Skin Disorders and Diseases-3 The invention relates to the use of nanocrystalline noble metals for the treatment of 4 hyperproliferative skin disorders and diseases such as psoriasis.
BACKGROUND OF THE INVENTION
6 In spite of many years of research on the treatment of hyperproliferative skin 7 disorders and diseases such as psoriasis, there are still many patients suffering from such skin 8 diseases for whom treatment regimes have been ineffective. Furthermore, many of the side 9 effects from the medications currently prescribed for the treatment of psoriasis are problematic. Thus, there still remains a need for a safe and effective treatment for 11 hyperproliferative skin disorders and diseases such as psoriasis and keratinization.

13 The inventors have discovered that nanocrystalline noble metals selected from one or 14 more of silver, gold, platinum and palladium, are effective in the treatment of psoriasis.
Preferably, these noble metals are formed with atomic disorder, such that ions, clusters, atoms 16 or molecules of the metals are released on a sustainable basis.
17 The nanocrystalline forms of these noble metals may be used in any of the following 18 formats:
19 i) nanocrystalline coatings of the noble metals on medical grade substrates, for example, dressings, fibers, and materials composed of for example polyethylene, high~density 21 polyethylene, polyvinylchloride, latex, silicone, cotton, rayon, polyester, nylon, 22 cellulose, acetate, carboxymethylcellulose, alginate, chitin, chitosan and hydrofibres;
23 ii) gels, formulated with nanocrystalline powders of the noble metals with such materials 24 as carboxymethylcellulose, alginate,. chitin, chitosar and hydrofibres, together with such ingredients as pectin and viscosity enhancers;
26 iii) creams, lotions, pastes and ointments formulated with nanocrystalline powders of the 27 noble metals, for example as emulsions or with drying emollients;
28 iv) liquids, formulated as solutions by dissolving nanocrystalline coatings or powders of 29 the noble metals, for example as topical solutions, aerosols or mists;
v) powders, prepared as nanocrystalline powders of the noble metals, or as 31 nanocrystalline coatings of the noble metals on biocompatible substrates in powder 32 form, preferably on bioabsorbable and/or hygroscopic substrates such as:

1 Synthetic Bioabsorbable Polymers: for example polyesters/polyactones such as polymers of 2 polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., 3 polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of 4 these and related polymers or monomers.
Naturally Derived Polymers:
6 Proteins: albumin, fibrin, collagen, elastin;
7 Polysaccharides: chitosan, alginates, hyaluronic acid; and 8 Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
9 In the above formats, the nanocrystalline noble metals are formulated from nanocrystalline coatings or nanocrystalline powders of the nanocrystalline noble metals, or 11 from solutions prepared by dissolving the nanocrystalline coatings or powders therein. The 12 formulations include a therapeutically effective amount of the coatings or powders, and most 13 preferably, the following amounts:
14 For coatings: 150 - 3000 nm thick coatings For gels, creams and lotions: 0.01 - 5% by weight of the nanocrystalline noble metal 16 powder 17 For liquids 0.001 - 1 % by weight of the noble metal 18 Nanocrystalline coatings of the noble metals are most preferably deposited onto one 19 or more layers of medical dressing materials which can be laminated with uncoated layers of medical dressing materials. The coatings can be prepared by known techniques for preparing 21 nanocrystalline coatings, but are most preferably prepared by physical vapour deposition 22 under conditions which create atomic disorder. The nanocrystalline coatings are most 23 preferably prepared to create an interference colour so as to provide an indicator, as described 24 in prior patent application WO 98/41095, published September 24, 1998, and naming inventors R. E. Burrell and R. J. Precht.
26 Nanocrystalline powders of the noble metals may be prepared as nanocrystalline 27 coatings, preferably of the above thickness, on powdered substrates such as chitin, or may be 28 prepared as nanocrystalline coatings on a substrate such as a silicon wafer, and then scraped 29 off as a nanocrystalline powder. Alternatively, fine grained or nanocrystalline powders of the noble metals may be cold worked to impart atomic disorder, as disclosed in prior patent 31 application WO 93/23092, published November 25, 1993, naming Burrell et al., as inventors.
32 As used herein and in the claims, the terms and phrases set out below have the 1 meanings which follow.
2 "Metal" or "metals" includes one or more metals whether in the form of substantially 3 pure metals, alloys or compounds such as oxides, nitrides, borides, sulphides, halides or 4 hydrides.
"Noble metals" are silver, gold, platinum and palladium, or mixtures of such metals 6 with same or other metals, with silver metal being the most preferred.
7 "Biocompatible" means non-toxic for the intended utility. Thus, for human utility, 8 biocompatible means non-toxic to humans or human tissues.
9 "Sustained release" or "sustainable basis" are used to define release of atoms, molecules, ions or clusters of a noble metal that continues over time measured in hours or 11 days, and thus distinguishes release of such metal species from the bulk metal, which release 12 such species at a rate and concentration which is too low to be therapeutically effective, and 13 from highly soluble salts of noble metals such as silver nitrate, which releases silver ions 14 virtually instantly, but not continuously, in contact with an alcohol or electrolyte.
"Atomic disorder" includes high concentrations of: point defects in a crystal lattice, 16 vacancies, line defects such as dislocations, interstitial atoms, amorphous regions, grain and 17 sub grain boundaries and the like relative to its normal ordered crystalline state. Atomic 18 disorder leads to irregularities in surface topography and inhomogeneities in the structure on 19 a nanometer scale.
"Normal ordered crystalline state" means the crystallinity normally found in bulk 21 metal materials, alloys or compounds formed as cast, wrought or plated metal products. Such 22 materials contain only low concentrations of such atomic defects as vacancies, grain 23 boundaries and dislocations.
24 "Diffusion", when used to describe conditions which limit diffusion in processes to create and retain atomic disorder, i.e. which freeze-in atomic disorder, means diffusion of 26 atoms (adatom diffusion) and/or molecules on the surface or in the matrix of the material 27 being formed.
28 "Alcohol or water-based electrolyte" is meant to include any alcohol, water, or water-29 based electrolyte that the anti-microbial materials of the present invention might contact in order to activate (i.e. cause the release of species of the anti-microbial metal) into same. The 31 term is meant to include alcohols, water, gels, fluids, solvents, and tissues containing water, 32 including body fluids (for example blood, urine or saliva), and body tissue (for example skin, 1 muscle or bone).
2 "Bioabsorbable" as used herein in association includes substrates which are useful in 3 medical devices, that is which are biocompatible, and which are capable of bioabsorption in 4 period of time ranging from hours to years, depending on the particular application.
"Bioabsorption" means the disappearance of materials from their initial application 6 site in the body (human or mammalian) with or without degradation of the dispersed polymer 7 molecules.
8 "Colour change" is meant to include changes of intensity of light under 9 monochromatic light as well as changes of hue from white light containing more than one wavelength.
11 An "interference colour" is produced when light impinges on two or more partly 12 reflective surfaces separated by a distance which bears the right relationship to the 13 wavelength of the light to be removed by destructive interference.
14 "Partly reflective" when used to describe the base or top layer materials, means that the material has a surface which reflects a portion of incident light, but which also transmits a 16 portion of the incident light. Reflection occurs when a ray of incoming light encounters a 17 boundary or interface characterized by a change in refractive index between two media. For 18 the top layer of the anti-microbial materials of this invention, that interface is with air. For 19 the base layer, the interface is with the top layer. The reflectance of the base and top layers is balanced so as to generate an interference colour.
21 "Partly light transmissive" when used to describe a thin film of the top layer material 22 means that the thin film is capable of transmitting at least a portion of incident visible light 23 through the thin film.
24 "Detectable" when used to describe a colour change means an observable shift in the dominant wavelength of the reflected light, whether the change is detected by instrument, 26 such as a spectrophotometer, or by the human eye. The dominant wavelength,is the 27 wavelength responsible for the colour being observed.
28 "Cold working" as used herein indicates that the material has been mechanically 29 worked such as by milling, grinding, hammering, mortar and pestle or compressing, at temperatures lower than the recrystallization temperature of the material.
This ensures that 31 atomic disorder imparted through working is retained in the material.
32 "Therapeutically effective amount" is used herein to denote any amount of a 1 formulation of the nanocrystalline noble metals which will exhibit an antiproliferative effect 2 in a hyperproliferative skin disorder or disease such as psoriasis when applied to the affected 3 area. A single application of the formulations of the present invention may be sufficient, or 4 the formulations may be applied repeatedly over a period of time, such as several times a day for a period of days or weeks. The amount of the active ingredient, that is the nanocrystalline 6 noble metal in the form of a coating, powder or dissolved in liquid solution, will vary with 7 the conditions being treated, the stage of advancement of the condition, and the type and 8 concentration of the formulation being applied. Appropriate amounts in any given instance 9 will be readily apparent to those skilled in the art or capable of determination by routine experimentation.
11 "Nanocrystalline" is used herein to denote single-phase or mufti-phase polycrystals, 12 the grain size of which is less than about 100, more preferably < 50 and most preferably < 25 13 nanometers in at least one dimension. The term, as applied to the crystallite or grain size in 14 the crystal lattice of coatings, powders or flakes of the noble metals, is not meant to restrict the particle size of the materials when used in a powder form.
16 "Powder" is used herein to include particulate sizes of the nanocrystalline noble 17 metals ranging from nanocrystalline powders to flakes.
18 "Grain size", or "crystallite size" means the size of the largest dimension of the 19 crystals in the noble metal coating or powder.
"Hyperproliferative skin disorders" is used herein to include psoriasis and its varied 21 clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of 22 the disorders of keratinization.
23 "Antiproliferative" is used herein to denote effects on the skin including, but not 24 limited to decreasing inflammation, to retarding or normalizing epidermal proliferation and keratinization to produce beneficial effects on hyperproliferative disorders of the skin.

27 Nanocrystalline forms of the noble metals Ag, Au, Pt, and Pd can be prepared as 28 nanocrystalline powders or coatings, or as solutions prepared by dissolving the 29 nanocrystalline coatings or powders. The nanocrystalline coatings or powders are most preferably prepared with atomic disorder, in accordance with the techniques published in the 31 prior patent applications of Burrell et czl., see for example WO 93123092, published 32 November 25, 1993, WO 95/13704, published May 26, 1995 and WO 98/41095, published 1 September 24, 1998.
2 A. Nanocrystalline Noble Metal Coatings on Dressings 3 Dressings carrying nanocrystalline coatings of noble metals in accordance with the 4 invention include at least one, and preferably at least two or three layers of medical dressing materials, laminated together by known means such as low temperature thermal fusing, 6 stitching or, most preferably, ultrasonic welding. A three layer dressing preferably includes a 7 first layer which will be skin facing in use, a second layer which preferably forms an 8 absorbent core, and a third layer above the second layer. The layers can be laminated 9 together by ultrasonic welds at intermittent locations across the dressing.
The first, and preferably the third layer, includes a nanocrystalline coating of one or more of the noble 11 metals.
12 The dressing may include an occlusive or semi-occlusive layer such as an adhesive 13 tape or polyurethane film in order to secure the dressing in place, and retain moisture for 14 release of ions, atoms, molecules or clusters of the noble metal (hereinafter noble metal species).
16 The preferred and alternate compositions of the dressing layers, together with the 17 preferred nanocrystalline noble metal coatings, are set out in further detail below.
18 i) Dressing Materials 19 The first layer of the dressing is formed of a perforated, preferably non-adherent material which allows for fluids to penetrate or diffuse there through in either or both 21 directions. The perforated material may be formed of a woven or non-woven, non-woven 22 being preferred, fabric such as cotton, gauze, a polymeric net or mesh such as polyethylene, 23 nylon, polypropylene or polyester, an elastomer such as polyurethane or polybutadiene 24 elastomers, or a foam such as open cell polyurethane foam. Exemplary perforated, non-adherent materials useful for the dressing include non-woven meshes such as DELNET~'~'' 26 P530, which is a non-woven veil formed of high density polyethylene using extrusion, 27 embossing and orientation processes, produced by Applied Extrusion Technologies, Inc. Of 28 Middletown, Delaware, USA. This same product is available as Exu-Dry CONFORMANT
29 2~ Wound Veil, from Frass Survival Systems, Inc., Bronx, New York, USA as a subset of that company's Wound Dressing Roll (Non-Adherent) products. Other useful non-woven 31 meshes include CARELLET"' or NYLON 90Tr'', available from Carolina Formed Fabrics 32 Corp., N-TERFACETM, available from Winfield Laboratories, Inc., of Richardson, Texas, 1 USA. Exemplary woven meshes may be formed from fibreglass or acetate, or cotton gauze.
2 An exemplary hydrophilic polyurethane foam is HYPOLT"', available from W.R.
Grace &
3 Co., New York, NY, USA.
4 , For ease of ultrasonic welding for lamination, at least one of the first and second dressing layers is preferably formed from a polymeric material which is amenable to 6 ultrasonic welding, that is which will melt on the application of localized heat and then fuse 7 the layers together on cooling.
8 The second, absorbent layer is formed from an absorbent material for holding 9 sufficient moisture next to the skin in order to activate the noble metal coating, that is to cause release of ions, molecules, atoms or clusters of the noble metal in order to cause an 11 anti-proliferative effect. Preferably, the absorbent material is an absorbent needle punched 12 non-woven rayon/polyester core such as SONTARATM 84.11, a 70/30 rayon/polyester blend 13 commercially available from Dupont Canada, Mississauga, Ontario, Canada.
This product is 14 sold by National Patent Medical as an American White Cross sterile gauze pad. However, other suitable absorbent materials include woven or non-woven materials, non-woven being 16 preferred made from fibers such as rayon, polyester, rayon/polyester, polyester/cotton, cotton 17 and cellulosic fibers. Exemplary are creped cellulose wadding, an air felt of air laid pulp 18 fibers, cotton, gauze, and other well known absorbent materials suitable for medical 19 dressings.
The third layer of the dressing is preferably formed of perforated, non-adherent 21 material such as used in the first layer. This allows moisture penetration as sterile water and 22 the like are added in order to activate the noble metal coating.
23 Additional layers may be included between or above the first, second and third layers 24 as is well known in medical dressings. Thus the use of the terms first, second and third layer, as used herein and in the claims is not meant to exclude such additional layers.
26 The first, second and third dressing layers are laminated together at intermittent 27 spaced locations across the dressing by ultrasonic welds. Ultrasonic welding is a known 28 technique in the quilting art. Briefly, heat (generated ultrasonically) and pressure are applied 29 to either side of the dressing at localized spots through an ultrasonic horn so as to cause flowing of at least one of the plastic materials in the first and second layers and the 31 subsequent bonding together of the layers on cooling. The welds appear at localized circular 32 spots and are preferably less than 0:5 cm in diameter. If the third layer is present, the 1 ultrasonic welding can be performed from either side of the dressing, and will bind all three 2 layers together.
3 The use of ultrasonic welding of the layers at spaced locations has the advantage of 4 retaining the absorbent and moisture penetration properties of the dressing layers, while retaining the conforming properties of the dressing. Edge seams, stitching, adhesives, or 6 other lamination techniques may be used, but have the disadvantage of interfering with one or 7 more of these desirable properties of the dressings. Furthermore, by spacing the welds at 8 intermittent locations across the dressing, the dressing may be cut to smaller sizes, as needed, 9 without causing delamination. Preferred spacings of about 2.5 cm between welds allows the dressing to be cut down to about 2.5 cm sizes, while maintaining at least one weld to hold the 1 I laminated layers together.
12 ii) Nanocrystalline Coatings of Noble Metals 13 The dressing preferably includes a nanocrystalline coating of one or more of the noble I4 metals. The coating is applied to one or more of the dressing layers, but is most preferably applied at least to the first and third layers.
16 The nanocrystalline coating is most preferably formed with atomic disorder in 17 accordance with the procedures set out above and as described in WO
93/23092, WO
18 95/13704, and W098/41095, and as set out below. Most preferably, the coating is formed as 19 a multilayer coating of the noble metals, having a top and a base layer, as set below, to produce an interference colour. In this way, the coating provides not only the active 21 ingredient for the treatment of psoriasis, but also acts as an indicator of activation of the 22 dressing. As the top layer of the coating is activated with an alcohol or water-based 23 electrolyte, such as sterile water or ethanol, even minor dissolution of the noble metal results 24 in a detectable colour change, indicating that the coating has been activated. If there is no colour change, additional moisture might be provided to the dressing by adding water, until a 26 colour change is detected. Once activated, the dressing should be maintained in a moist 27 condition, for example by the addition of sterile water, if necessary.
28 iii) Sterilization 29 Dressings with nanocrystalline coatings of a noble metal formed with atomic disorder are preferably sterilized without applying excessive thermal energy, which can anneal out the 31 atomic disorder, thereby reducing or eliminating a useful release of noble metal species.
32 Gamma radiation is preferred for sterilizing such dressings, as discussed in WO 95113704.

1 Electron beam and ethylene oxide sterilization techniques can also be used.
2 It should be appreciated that the use of ultrasonic welding to laminate the layers of 3 dressings with nanocrystalline coatings formed from noble metals with atomic disorder is 4 advantageous since it achieves bonding in localized spots and avoids applying heat to any significant portion of the dressing, thereby avoiding any significant reduction in the solubility 6 of the noble metals through annealing out of the atomic disorder.
7 The sterilized dressings should be sealed in packaging which excludes light 8 penetration to avoid additional oxidation of the noble metal coating.
Polyester peelable 9 pouches are preferred. The shelf life of dressings thus sealed is over one year.
iv) Directions for Use of Dressings for Hyperproliferative Skin Disorders and Diseases 11 The dressing is placed on the affected portion of the skin and is then moistened with 12 drops of sterile water or, for example 70% ethanol, in order to activate the coating for release 13 of noble metal species. The dressing is then secured in place with an occlusive or semi-14 occlusive layer, such as an adhesive tape or polyurethane film, which keeps the dressing in a moist environment.
16 As set out in Examples 3 and 4, dressings carrying a bi-layer nanocrystalline noble 17 metal coating formed with silver having atomic disorder, manufactured as set out above and 18 as described in greater detail in Example 1, have shown substantial clinical response in 19 treating psoriasis. In use, the dressings are kept moist, at 100% relative humidity. Adding sterile water initially to activate the noble metal coating is needed, and then as needed to 21 maintain the dressing in a moist condition. Dressings may be changed as required for 22 observation and cleaning, but need not be changed more frequently than every 7 days, and 23 can provide a therapeutic effect for a much Ionger period of time.
24 v) Multilayer Nanocr~stalline Coatings of Noble Metals With Interference Colour The dressings preferably include the noble metal coating formed with at least two 26 metal layers, a base layer and a top layer over the base layer, so as to produce an interference 27 colour, as set forth in WO 98/41095. Both layers are partly reflective; the top layer is partly 28 light transmissive. The top Iayer is a thin film containing at least one noble metal formed 29 with sufficient atomic disorder such that the top layer, in contact with an alcohol or water based electrolyte, releases ions, atoms, molecules or clusters of the noble metal, at a 31 concentration sufficient to provide a therapeutic effect, on a sustainable basis. In this way, 32 the top layer, in contact with the alcohol or electrolyte, will undergo a change in optical path 1 length, either by a change in thickness resulting from some dissolution, or through a change 2 in the refractive index of the top layer resulting from a change in the composition of a newly 3 formed thin layer formed on the top layer. Either or both of these results are sufficient to 4 cause a detectable colour change, thus providing an indicator that the top layer has been activated.
6 Both the base layer and the top layer are formed from a partly reflective maternal. In 7 this way, at least a portion of the incoming light is reflected from the surface of the layer 8 ~ while another portion is transmitted through the layer. The top layer is partly light 9 transmissive to allow incident light to reach the interface with the base layer. The top layer thus cannot approximate 100% reflectivity, such as in pure A1 or Ag, or interference colours 11 cannot be generated, as is well known in the art. The materials for the top and base layers 12 should be balanced in their reflectances in order to generate an interference colour.
13 Generally, the top layer is deposited as a thin film having a thickness which maintains 14 adequate transmittance to generate an interference colour. Furthermore, the refractive index for the materials in layers is different, accomplished by differences in their actual or effective 16 compositions. For instance different materials in the two layers will result in the materials 17 having different actual refractive indexes. However, if it is desired to make the layers from I8 the same material, the layers can be deposited with different porosities or different 19 levelsltypes of atomic disorder, in order to achieve different effective compositions, and thus different refractive indexes.
21 In this manner, incoming light reflects off the interface of the base and top layers.
22 Tncoming light reflects from the interface of the top layer with air, and interferes with the 23 light reflected from the interface with the base layer so as to generate an "interference 24 colour". The particular colour which is generated and its brightness will depend on the properties of the layers, most importantly on the composition of the layers, which determines 26 its transmittance and absorption properties, along with its refractive index, and on the 27 thickness of the layers. Generally, it is desirable to generate first and second order 28 interference colours, by limiting the thickness of the base layer and top layers to minimize the 29 number of internal reflections. First and second order interference colours are generally brighter than third and fourth order etc. colours, making them more aesthetically pleasing, 31 more consistently reproducible in manufacturing, and more susceptible to detectable colour 32 change on variations in thickness on dissolution of even a minor amount of the top layer.
IO

1 The property which determines the particular colour which is generated is the 2 effective optical thickness of the top layer, that is the product of the refractive index of the 3 top layer material and the actual thickness of the top Layer. Thus the colour which is desired 4 can be altered by changing the actual thickness or the top layer or its refractive index.
Preferably, the material in the base layer is a reflective metal. Such metals are known 6 in the art and include, for example one or more of the valve metals; e.g.
Ta, Nb, Ti, Zr and 7 . Hf, as well as transition metals such as Au, Ag, Pt, Pd, Sn, Cu, V, W and Mo, or the metal Al.
8 More preferably, the base layer is formed from one or more of the noble metals Ag, Au, Pt, 9 and Pd, most preferably Ag, in a partly reflective form.
The base layer may be formed by known techniques, such as the vapour deposition 11 techniques of evaporation or physical vapour deposition. Preferably, the base layer is formed 12 as a thin film by physical vapour deposition with atomic disorder, as set out below and in WO
I3 95/13704, in order to produce a sustainable release of the noble metal species when the base 14 layer is ultimately exposed to an alcohol or water based electrolyte. The thickness of the base layer is generally not critical, provided that it is partly reflective.
Preferred thicknesses I6 will vary widely with the material composition. However, in that the layer is preferably a 17 thin film formed by physical vapour deposition techniques, it should be at least about 25 nm 18 thick to create a useful colour. The base layer should be greater than 60 nm thick, more 19 preferably 300 to 2500 nm thick, and most preferably 600 to 900 nm thick.
The top layer is formed of a partly reflective, partly light transmissive thin film 21 containing at least one noble metal, most preferably Ag, formed with atomic disorder so as to 22 produce a sustainable release of the noble metal species, and ultimate colour change, when 23 exposed to an alcohol or a water based electrolyte. The thickness of the top layer formed 24 from these metals is preferably less than 400 nm in order to maintain the preferred level of light transmission. The desired thickness will vary with the composition of the top layer, and 26 with the desired end colour and colour change. For first and second order interference 27 colours, the thickness will generally be less than about 400 nm. More preferably, the 28 thickness will range from 5 to 210 nm, most preferably from 10 to 100 nm.
29 The top layer may be a thin film of the base Iayer material, formed with a different refractive index for instance by altering the deposition conditions to change the porosity, 31 composition and/or degree of atomic disorder in the layers.
32 When the base layer is itself formed from a noble metal with atomic disorder, the top 1 layer may be provided as an in situ generated top layer by virtue of its thickness andlor 2 composition changing on contacting an alcohol or water based electrolyte, so as to produce an 3 interference colour which differs from the initial colour of the base layer.
4 Most preferably, the top layer is a thin film of a composite material formed by co-, sequentially or reactively depositing a noble metal in a matrix with atoms or molecules of a 6 different material to create atomic disorder in the matrix, in the manner set out below. The 7 different material is selected from a) biocompatible metals, b) oxygen, nitrogen, hydrogen, 8 boron, sulphur or halogens, or c) an oxide, nitride, carbide, boride, halide, sulphide or hydride 9 of either or both of a noble metal or a biocompatible metal. Most preferably, the top layer material is a composite material containing silver, and one or both of silver oxide and atoms l 1 or molecules containing oxygen trapped or absorbed in the silver matrix.
The term "silver 12 oxide" is meant to include any oxide or mixture of oxides of silver.
However, the top layer is 13 preferably not formed solely of Ag0 and/or Ag,O, since the solubility of these materials is 14 low.
vi) Nanocrystalline Coatings of Noble Metals Containin ~ Atomic Disorder 16 At least the top layer, and preferably also the base layer, is formed in a crystalline 17 form from one or more noble metals with atomic disorder. The production of atomic disorder 18 through physical vapour deposition techniques is described in WO 93/23092 and WO
19 95/13704, and as outlined below.
The noble metal is deposited as a thin metallic film on one or more surfaces of the 21 dressing by vapour deposition techniques. Physical vapour techniques, which are well known 22 in the art, all deposit the metal from the vapour, generally atom by atom, onto a substrate 23 surface. The techniques include vacuum or arc evaporation, sputtering, magnetron sputtering 24 and ion plating. The deposition is conducted in a manner to create atomic disorder in the coating as defined above. Various conditions responsible fox producing atomic disorder axe 26 useful. These conditions are generally those which one has been taught to avoid in thin film 27 deposition techniques, since the object of most thin film depositions is to create a defect free, 28 smooth and dense film (see for example J.A. Thornton, "Influence of Apparatus Geometry 29 and Deposition Conditions on the Structure and Topography of Thick Sputtered Coatings" J.
Vac. Sci. Technol., 11 (4), 666-670, 1974).
3I The preferred conditions which are used to create atomic disorder during the 32 deposition process include:

1 - a low substrate temperature, that is maintaining the surface to be coated at a 2 temperature such that the ratio of the substrate temperature to the melting point of the metal 3 (in degrees I~.elvin) is less than about 0.5, more preferably less than about 0.35 and most 4 preferably less than about 0.3; and optionally one or both of:
- a higher than normal working (or ambient) gas pressure, i.e. for vacuum evaporation:
6 e-beam or arc evaporation, greater than 0.001 Pa (0.01 mT), gas scattering evaporation 7 (pressure plating) or reactive arc evaporation, greater than 2.67 Pa (20 mT); for sputtering:
8~ greater than 10 Pa (75 mT); for magnetron sputtering: greater than about I.33 Pa (10 mT);
9 and for ion plating: greater than about 26.67 Pa (200 mT); and .
- maintaining the angle of incidence of the coating flux on the surface to be coated at 11 less than about 75°, and preferably less than about 30°.
12 For economic reasons, the thin metal film has a thickness no greater than that needed 13 to provide release of noble metal species on a sustainable basis over a suitable period of time, 14 and to generate the desired interference colour. Within the preferred ranges of thicknesses set out above, the thickness will vary with the particular metal in the coating (which varies the 16 solubility and abrasion resistance), and with the degree of atomic disorder in (and thus the 17 solubility of) the coating. The thickness will be thin enough that the coating does not 18 interfere with the dimensional tolerances or flexibility of the device for its intended utility.
19 The therapeutic effect of the material so produced is achieved when the coating is brought into contact with an alcohol or a water based electrolyte, thus releasing metal ions, 21 atoms, molecules or clusters. The concentration of the metal species which is needed to 22 produce a therapeutic effect will vary from metal to metal.
23 The ability to achieve release of metal atoms, ions, molecules or clusters on a 24 sustainable basis from a coating is dictated by a number of factors, including coating characteristics such as composition, structure, solubility and thickness, and the nature of the 26 environment in which the device is used. As the level of atomic disorder is increased, the 27 amount of metal species released per unit time increases. For instance, a silver metal film 28 deposited by magnetron sputtering at T/Tm < 0.5 and a working gas pressure of about 0.93 Pa 29 (7 mT) releases approximately 1/3 of the silver ions that a film deposited under similar conditions, but at 4 Pa (30 mT), will release over 10 days. Films that are created with an 31 intermediate structure (ex. lower pressure, lower angle of incidence etc.) have Ag release 32 values intermediate to these values as determined by bioassays. This then provides a method 1 for producing controlled release metallic coatings. Slow release coatings are prepared such 2 that the degree of disorder is low while fast release coatings are prepared such that the degree 3 of disorder is high.
4 For continuous, uniform coatings, the time required for total dissolution will be a function of film thickness and the nature of the environment to which they are exposed. The 6 relationship in respect of thickness is approximately linear, i.e. a two fold increase in film 7 thickness will result in about a two fold increase in longevity.
8 It is also possible to control the metal release from a coating by forming a thin film 9 coating with a modulated structure. For instance, a coating deposited by magnetron sputtering such that the working gas pressure was low (ex. 2 Pa or 15 mT) for 50% of the ,' 11 deposition time and high (ex.4 Pa or 30 mTorr) for the remaining. time, has a rapid initial 12 release of metal ions, followed by a longer period of slow release. This type of coating is 13 extremely effective on devices such as urinary catheters for which an initial rapid release is 14 required to achieve immediate anti-microbial concentrations followed by a lower release rate to sustain the concentration of metal ions over a period of weeks.
16 The substrate temperature used during vapour deposition should not be so low that 17 annealing or recrystallization of the coating takes place as the coating warms to ambient 18 temperatures or the temperatures at which it is to be used (ex. body temperature). This 19 allowable 0T, that the temperature differential between the substrate temperature during deposition and the ultimate temperature of use, will vary from metal to metal.
For the most 21 preferred metal, Ag, preferred substrate temperatures of -20 to 20(~C , more preferably -10°C
22 to 100°C are used.
23 Atomic order may also be achieved, in either or both of the base and top layers by 24 preparing composite metal materials, that is materials which contain one or more noble metals in a metal matrix which includes atoms or molecules different from the noble metals.
26 The preferred technique for preparing a composite material is to co- or sequentially 27 deposit the noble metals) with one or more other inert, biocompatible metals selected from 28 Ta, Ti, Nb, Zn, V, Hf, Mo, Si, Al and alloys of these metals or other metal elements, typically 29 other transition metals. Such inert metals have a different atomic radii from that of the noble metals, which results in atomic disorder during deposition. Alloys of this kind can also serve 31 to reduce atomic diffusion and thus stabilize the disordered structure.
Thin film deposition 32 equipment with multiple targets for the placement of each of the noble and biocompatible 1 metals is preferably utilized. When layers are sequentially deposited the layers) of the 2 biocompatible metals) should be discontinuous, for example as islands within the noble 3 metal matrix. The final ratio of the noble metals) to biocompatible metals) should be 4 greater than about 0.2. The most preferable biocompatible metals are Ti, Ta, Zn and Nb. It is also possible to form the anti-microbial coating from oxides, carbides, nitrides, sulphides, 6 borides, halides or hydrides of one or more of the noble metals and/or one or more of the 7 biocompatible metals to achieve the desired atomic disorder.
8 Another composite material may be formed by reactively co- or sequentially 9 depositing, by physical vapour techniques, a reacted material into the thin film of the noble metal(s). The reacted material is an oxide, nitride, carbide, boride, sulphide, hydride or halide 11 of the noble and/or biocompatible metal, formed in situ by injecting the appropriate reactants, 12 or gases containing same, (ex. air, oxygen, water, nitrogen, hydrogen, boron, sulphur, 13 halogens) into the deposition chamber. Atoms or molecules of these gases may also become 14 absorbed or trapped in the metal film to create atomic disorder. The reactant may be continuously supplied during deposition for codeposition or it may be pulsed to provide for 16 sequential deposition. The final ratio of reaction product to the noble metaI(s) should be 17 greater than about 0.05. Air, oxygen, nitrogen and hydrogen axe particularly preferred 18 reactants, with oxygen being most preferred.
19 The above deposition techniques to prepare composite coatings may be used with or without the conditions of lower substrate temperatures, high working gas pressures and low Z I angles of incidence previously discussed. One or more of these conditions are preferred to 22 retain and enhance the amount of atomic disorder created in the coating.
23 B. Nanocrystalline Powders of Noble Metals 24 Nanocrystalline powders (i.e., powders formed from particulates having nanocrystalline grain size) of one or more noble metals are most preferably prepared with 26 atomic disorder by the procedures set out in WO 93/23092 and WO 95/13704, or as 27 otherwise known in the art. The powders may be prepared as pure metals, metal alloys or 28 compounds such as metal oxides or metal salts, by vapour deposition, mechanical working, or 29 compressing in order to impart atomic disorder, as set out below, and as in the above-mentioned patent application. Mechanically imparted disorder is conducted by milling, 31 grinding, hammering, mortar and pestle or compressing, under conditions of low temperature 32 (i.e., temperatures less than the temperature of recrystallization of the material) to ensure that I annealing or recrystallization does not take place. Alternatively, nanocrystalline powders 2 may be prepared by preparing nanocrystalline coatings by physical vapour deposition to 3 include atomic disorder in the manner set out above, onto a substrate such as a cold finger or 4 a silicon wafer (or larger substrates), and then scraping off the coating to form a powder. A
still further alternative method of powder preparation is to prepare nanocrystalline coatings, 6 such as by physical vapour deposition to include atomic disorder as set out above, onto 7 powdered substrates which are biocompatible. Particularly preferred substrates are 8 bioabsorbable and/or hygroscopic powders such as chitin. Exemplary bioabsorbable and/or 9 hygroscopic powders are composed of Synthetic Bioabsorbable Polymers: for example polyesters/polyactones such as polymers of 11 polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc.;
12 polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of 13 these and related polymers or monomers.
14 Naturally Derived Polymers:
Proteins: albumin, fibrin, collagen, elastin;
16 Polysaccharides: chitosan, alginates, hyaluronic acid; and 17 Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
18 Most preferably, powders of the present invention are sized at less than 100,um, and 19 more preferably less than 40 ,um.
The prepared nanocrystalline powders may then be incorporated into or onto medical 21 dressings or pharmaceutical formulations, by methods known in the art. For example, the 22 powders may be layered onto the substrates (dressings or powders), mechanically mixed 23 within the fibers of the dressings, impregnated into dressings by, for example, physical 24 blowing, or added to topical pharmaceutically acceptable composition ingredients.
The antiproliferative effects of the nanocrystalline powder is achieved when the 26 powder is brought into contact with an alcohol or a water-based electrolyte, thus releasing the 27 noble metal ions, atoms, molecules or clusters.
28 Nanocrystalline powders may be sterilized as described above, or may be prepared as 29 preserved materials with known preservatives such as methyl paraben or propyl paraben.
Alternatively, given the anti-microbial activity of the nanocrystalline powders themselves, 31 they may be considered as being in a preserved form without the addition of preservatives.

1 C. Formulations and Dosages 2 Typically, the nanocrystalline noble metals will be formulated from the active 3 ingredient, namely nanocrystalline powders or coatings of the noble metals, or dissolved 4 species from such powders or coatings, in the form of:
~ coatings on medical dressings or biocompatible powdered substrates, 6 ~ powders included in medical dressings, 7 ~ topical pharmaceutical compositions such as gels, pastes, ointments, creams, lotions, 8 emulsions, suspensions or powders, 9 ~ liquid pharmaceutical compositions prepared by dissolving nanocrystalline coatings or powders of the noble metals in pharmaceutically acceptable carriers such as water, 11 for application in drop, mist or aerosol forms.
12 In the pharmaceutical compositions, the amount of the nanocrystalline metal powder 13 may range broadly from about 0.001 % to about 30% by weight, but will more preferably fall 14 in the range of from about 0.01 to 5% by weight. Coatings of the nanocrystalline noble metals may be very thin, or thicker, depending on the desired duration of application on the 16 patient. Typical coating thicknesses are in the range of 150 to 3000 nm thick. As liquid 17 formulations, the amount of dissolved noble metal will typically range between about 0.001 18 to 1 % by weight.
19 Nanocrystalline gels may be formed from the nanocrystalline metal powder in admixture with gelling.agents such as carboxymethyl cellulose (CMC), polyvinyl alcohol 21 (PVA), collagen, pectin, gelatin, agarose, chitin, chitosan, and alginate, with the gelling agent 22 comprising between about 0.01 - 20 % w/v.
23 Besides the active ingredient, pharmaceutical compositions may also include non-24 toxic, pharmaceutically and dermatologically acceptable carriers, diluents and excipients, suitable for topical application, as are well known, see for example Merck Index, Merck &
26 Co., Rahway, N.J., Bioreversible Carriers in Drug Design, Theory and Application, Roche 27 (ed.) Pergamon Press, (1987), Gilman et al., (eds) (1990) Goodman and Gilman's: The 28 Pharmacological Bases of Therapeutics, 8"' Ed., Pergamon Press; Novel Drug Delivery 29 Systems, 2°d Ed., Norris (ed.) Marcel Dekker Inc., (1989), and Remington's Pharmaceutical Sciences. For standard dosages of conventional pharmacological agents, see, e.g., Physicians 31 Desk Reference (1997 Edition); and American Medical Association (1997) Drug Evaluations 32 (Subscriptions).

Dosage forms for the topical administration of compositions of the nanocrystalline 2 noble metals include various mixtures and combinations that can be applied topically and will 3 permit even spreading and absorption into the cutaneous surfaces. Examples include sprays, 4 mists, aerosols, lotions, creams, solutions, gels, ointments, pastes, emulsions, and suspensions. The active compound can be mixed under sterile conditions with a 6 pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which 7 may be required. Topical preparations can be prepared by combining the noble metal powder 8 with conventional pharmaceutically acceptable diluents and carriers commonly used in 9 topical dry, liquid, cream and aerosol formulations. Ointment and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or 11 gelling agents. An exemplary base is water. Thickening agents which can be used according 12 to the nature of the base include aluminum stearate, hydrogenated lanolin, and the like.
13 Lotions can be formulated with an aqueous or oily base and will, in general, also include one 14 or more of the following: stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes, and the like.
Powders can 16 be formed with the aid of any suitable powder base, e.g., talc, lactose starch and the like.
17 Drops can be formulated with an aqueous base or non-aqueous base, and can also include one 18 or more dispersing agents, suspending agents, solubilizing agents, and the like.
19 Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and 2I talc, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, 22 talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures 23 of these substances. Solutions of nanocrystalline noble metals can be converted into aerosols 24 or sprays by any of the known means routinely used for making aerosol pharmaceuticals. In general, such methods comprise pressurizing or providing a means for pressurizing a 26 container of the solution, usually with an inert carrier gas, and passing the pressurized gas 27 through a small orifice. Sprays can additionally contain customary propellants, such a 28 chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and 29 propane.
3Q Multiple inactive ingredients are generally incorporated in topical formulations to 31 improve cosmetic acceptability, and are optional ingredients in the formulations. Examples 32 of ingredients are emulsifiers, thickening agents, solvents, anti-foaming agents, preservatives, 1 fragrances, coloring agents, emollients, and fillers.
2 Materials to avoid in formulations of the present invention in amounts greater than 3 0.01 % w/v. include chloride salts, aldehydes, ketones, long chain alcohols (with the 4 exception of polyvinyl alcohols, preferably no greater than C8-alcohols, and preferably no greater than C6-alcohols), glycerol, and triethanolamine.
6 The dosage of the active ingredients depends upon many factors that are well known 7 to those skilled in the art, for example, the particular form of the active ingredient, the 8 condition being treated, the age, weight, and clinical condition of the recipient patient, and 9 the experience and judgement of the clinician or practitioner administering the therapy. A
therapeutically effective amount of the nanocrystalline noble metal is that which provides 11 either subjective relief of symptoms or an objectively identifiable improvement as noted by 12 the clinician or other qualified observer. The dosing range varies with the metal used, its 13 form, the route of administration and the potency of the particular compound.
14 D. Methods of Treatin~Hyperproliferative Skin Disorders and Diseases The invention provides methods of treating hyperproliferative skin disorders and 16 diseases such as psoriasis, by administering a therapeutically effective amount of a 17 nanocrystalline noble metal powder, or a solution derived from a nanocrystalline noble metal, 18 as either a topical formulation, or as a coating on medical dressing, applied to the locally 19 affected diseased or abnormal skin area. A therapeutically effective amount may be determined by applying formulations containing the nanocrystalline noble metals to test 21 animal models. Topical applications may be applied one or more times a day.
Dressings 22 coated with the nanocrystalline noble metals may be changed daily, or even less frequently, 23 and should be kept in a moist condition with the addition of saline, alcohols, or more 24 preferably sterile water, in order to release ions, atoms, molecules or clusters of the nanocrystalline metal, on a sustained basis.
26 E. Examples 27 Example 1 - Preparation of Nanocrystalline Silver Coatings on Dressings 28 This example shows the preparation of a bilayer nanocrystalline silver coating on a 29 dressing material. A high density polyethylene dressing, DELNETT"'' or CONFORMANT
2Tn'' was coated with a silver base layer and a silver/oxide top layer to generate a coloured 31 anti-microbial coating having indicator value. The coating layers were formed by magnetron 32 sputtering under the conditions set out in Table 1.

1 Table 1 2 Sputtering Conditions: _Base Layer Top Layer 3 Target 99.99% Ag 99.99% Ag 4 Target Size 20.3 cm diameter 20.3 cm diameter Working Gas 96/4 wt% Ar/O~ 96/4 wt% Ar/O?

6 Working Gas Pressure 5.33 Pa (40 mT) 5.33 Pa (40 mT) 7 Power 0.3 kW 0.15 kW

8 Substrate Temperature 20C 20C

9 Base Pressure 3.0 X 10-6 Torr 3.0 X 10-6 Torr AnodelCathode Distance 100 mm 100 mm 11 Sputtering Time 7.5 - 9 min 1.5 min 12 Voltage 369 - 373 V 346 V

13 The resulting coating was blue in appearance. A fingertip touch was sufficient to 14 cause a colour change to yellow. The base layer was about 900 nm thick, while the top layer was 100 nm thick.
16 To establish that silver species were released from the coated dressings, a zone of 17 inhibition test was conducted. Mueller Hinton agar was dispensed into Petri dishes. The agar 18 plates were allowed to surface dry prior to being inoculated with a lawn of Staphylococcus 19 aureus ATCC#25923. The inoculant was prepared from Bactrol Discs (Difco, M.), which were reconstituted as per the manufacturer's directions. Immediately after inoculation, the 21 coated materials to be tested were placed on the surface of the agar. The dishes were 22 incubated for 24 hr. at 37°C. After this incubation period, the zone of inhibition was 23 calculated (corrected zone of inhibition = zone of inhibition - diameter of the test material in 24 contact with the agar). The results showed a corrected COI of about 10 mm, demonstrating good release of silver species.
26 The coating was analyzed by nitric acid digestion and atomic absorption analysis to 27 contain 0.24 +/- 0.04 mg silver per mg high density polyethylene. The coating was a binary 28 alloy of silver (>97%) and oxygen with negligible contaminants, based on secondary ion 29 mass spectroscopy. The coating, as viewed by SEM, was highly porous and consisted of equiaxed nanocrystals organized into coarse columnar structures with an average grain size of 31 IO nm. Silver release studies in water demonstrated that silver was released continuously 32 from the coating until an equilibrium concentration of about 66 mg/L was reached 33 (determined by atomic absorption), a level that is 50 to 100 times higher than is expected 34 from bulk silver metal (solubility _< lmg/L).
By varying the coating conditions for the top layer to lengthen the sputtering time to 2 1 min, 15 sec., a yellow coating was produced. The top layer had a thickness of about 140 nm 2 and went through a colour change to purple with a fingertip touch.
Similarly, a purple 3 coating was produced by shortening the sputtering time to 1 min, to achieve a top layer 4 thickness of about 65 nm. A fingertip touch caused a colour change to yellow.
To form a three layer dressing, two layers of this coated dressing material were 6 placed above and below an absorbent core material formed from needle punched 7 rayon/polyester (SONTARATM 8411). With the silver coating on both the first and third 8 layers, the dressing may be used with either the blue coating side or the silver side in the skin 9 facing position. For indicator value, it might be preferable to have the blue coating visible.
The three layers were laminated together by ultasonic welding to produce welds between all 11 three layers spaced at about 2.5 cm intervals across the dressing. This allowed the dressing to 12 be cut down to about 2.5 cm size portions for smaller dressing needs while still providing at 13 least one weld in the dressing portion.
14 The coated dressings were sterilized using gamma radiation and a sterilization dose of 25 kGy. The finished dressing was packaged individually in sealed polyester peelable I6 pouches, and has shown a shelf life greater than 1 year in this form. The coated dressings can 17 be cut in ready to use sizes, such as 5.1 x 10.2 cm strips, and slits formed therein before I8 packaging. Alternatively, the dressings may be packaged with instructions for the clinician to 19 cut the dressing to size and form the desired length of the slit for the medical device.
Additional silver coated dressings were prepared in a full scale roll coater under 21 conditions to provide coatings having the same properties set out above, as follows:
22 ~ the dressing material included a first layer of silver coated DELNET, as set out 23 above, laminated to STRATEX, AET, 8.ONP2-A/QW, which is a layer of 100%
rayon 24 on a polyurethane film.
~ Silver Foam Dressing - three layers of silver coated high density polyethylene 26 prepared as above, alternating with two layers of polyurethane foam, L-27 Medical Foam, available from Rynel Ltd., Bootbay, Maine, USA.
28 Example 2 - Preparation of Nanocrystalline Silver Powders 29 Nanocrystalline silver powder was prepared by preparing silver coatings on silicon wafers, under the conditions set forth in Table l, and then scraping the coating off using a 31 glass blade.
32 Nanocrystalline silver powder was also prepared by sputtering silver coatings on 1 silicon wafers using Westaim Biomedical NGRC unit, and then scraping the coating off. The 2 sputtering conditions were as follows:
3 Table 2 - Sputtering Conditions 4 Target: 99.99% Ag Target Size: 15.24 cm X 1216.125 cm 6 Working Gas: 75:25 wt% Ar/OZ
7 Working Gas Pressure: 40 mTorr 8 Total Current: 40 A
9 Base Pressure: 5.0 X10-5 Torr Sandvik Belt Speed: 340 mmlmin 11 Voltage: 370 V
12 The powder has a particle size ranging from 2 ~,m to 100 ~,m, with crystallite size of 8 13 to 10 nm, and demonstrated a positive rest potential.
14 Example 3 - Treatment of Psoriasis This patient was a 58 year old female with psoriatic plaques covering up to sixty 16 percent of her body. For this patient, psoriatic plaques first occurred ten years ago and have 17 been treated with the following:
18 1. Adrenal corticosteroids. Injections gave relief from pruritus and general discomfort.
19 Treatments led to a rebound effect; i.e. psoriasis would flare up after treatments wore off.
Corticosteroids were discontinued.
21 2. UV Light and Methotrexate treatments. UV light treatments were given in conjunction 22 with methotrexate. The UV light treatments caused burns and new lesions.
The methotrexate 23 caused severe nausea. Both treatments were discontinued.
24 3. Ice Cap Spray. This treatment contained a potent corticosteroid, and gave some relief but it was taken off the market and is no longer available.
26 4. Soriatone (acetretin 10 mg). This systemic retinoid treatment was associated with joint 27 aches and was discontinued.
28 5. Diet. The patient was attempting to control the disease through diet 29 Nanocrystalline silver was tested as follows. Nanocrystalline silver was deposited on sheets of high-density polyethylene (HDPE) using a vapour deposition process as set forth in 31 Example 1. Two sheets of this coated HDPE were laminated together around a core of non-32 woven rayon polyester, as set forth in Example 1. A 50 mm X 50 mm (2" X 2") piece of this 33 composite material was saturated with water and placed centrally on a one and a half year old 34 150 mm X 100 mm (6" X 4") psoriatic plaque on the patient's flank. The nanocrystalline 1 silver coated material was covered with a piece of low moisture vapour transmission thin 2 polymer film. The polymer sheet extended 50 mm (2") beyond the nanocrystalline silver 3 coated HDPE to provide control data regarding occlusion of the psoriatic plaque.
4 The dressing was removed after three days. There was no discernible change in the plaque at this time. However two days later the area that was covered with the 6 nanocrystalline silver had the appearance of normal skin while the rest of the plaque was still 7 rough and unchanged, including the untreated but occluded area.
8 The nanocrystalline silver therapy caused the treated psoriatic plaque to resolve.
9 Example 4 - Treatment of Psoriasis This patient was a 58 year old female with psoriatic plaques over up to sixty percent 1 I of her body. Psoriatic plaques had first occurred ten years ago and had been treated with the 12 following:
13 1. Adrenal corticosteroids. Injections gave relief from pruritus and general discomfort.
14 Treatments led to a rebound effect i.e. psoriasis would flare up after treatments wore off.
Corticosteroids were discontinued.
16 2. UV Light and Methotrexate treatments. UV light treatments were given in conjunction 17 with methotrexate. The UV light treatments caused burns and new lesions.
The methotrexate 18 caused severe nausea. Both treatments were discontinued.
19 3. Ice Cap Spray. This treatment contained a potent corticosteroid, and gave some relief but it was taken off the market and is no longer available.
21 4. Soriatone (acetretin 10 mg). This systemic retinoid treatment was associated with joint 22 aches and was discontinued.
23 S. Diet. The patient was attempting to control the disease through diet.
24 Nanocrystalline silver was tested as follows. Nanocrystalline silver was deposited on sheets of high-density polyethylene (HDPE) using a vapour deposition process as set forth in 26 Example 1 (top layer). Two sheets of this coated HDPE were laminated together around a 27 core of non-woven rayon polyester, as set forth in Example 1. A 50 mm X 50 mm (2" X 2") 28 piece of this composite material was saturated with water and placed centrally on a 125 mm 29 X 100 mm (5" X 4") psoriatic plaque on the patient's upper left thigh. The nanocrystalline silver coated material was covered with a piece of low moisture vapour transmission thin 31 polymer film. The polymer sheet extended 50 mm (2") beyond the nanocrystalline silver 32 coated HDPE to provide control data regarding occlusion of the psoriatic plaque.

1 The dressing was removed and the plaque examined after two days. The area that 2 was covered with the nanocrystalline silver was free of scaling and only slightly 3 erythenatous while the rest of the plaque was still erythenatous and scaly, including the 4 untreated but occluded area. The plaque was redressed with a similar 50 mm X
50 mm (2"
X 2") piece of nanocrystalline silver coated dressing, which was left in place for a further 6 period of 2 days. The area that was covered with the nanocrystalline silver remained free 7 of scale and only slightly erythenatous, while the rest of the plaque was still erythenatous 8 and scaly, including the area under the occlusive film.
9 The nanocrystalline silver therapy caused the treated psoriatic plaque to resolve.
Example 5-Preparation of Nanocrystalline Gels 11 A commercial carboxymethyl cellulose/pectin (Duoderm ConvatecTM) was 12 combined with nanocrystalline silver powder prepared as in Example 2 to produce a gel 13 with 0.1 % w/v. silver. Carboxymethyl cellulose (CMC) fibers were coated by magnetron 14 sputtering, under conditions similar to those set out in Example 1 for the top layer to produce a defective nanocrystalline silver coating. The CMC was then gelled in water by 16 adding 2.9 g to 100 mL volume. An alginate fibrous substrate was directly coated with a 17 defective nanocrystalline silver coating by magnetron sputtering under coating conditions 18 similar to those set forth in Example 1 for the top layer. The alginate (5.7 g) was added to 19 100 mL volume of water to create a gel. A commercial gel containing CMC and alginate (Purilon gel ColoplastTM) was mixed with an atomic disordered nanocrystalline silver 21 powder prepared as in Example 2 to give a gel product with 0.1 % w/v silver. A
22 commercially available gel (LubridermTM - glyceryl polymethacrylate) was blended with 23 atomic disordered nanocrystalline silver powder prepared as in Example 2, to prepare a gel 24 with a silver content of 0. I % w/v. A further gel was formulated with, on w/v basis, 0.1 %
methyl paraben, 0.02 % propyl paraben, 0.5 % polyvinyl alcohol(AirvolTM PVA
540), 2 %
26 CMC, 0.1 % nanocrystalline silver powder prepared as in Example 2, and was then 27 brought up to 1000 g with water.
28 All publications mentioned in this specification are indicative of the level of skill 29 in the art of this invention. , The terms and expressions used are, unless otherwise defined herein, used as terms 31 of description and not limitation. There is no intention, in using such terms and expressions, of excluding equivalents of the features illustrated and described, it being 2 recognized that the scope of the invention is defined and limited only by the following 3 claims.

Claims (30)

We claim:

1. The use of one or more noble metals in a nanocrystalline form, for the treatment of a hyperproliferative skin disorder, wherein:
nanocrystalline indicates a grain size which is less than 100 nm in at least one dimension;
the one or more noble metals have sufficient atomic disorder so that, when in contact with an alcohol or water-based electrolyte, the one or more noble metals release atoms, ions, molecules, or clusters of the at least one noble metal into the alcohol or water-based electrolyte on a sustainable basis; and the hyperproliferative skin disorder is selected from the group consisting of one or more of psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of the disorders of keratinization.

2. The use as set forth in claim 1, wherein the one or more noble metals is nanocrystalline silver, and wherein the hyperproliferative skin disorder is psoriasis.

3. The use as set forth in claim 1, wherein the one or more noble metals are provided as a coating on, or filler in, a dressing, or in a pharmaceutical composition with one or more pharmaceutically and dermatologically acceptable Garners, diluents, or excipients suitable for topical application.

4. The use as set forth in claim 3, wherein the pharmaceutical composition comprises a nanocrystalline powder of the one or more noble metals, or a solution containing dissolved species from a nanocrystalline powder or coating of the one or more noble metals.

5. The use as set forth in claim 4, wherein the pharmaceutical composition is a gel, cream or lotion containing the nanocrystalline powder of the one or more noble metals in an amount of 0.01 - 5 % by weight, or a liquid containing 0.001 - 1 % by weight of the one or more noble metals.

6. The use as set forth in claim 5, wherein the hyperproliferative skin disorder is psoriasis, and wherein the one or more noble metals is nanocrystalline silver formed with sufficient atomic disorder such that, in contact with an alcohol or water based electrolyte, the silver releases ions, atoms, molecules or clusters of the silver on a sustainable basis.

7. The use as set forth in claim 3, wherein the coating is provided on a dressing.

8. The use as set forth in claim 7, wherein the coating is 150 - 3000 nm thick.

9. The use as set forth in claim 7, wherein the nanocrystalline noble metal coating comprises:
a base layer of a partly reflective material capable of generating an interference colour when covered with a partly reflective, partly light transmissive top layer;
a top layer formed over said base layer, said top layer being a partly reflective, partly light transmissive thin film containing at least one noble metal and having a thickness such that a first or second order interference colour is produced, said top layer having a refractive index different from that of the base layer, and the noble metal being formed with sufficient atomic disorder such that the top layer, in contact with an alcohol or water based electrolyte, releases ions, atoms, molecules or clusters of the noble metal into the alcohol or water based electrolyte on a sustainable basis.

10. The use as set forth in claim 9, wherein the dressing is fixed in place with an occlusive or semi-occlusive layer which maintains the dressing in a moist condition.

11. The use as set forth in claim 10, wherein the occlusive or semi-occlusive layer is an adhesive tape or film.

12. The use as set forth in claim 1, wherein the nanocrystalline noble metal has a grain size which is less than 50 nm in at least one dimension.

13. The use as set forth in claim 1, wherein the nanocrystalline noble metal has a grain size which is less than 25 nm in at least one dimension.

14. A pharmaceutical composition in topical administration form which comprises a therapeutically effective amount of one or more noble metals in a nanocrystalline form, in admixture with one or more pharmaceutically and dermatologically acceptable carriers, diluents, or excipients suitable for topical application, wherein:
nanocrystalline indicates a grain size which is less than 100 nm in at least one dimension;
the one or more noble metals have sufficient atomic disorder so that, when in contact with an alcohol or water-based electrolyte, the one or more noble metals release atoms, ions, molecules, or clusters of the at least one noble metal into the alcohol or water-based electrolyte on a sustainable basis; and the pharmaceutical composition is for use in the treatment of a hyperproliferative skin disorder selected from the group consisting of one or more of psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of the disorders of keratinization.

15. The pharmaceutical composition as set forth in claim 14, wherein the nanocrystalline noble metal has a grain size which is less than 50 nm in at least one dimension.

16. The pharmaceutical composition as set forth in claim 14, wherein the nanocrystalline noble metal has a grain size which is less than 25 nm in at least one dimension.

17. The pharmaceutical composition as set forth in claim 14, wherein the hyperproliferative skin disorder is psoriasis or one of its varied clinical forms.

18. The pharmaceutical composition as set forth in claim 14, wherein the hyperproliferative skin disorder is Reiter's syndrome.

19. The pharmaceutical composition as set forth in claim 14, wherein the hyperproliferative skin disorder is pityriasis rubra pilaris.

20. The pharmaceutical composition as set forth in claim 14, wherein the hyperproliferative skin disorder is a hyperproliferative variant of the disorders of keratinization.

21. The pharmaceutical composition as set forth in claim 14, wherein the one or more noble metals is provided as a nanocrystalline powder of the one or more noble metals, or as a solution containing dissolved species from a nanocrystalline powder or coating of the one or more noble metals.

22. The pharmaceutical composition as set forth in claim 21, formulated as a gel, a cream, a paste, an ointment, a lotion, an emulsion or a suspension containing the nanocrystalline powder of the one or more noble metals in an amount of 0.01 -5 % by weight, or as a liquid containing 0.001 - 1 % by weight of the one or more noble metals.

23. The pharmaceutical composition as set forth in claim 22, for use in the treatment of psoriasis or one of its varied clinical forms, and wherein the one or more noble metals is nanocrystalline silver formed with sufficient atomic disorder such that, in contact with an alcohol or water based electrolyte, the silver releases ions, atoms, molecules or clusters of the silver on a sustainable basis.

24. The pharmaceutical composition as set forth in claim 14, wherein the composition contains from 0.001 weight percent to 30 weight percent of the at least one nanocrystalline noble metal.

25. The pharmaceutical composition as set forth in claim 14, wherein the composition contains from about 0.001 weight percent to abed one weight percent of the at least one nanocrystalline noble metal.

26. The pharmaceutical composition as set forth in claim 14, wherein the composition contains from about 0.01 weight percent to five weight percent of the at least one nanocrystalline noble metal.

27. The pharmaceutical composition as set forth in claim 14, wherein the at least one nanocrystalline noble metal is contained in a liquid.

28. The pharmaceutical composition as set forth in claim 14, wherein the at least one nanocrystalline noble metal is in the form of a powder.

29. The pharmaceutical composition as set forth in claim 14, wherein the at least one nanocrystalline noble metal is a coating on a medical dressing.

30. The pharmaceutical composition as set forth in claim 14, wherein the at least one nanocrystalline noble metal is a coating on a biocompatible substrate.