JP2005523317A - Use of topical compositions to control nail microbial disease - Google Patents

Abstract

A method for treating or preventing a nail microbial disease in a subject, such as onychomycosis, comprising locally administering an effective amount of copper silicate to the nail.

Description

  The present invention relates to the use of copper silicate for treating and preventing microbial infections and microbial diseases, in particular fungal diseases of the nail such as onychomycosis. The invention also relates to a copper silicate composition adapted for topical administration.

  Nail microbial disease cannot be ignored as a public health concern. While there are diseases and disorders caused by bacteria, the most prevalent and clinically significant nail diseases are caused by fungi.

  Onychomycosis refers to various fungi, mainly dermatophytes-Trichophyton mentagrophytes and Trichophyton rubrum, as well as Trichophyton megnini, Trichophyton schoenleini and Trichophyton tonslance It is a fungal disease of the nail caused by species belonging to the genus Trichophyton as well as species belonging to the genus Candida such as Candida albicans. Infection is to a nail unit (nail bed or nail plate) and is not life-threatening, but can cause inconvenience, pain, discomfort, and severe physical and professional It can cause restrictions.

  Currently, there are various internal medicines that can be used to treat onychomycosis. However, these are generally expensive and suffer from limited effectiveness, and it is desirable for practitioners to monitor constantly. And it can cause serious side effects such as liver and heart problems.

  While there is clearly a need for effective topical drugs to treat onychomycosis, the effectiveness of currently available drugs is limited. The most widely used topical drug is Penlac®. However, clinical studies on this drug have reported poor effectiveness.

  The main problems faced in developing effective topical drugs for the nail are that the nail plate is thick, hard and dense, and the nail plate reaches the site of infection with the amount of drug needed for treatment It is a representative of an awkward barrier to drugs that prevents it from doing so. In addition to this challenge, there is the fact that onychomycosis is associated with thickening of the nail plate. In order to overcome this difficult problem, a conventional topical drug for treating onychomycosis has been mixed with a drug that increases the permeability of the nail plate. However, these topical drugs contain multiple drugs, namely softeners and antifungal agents, so that the costs for production are relatively expensive. Furthermore, such drugs have only achieved some success.

  The present invention seeks to overcome the above difficulties by providing a safe and effective topical antimicrobial agent that can treat 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 locally administering an effective amount of copper silicate to the nail.

  An infection that is treated or prevented by the methods of the present invention may result in a medical condition that can be treated by the present invention. Accordingly, the present invention also provides a method for treating or preventing a nail microbial disease in a subject comprising the step of locally administering an effective amount of copper silicate to the nail.

  The present invention also provides a composition adapted for topical administration comprising an antimicrobially effective amount of copper silicate.

  The present invention provides a method of treating or preventing microbial infection of a subject's nail, the method comprising locally administering an effective amount of copper silicate to the nail.

  For the purposes of the present invention, the term “administering locally” includes the use of a nail plate with a tool suitable for puncturing the nail plate and between the nail plate and the nail bed. Including, but not limited to, using between them with a tool suitable for insertion.

  For the purposes of the present invention, the term “nail” means one or more elements of a nail unit (nail bed or nail plate), such as toes and toenails and nails such as animal hoofs, toes and claws. Such things are also included.

  Surprisingly, the copper silicate administered to the nail according to the present invention delivers an antibacterial effective dose to the infected area, or a dose sufficient to prevent infection of the nail with microbial pathogens I found out that Thus, Applicants have found that as soon as copper silicate is administered to the nail, a therapeutically effective amount of copper can reach the site of infection. Although the exact manner of this result has not been definitively verified, the Applicant knows that the copper silicate remains at the site of use and / or the site of infection.

  Local administration can be achieved in any one of a number of ways. It is preferred to use the compound on the nails by applying, wiping, tapping or spraying the compound onto the nails. Alternatively, topical administration may be accomplished by immersing the nail in a copper silicate solution or by contacting the nail with a means for dispensing an effective amount of copper silicate. The dispensing means can vary, and the dispensing means include sustained release carriers and materials such as patches, bandages, cotton wool and gauze impregnated with copper silicate. The dispensing means is preferably adapted so that copper silicate can be delivered to the nail over a predetermined time and / or in a predetermined dose and is fixed so that it can be removed.

  The methods of the invention can be used to treat infection of microorganisms such as fungi in any animal, particularly any mammal. However, the subject is preferably a human. Accordingly, the present invention also provides the use of copper silicate for the preparation of a medicament for treating microbial infections such as fungal infections including onychomycosis.

  It is well known that various microorganisms such as bacteria and fungi (including yeast) infect nails. Thus, there can be bacterial microbial infections. However, the methods of the present invention are particularly useful for treating fungal infections.

  The amount of copper silicate used in the methods of the present invention will be sufficient to effectively treat or prevent infection. Thus, the amount will necessarily vary depending at least on the severity and type of infection, the concentration of the composition and the behavior of the individual patient in response to treatment. However, it is preferred to use a composition containing 1-100 μg copper for each infected nail, more preferably a composition containing 2-50 μg copper for each infected nail, and 5-20 μg More preferably, a composition comprising copper is used for each infected nail. In one particular embodiment of the invention, a composition comprising at least about 10 μg of copper is used for each infected nail.

  Similarly, the frequency with which copper silicate is used, and the duration with which copper silicate is used, will be sufficient to effectively treat or prevent infection. Thus, the frequency and duration will also vary depending at least on the severity and type of infection, the concentration of the composition and the behavior of the individual patient in response to treatment. It is preferred to use copper silicate 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 used once every 2-14 days as needed to treat or prevent infection.

  Accordingly, the present invention also provides a method for treating or preventing microbial infection of a subject's nail, said method also comprising the step of locally administering an effective amount of copper silicate to the nail repeatedly. To do.

  As mentioned above, the present invention may be applied to the treatment of fungal infections. In this regard, fungal infections that may be treated according to the method of the present invention include Trichophyton mentagrophytes (including Mentagolophytes subspecies and Interdigitalales subspecies), Trichophyton rubrum, Trichophyton megnini Dermatophytes such as species belonging to the genus Trichophyton, including Trichophyton schoenleini, Trichophyton tonlances; yeasts belonging to the genus Candida, in particular Candida albicans, Candida glabrata, Candida schiferlii; Species belonging to the genus Microsporum, including canis and Microsporum gypsum; Species belonging to the genus Malassezia, including Malassezia fulfur and Malassezia symposiaris; belonging to the genus Epidermophyton, such as Epidermophyton floccosum Include infection from species belonging to the species and Aspergillus belonging to Acremonium; species belonging to Sukopuraroshisu genus; species.

  Accordingly, the present invention relates to Trichophyton Mentagrophytes (including Mentagolophytes subspecies and Interdigitalales subspecies), Trichophyton rubrum, Trichophyton megnini, Trichophyton schönleinii, Trichophyton tonslance. Dermatophytes such as species belonging to the genus Trichophyton; species belonging to the genus Candida, particularly yeasts such as Candida albicans, Candida glabrata, Candida sifelli; species belonging to the genus Microsporum including Microsporum canis and Microsporum gypsum Species belonging to the genus Malassezia, including Malassezia fulfur and Malassezia symposiaris; Species belonging to the genus Epidermophyton, such as Epidermophyton floccosm; A method for treating or preventing nail infection in a subject of one or more species belonging to the genus Mus and the species belonging to the genus Aspergillus, the method comprising locally applying an effective amount of copper silicate to the nail Also provided is a method comprising the step of administering.

  Fungal infection of the nail that can be treated using the method of the present invention is usually characterized by the nail becoming clouded, yellowed or blackened. The nail may be peeled from the pink nail bed along the side or outer edge. And infections are usually exacerbated by warm and moist conditions, such as inside footwear or in an environment where limbs are frequently exposed to moisture. Fungal infections can spread from toe to toe, foot to foot, and foot to hand.

[Method of treating or preventing microbial diseases]
The present invention also provides a method of treating or preventing a nail microbial disease in a subject comprising the step of locally administering an effective amount of copper silicate to the nail.

  While the method of the invention can be used to treat a wide range of nail microbial diseases, it is particularly useful for treating nail fungal diseases. Accordingly, the present invention also provides a method of treating or preventing a fungal disease of a nail in a subject comprising the step of locally administering an effective amount of copper silicate to the nail.

  Specific fungal diseases that can be treated by the method of the present invention include, for example, distal subungual onychomycosis, superficial white onychomycosis, Onychomycosis such as proximal white subungual onychomycosis; total secondary dystrophic onychomycosis; and total dystrophic primary onychomycosis Etc.

  In some situations, it may be desirable to combine methods of treating or preventing fungal diseases with other therapies according to the present invention. Accordingly, the present invention provides a method for treating or preventing a fungal disease of a nail in a subject, comprising locally administering an effective amount of copper silicate to the nail, and (ii) an effective amount of other And at least one antifungal agent is administered to the subject.

  Other antifungal agents may vary, e.g., miconazole, ketoconazole, itraconazole, fluconazole, econazole, ciclopirox, oxyconazole, clotrimazole, terbinafine, naphthifine, their pharmaceutically acceptable salts and One or more antifungal agents capable of oral administration selected from the group consisting of their stereoisomers, Lamisil ™, Sporanox ™ and Diflucan ™.

  The present invention also provides the use of copper silicate for the preparation of a medicament for treating or preventing a disease caused by a fungal infection.

[Topical preparation]
The present invention also provides a composition adapted for topical administration to the nail comprising an antimicrobially effective amount of copper silicate.

  As long as the antibacterial property is maintained, the form of the composition of the present invention may be changed. A solution is preferred as the composition. However, the composition may be a solid as long as it can be formulated appropriately. In this regard, the composition may be copper silicate in the form of a solid fine powder such as silicic peacock.

  When copper silicate is provided in the form of a solution, it is preferably provided as an aqueous acidified solution. Acidified solutions are particularly preferred because copper silicate is more soluble at acidic pH. Particularly preferred pH is 3-6, 4-6 and 5-6. In one example, copper silicate is prepared according to the method described and claimed in US Pat. No. 5,474,972.

  A composition adapted for topical administration may be in any one of the following forms: solution, lotion, suspension, emulsion, cream, gel, ointment, coating, and salve. Particularly preferred forms are ointments, creams or gels.

  In general, it absorbs (1) oily bases, ie consisting of non-volatile oils or hydrocarbons such as white petrolatum or mineral oil, or (2) water-absorbing bases, ie anhydrous substances such as dehydrated lanolin or water. An ointment is prepared using any of the possible substances. Usually, following the formation of either an oily or water-absorbing base, an amount of active ingredient that provides the desired concentration is added.

  Cream is an oil-in-water emulsion. These are generally an oil phase (internal phase) containing non-volatile oils, hydrocarbons, waxes, petroleum, mineral oils, etc., and any water-soluble substance water phase (continuous phase) such as water and added salts. Consists of. The two phases are stabilized by using emulsifiers, for example surfactants such as sodium lauryl sulfate; hydrocolloids such as acacia, colloidal clay, veegum, and the like. For purposes of the present invention, an amount of compound that achieves the desired concentration may be added to the aqueous phase prior to the formation of the emulsion.

  The gel comprises a base selected from an oily base, water, or an emulsion-suspension base. To this base is added a gelling agent that forms a matrix in the base and increases its viscosity. Examples of gelling agents include hydroxypropyl cellulose and acrylic acid polymers. For purposes of the present invention, the compound may be added to the formulation at the desired concentration prior to the addition of the gelling agent.

  The composition of the present invention can also be produced by dissolving or mixing copper silicate in an aqueous or non-aqueous carrier. In general, any liquid, cream or gel or similar substance that does not appreciably react with silicates or any other active ingredient that can be incorporated and is non-irritating is suitable. is there.

  Accordingly, the present invention also provides a method of producing copper silicate adapted for topical administration, comprising dissolving or mixing the copper silicate in an aqueous or non-aqueous topical carrier.

  The composition of the present invention may further contain any one or more auxiliary agents such as preservatives, stabilizers, emulsifiers, wetting agents, fragrances, colorants, odor adjusting components, and thickeners such as natural rubber.

  The concentration of copper in the composition will vary depending at least on the severity and type of infection the composition is to be used for treatment or prevention. However, the concentration of copper is preferably about 100 mg / L to 10 g / L as Cu. The concentration of copper is more preferably a final concentration of about 1 g / L to 5 g / L or 2 g / L to 3 g / L as Cu.

  The present invention will now be described with reference to the following examples. The description of these examples does not limit the generality of the above description.

[Example 1: In vitro fungicidal activity of copper silicate solution]
A test was conducted to evaluate the fungicidal properties of copper silicate against various fungi. The results of this study are shown in Tables 1a and 1b below.

[Example 2: In vitro bactericidal property of copper silicate solution]

[Example 3: Treatment of onychomycosis with copper silicate]
In this study, copper silicate as a topical antifungal agent such as the treatment of onychomycosis is evaluated and compared to solution and cream formulations.

[Material / Method]
(A) Antifungal solution (CSSOL1)
〔material〕
Sodium silicate solution (30% SiO ₂ , 10% Na ₂ O)
Empimin LSM 30AU ™-Huntsman International LLC (sodium alkyl ether sulfate)
Copper sulfate pentahydrate acetic acid (90% solution)
Water (deionized)

[ Technical instructions]
1. Prepare two different solutions (A and B) as follows:

Method: Sodium silicate solution (30% SiO ₂ , 10% Na ₂ O) and empimin LSM 30AU ™ are added to water with stirring and filtered.

Method: Copper sulfate pentahydrate is added to water with stirring and stirring is continued until a clear solution is obtained. Add acetic acid with stirring and filter.

2. The final solution is then obtained by diluting the combined parts.

Method: Add Part A to water with stirring. Continue stirring while adding Part B and filter.

  The final product should be a light blue clear solution with an irritating odor.

Product specification:
pH: 3.3-3.7
Copper content: 2.8 +/− 0.28 g / L as Cu

(B) Copper silicate solution concentrate for use in cream (CSC1)
[ Required materials]
Sodium silicate solution (30% SiO ₂ , 10% Na ₂ O)
Copper sulfate pentahydrate acetic acid (90% solution)
Water (deionized)

[ Technical instructions]
1. Prepare two different solutions (A and B) as follows:

Method: Sodium silicate solution (30% SiO ₂ , 10% Na ₂ O) is added to water with stirring and filtered.

Method: Add copper sulfate pentahydrate to water with stirring and continue stirring until a clear solution is obtained. Acetic acid is added with stirring and filtered.

2. Then, the final concentrated solution is obtained by diluting the combined components.

Method: Add Part A to water with stirring. Continue stirring while adding Part B and filter.

  The final product should be a light blue clear solution with an irritating odor.

Copper content: 11.2 g / L as Cu

(C) Antifungal cream 1. Formulation

2. Method a. Place in a main mixing vessel to which a variable speed “Silverson” mixer and sweep-blade inverted stirrer should be attached and weigh the B-phase material. Stir until uniform. Adjust temperature to 75 ° C.
b. Place in a separate container, weigh Phase A material, and mix with propeller stirrer until all solids are dissolved. Adjust temperature to 75 ° C.
c. Add Phase A to Phase B and make a smooth and uniform emulsion using a "Silverson" mixer.
d. Start the cooling of the vessel by operating the sweeping blade stirrer.
e. Continue cooling and mixing until the temperature is 35 ° C.
f. The pH should be between 5.3 and 5.5.

  A clinical diagnosis of onychomycosis was evaluated for subjects who had not yet been treated for fungi, photographs were taken, and cut nails were collected. Tests were allowed for those positive for these tests for onychomycosis.

  The antifungal composition (cream or solution) was used on infected nails twice daily during the treatment period.

During the clinical observation period, measurement of relevant nail area and photography were performed. Cut nails were collected for culture of KOH and dermatophytes. Clinicians evaluated subjects for onychomycosis using the following criteria:
"Ineffective" means that the nail that is positive for KOH and positive for culture is 10% or more;
“Bacteriological cure” means negative KOH and negative culture;
“Effective treatment” means that the nail involved in KOH is 10% or less and culture is negative; and • “Complete cure” is KOH and culture negative and target The nail is clinically transparent.

[ Result]
The results shown below are intermediate results from a 12-month study. Patients entered the study on different days and started treatment. Of the 18 patients enrolled in the study, at the time of reporting these results, 13 treatments reached 6 weeks, and 10 of them reached 12 weeks. Patients on Day 0 (Start), Week 6 and Week 12 were evaluated. These evaluation results are summarized in Table 3 in a table format. In any evaluation, no difference in effectiveness between the cream and the solution was recorded.

  The effect of the treatment method of this example is illustrated in FIGS. 1-4, which includes photographs of the patient's nails treated in this study.

  No side effects were reported

[Example 4: Treatment of onychomycosis with copper silicate]
The test reported in Example 3 was continued and the latest results are shown in Table 4, Table 5 and Table 6 below. Here, the results of clinical, mycological and efficacy measurements are listed respectively.

  The effect of the treatment method of this example is illustrated in FIGS. 5-7 including photographs of the patient's nails treated in this study.

  No side effects were reported.

[ Summary]
At week 26, three patients reached a major end point of “complete cure” and remained there for 26 weeks, 52 weeks after treatment. By 26 weeks after treatment, 4 patients (22%) became “effective treatments”. Beyond week 26, it increased by 1 patient and at week 39 only 3 “completely cured” patients were included.

  Since week 26, 5 (28%) patients have reached “mycological cure”. However, two of them returned to positive KOH at week 39. At 52 weeks, the rate of “mycological cure” was 22%.

  At 26 and 39 weeks, another 7 patients reached a “bacteriological change”, ie a change from positive culture to negative culture. A total of 12 patients were negative at week 26 and 10 patients were negative at 39 weeks.

  Overall, 67% of patients had negative cultures at the end of treatment, 55% at 13 weeks after treatment, and 50% (9 patients) at the end of the study.

  Both “complete cure” and “effective treatment” of primary and secondary endpoints depend on the rate of bacteriological cure. “Mycological cure” is defined as both KOH and culture are negative. However, the patient's KOH may not become negative until the sick nail is fully extended. It usually takes 12-18 months for a big toenail to completely grow. At the start of the study, 12 of 18 patients had a target nail infection rate of over 50% and 7 of them were involved in the epidermis (half moon). As a consequence of the severity of the disease, these patients may not have reached “bacteriological cure” and “effective treatment” and “full cure” within the time allotted to this study. Absent.

  The 26-week treatment period is much shorter than the 48-week period when most topical drugs are minimally used. From this study it is clear that by extending the treatment period, patients with more than 50% of the affected nail plate will benefit. Results at week 26 indicate that a large number (50%) improved clinically significantly, with nail plate disease decreasing to less than 50%.

  The present invention encompasses all modifications and adaptations apparent to those skilled in the art.

  Throughout this specification, unless the context requires another, the term `` comprise '' or variations thereof `` comprises '' or `` comprising '' It is understood that it is meant to encompass the presented integer or group of integers and does not exclude any other integer or group of integers.

2 is a set of photographs showing the time course of treatment of a nail dermatophyte infection in a first subject according to an example method of the present invention (day 0: untreated, weeks 6 and 12). 2 is a set of photographs showing the time course of treatment of a nail dermatophyte infection in a second subject according to an example method of the present invention (Day 0: untreated, weeks 6 and 12). 2 is a set of photographs showing the time course of treatment of nail dermatophyte infection in a third subject according to an example method of the present invention (day 0: untreated and week 6). FIG. 4 is a set of photographs showing the time course of treatment of nail dermatophyte infection in a fourth subject according to an example method of the present invention (Day 0: untreated and week 6). FIG. 6 is a set of photographs showing the time course of treatment of nail dermatophyte infection in a fifth subject according to an example method of the present invention (day 0: untreated, 12 weeks and 12 weeks after treatment). ). FIG. 6 is a set of photographs showing the time course of treatment of nail dermatophyte infection in a sixth subject according to an example method of the present invention (Day 0: untreated, weeks 6, 26 and treatment). 12 weeks later). FIG. 3 is a set of photographs showing an extended time course of treatment of a nail dermatophyte infection in a second subject according to an example method of the present invention (Day 0: untreated, Week 6, Week 26). Eyes and 12 weeks after treatment).

Claims (24)

  A method of treating or preventing microbial infection of a subject's nail, comprising locally administering an effective amount of copper silicate to the nail.   The method of claim 1, wherein the microbial infection is a fungal infection.   The method according to claim 1 or 2, wherein the subject is a mammal.   4. The method of claim 3, wherein the subject is a human.   Use of copper silicate to prepare a medicament for treating microbial nail infections.   Use of copper silicate to prepare a medicament for treating fungal nail infection.   The method according to claim 1, wherein the effective amount of copper silicate comprises 1 to 100 μg of copper.   7. A method according to any preceding claim, wherein the effective amount of copper silicate comprises 2 to 50 [mu] g copper.   7. A method according to any preceding claim, wherein the effective amount of copper silicate comprises 10 [mu] g copper.   The method according to claim 1, wherein the copper silicate is used at least 1 to 3 times a day.   The method according to claim 1, wherein the copper silicate is used at least once every 2 to 14 days.   Belonging to the genus Trichophyton, including Trichophyton Mentagrophytes (including Mentagolophytes subspecies and Interdigitalales subspecies), Trichophyton rubrum, Trichophyton megnini, Trichophyton schoenreiny, Trichophyton tonnes lance Dermatophytes such as seeds; yeasts such as Candida albicans, Candida glabrata, Candida sp. Species belonging to the genus Malassezia including symposiaris; species belonging to the genus Epidermophyton such as epidermophyton floccosm; species belonging to the genus scoplalosis; A method comprising one or more species belonging to the genus Aspergillus, a method of treating or preventing infection of a nail of the subject, the step of topically administering an effective amount of silicic acid copper nail on.   A method of treating or preventing a microbial disease of a nail in a subject, the method comprising locally administering an effective amount of copper silicate to the nail.   The microbial diseases are onychomycosis, onychomycosis of the distal nail, superficial white matter layer, onychoproximal onychomycosis; all secondary dystrophy onychomycosis; and all primary 14. The method of claim 13, selected from the group consisting of dystrophic onychomycosis.   A method of treating or preventing a fungal disease of a nail of a subject, comprising locally administering an effective amount of copper silicate to the nail, and (ii) an effective amount of another antifungal agent at least A method comprising administering to the subject.   Use of copper silicate for the preparation of a medicament for treating or preventing onychomycosis.   A composition adapted for topical administration to the nail comprising an antimicrobially effective amount of copper silicate.   The composition of claim 17 in the form of a solution.   The composition of claim 18 in the form of an aqueous acidified solution.   18. A composition according to claim 17 in solid form.   A method for producing a copper silicate composition adapted for topical administration comprising dissolving or mixing copper silicate in an aqueous or non-aqueous topical carrier.   The composition according to any one of claims 17 to 20, comprising about 100 mg / L to 10 g / L as Cu.   21. A composition according to any of claims 17 to 20 comprising about 1 g / L to 5 g / L.   21. The composition according to any one of claims 17 to 20, comprising about 2 g / L to 3 g / L as Cu.

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