Artificial nails for use in the treatment of nail diseases

Abstract

The present invention relates to an artificial nail for use in the treatment of nail disorders, particularly fungal nail disorders. The present invention further relates to methods for treating nail disorders using said artificial nail for extended and effective exposure of an antifungal composition to an infected nail, including cosmetic treatment of the infected nail.

Description

Technical Field

[0001] 〔Description〕 The present invention relates to artificial nails for use in the treatment of nail diseases, particularly fungal diseases of the nails. The present invention further relates to a method for treating nail diseases using said artificial nails for extended and effective exposure of an antifungal composition to infected nails, including cosmetic treatment methods for infected nails.

Background Art

[0002] Onychomycosis is a fungal infection of the nails and is the most common nail disease, accounting for approximately half of all nail abnormalities. Onychomycosis occurs in approximately 10% of the adult population. Onychomycosis can occur in both toenails and fingernails, but toenail infections are particularly common. One of the most common symptoms of a fungal infection of the nails is thickening and discoloration of the nails (mainly white or yellow). As the infection progresses, the nails become brittle and detach from the toenails or fingernails. If left untreated, the skin becomes inflamed under and around the nails and becomes painful. From a cosmetic perspective, nail infections can be unsightly and may cause significant discomfort to the body.

[0003] Several methods for treating nail infections are available, including systemic treatment (tablets or capsules) and topical treatment (e.g., creams or lacquers). The systemic treatment approach consists of administering an antibacterial or antifungal compound or agent to a subject suffering from a nail infection that is sufficiently absorbed from the gastrointestinal tract. Such compounds are formulated as tablets or capsules and are administered to the patient continuously or at regular intervals for the treatment of nail infections. Topical treatment is applied directly to the nails.

[0004] However, it is known that fungal infections of the nails accumulate in the deeper layers of the skin and nail bed. These areas do not form angiogenesis, and therefore, systemic treatment, for example, via systemic circulation, is difficult or impossible to achieve. As a result, healthy nails continue to grow, while the fungal infection continues to grow in the deeper layers of the nail. Another limitation associated with systemic treatment approaches is that the slow nail growth necessitates a prolonged treatment period (e.g., at least about 3-6 months), which can lead to the occurrence of potential systemic drug interactions and side effects, such as systemic toxicity, drug-drug interactions, and in some cases, even more severe hepatotoxicity. In summary, these limitations contribute to limited treatment compliance (e.g., patients may discontinue treatment), followed by a decrease in cure rates.

[0005] Topical treatments are applied directly to the nail. Topical treatments consist of applying an active compound or drug with antifungal or antibacterial activity directly to the surface of the infected nail (e.g., in the form of lacquer or cream). However, because the nail is an excellent natural rigid barrier against the entry of foreign substances, it still prevents the drug components from reaching the infected site of the nail and becoming effective. Therefore, the use of topical drugs to treat the nail directly is rather ineffective due to their poor penetration into the entire nail layer. Other topical treatment approaches aimed at softening the nail surface (e.g., targeting α-keratin) have been attempted to improve the penetration of therapeutic compounds, but have been found to be only moderately successful. Furthermore, topical treatments are usually left to dry after application. As a result of this procedure, the active ingredient and any additives constituting the formulation precipitate in the upper layers (surface or sublayer) of the nail with little access to or penetration into the nail bed. If the precipitated drug remains unactivated and, in fact, solubilized, it will block any channels that would have allowed access through diffusion into the deeper layers of the nail.

[0006] Therefore, a major challenge in treating onychomycosis is that existing systemic treatments (tablets or capsules) and topical treatments applied to the nails are often ineffective and frequently fail to cure the condition (nail diseases such as onychomycosis). Strategies for topical treatment of onychomycosis are constrained by the requirements of the formulation. Lacquers must harden within a specific time. While increasing the fluidity of the antifungal composition improves penetration into the nail, creams require a precise viscosity, as this also affects the evaporation and exposure time of the active compound at the site of infection. Furthermore, achieving prolonged and effective exposure of a liquid antifungal composition to the treatment site to produce an effective treatment is extremely difficult. In addition, in both lacquer and cream formulations, the additives necessary to inhibit the fungus must be absorbed, reach the precise location, and bind to their targets before crystallizing, evaporating, or migrating.

[0007] Considering the above, there is a need in the art for a treatment of nail diseases, including cosmetic procedures for nail fungal infections, that has improved efficacy, such as improved penetration of the active compound into the nail or infected site, is easy to use for long periods to ensure treatment compliance, prevents side effects from long-term drug regimen exposure, and ensures a high probability of successful treatment of nail diseases. Furthermore, there is a need for a treatment that reduces the negative cosmetic adverse effects and physical discomfort associated with nail infections. [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is, among other things, to address the above-mentioned needs in the art. The object of the present invention is achieved, among other things, as outlined in the appended claims.

[0009] More specifically, the above objectives are achieved, in particular, according to a first aspect of the present invention, by an artificial nail for use in the treatment of nail diseases, the artificial nail taking the shape of a nail to seal the surface of the nail and / or nail bed, the artificial nail comprising a polymer surface side similar to the keratinous plate of the nail and a ventral side directed toward the nail and / or nail bed to be treated, the ventral side comprising one or more reservoirs for holding a liquid composition containing an antimicrobial compound and / or the ventral side comprising one or more protrusions for providing adhesion of the liquid composition to the ventral side of the polymer layer, the one or more reservoirs being configured so that the liquid composition containing the antimicrobial compound can be applied to the nail and / or nail bed to be treated. [Means for solving the problem]

[0010] The artificial nail of the present invention provides continuous administration of an active antimicrobial compound or therapeutic agent, i.e., improved transungual delivery of the active compound to the site of infection or disease over a long period of time. As a result, higher compliance to treatment (e.g., adhesion), significantly improved efficacy, and / or cure rates are achieved. One or more reservoirs are located on the ventral inner surface facing the surface area to be treated of the nail or nail bed of the finger or toe to which the antimicrobial compound needs to be applied for treatment. Combined with specifically sealing the nail (i.e., creating a barrier that prevents evaporation of the liquid solution containing the antimicrobial compound), prolonged exposure of the site to be treated of the nail with the antimicrobial compound allows sufficient time for the antimicrobial compound to reach the site of action in a sufficient amount to be effective, thus improving transungual delivery of the active compound to the site of infection or disease. The sealed bond between the artificial nail and the nail or nail bed to be treated is such that it is protected or shielded from the external environment (e.g., not in contact with or substantially not in contact with ambient air). Under sealed or blocked conditions, nails have a greater ability to absorb liquid compositions and the solubilizing agents contained therein, meaning that liquids containing solubilizing agents can easily diffuse to the deeper layers of the nail. A further advantage of using artificial nails is that the blocking coverage of infected nails prevents or reduces cross-contamination by infected nails or reinfection of curing nails. The artificial nail precisely follows the contour of the nail plate as seen from the inside, covering at least 90%, preferably at least 95%, more preferably at least 98%, even more preferably 99%, and most preferably 100% of the nail plate surface.

[0011] Furthermore, to improve the therapeutic and cosmetic effects of the artificial nail of the present invention, it is preferable that it precisely conforms to the visible contour of the nail plate from the outside. Therefore, the outer surface of the artificial nail of the present invention may consist of a convex surface having the shape of a natural nail, and the inner surface facing the infected nail consists of a convex zone and a concave zone according to the three-dimensional geometric shape of the infected nail. The artificial nail is suitable for application to the nail and / or nail bed by attaching it to the edge of the nail epithelium, the lateral nail fold, and the epidermis beneath the nail plate, preferably at the distal end of the nail plate where the maximum distance to the distal end of the nail plate is at most 1 mm. The distance between the artificial nail and the lateral nail fold and nail epithelium of the nail and / or nail bed to be treated is at most 1 mm.

[0012] The artificial nail of the present invention comprises a ventral side consisting of one or more reservoirs for holding a liquid composition containing an antimicrobial compound, the ventral side comprising one or more protrusions for providing adhesion of the liquid composition to the ventral side. The one or more protrusions reduce the gaps required for the liquid meniscus to crosslink and provide an additional surface for the liquid to "stick" to the ventral side of the artificial nail. Thus, the protrusions result in a more uniform liquid film, improving the adhesion of the liquid to the artificial nail and resulting in improved antimicrobial effects and treatment of infected nail beds. Consequently, when the liquid composition is placed on the affected nail or nail bed, it is retained in place, more dispersed on the second polymer, and does not easily drip.

[0013] Another advantage of the present invention is that the artificial nail has an outer surface that is similar to the natural, non-infected nail surface, i.e., the natural appearance of a non-infected nail, such as shape, color, structure, size, and translucency, thereby improving the visual or cosmetic aspects, reducing the unpleasant appearance and physical discomfort associated with nail disease, further improving treatment compliance, and thus providing a more comprehensive cosmetic treatment method for infected nails. The artificial nail can be fitted to the specific natural nail to be treated, for example, by using 3D printing technology.

[0014] The artificial nails of the present invention are free from limitations on application or incubation time, limitations on the viscosity or evaporation of the antimicrobial composition, substitution challenges, or challenges in the absorption of compounds in the area of ​​the nail to be treated. The formulation may vary in fluidity and viscosity and may be a solution, suspension, gel, liposome formulation, or a combination thereof, but is preferably an aqueous, alcohol, or solvent-based liquid composition to improve impregnation into the infected nail or nail bed and enhance the therapeutic effect.

[0015] According to a preferred embodiment, the present invention relates to an artificial nail in which the one or more reservoirs consist of a liquid-permeable polymer matrix to allow the passage of a liquid composition and contact between the liquid composition and the nail and / or nail bed to be treated, the liquid-permeable polymer matrix being composed of one or more materials selected from the group consisting of keratin, polyester, polyurethane, polytetrafluoroethylene, polyethylene, polysiloxane, polyisocyanate, polymethyl methacrylate, modified polyacrylonitrile, polyetherimide, polylactide, polyglycolide, polycaprolactone, polyhyaluronic acid, cyclic olefin copolymer, collagen, chitosan cellulose acetate, and combinations thereof, preferably keratin and combinations thereof. The permeable polymer matrix may be provided with small openings to further improve the distribution of the liquid composition of the artificial nail in the one or more reservoirs. The liquid-permeable polymer matrix may be a liquid-permeable polymer closure element, opening, and / or end cap having an open sponge-like structure, allowing a liquid composition containing an antimicrobial agent to flow into and reach the infected nail or nail bed and to come into direct and continuous contact with the infected nail or nail bed throughout the treatment period, for the purpose of transnail delivery of active compounds to the site of infection or disease and to improve the effectiveness of treatment.

[0016] In yet another preferred embodiment, the present invention relates to an artificial nail in which the one or more protrusions have a 3D shape selected from the group consisting of mushrooms, wood (i.e., branched columns or microvilli), gyroids, lattices, cubes, cones, cylinders, pyramidal structures, and spheres, preferably having a mushroom shape. The specific 3D shape of the one or more protrusions provides an improved adhesive contact area for a liquid composition containing an antimicrobial compound from one or more reservoirs, which is held between the artificial nail of the present invention and the nail to be treated and a second polymer nail. These 3D structures improve the distribution of the liquid composition in the artificial nail and prevent dripping and overflow of the liquid composition while applying the artificial nail to the area to be treated. The liquid composition containing the antimicrobial compound may be in direct contact with the nail plate.

[0017] In another preferred embodiment, the present invention relates to an artificial nail in which the polymer layer is composed of one or more materials selected from the group consisting of keratin, polymethyl methacrylate, polyacrylate, polycarbonate, polyether, polyethersulfone, polyethylene terephthalate, polyisocyanate, polypropylene, polysiloxane, polystyrene, polysulfone, polyvinyl chloride, polyvinyl butyral, polyurethane, cellulose acetate, chitosan, and epoxy, preferably keratin and combinations thereof.

[0018] In another preferred embodiment, the present invention relates to an artificial nail comprising a liquid-permeable polymer matrix further comprising an adhesive polymer material selected from the group consisting of resins, rosin, TSF resins, polyepoxides, copal, latex, gum resins, styrax liquid, methyl salicylate, methacrylate, acrylate, diacrylate, triacrylate, sobornyl acrylate, dimethylacrylamide, ethyl cyanoacrylate, methacrylic acid, methyl methacrylate, N-butyl methacrylate, iso-butyl methacrylate, ethyl methacrylate, 2-ethylhexyl methacrylate, N,N-dimethyl-p-toluidine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, 2-hydroxy-4-(octyloxy)benzophenone, (2H-benzotriazole-2-yl)-4,6-diterpentylphenol, polyfunctional amines, preferably isophorone diamines, and combinations thereof. Adhesive polymer materials provide improved adhesion of polymer artificial nails to infected nails or nail beds and offer further enclosure of one or more reservoirs. The adhesive polymer material needs to be a liquid-permeable polymer material to allow the liquid composition to pass through and maintain continuous contact with the infected nail or nail bed surface. Furthermore, when applying artificial nails to infected nails, they can be further covered with an adhesive top layer, such as Tegaderm®.

[0019] According to another preferred embodiment, the present invention relates to an artificial nail in which one or more reservoirs contain a volume of 5 to 250 μl, preferably 10 to 150 μl, more preferably 25 to 125 μl, even more preferably 50 to 100 μl, and most preferably 75 to 85 μl. A minimum volume is required to facilitate the mimicry of a natural nail, depending on the efficacy of the liquid antimicrobial agent composition and the drug release rate obtained from the artificial nail.

[0020] In yet another preferred embodiment, the present invention relates to an artificial nail in which one or more reservoirs are at least two, preferably at least three, more preferably at least four, and most preferably at least five reservoirs. The presence of multiple separate reservoirs enables concomitant treatment of nail diseases, and the reservoirs are filled with different liquid compositions containing various antimicrobial compounds or different regimens. Another preferred embodiment is the sequential administration of different antimicrobial compositions on a weekly basis, for example, an aqueous composition in the first week and an alcohol-based composition containing an antifungal agent in the second week. The liquid composition containing the antimicrobial compound is preferably in direct contact with the nail plate. Direct contact with the nail plate improves the penetration and permeation of the drug into and through the nail plate.

[0021] In another preferred embodiment, the present invention relates to an artificial nail having a rigid structure of non-uniform thickness, wherein the dorsal side of the nail has a smooth surface, and the ventral side conforms to the nail and / or nail bed to be treated, that is, to the altered anatomical form of the nail plate developed by onychomycosis.

[0022] In yet another preferred embodiment, the present invention relates to an artificial nail in which the ventral (3) surface of the artificial nail is composed of a plurality of convex and concave surfaces that conform to the shape of the surface of the nail and / or nail bed (1) to be treated and / or conform to the contour of the nail and / or nail bed (1) to be treated. Thus, the outer surface of the artificial nail of the present invention may consist of convex surfaces having the shape of a natural nail, and the inner surface facing the infected nail may consist of convex and concave zones depending on the three-dimensional geometry of the infected nail. For precise shape, fit, and barrier properties, the artificial nail of the present invention is preferably obtained by 3D printing. The process of 3D scanning and 3D printing makes it possible to obtain an artificial nail with shape and precision. The anatomical morphology of the affected nail changes in onychomycosis. Onychomycosis causes the nail to become brittle, partially peel off, thicken due to hyperkeratosis, increase the porosity of the nail plate, and decrease structural integrity, resulting in a rougher surface. While not requiring an open compartment, if the 3D-printed artificial nail comes into direct contact with the nail plate (for example, close to the lateral fold and on the side), matching the geometric shape of the surface of the 3D-printed artificial nail can provide strong adhesion without the need to wear down the nail plate.

[0023] The artificial nail is attached to the lateral nail fold, nail epidermis, and the epidermis at the distal end of the nail plate, or in another embodiment, the artificial nail is attached directly to the nail plate. The artificial nail of the present invention can be attached to the surrounding epidermis, allowing and sealing the entire and / or the upper outward portion of the nail plate, thereby improving the hydration state. The lateral nail fold and the epidermis at the distal end of the nail are where liquid evaporates and affect the hydration state of the nail plate. Since the hydration state and water content are considered to be one of the most important parameters affecting the drug diffusion rate and the penetration and permeation of drugs, this is a feature that is very difficult to achieve and therefore is preferably replicated by using 3D printing in the manufacture of the artificial nail of the present invention.

[0024] According to yet another preferred embodiment, the present invention relates to an artificial nail in which the polymer layer is composed of at least one UV-curable polymer. UV-curable polymers are a specific group of polymers that can be easily 3D printed.

[0025] According to another preferred embodiment, the present invention relates to an artificial nail comprising at least one valve or at least one opening, in combination with closing means, such as a stopper, etc., for (re)filling one or more reservoirs (4) for holding a liquid composition containing an antibacterial compound in the polymer layer of the artificial nail. The valve may be a slit or a gap in a flexible polymer layer that contains the liquid composition and is small enough to maintain the sealing function of the artificial nail. However, the valve can be opened by the applied force, for example, using a needle or a syringe on the valve to re-(fill) the reservoir of the artificial nail with the liquid composition.

[0026] According to a second aspect, the present invention a) providing the artificial nail of the present invention; b) preparing the artificial nail by adding a liquid composition containing an antibacterial compound to one or more reservoirs; c) applying the prepared artificial nail to the nail and / or nail bed to be treated, thereby sealing the nail and / or its nail bed from the environment. The present invention relates to a method for treating nail diseases using an artificial nail, which includes these steps.

[0027] Preferably, the present invention relates to a cosmetic method for treating nail diseases using the artificial nails disclosed above. The method provides an artificial nail on top of the infected nail that has an outer surface which is the surface side that resembles the natural, uninfected nail surface, i.e., the natural appearance of an uninfected nail, such as shape, color, structure, and size, thereby reducing the unpleasant appearance and physical discomfort associated with nail diseases, further improving treatment compliance, and providing a cosmetic treatment method for infected nails by improving the visual or cosmetic aspects. The artificial nail may include means for adhering it to the natural nail to be treated. Similarly, the artificial nail may be attached to the natural nail to be treated and treated with an additional adhesive cover layer. The sealed bond between the artificial nail and the nail or nail bed to be treated is such that it is protected or shielded from the external environment (e.g., not in contact with or substantially not in contact with ambient air).

[0028] According to another preferred embodiment, the present invention relates to a method for treating a nail disease using an artificial nail, wherein the step of applying a prepared artificial nail includes bringing one or more reservoirs into direct contact with the nail and / or its nail bed to be treated.

[0029] In yet another preferred embodiment, the present invention relates to a method for treating nail diseases using artificial nails, wherein the liquid composition containing an antimicrobial compound is a solution comprising water and / or alcohol, propylene glycol, hydroxypropyl-β-cyclodextrin, hydrochloric acid, sodium hydroxide, and the antimicrobial compound. The water or alcohol-based liquid composition facilitates drug transport throughout the nail by promoting nail swelling, resulting in increased drug mobility in barrier and pore formation in the infected nail or nail bed. The liquid composition may be any fluid, gel, suspension, or colloid system (e.g., including liposomes or micelles). The aqueous composition enhances nail penetration.

[0030] According to another preferred embodiment, the present invention relates to a method for treating nail diseases using artificial nails, wherein the liquid composition comprises one or more compounds containing a sulfhydryl (-SH) group selected from the group consisting of acetylcysteine, cysteine, mercaptoethanol, and thioglycolic acid, preferably further comprising acetylcysteine.

[0031] Compounds containing sulfhydryl (-SH) groups, such as acetylcysteine, cysteine, and mercaptoethanol, can reduce and cleave disulfide bonds in nail proteins, destabilizing the nail keratin network and thereby increasing its permeability to antimicrobial agents.

[0032] In a preferred embodiment, the present invention relates to a method for treating nail diseases using artificial nails, wherein the nail and / or nail bed to be treated is abraded before the prepared artificial nail is applied to the nail and / or nail bed to be treated. Abrasion can help ensure proper adhesion of the artificial nail to the underlying nail and / or remaining structure, especially when the nail is thickened. While nails are an excellent barrier against the entry of foreign substances, they can also hinder effective topical treatment. Nails are composed of alpha-keratin, which provides structural rigidity. Mechanical methods such as nail abrasion can further reduce the structural integrity of the nail to be treated by partially removing the nail plate, and as a result, may be effective in increasing the penetration of antimicrobial compounds at the site of infection or disease.

[0033] In another preferred embodiment, the present invention relates to a method for treating nail diseases using artificial nails, wherein the antimicrobial compound is one or more selected from the group consisting of antifungal agents, itraconazole, tababolol, efinaconazole, terbinafine, miconazole, clotrimazole, bifonazole, butoconazole, econazole, fenticonazole, ketoconazole, oxyconazole, sulconazole, voriconazole, albaconazole, fluconazole, ravconazole, amorolfine, butenafine, chlorhexidine, naphthifine, andyrafungin, caspofungin, micafungin, benzoic acid, cyclopirox, tolnaphthate, undecylenic acid, crystal violet, and methylene blue, and preferably itraconazole.

[0034] In yet another preferred embodiment, the present invention relates to a method for treating a nail disease using an artificial nail, wherein the nail disease is one or more selected from the group consisting of onychomycosis, Pseudomonas infection, nail psoriasis, and paronychia, and is preferably onychomycosis.

[0035] According to a preferred embodiment, the present invention relates to a method for treating a nail disease using an artificial nail, wherein the prepared artificial nail is maintained on the nail and / or nail bed to be treated for a period of at least one day, preferably one week, more preferably at least two weeks, even more preferably at least four weeks, and most preferably at least two months.

[0036] According to a preferred embodiment, the present invention relates to a method for treating nail diseases using an artificial nail, applied to the nail and / or nail bed, by attaching the artificial nail to the edge of the nail epithelium, the lateral nail fold, and the epidermis beneath the nail plate, preferably at the distal end of the nail plate, where the maximum distance to the distal end of the nail plate is at most 1 mm, preferably at most 0.5 mm, more preferably at most 0.2 mm, even more preferably at most 0.1 mm, preferably at most 0.05 mm, and most preferably at most 0.01 mm. When the artificial nail of the present invention is attached to the nail plate, the further away from the distal end of the nail plate, the more surface area is not covered by the antimicrobial compound, and as a result, is exposed to lower concentrations of antifungal agents. Furthermore, the exposed nail plate may be exposed to air, which may reduce its hydration state.

[0037] In another preferred embodiment, the present invention relates to a method for treating nail diseases using an artificial nail, wherein the distance between the artificial nail and the lateral nail fold and nail epithelium of the nail and / or nail bed to be treated is at most 1 mm, preferably at most 0.5 mm, more preferably at most 0.2 mm, even more preferably at most 0.1 mm, preferably at most 0.05 mm, and most preferably at most 0.01 mm. The lateral nail fold and the epidermis at the distal end of the nail are areas where liquids evaporate and affect the hydration state of the nail plate. Therefore, as described above, by placing the artificial nail, the evaporation effect is prevented or reduced, thereby improving the antibacterial efficacy, since the hydration state and water content are considered to be one of the most important parameters affecting the diffusion kinetics of drugs. When the artificial nail is attached to the surrounding epidermis (nail epithelium), if it is further separated from the nail plate, the artificial nail will not have a natural appearance and feel, the comfort when worn will be reduced, and the surrounding healthy epidermis will be unnecessarily exposed to the drug. When artificial nails are simply attached to the nail plate, this merely seals the surface of the nail plate, which may be preferable if exposure of the lateral nail fold and nail epithelium to air is necessary for the healthy homeostasis of the nail plate environment.

[0038] In a further embodiment, the present invention relates to the use of the artificial nail of the present invention for the treatment of nail diseases. The use involves placing an artificial nail, which has one or more reservoirs containing a liquid composition having an antimicrobial agent, on an infected nail or nail bed such that the liquid composition having an antimicrobial agent comes into direct contact with the nail to be treated and the artificial nail seals (in a barrier manner) the nail or nail bed to be treated. [Brief explanation of the drawing]

[0039] [Figure 1] This figure shows a fungalally infected nail (1) on the foot being treated by applying the artificial nail (2) of the present invention. [Figure 2] This is a side view of the artificial nail (2) of the present invention, which consists of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) directed toward the nail and / or nail bed to be treated. [Figure 3] This figure shows the ventral side (3) of the artificial nail (2) of the present invention. [Figure 4] This is a magnified view of the ventral side (3) of an artificial nail (2) equipped with multiple reservoirs (4) for holding a liquid composition containing an antimicrobial compound for the treatment of an infected nail. [Figure 5] This figure shows the ventral side (3) of the artificial nail (2) of the present invention. [Figure 6] The figure shows that certain 3D structures, such as wood-like (7), mushroom-shaped (8), gyroid-shaped (9), etc., improve the adhesive contact area with the ventral side of the artificial nail (2) of the present invention, increase the surface tension of the liquid composition, and prevent the liquid composition from dripping and overflowing while the artificial nail is applied to the treatment site. [Figure 7] The figure shows that certain 3D structures, such as wood-like (7), mushroom-shaped (8), gyroid-shaped (9), etc., improve the adhesive contact area with the ventral side of the artificial nail (2) of the present invention, increase the surface tension of the liquid composition, and prevent the liquid composition from dripping and overflowing while the artificial nail is applied to the treatment site. [Figure 8]The figure shows that certain 3D structures, such as wood-like (7), mushroom-shaped (8), gyroid-shaped (9), etc., improve the adhesive contact area with the ventral side of the artificial nail (2) of the present invention, increase the surface tension of the liquid composition, and prevent the liquid composition from dripping and overflowing while the artificial nail is applied to the treatment site. [Figure 9] This is a side view of an artificial nail (2), which consists of a polymer surface side (5) that resembles the keratin plate of a nail and a ventral side (3) that faces the infected nail. [Figure 10] This is a cross-sectional view of the artificial nail (2) of the present invention, which is composed of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) facing the infected nail (1). [Figure 11] This is a cross-sectional view of the artificial nail (2) of the present invention, which is composed of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) facing the infected nail (1). [Figure 12] This is a cross-sectional view of the artificial nail (2) of the present invention, which is composed of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) facing the infected nail (1). [Figure 13] This figure shows a healthy nail and its anatomical morphology; the distal edge or end of the nail plate (15), the lateral nail fold (paranychium) (16), the nail epithelium (eponychium) (17), the nail plate (18), the lunula (19), and the proximal nail fold (20). [Figure 14] This figure shows an artificial nail (2) according to one embodiment of the present invention, wherein the ventral (3) surface of the artificial nail is composed of a plurality of convex (21) and concave (22) surfaces that conform to the shape of the surface of the nail and / or nail bed (1) to be treated. [Figure 15] This figure shows an artificial nail (2) according to one embodiment of the present invention, wherein the ventral (3) surface of the artificial nail is composed of a plurality of convex surfaces (23) and a plurality of concave surfaces (24) that follow the contour of the nail and / or nail bed (1) to be treated. [Modes for carrying out the invention]

[0040] The present invention will be described in more detail in the following embodiments and figures:

[0041] Figure 1 shows a fungalally infected nail (1) on a foot being treated by applying the artificial nail (2) of the present invention. When applied to the nail or nail bed to be treated, the artificial nail completely seals the infected nail from the environment along the contour of the natural nail and nail bed. By specifically sealing the nail (i.e., creating a barrier that prevents evaporation of the liquid solution containing the antimicrobial compound), transnail delivery of the active compound to the site of infection or disease is improved, giving the antimicrobial compound sufficient time to reach the site of action in an effective amount. Under sealed or barrier conditions, the nail has a greater ability to absorb the liquid composition and the solubilizing drug therein, which means that the liquid containing the solubilizing drug can easily diffuse to the deeper layers of the nail.

[0042] Figure 2 is a side view of the artificial nail (2) of the present invention, which comprises a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) directed toward the nail and / or nail bed to be treated. The ventral side comprises one or more reservoirs (4) for holding a liquid composition containing an antimicrobial compound for treating the infected nail and / or nail bed (1) to be treated. The reservoirs of the artificial nail are located on the inner surface of the ventral side facing the surface area of ​​the nail to be treated in the nail bed of a finger or toe where the antimicrobial compound needs to be applied for treatment. The artificial nail of the present invention provides continuous administration of the active antimicrobial compound to the site of infection over a long period of time.

[0043] Figure 3 shows the ventral side (3) of the artificial nail (2) of the present invention. The ventral side comprises a plurality of reservoirs (4) for holding a liquid composition containing an antimicrobial compound for the treatment of an infected nail.

[0044] Figure 4 is a magnified view of the ventral side (3) of an artificial nail (2) having multiple reservoirs (4) for holding a liquid composition containing an antimicrobial compound for the treatment of an infected nail. The reservoirs consist of a liquid-permeable polymer matrix that allows the liquid composition to pass through, providing liquid connectivity between the reservoirs, and to make contact between the liquid composition and the infected nail or nail bed to be treated. The permeable polymer matrix may also be provided with small openings (10) to further improve the distribution of the liquid composition in the artificial nail within one or more reservoirs (4), allowing the artificial nail (2), when placed on the infected nail or nail bed, to flow and make direct and continuous contact with the infected nail or nail bed during the course of treatment, for improved transnail delivery of the active compound to the site of infection or disease and improved efficacy of the treatment. These openings (4) may be located anywhere in the liquid polymer matrix of the reservoirs (4) that provide liquid connectivity between the reservoirs, but openings located closer to the infected nail or nail bed to be treated are preferred for optimal and continuous contact of the liquid with the infected nail or nail bed during the course of treatment.

[0045] Figure 5 shows the ventral side (3) of the artificial nail (2) of the present invention. The ventral side comprises one or more protrusions (6) which may have a specific 3D shape for providing adhesion of the liquid composition to the ventral side. The specific 3D shape of the protrusions improves the contact area of ​​the adhesive and increases the surface tension of the liquid composition from one or more reservoirs held between the infected nail and the ventral side of the artificial nail.

[0046] Figures 6 to 8 illustrate how certain 3D structures, such as wood-like (7), mushroom-shaped (8), gyroid-shaped (9), etc., improve the adhesive contact area with the ventral side of the artificial nail (2) of the present invention, increase the surface tension of the liquid composition, and prevent the liquid composition from dripping and overflowing when the artificial nail is applied to the treatment site.

[0047] Figure 9 is a side view of an artificial nail (2) comprising a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) directed toward the infected nail. The ventral side includes a reservoir (4) for holding a liquid composition containing an antimicrobial compound for the treatment of the infected nail and a plurality of protrusions (6) that provide an improved adhesive contact area with respect to the liquid composition in the reservoir. The reservoir (4) is composed of a liquid-permeable polymer matrix, which is composed of an adhesive polymer material (11) to enhance the adhesion of the artificial nail and provide further enclosure of the reservoir (4).

[0048] Figure 10 is a cross-sectional view of the artificial nail (2) of the present invention, which consists of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) directed toward the infected nail (1). The ventral side includes a reservoir (4) for holding a liquid composition containing an antimicrobial compound and a projection (6) for providing adhesion of the liquid composition to the ventral side of the polymer layer of the artificial nail. The artificial nail reservoir (4) is composed of a liquid-permeable polymer matrix, which consists of a layer of adhesive polymer material (11) that is liquid-permeable and allows the liquid composition to pass through and to make contact between the liquid composition and the nail and / or nail bed to be treated, as well as improving the adhesion of the artificial nail and providing further enclosure of the reservoir (4). The reservoir (4) further includes small openings (10) to further improve the dispersion of the liquid composition within one or more reservoirs (4), allowing for flow and direct and continuous contact with the infected nail or nail bed (1) during the treatment period. Furthermore, the artificial nail can be further coated with an adhesive top layer (11), for example, Tegaderm.

[0049] Figure 11 is a cross-sectional view of the artificial nail (2) of the present invention, which consists of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) facing the infected nail (1). The ventral side includes a reservoir (4) for holding a liquid composition containing an antimicrobial compound. The polymer layer of the artificial nail (2) includes a valve (14) for adding or (re)filling the reservoir (4).

[0050] Figure 12 is a cross-sectional view of the artificial nail (2) of the present invention, which consists of a polymer surface side (5) similar to the keratin plate of a nail and a ventral side (3) facing the infected nail (1). The ventral side includes a reservoir (4) for holding a liquid composition containing an antimicrobial compound. The polymer layer of the artificial nail (2) includes an opening combined with a closure means (14), such as a stopper, for adding or (re)filling the reservoir (4).

[0051] Figure 13 shows a healthy nail and its anatomical form; the distal edge or end of the nail plate (15), the lateral nail fold (paranychium) (16), the nail epithelium (eponychium) (17), the nail plate (18), the lunula (19), and the proximal nail fold (20). The artificial nail is suitable for application to the nail and / or nail bed by attaching it to the edge of the nail epithelium, the lateral nail fold, and the epidermis beneath the nail plate, preferably at the distal end of the nail plate, where the maximum distance to the distal end of the nail plate is at most 1 mm. The distance between the artificial nail and the lateral nail fold and nail epithelium of the nail and / or nail bed to be treated is at most 1 mm.

[0052] Figure 14 shows an artificial nail (2) according to one embodiment of the present invention, wherein the ventral (3) surface of the artificial nail is composed of a plurality of convex (21) and concave (22) surfaces that conform to the shape of the surface of the nail and / or nail bed (1) to be treated. The ventral side includes a reservoir (4) for holding a liquid composition containing an antimicrobial compound.

[0053] Figure 15 shows an artificial nail (2) according to one embodiment of the present invention, wherein the ventral (3) surface of the artificial nail is composed of a plurality of convex surfaces (23) and a plurality of concave surfaces (24) that follow the contour of the nail and / or nail bed (1) to be treated.

[0054] (Example 1) Ability to maintain high moisture content and humidity at the site of infection For the effective treatment of fungal nail diseases, it is known that 100% relative humidity (RH) or high water content promotes transnail drug delivery, resulting in more effective and efficient treatment of the affected nail. In this experiment, treatments for known nail diseases—creams, liquids, and lacquers—are tested in comparison to the artificial nails of the present invention, which are applied to a semipermeable membrane (a semipermeable transparent wound dressing film made of polyurethane using an acrylic adhesive Tegaderm) that mimics the condition of a nail. Before application of the treatment, the membrane was weighed using a calibrated weighing instrument (Mettler Toledo). The treatment was applied and maintained at room temperature for 1 hour and 24 hours. After 24 hours of exposure, the membrane was cleaned with a wipe (Kimtech). The membrane was weighed again to determine an approximate value of the water content.

[0055] As observed in this experiment, with known treatments such as creams, liquids, and lacquers, the moisture content after one hour fell well below 100%. However, when using the artificial nail of the present invention, the moisture content remained close to 90%, maintaining a high level of hydration even after 24 hours. Due to the evaporation and rapid removal of liquid formulations, the use of liquid formulations for the treatment of nail diseases is undesirable with the current state of technology. However, these results indicate that when high moisture content and hydration, more specifically aqueous liquid compositions, are used in combination with the artificial nail of the present invention, transnail drug delivery to the infected or diseased site is promoted, and treatment is improved.

[0056] (Example 2) Nail penetration assay This experiment investigates the effects of blocking and hydrating antimicrobial compounds on nail penetration and medicinal antifungal agents on nail permeability. Collected human nail clippings, approved by the relevant ethics committee, were used. Clippings of at least 8 mm in length were donated by healthy volunteers after written informed consent. Nail thicknesses ranged from 300 μm to 550 μm. Five different formulations using different antifungal agents (terbinafme, cyclopirox, voriconazole, chlorhexidine, and efmoconazole, obtained from Novartis, Pierre Fabre Dermatologie, Sandoz, Cedium, Valeant, and Ortho Dermatologics) were compared in modified Franz-type diffusion cell setups with both blocking and non-blocking configurations.

[0057] The penetration of antifungal formulations into nails under blocked conditions was tested using a vertical diffusion cell setup, or using an improved Franz-type diffusion cell (Permegear.com) with a small 0.5 mL receptor compartment, consisting of a donor chamber, a nail or a mount with a semipermeable membrane, and a receptor chamber with a stirrer. The nail was placed between the donor chamber and the receptor chamber, with the ventral side of the nail facing the receptor chamber.

[0058] The receptor solution (5 mL) was phosphate-buffered saline (pH 7.4), which was mixed with 0.5% polysorbate 80. The nail tip was hydrated in deionized water for 30 minutes. The nail tip was placed in a nail adapter sandwiched between the donor compartment and the receptor compartment of a diffusion cell. Each formulation was tested three times in both blocked and unblocked setups. For each condition, a single dose was applied to the donor compartment. In the blocked condition, the donor compartment of the inline cell setup was covered with an impermeable packaging material to limit evaporation and mimic NAIL-IT conditions. In the unblocked condition, the solution was administered while the donor compartment was kept open. The assembly was shaken in a horizontal shaker for 7 days. Next, receptor samples (0.4 mL) were collected after 24 hours and every 24 hours thereafter, and replaced with fresh culture medium for the entire 7 days. The samples were collected in glass tubes and stored in the dark at below -18°C until thawed for analysis. The concentration of the antifungal agent in the receptor chamber was quantified by HPLC.

[0059] Next, areas of nails exposed to the formulation were shredded, and the antifungal agent was extracted by shaking in 1 mL of methanol:water (80:20) or another solvent for 7 days. The concentration of the antifungal agent in the extract was determined by HPLC. The concentration of the antifungal agent in the extract was determined by LC-MS / MS using an AB Sciex API 3000 triple quadrupole mass spectrometer (Concord, ON, Canada) and an Agilent 1100 series HPLC system (Agilent Technologies, Palo Alto, USA), and a refrigerated autosampler. The antifungal assay was validated with respect to common validation parameters (accuracy, precision, limit of quantification, selectivity, matrix effect, recovery, carryover). Flow rate (μg cm⁻¹) -2 s -1 The permeability (cm² s) was calculated and expressed as micrograms of antifungal agent per square centimeter of nail. -1 ) is the flow rate at the starting concentration (μg cm⁻¹). -3It is derived from the flow rate by dividing by ). Table 1 summarizes the results for each compound and for each blocking and non-blocking test condition.

[0060] [Table 1]

[0061] The barrier-type nail according to the present invention provides significantly improved flow rate (>50% to 400% increase) and resulting permeability, as well as a significantly improved percentage of total recovery of the treated nail surface, demonstrating that therapeutic and cosmetic treatments using the artificial nail of the present invention have been enhanced.

[0062] (Example 3) In vivo case studies The artificial nails of the present invention were tested in subjects with mild to moderate onychomycosis, where up to three nails were affected. All affected nails were treated to avoid the risk of co-infection of untreated nails during treatment. The treatment procedure for infected toenails is described below.

[0063] The affected and thickened nail was thinned down to a normal, uninfected portion and removed as much as possible. The remaining nail or nail plate was worn down to the extent that it did not directly damage the nail. Subsequently, a 3D scan of the affected nail was performed to obtain its dimensions (length, width, curvature, and outline). Based on the nail dimensions, a polymer material (SLA material) in the shape of an artificial nail was fabricated to completely block the surface area to be treated. Attached to the polymer material was a polypropylene reservoir with a 3D mushroom structure, which was filled (approximately 200 ul) with an antifungal fluid composition, i.e., a formulation containing itraconazole as the active antifungal agent. This formulation contained 10 mg / ml of itraconazole in a solution containing propylene glycol, hydroxypropyl-β-cyclodextrin, hydrochloric acid, sodium hydroxide, and water. A polypropylene sponge was placed in the reservoir to hold the fluid composition in place. The open structure of this material allows the itraconazole solution to directly access the nail. Maintain the blocked state for the duration of the application period.

[0064] Before applying the present invention to the nail, a photograph of the nail at t=0 was taken. Immediately thereafter, the nail and nail bed contours were bonded with cyanoacrylate, and the nail was fixed by covering it with an oversized sheet of Fixiomull (BSN Medical). The nail was treated for at least 8 hours for 36 consecutive days. After treatment, the nail was removed, the treated nail and area were visually observed, and photographs were taken. The nail was then left untreated for 3 weeks, after which a visual observation was performed again. Furthermore, the above procedure was repeated 36 times in a cycle of once-daily application (total of 5 weeks). With each application cycle, the antifungal solution in the reservoir was replaced with a fresh solution.

[0065] These results indicate that, when properly treated, no leakage or overflow occurred during treatment. Visual improvement of infected nails was observed during the first 30 days (demonstrated by healthy nail growth), after which improvement ceased and treatment was discontinued. Comfort while wearing the device was indicated as "good" by the test subjects. [Explanation of symbols]

[0066] 1. Fungal infection of the nail 1. The nail and / or nail bed to be treated. 2 artificial nails 3 ventral side 4 Reservoirs 5. Polymer surface side 6 protrusions 7 woody 8 Mushroom shape 9. Gyroid 10 Small openings 11 Adhesive polymer materials 11. The top adhesive layer 14 valves 14 Closing means 15. The distal edge or end of the nail plate. 16. Lateral nail fold (paranicium) 17. Nail cuticle (eponychium) 18 Nail plate 19 Claw half moon 20 Proximal nail fold 21 Convex 22 Concave 23 Multiple convex surfaces 24 Multiple concave surfaces

Claims

1. An artificial nail (2) for use in the treatment of nail disease, wherein the artificial nail (2) takes the shape of a nail to seal the surface of the nail and / or nail bed of the nail, and the artificial nail is composed of a polymer layer comprising a surface side (5) similar to the keratin plate of the nail and a ventral side (3) directed toward the nail and / or nail bed (1) to be treated, wherein the ventral side includes one or more reservoirs (4) for holding a liquid composition containing an antimicrobial compound, and the ventral side (3) includes one or more protrusions (6) for providing adhesion of the liquid composition to the ventral side (3) of the polymer layer, wherein the one or more reservoirs (4) are provided with openings (10) to improve the distribution of the liquid composition within the one or more reservoirs (4), and the one or more reservoirs (4) are configured so that the liquid composition containing the antimicrobial compound can be applied to the nail and / or nail bed (1) to be treated. An artificial claw (2) in which one or more of the aforementioned protrusions (6) have a 3D shape selected from the group consisting of mushroom, wood, gyroid, cube, cone, cylinder, and sphere.

2. The artificial nail (2) according to claim 1, wherein the one or more reservoirs (4) are composed of a liquid-permeable polymer matrix for allowing the liquid composition to pass through and for contact between the liquid composition and the nail and / or nail bed (1) to be treated, the liquid-permeable polymer matrix being composed of one or more materials selected from the group consisting of keratin, polymethyl methacrylate, polyamide, polyester, polyetherimide, polyethersulfone, polyethylene, polyglycolide, polyisocyanate, polylactide, polypropylene, polysiloxane, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polyvinyl butyral, polyurethane, cellulose acetate, chitosan, collagen, and modified polyacrylonitrile.

3. The artificial nail (2) according to claim 1 or 2, wherein the polymer layer is composed of one or more materials selected from the group consisting of keratin, polymethyl methacrylate, polyacrylate, polycarbonate, polyether, polyethersulfone, polyethylene terephthalate, polyisocyanate, polypropylene, polysiloxane, polystyrene, polysulfone, polyvinyl chloride, polyvinyl butyral, polyurethane, cellulose acetate, chitosan, and epoxy.

4. The artificial nail (2) according to claim 1 or 2, wherein the one or more reservoirs (4) are composed of a liquid-permeable polymer matrix, further comprising an adhesive polymer material (1) selected from the group consisting of resin, rosin, TSF resin, polyepoxide, copal, latex, gum resin, Styrax ivy sap, methyl salicylate, methacrylate, acrylate, diacrylate, triacrylate, sovomyl acrylate, dimethylacrylamide, ethyl cyanoacrylate, methacrylic acid, methyl methacrylate, N-butyl methacrylate, iso-butyl methacrylate, ethyl methacrylate, 2-ethylhexyl methacrylate, N,N-dimethyl-p-toluidine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, 2-hydroxy-4-(octyloxy)benzophenone, (2H-benzotriazole-2-yl)-4,6-diterpentylphenol, polyfunctional amines, isophorone diamines, and combinations thereof.

5. The artificial nail (2) according to claim 1 or 2, wherein one or more reservoirs (4) contain a volume of 5 to 250 μl.

6. The artificial nail (2) according to claim 1 or 2, wherein one or more reservoirs (4) are at least two reservoirs.

7. The artificial nail (2) according to claim 1 or 2, wherein the artificial nail has a rigid structure of non-uniform thickness, the dorsal side of the nail has a smooth surface, and the ventral side conforms to the nail and / or nail bed to be treated.

8. The artificial nail (2) according to claim 1 or 2, wherein the ventral (3) surface of the artificial nail is composed of a plurality of convex and concave surfaces that conform to the shape of the surface of the nail and / or nail bed (1) to be treated, and / or conform to the contour of the nail and / or nail bed (1) to be treated.

9. The artificial nail (2) according to claim 1 or 2, wherein the polymer layer is composed of at least one UV-curable polymer.

10. The artificial nail (2) according to claim 1 or 2, wherein the polymer layer of the artificial nail comprises at least one valve or at least one opening combined with a closing means for (re)filling one or more reservoirs (4) for holding a liquid composition containing an antimicrobial compound.

11. A method of non-therapeutic cosmetic treatment for diseased nails using artificial nails, a) A step of preparing an artificial nail as defined in claim 1 or 2, b) A step of preparing an artificial nail by adding a liquid composition containing an antimicrobial compound to one or more reservoirs, c) A method comprising the step of applying a prepared artificial nail to a nail and / or nail bed, thereby sealing the nail and / or nail bed from the environment.

12. The method according to claim 11, wherein the step of applying the prepared artificial nail includes bringing one or more reservoirs into direct contact with the nail and / or its nail bed.

13. The method according to claim 11, wherein the liquid composition containing the antimicrobial compound is a solution containing water and / or alcohol, propylene glycol, hydroxypropyl-β-cyclodextrin, hydrochloric acid, sodium hydroxide, and the antimicrobial compound.

14. The method according to claim 13, wherein the liquid composition further comprises one or more compounds comprising a sulfhydryl (-SH) group selected from the group consisting of acetylcysteine, cysteine, mercaptoethanol, and thioglycolic acid.

15. The method according to claim 11, wherein the nail and / or nail bed are worn down before the prepared artificial nail is applied to the nail and / or nail bed.

16. The method according to claim 11, wherein the antibacterial compound is one or more selected from the group consisting of antifungal agents, itraconazole, tababolol, efinaconazole, terbinafine, miconazole, clotrimazole, bifonazole, butoconazole, econazole, fenticonazole, ketoconazole, oxyconazole, sulconazole, voriconazole, albaconazole, fluconazole, ravconazole, amorolfine, butenafine, chlorhexidine naphthifine, andyrafungin, caspofungin, micafungin, benzoic acid, cyclopirox, tolnaphthate, undecylenic acid, crystal violet, and methylene blue.

17. The method according to claim 11, wherein the nail disease is one or more selected from the group consisting of onychomycosis, pseudomonas infection, onychopsoriasis and paronychia.

18. The method according to claim 11, wherein the prepared artificial nail is maintained on the nail and / or nail bed for a period of at least one day.

19. The method according to claim 11, wherein the artificial nail is applied to the nail and / or nail bed by attaching it to the edge of the nail surface, the lateral nail fold, and the epidermis beneath the nail plate.

20. The method according to claim 11, wherein the distance between the artificial nail and the lateral nail fold and nail epithelium of the nail and / or nail bed is at most 1 mm.

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