Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/25—Silicon; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/34—Copper; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/02—Local antiseptics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q3/00—Manicure or pedicure preparations

Definitions

• the present invention relates to the use of copper silicate for treating and preventing microbial infections and diseases and in particular fungal diseases of the nail such as onychomycosis.
• the present invention also relates to copper silicate compositions adapted for topical administration.
• Microbial diseases of the nail are a considerable public health concern. Whilst there are diseases and disorders caused by bacteria, the most prevalent and clinically significant nail diseases are caused by fungi.
• Onychomycosis is a fungal disease of nails caused by a range of fungi, principally dermatophytes - T ⁇ chophyton species such as Trichophyton mentagrophytes and Trichophyton rubrum, but also Trichophyton megninii, Trichophyton schoenl ⁇ inii and Trichophyton tonsurans and Candida species, such as C. albicans.
• Infection is of the nail unit (the nail matrix, bed or plate) and although not life threatening it can cause inconvenience, pain, discomfort and sometimes serious physical and occupational limitations.
• the present invention seeks to overcome the above problems by providing a safe and effective topical anti-microbial that is capable of treating microbial infections of the nail.
• the present invention provides a method of treating or preventing microbial infection of a subject's nail, the method comprising the step of topically administering to said nail an effective amount of copper silicate.
• the infections treated or prevented by the method of the present invention may manifest themselves into disease states that may also be treated according to the present invention.
• the present invention also provides a method of treating or preventing a microbial disease of a subject's nail, the method comprising the step of topically administering to the nail an effective amount of copper silicate.
• the present invention also provides a composition adapted for topical administration comprising an anti-microbial effective amount of copper silicate.
• Figure 1 is a series of photos showing the time course of treatment (Day 0: untreated, week 6 and week 12) of a dermatophyte infection of a first subject's nail, according to one exemplary method of the present invention
• Figure 2 is a series of photos showing the time course of treatment (Day 0: untreated, week 6 and week 12) of a dermatophyte infection of a second subject's nail, according to one exemplary method of the present invention
• Figure 3 is a series of photos showing the time course of treatment (Day 0: untreated and week 6) of a dermatophyte infection of a third subject's nail, according to one exemplary method of the present invention
• Figure 4 is a series of photos showing the time course of treatment (Day 0: untreated and week 6) of a dermatophyte infection of a fourth subject's nail, according to one exemplary method of the present invention
• Figure 5 is a series of photos showing the time course of treatment (Day 0: untreated, week 12 and week 12 - post-treatment) of a dermatophyte infection of a fifth subject's nail, according to one exemplary method of the present invention
• Figure 6 is a series of photos showing the time course of treatment (Day 0: untreated, week 6, week 26 and week 12 - post-treatment) of a dermatophyte infection of a sixth subject's nail, according to one exemplary method of the present invention.
• Figure 7 is a series of photos showing the extended time course of treatment (Day 0: untreated, week 6, week 26 and week 12 - post-treatment) of a dermatophyte infection of the second subject's nail, according to one exemplary method of the present invention.
• the present invention provides a method of treating or preventing microbial infection of a subject's nail, the method comprising the step of topically administering to said nail an effective amount of copper silicate.
• topically administering includes, but is not limited to, application through the nail plate with a device adapted to perforate the nail plate and application between the nail plate and nail bed with a device adapted to be inserted therebetween.
• nail refers to one or more of the elements of the nail unit (the nail matrix, bed or plate) and also includes toe and fingernails and animal nail like features such as hooves, trotters and claws.
• the copper silicate administered to a nail according to the present invention delivers either an effective anti-microbial dose to the infected area or a dose sufficient to prevent infection with a microbial nail pathogen.
• the applicant has discovered that upon administration of the copper silicate to the nail, therapeutically effective amounts of the copper are able to reach the site of infection. The precise mode of this effect has not been established conclusively, but the Applicant is aware that the copper silicate persists at the site of application and/or the site of infection.
• Topical administration may be achieved in any one of a number of ways.
• the compound is applied to the nail by painting, wiping, dabbing or spraying the nail with the compound.
• topical administration may be achieved by submerging the nail in a copper silicate solution or contacting the nail with a means for dispensing an effective amount of copper silicate.
• Dispensing means can be varied and include slow release carriers and materials impregnated with copper silicate such as patches, bandages, cotton wool and gauze.
• the dispensing means is adapted to be removably fixed to the nail to deliver the copper silicate over a predetermined time and/or at a predetermined dose.
• the methods of the present invention may be used to treat microbial, such as fungal, infection in any animal and more particularly any mammal. However, preferably, the subject is human.
• the present invention also provides for the use of copper silicate for preparing a medicament for treating microbial infections such as fungal infections including onychomycosis. It is common for nails to be infected with a range of microbes such as bacteria and fungi (including yeast). Thus, the microbial infection may be bacterial.
• the method of the present invention is particularly useful for treating fungal infections.
• the amount of copper silicate applied in the method of the present invention will be sufficient to effectively treat or prevent the infection and thus will necessarily vary depending at least on the severity and type of the infection, the strength of the composition and the manner in which individual patients respond to the treatment.
• a composition containing 1-100 ⁇ g of copper is applied to each infected nail, more preferably a composition containing 2-50 ⁇ g of copper is applied to each infected nail and even more preferably, a composition containing 5-20 ⁇ g of copper is applied to each infected nail.
• a composition containing at least about 10 ⁇ g of copper is applied to each infected nail.
• the frequency with which, and the duration for which, the copper silicate is applied will be sufficient to effectively treat or prevent the infection and thus will also vary depending at least on the severity and type of infection, the strength of the composition and the manner in which individual patients respond to the treatment.
• the copper silicate is applied at least once, twice or three times a day for at least 1 , 3, 6, 12, 26, 30, 40, 45, 48 or 52 weeks. Alternatively, it may be applied once every 2 - 14 days for as long as necessary to treat or prevent infection.
• the present invention also provides a method of treating or preventing microbial infection of a subject's nail, the method comprising the step of repeatedly topically administering to said nail an effective amount of copper silicate.
• fungal infections which may be treated according to the present invention include infections from dermatophytes, such as Trichophyton species including Trichophyton mentagrophytes (Including varieties mentagrophytes and interdigitales) , T ⁇ chophyton rubrum, Trichophyton megninii, Trichophyton schoenleinii, T ⁇ chophyton tonsurans; yeasts, such as Candida species, most notably Candida albicans, Candida glabrata, Candida ciferrii; Microsporum species including Microsporum canis and Microsporum gypseum; Malassezia species including Malassezia furfur and Malassezia sympodialis; Epidermophyton species such as Epidermophyton floccosum; Scopularosis species; Acremonium species and Aspergillus species.
• Trichophyton species including Trichophyton mentagrophytes (Including varieties mentagrophytes and interdigitales) , T ⁇ chophyton rubrum, Trichophyton megnini
• the present invention also provides a method of treating or preventing infection of a subject's nail with one or more of: dermatophytes, such as Trichophyton species including Trichophyton mentagrophytes (Including varieties mentagrophytes and interdigitales), Trichophyton rubrum, Trichophyton megninii, T ⁇ chophyton schoenleinii, Trichophyton tonsurans; yeasts, such as Candida species, most notably Candida albicans, Candida glabrata, Candida ciferrii; Microsporum species including Microsporum canis and Microsporum gypseum; Malassezia species including Malassezia furfur and Malassezia sympodialis; Epidermophyton species such as Epidermophyton floccosum; Scopularosis species; Acremonium species and Aspergillus species, the method comprising the step of topically administering to said nail an effective amount of copper silicate.
• Trichophyton species including Trichophyton mentagrophytes
• Fungal nail infections that may be treated using the methods of the present invention are usually characterized by tarnished white, yellowed, or blackened nails.
• the nails may pull away from the pink nail bed along the sides or outer edges, and infections are usually exacerbated by hot, damp conditions, such as inside footwear or in environments where hands or feet are continually exposed to moisture.
• the fungal infections can spread from toe to toe, foot to foot, and foot to hand.
• the present invention also provides a method of treating or preventing a microbial disease of a subject's nail, the method comprising the step of topically administering to the nail an effective amount of copper silicate. Whilst the method of the present invention may be applied to treat a wide range of microbial diseases of the nail it is particularly useful for treating fungal diseases of the nail. Thus, the present invention also provides a method of treating or preventing a fungal disease of a subject's nail, the method comprising the step of topically administering to the nail an effective amount of copper silicate.
• Specific fungal diseases that can be treated by the methods of the present invention include onychomycosis such as distal subungual onychomycosis, superficial white onychomycosis, proximal white subungual onychomycosis; total secondary dystrophic onychomycosis; and total dystrophic primary onychomycosis.
• onychomycosis such as distal subungual onychomycosis, superficial white onychomycosis, proximal white subungual onychomycosis; total secondary dystrophic onychomycosis; and total dystrophic primary onychomycosis.
• the present invention also provides a method of treating or preventing a fungal disease of a subject's nail, the method comprising the step(s) of topically administering to said nail an effective amount of copper silicate and (ii) administering to said subject an effective amount of at least one other anti-fungal agent.
• the other anti-fungal agent may be varied and includes, for example, one or more orally administrable anti-fungal agents selected from the group consisting of: miconazole, ketoconazole, itraconazole, fluconazole, econazole, ciclopirox, oxiconazole, clotrimazole, terbinafine, naftifine, pharmaceutically acceptable salts thereof and stereoisomers thereof , LamisilTM, SporanoxTM and DiflucanTM.
• one orally administrable anti-fungal agents selected from the group consisting of: miconazole, ketoconazole, itraconazole, fluconazole, econazole, ciclopirox, oxiconazole, clotrimazole, terbinafine, naftifine, pharmaceutically acceptable salts thereof and stereoisomers thereof , LamisilTM, SporanoxTM and DiflucanTM.
• the present invention also provides for the use of copper silicate for preparing a medicament for treating or preventing a disease caused by a fungal infection.
• the present invention also provides a composition adapted for topical administration to a nail comprising an anti-microbial effective amount of copper silicate.
• the form of the composition of the present invention may also be varied provided it retains its anti-microbial properties.
• the composition is a solution.
• the composition may also be in solid form provided it is properly formulated.
• the composition could comprise copper silicate in the form of a micronized solid such as chrysocolla.
• the copper silicate When the copper silicate is provided in the form of a solution, it preferably is provided as an aqueous acidified solution. Acidified solutions are particularly preferred because copper silicate is more soluble at acidic pH. Particularly preferred pHs are 3-6, 4-6 and 5-6. In one example, the copper silicate is prepared according to the methods described and claimed in US patent 5,474,972.
• composition adapted for topical administration may be in the form of any one of the following: solution, lotion, suspension, emulsion, cream, gel, ointment, liniment and salve. Particularly preferred forms are ointments, creams or gels.
• Ointments generally are prepared using either (1) an oleaginous base, i.e., one consisting of fixed oils or hydrocarbons, such as white petroleum or mineral oil, or (2) an absorbent base, i.e., one consisting of an anhydrous substance or substances that can absorb water, for example anhydrous lanolin.
• an oleaginous base i.e., one consisting of fixed oils or hydrocarbons, such as white petroleum or mineral oil
• an absorbent base i.e., one consisting of an anhydrous substance or substances that can absorb water, for example anhydrous lanolin.
• the active ingredient is added to an amount affording the desired concentration.
• Creams are oil/water emulsions. They consist of an oil phase (internal phase), comprising typically fixed oils, hydrocarbons and the like, waxes, petroleum, mineral oil and the like and an aqueous phase (continuous phase), comprising water and any water-soluble substances, such as added salts.
• the two phases are stabilised by use of an emulsifying agent, for example, a surface active agent, such as sodium lauryl sulfate; hydrophilic colloids, such as acacia colloidal clays, veegum and the like.
• the compound may be added to the water phase prior to formation of the emulsion, in an amount to achieve the desired concentration.
• Gels comprise a base selected from an oleaginous base, water, or an emulsion- suspension base.
• a gelling agent that forms a matrix in the base, increasing its viscosity.
• gelling agents are hydroxypropyl cellulose, acrylic acid polymers and the like.
• the compound may be added to the formulation at the desired concentration at a point preceding addition of the gelling agent.
• compositions of the present invention may be produced by dissolving or combining the copper silicate in an aqueous or non-aqueous carrier.
• aqueous or non-aqueous carrier any liquid, cream, or gel, or similar substance that does not appreciably react with the silicate or any other active ingredient that may be introduced and which is non-irritating is suitable.
• the present invention also provides a method of producing copper silicate adapted for topical administration comprising the step of dissolving or combining the copper silicate in an aqueous or non-aqueous topical carrier.
• composition of the present invention may further comprise an auxiliary agent such as any one or more of: preservatives, stabilizers, emulsifiers, wetting agents, fragrances, colouring agents, odour controllers and thickeners such as natural gums.
• auxiliary agent such as any one or more of: preservatives, stabilizers, emulsifiers, wetting agents, fragrances, colouring agents, odour controllers and thickeners such as natural gums.
• the concentration of the copper in the composition may be varied depending at least on the severity and type of infection that the composition is to be used to treat or prevent. However, preferably, the concentration of the copper is approximately 100 mg/L - 10 g/L (as Cu). More preferably, the copper concentration is to a final concentration of approximately 1 g/L - 5 g/L or 2g/L - 3 g/L (as Cu).
• Example 1 In vitro funigicidal activity of a copper silicate solution
• Table 1a Minimum inhibitory (MIC) and fungicidal (MFC) concentrations of a copper silicate solution (ppm Cu) for Candida spp., Malassezia spp. and various dermatophytes.
• MIC Minimum inhibitory
• MFC fungicidal
• Table 1b Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) of copper silicate (% w/w as Cu) for various dermatophytes and non-dermatophytes that cause onychomycosis, and Candida spp.
• MIC Minimum Inhibitory Concentration
• MFC Minimum Fungicidal Concentration
• Trichophyton rubrum 26 0.0175 0.0350 T. mentagrophytes 19 0.0175 0.0350 var interdigitale T. mentagrophytes 12 0.0175 0.0350 T. tonsurans 10 0.0350 0.0350 Epidermophyton floccosum 11 0.0350 0.0350 Microsporum canis 9 0.0350 0.0700
• Example 2 In vitro bactericidal activity of a copper silicate solution
• Table 2 Minimum inhibitory concentrations (MIC) of copper silicate solution (ppm Cu) for a variety of bacteria
• the final product should be a light blue, clear solution with an acrid odour.
• the final concentrated solution is then produced by dilution of the combined parts.
• the final product should be a light blue, clear solution with an acrid odour.
• Germaben HETM (Sutton Laboratories 0.50
• the anti-fungal composition cream or solution was applied to the infected nail twice daily for the duration of the treatment.
• results presented hereunder are interim results of a 12 month study. Patients entered the trial and commenced their treatment at different dates. Of the 18 patients enrolled in the trial, 13 had reached 6 weeks of treatment, and of these, 10 had reached 12 weeks of treatment, at the time of reporting these results. Patients were assessed at 0 (commencement), 6 weeks and 12 weeks. The results of these assessments are tabulated below in Table 3. No differences were noted in efficacy between the cream and solution at any of the assessments. Table 3
• Mycological cure was achieved in 5 (28%) patients after 26 weeks, but 2 of these had reverted to KOH positive at 39 weeks. At 52 weeks the "mycological cure” rate was 22%.
• Mycological change or the change from culture positive to culture negative, was achieved by another 7 patients at weeks 26 and 39. This gave a total of 12 culture negative patients at 26 weeks and 10 at 39 weeks.
• mycological cure is defined as both KOH and culture negative, but patients may not become KOH negative until the diseased nail has grown out. It is usual for a great toenail to take 12-18 months to totally regrow. At the commencement of this trial, 12 of the 18 patients had >50% of their target nail infected, and of these 7 had cuticle (lunula) involvement. As a result of extensive disease, "mycological cure” and thus “effective treatment” and "complete cure” may not have been achievable by these patients in the time allotted to this study. The treatment time of 26 weeks is considerably shorter than for most topicals that are applied for a minimum of 48 weeks. It is evident from this trial that patients with >50% of the nail plate diseased would have benefited from an extended treatment time. The results at 26 weeks show that many (50%) had significant clinical improvement with a reduction in the extent of their disease to ⁇ 50% of the nail plate.
• the present invention includes any and all modifications and adaptations apparent to one skilled in the art.

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• 2002
  • 2002-04-17 AU AUPS1793A patent/AUPS179302A0/en not_active Abandoned
• 2003
  • 2003-04-17 CN CNA03809987XA patent/CN1649605A/zh active Pending
  • 2003-04-17 AU AU2003227095A patent/AU2003227095B2/en not_active Ceased
  • 2003-04-17 ZA ZA200408372A patent/ZA200408372B/en unknown
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  • 2003-04-17 CA CA002482439A patent/CA2482439A1/en not_active Abandoned
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  • 2003-04-17 WO PCT/AU2003/000471 patent/WO2003088983A1/en active IP Right Grant
  • 2003-04-17 AP APAP/P/2004/003163A patent/AP1777A/en active
  • 2003-04-17 JP JP2003585735A patent/JP2005523317A/ja active Pending
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  • 2003-04-17 EP EP03746769A patent/EP1494688A4/en not_active Withdrawn
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• 2006
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