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    • 专利摘要:
    The present invention relates to a plaster for the prevention or treatment of dysfunction or disease of nail growth, the use of the plaster and a method of preventing or treating dysfunction or disease of nail growth using the plaster. The present invention has the effect of providing a plaster for the prevention or treatment of nails, nail structure, nail growth and dysfunction or disease, not due to nail fungus. And this effect can be obtained through the use of the plaster of the independent claim, the claim of the treatment method and the plaster.
    公开号:KR20040031046A
    申请号:KR10-2004-7003255
    申请日:2002-09-04
    公开日:2004-04-09
    发明作者:루디 수실로
    申请人:트롬스도르프 게엠베하 운트 코. 카게 알츠나이미텔；
    IPC主号:
    专利说明:

    Plaster for treating dysfunction and disease of nail growth {PLASTER FOR THE TREATMENT OF DYSFUNCTIONS AND DISORDERS OF NAIL GROWTH}
    [2] For example, plasters for the treatment of nail fungus are known, but nothing has been written about plasters for the prevention or treatment of dysfunction or disease of nail growth. For example, WO-A-99 / 40955 discloses a pressure-sensitive adhesive substrate patch for the treatment of nail fungus. The device for treating fungal infections of toenails and nails consists of an occlusive layer and a pressure-sensitive adhesive layer, with an even amount of antifungal agent spread evenly. Spread together The matrix layer has a first surface attached to the backing layer and a second surface in contact with the infected nail and the surrounding skin area.
    [3] Methods for treating nail fungus are disclosed in US-A-5 464 610. Plaster preparations in this method consist of salicylic acid or salts, esters or mixtures thereof. The plaster agent is adhered to a carrier and salicylic acid is present in the plaster formulation in the range of 10% to 80% by weight of the plaster agent.
    [4] The composition taken out of nails, how to pull them out and how to treat nail and nail bottom infections are disclosed in US-A-5 993 790. Claimed is a local nail enamel composition consisting of an aqueous nail lacquer, preservative, urea and natural additives. The nail enamel composition is suitable for the treatment of fungi, yeast, bacterial infections of nails and nail bases.
    [5] US-A-5 753 256 discloses a plaster for the treatment of nail fungus comprising a flexible cover film, an acrylate polymer matrix layer, and an acrylate polymer matrix layer inseparably linked to the cover film. And miconazole, ecoconazole, isoconazole, thiconazole, terconazole, oxconazole, ketoconazole, itraconazole , Tolciclate, sulbentine, haloprogin, griseofulvin, cyclopirox, terbinafin and salts of these compounds.
    [6] It is an object of the present invention to provide a plaster for the prevention or treatment of nails, nail structure, nail growth, or dysfunction, which is not caused by nail fungus.
    [7] This object can be solved through the plaster of the independent claim, the claims of the method of treatment and the use of the plaster. Advantageous features, aspects, and details of the invention are apparent from the dependent claims, the description and the embodiments of the invention.
    [1] The present invention relates to a plaster for the prevention or treatment of dysfunction or disease of nail growth, the use of the plaster and a method of preventing or treating dysfunction or disease of nail growth using the plaster.
    [8] The present invention relates to a plaster for the prevention or treatment of dysfunction or disease of nail or nail growth. The plaster comprises a layer, which layer is designed to be in close contact with the nail and optionally close to the surrounding skin.
    [9] The layer comprises:
    [10] a) adhesive;
    [11] b) at least one skin or nail permeation enhancer;
    [12] c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    [13] d) at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants.
    [14] Plasters of two or more layers are also useful for the purposes described in the present invention. Preferred embodiments according to the invention comprise layers, which are distinguished as support layers and contact layers. The contact layer is attached to the support layer and is designed to be in close contact with the nail and, optionally, the surrounding skin. The contact layer includes the following.
    [15] a) adhesive;
    [16] b) at least one skin or nail permeation enhancer;
    [17] c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    [18] d) at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants.
    [19] The soft support layer holds the plaster and presses the plaster against the nails and skin to increase migration from the layer to the nail, nail base and surrounding skin. In addition, the support layer protects the contact layer from contamination. A preferred embodiment of the plaster is that the support layer is colorless or amber in color. Plaster has enough ductility to seal the affected nail correctly, even if it has an affected bumpy surface.
    [20] Another preferred embodiment of the present invention comprises a contact layer divided into a central layer and a drug containing layer. The central layer is designed to be in close contact with the support layer and the drug-containing layer and does not contain a pharmaceutically active drug, but the drug-containing layer contains a pharmaceutically effective amount of the pharmaceutically active drug as summarized below.
    [21] The support layer is preferably polyethylene (eg low density polyethylene, Plastotrans ), Polypropylene, polyurethane, polyester (eg Revatrans , TRICON GmbH, Freiburg), Guttagena Pibeuyisi (PVC) acrylonitrile-butadiene rubber (NBR) foil (foil) (e. G., Guttagena WK 68, Kalle Pentaplast, Germany ), Cotton, cotton / viscose, silk, polyethylene terephthalate lane (e.g., Hostaphan RN 36 sil; Hostaphan RN 100 sil, Loparex, Apeldoorn, The Netherlands), ethylene-methacrylic acid copolymers and mixtures of these materials. More preferably, it is a siliconized polymer or copolymer.
    [22] As used herein, the term 'contact layer' refers to a biocompatible adhesive, which adhesive is suitable to allow and assist the pharmacologically active agent and, optionally, the pharmacologically active agent to move and permeate to the nails, toenails and associated skin. Contains ingredients or additives with specific biological functions. The contact layer is inseparably bonded to the support layer and is preferably bonded to the soft or occluded support layer.
    [23] A sufficient amount of the pharmaceutically active agent may be included in the adhesive. Such adhesives are preferably adhesives such as gels or rubbers in order to allow and maintain the continued flow of the pharmaceutically active agent for a long time, preferably a week, through the skin and nails.
    [24] The plaster according to the invention can be produced in any form, such as in the form of circles, ellipses, right angles, quadratic curves. Preferred plaster sizes are 0.5cm 2, is 0.85cm 2, 1.5cm 2, 2.3cm 2 , 2.5cm 2 and 4.5cm 2.
    [25] Suitable therapeutically effective amounts of the pharmaceutically active drug are from 0.005 mg to 10 mg per cm 2 plaster, preferably from 0.01 mg to 5 mg per cm 2 plaster, more preferably from 1 mg to 4 mg per cm 2 plaster, most preferably Preferably from 1 mg to 2 mg per cm 2 plaster.
    [26] Such pharmaceutically active agents include polyenes such as amphotericin B and nystatin; Azoles such as miconazole and sertaconazole, in particular imidazole; Triazoles such as itraconazole, fluconazole and voriconazole; Allylamines such as naftifidine and terbinafine; And it can be classified into five groups consisting of benzofuranes such as griseofuvin (griseofuvin).
    [27] Plaster according to the present invention is fluconazole (Diflucan ), Butaconazole (butoconazole), enilconazole (enilconazole), penticonazole (sulconazole), sulconazole (naftifidine), Clioquinol, iodoquinol, limoprogin, griseofulvin, terbinafine [terbinafine (Lamisil , Novartis Pharma)], clotrimazole, itraconazole [ itraconazole (Sempera, Janssen Pharmaceutical)], thioconazole, miconazole, tolnftate, pyrogallol, econazole, isoconazole, tercona Terconazole, oxyconazole, voriconazole, amphotericin B, nystatin, tolciclate, sulbentine, tetoconazole (ketoconazole), cyclopyrox [ciclopirox (Batrafen , Aventis Pharma)], amorolfine, At least one of such drugs as bifonazole, sodium pyrithione, salicylic acid and salts of antifungal agents may be included in the pharmaceutically active content.
    [28] At the present technical level, plasters and plasters use these pharmaceutically active agents for the treatment of fungal infections of the nail, such as nail fungus. The present invention shows for the first time a pharmaceutically active drug for the prevention or treatment of nails, nail structure, nail growth, or dysfunction, not caused by nail fungus. In particular, it shows prevention or treatment of nail dystrophy that is not caused by nail fungus.
    [29] Nail fungus as a fungal infection is a subgroup of nail dystrophy. Thus, infections caused by fungi are excluded from the scope of the present invention.
    [30] Nail dystrophy includes onychocryptosis, melanonychia striata, white line disease, chronic paronychia, discolored nails, and thick nails , Unguis inflexus, spoon nails (koilonychia), scleronychia, onychogryphosis, onychouxis, onychoschisis, onychorrhexis, onychorrhexis It consists of many nail dysfunctions and diseases such as trachyonychia, split and split nails.
    [31] Onychomycosis caused and induced by onychomycosis is excluded from the scope of the present invention.
    [32] Among nail dystrophy, the most famous group, except for nail fungus, is caused by skin diseases such as neurodermitis (atopic eczema) and psoriasis. Moreover, bacterial or viral infections can cause or induce nail dystrophy.
    [33] In addition, drugs such as antibiotics, anticoagulants, angiotensin converting enzyme inhibitors (ACE inhibitors), betablockers, thiazides, and cytostatic agents (cytostatic agents) can prevent nail fungus. It is known to cause. Other causes of nail dystrophy are systemic diseases such as vitamin deficiency, kidney disease and heart disease. Another cause of nail dystrophy is contact with chemicals such as acids, bases, oxidants, and the like. Acids, bases, and oxidants have physical effects that can cause burns, cauterization, and mechanical destruction of the nail. Finally, idiopathic causes exist as a cause of dysfunction or disease in the nail.
    [34] The term nail is used here to refer to mammals, especially human nails and toenails.
    [35] A preferred embodiment of the plaster includes a contact layer. This contact layer is provided to completely enclose the infected nail to block the air. In addition, the plaster according to the invention may optionally comprise an additional oxygen cleaning agent. Suitable oxygen scavengers include transition metal chelates or complexes. Such a complex refers to a complex of salicylic acid or salicylate or polycarboxylic acid or complexed with an oxidizable organic acid or catalyzed.
    [36] Suitable skin or nail permeation enhancers are well known to those of ordinary skill in the art. Skin or nail permeation enhancers include fatty acid esters, fatty acid amides, fatty alcohols, 2- (2-ethoxyethoxy) -ethanol, esters of glycerol, glycerol monolaurate (glycerol monolaurate), propylene glycol (propylene glycol), polyethylene glycol (polyethylene glycols), unsaturated polyglycolic rise de glyceryl light (LabrafilTM M1944CS , gate Posay) [unsaturated polyglycolized glycerides (Labrafil M1944CS , Gattefosse) ], saturated polyester glycerides (Labrasol , gate Posay) [saturated polyglycerides (Labrasol , Gattefosse)], receiver linoleate acid partial glycerides light of (Softigen , Hulse) [a partial glyceride of ricinoleic acid (Softigen , Huls) ], Labrapak Hydro WL1219 (Global defoamer) [Labrafac HydroWL1219 (Gattefosse)], Estasan (Foaming agent), α-hydroxy acids, dimethylsulfoxide, decylmethylsulfoxide, pyrrolidones, salicylic acid, lactic acid (lactic acid), myristol, isopropyl myristate, dimethylformamide, dimethylacetamide, sodium dodecylsulfate, phospholipides, Transcutol (Gapepose) and Eutanol (Henkel). Also included are oleic acid / 2- (2-ethoxyethoxy) -ethanol, oleic acid / Labrafil and oleic acid (oleic acid) / Labrafac It is also natural to include mixtures such as (gapepose) and preferably about 1: 1 mixing is preferred.
    [37] In addition, enzymes such as proteolytic enzymes that facilitate the penetration of chemicals through hard nails or keratinous tissue may be used as penetration enhancers.
    [38] Examples of many common fatty acids include capric-, lauric-, myristic-, palmitic-, margaric-, stearic- and araki Arachidic, behenic-, lignoceric-, myristoleic-, palmitoleic-, petroselinic-, bascenic- ), Gadoleic-, gondoic-, urucic-, nervonic-, linoleic-, γ-linolenic-, dihomo -homo-γ-linolenic-, arachidonic-, 7,10,13,16-docosatetraenoic (7,10,13,16-docosatetraenoic-), 4,7 , 10,13,16-docosapentaenoic (4,7,10,13,16-docosapentaenoic-), α-linolenic-, stearridonic-, 8,11, 14,17-eicosatetraenoic (8,11,14,17-eicosatetraenoic-), 5,8,11,14,17-eicosapentaenoic (5,8,11,14,17-eicosapentaenoic- ), 7,10,13,16,19-docosahexaenoic (7, 10,13,16,19-docosahexaenoic-), 5,8,11-eicosatrienoic (5,8,11-eicosatrienoic-), taricric, santalbic-, stearic (stearolic-), 6,9-octadecenynoic- (6,9-octadecenynoic-), pyrulic-, crepenynic-, haysteric-t8, t10-octadecadiene-12 -Heisteric-t8, t10-octadecadiene-12-ynoic-, 5,8,11,14-eicosatetrainoic (5,8,11,14-eicosatetraynoic-), cerebronic-, Hydroxynervonic-, brasylic- and thapsic acid. Also useful are low alkyl esters and amides of the fatty acids or their corresponding alcohols. Glycerol esters contain one or more of these fatty acids.
    [39] Skin or nail permeation enhancers support and increase the penetration and penetration of pharmaceutically active agents through the skin to the nail and nail base. The term 'enhancement of penetration' or 'enhancement of penetration' refers to an increase in the permeability of the biofilm or skin and nails. Skin or nail permeation enhancers are most often used to increase the rate at which the pharmaceutically active agent penetrates the biofilm. The effect of permeation enhancement can be determined using a diffusion cell device called Merrit et al (Diffusion Apparatus for Skin Penetration, J Controlled Release, 1984, 1, 161-162). The device measures the rate of drug diffusion through the skin of an animal or human.
    [40] The active ingredient of the skin or nail permeation enhancer means an amount sufficient to provide the desired increase in membrane permeability and thus a sufficient amount of the pharmaceutically active agent in sufficient amount can achieve the desired permeation and penetration depth. .
    [41] In the plaster according to the present invention, the skin or nail permeation enhancer contains 0.1% to 30% of the weight of the adhesive in the contact layer in the layer. The content of permeation enhancer is preferably from 0.1% to 15% of the weight of the adhesive, more preferably from 0.5% to 10% of the weight of the adhesive and most preferably from 0.7% to 6% of the weight of the adhesive layer.
    [42] The plaster according to the invention optionally further comprises an additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants.
    [43] The additive, or if present, is present in the layer in an amount of 2% to 80% by weight of the contact layer. The content of the additive is preferably 5% to 40% of the contact layer, more preferably 8% to 30% of the contact layer, even more preferably 12% to 25% of the contact layer, most preferably 15 of the contact layer. % To 20% are included.
    [44] Binders are characterized by materials that bind or stick the powders together so that they form an adhesive layer to make them adhesive and further function in the form of an adhesive. Suitable binders are unnatural sugars, natural sugars such as sugar, starches from wheat, corn rice and potatoes, natural gums such as synthetic and acacia, gelatin and tragacanth, alginic acid, sodium alginate such as sodium alginate and ammonium calcium alginate, cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropyl-methylcellulose, and magnesium aluminate silicates, polyethylene glycols and waxes Contains inorganic materials.
    [45] If present, the binder content in the adhesive is 1% to 50% by weight of the adhesive. The content of the binder in the adhesive is preferably 10% to 50% by weight of the adhesive, more preferably 20% to 50% by weight of the adhesive, even more preferably 30% to 40 by weight of the adhesive %to be.
    [46] The crosslinking agent is aluminum acetylacetonate, acrylate-vinylacetate copolymer, aluminum acetonate, titanium acetylacetonate, titanium acetonate and It may be selected from the group comprising a crosslinking agent consisting of succinic acid.
    [47] If present, the content of crosslinker in the adhesive is 0.01% to 30% by weight of the adhesive. The content of the crosslinking agent in the adhesive is preferably 0.1% to 50% by weight of the adhesive, more preferably 10% to 50% by weight of the adhesive, even more preferably 30% to 40 by weight of the adhesive %to be.
    [48] Softeners include dibutyl sebacate (DBS, dibutylsebacate), Macrogol (Clariant, Frankfurt, Germany) and the like.
    [49] If present, the softener content in the adhesive is 0.001% to 25% by weight of the adhesive. The content of the softener in the adhesive is preferably 0.01% to 10% by weight of the adhesive, more preferably 0.1% to 6% by weight of the adhesive, even more preferably 0.5% to 3 by weight of the adhesive %to be.
    [50] Suitable solvents for plasters according to the invention include purified water; Ketones such as acetone, butanone, 2-pentanone, 3-pentanone; Alcohols such as ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol; It may be selected from esters such as acetic acid ethyl ester, acetic acid propyl ester and the like. Furthermore, mixtures of these solvents may also be used. Suitable cosolvents can be used with the abovementioned solvents or mixtures of solvents. The cosolvent is lactic acid, salicylic acid, succinic acid, urea, Miglyol 812 (Chemische Werke Huls, Marl, Germany), triglycerides, ethyl oleate, glycerylmonododecanoate, olein, oleate, Macrogol 6000 and lecithin.
    [51] If present, the solvent content in the adhesive or the total content of solvent and cosolvent is from 0.5% to 70% by weight of the adhesive. The content of the solvent or the total content of the solvent and cosolvent in the adhesive is preferably 3% to 60% by weight of the adhesive, more preferably 10% to 50% by weight of the adhesive, even more preferably the adhesive 20% to 40% by weight and most preferably 10% to 30% by weight of the adhesive.
    [52] The fillers are silica, silicic acid, preferably colloidal silica and colloidal silicic acid, lactose, Aerosil 200 Aerosil such as (Degussa-Huls, Frankfurt, Germany ) , Starch, Bentonit (Sudchemie, Mannheim, Germany) and the like.
    [53] If present, the filler content in the adhesive is 0.01% to 15% by weight of the adhesive. The content of the fillers in the adhesive is preferably 0.1% to 10% by weight of the adhesive, more preferably 0.3% to 6% by weight of the adhesive, even more preferably 0.5% to 3 by weight of the adhesive %to be.
    [54] Butylhydroxytoluene (BHT) is one example of a suitable antioxidant. Antioxidants are well known to those skilled in the art and may be selected from antioxidants in the art.
    [55] If present, the content of antioxidant in the adhesive is from 0.001% to 10% by weight of the adhesive. The content of antioxidant in the adhesive is preferably from 0.005% to 6% by weight of the adhesive, more preferably from 0.01% to 3% by weight of the adhesive, even more preferably from 0.05% to by weight of the adhesive 1%.
    [56] Suitable adhesives for plasters according to the invention include National Starch Durotak® . 80-1196 (National Starch Durotak 80-1196), National Starch Durotak 387-2825 ( National Starch Durotak 387-2825) or Monsanto gelba 737 (Monsanto Gelva 737) acrylic copolymer (acrylic copolymer) known as acrylic adhesive (acrylic adhesives) such as; Rubber adhesives such as polyisobutylene (PIB) (eg Adhesive Research MA-24), polyisoprene, styrene-isoprene copolymer or urethane rubber rubber-based adhesives known as adhesives; And silicone related silicone based adhesives known as silicone adhesives such as Dow Bio-PSA.
    [57] Adhesives that can be used for the present invention represent polymers, preferably acrylate copolymers. Suitable monomers or a mixture of monomers for making the acrylic lake polymer is methyl acrylate (methyl acrylate), methyl methacrylate (methyl methacrylate), butyl acrylate (butyl acrylate), butyl methacrylate, isooctyl acrylic Isooctyl acrylate, isooctyl methacrylate, aminoalkyl acrylate, amitoalkyl methacrylate, aminoalkyl methacrylate copolymers (Rohm) , Degussa-Huls Group EUDRAGIT available commercially from E 100, EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT NE 30 D), hydroxyethyl acrylate (hydroxyethyl acrylate), hydroxyethyl methacrylate (hydroxyethyl methacrylate ), 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate (2-ethylhex It consists of yl methacrylate, acrylic acid, methacrylic acid, vinyl acetate and glycidyl methacrylate. Acrylate based adhesives are commercially available from National Starch Chemical BV, Zutphen, NL, under the name Duratak. The type of product grade is Durotak 280-2287 (51% solution or solid material), Durotak 326-1753 (37% solution or solid matter), Durotak 280-1753 (33% solution or solid material), Durotak 901-1052 (48% solution or solid material), Durotak 80-1196 (solid material), Durotak 387-2825 (50% solution).
    [58] The adhesive is included in the plaster according to the invention in an amount of 40% to 95% by weight of the plaster. Preferably it is 60%-90% content, More preferably, it is 70%-90% content, Most preferably, it is 80%-90% content.
    [59] The present invention includes combination therapies. In such combination therapy, the plaster according to the invention can be used in combination with systemic treatment of nail fungus or with other systemic treatments for dysfunction or disease of nail or nail development.
    [60] The combination therapy is particularly useful for the prevention or treatment of nail fungus, nail depression, nail dry scleroderma, black nail striation, ringworm, eczema, chronic nail loss, nail discoloration, thick nail disease and nail dystrophy useful.
    [61] 'Plaster' as used herein refers to a device that can be applied to a nail and includes a contact layer that can be pressed against the nail surface. Suitable plaster devices include plaster or rubber, acrylics, urethanes, silicone materials, polyvinylalkyl ethers, gels and microporous membranes embedded therein. The plaster device may be combined with, integrated with or shaped into an artificial or fake nail shape to enhance cosmetic appearance.
    [62] 'Plaster' as used herein refers to the preparation of at least one pharmaceutically active agent, optionally suitable additives or binders together in a plaster apparatus.
    [63] In addition, the present invention represents the use of plasters for the prevention or treatment of transdermal or transnail malnutrition of a fingernail dysfunction, disease or growth disorder. The use of such plasters can be achieved by sticking them securely to protect the nails and, optionally, the surrounding skin, which includes:
    [64] a) adhesive;
    [65] b) at least one skin or nail permeation enhancer;
    [66] c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    [67] d) at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants.
    [68] Embodiments comprising two or more layers instead of the above mentioned plasters can also be used to prevent dysfunction or disease of nail or nail growth. The use of such plasters can be achieved by sticking them securely to protect the nails and, optionally, the surrounding skin, which includes:
    [69] a) support layer; And
    [70] b) a contact layer attached to the support layer and designed to be in close contact with the nail and, optionally, the surrounding skin;
    [71] The contact layer includes the following.
    [72] aa) an adhesive;
    [73] bb) at least one skin or nail permeation enhancer;
    [74] cc) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    [75] dd) at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants.
    [76] One important aspect of the present invention is that the use of plaster does not require the procedure of drilling at least one hole in the nail or removing the nail from day to day. Another advantage of the present invention is that the plaster is both convenient and convenient to use and familiar to the user.
    [77] In addition, the plaster according to the present invention can be used for nail fungus, nail claw depression, nail dry scleroderma, black nail striation, ringworm, eczema, chronic nail anopathy, nail discoloration, thick nail claw and nail dystrophy It can be used in combination with systemic treatment of dysfunction and disease of nail or nail growth.
    [78] In the present invention, in order to treat the nail or the dysfunction of the growth of the nail, the nail, sticking to the nail to protect the nail and optionally the surrounding skin by the sufficient content of at least one pharmaceutically active drug nail, nail base It also shows how percutaneous or hyperparaplegic delivery can be made to surrounding tissues.
    [79] One advantage of the method according to the invention is that the method does not require a procedure for punching the nail or having to peel off the nail every day.
    [80] The method according to the invention can also be applied in combination with systemic treatment of nail fungus or systemic treatment for dysfunction or disease of nail or nail growth. In particular, the combination of the method according to the invention with systemic treatment of nail fungus or systemic treatment for dysfunction or disease has proven to be effective.
    [81] The following examples illustrate the invention but are not intended to limit the scope of the invention to this particular embodiment.
    [82] The plaster or nail patch preferably comprises a support layer or a release liner. If present, the support layer is preferably made of PVC, such as a beating agent or PVC NBR foil, and the release liner is made of PET, such as a PET foil having a double sided cone cone (100 μm). It is desirable to be made.
    [83] Example 1
    [84] Plaster 1: composition of contact layer for 1.0 cm 2 plaster
    [85] No.Furtherancedensity OneCertaconazole1.4mg 2Durotak 387-28258.80mg 3Lactic acid0.11mg 4Aerosil 2000.33mg 5Aluminum acetylacetonate0.11mg
    [86] The efficiency of plaster was investigated in patients suffering from fingernail dystrophy.
    [87] One patient had 40% dystrophic nails at the start of treatment. This level could drop to 15% after 24 weeks of treatment with plaster. The other patient was treated for 24 weeks and the area of ditrophic nails could be reduced from 20% to 5%. Other patients also reduced the area of affected nails from 30% to 10% after treatment with plaster for 24 weeks.
    [88] Few patients had only minor side effects during the treatment period. The side effect is characterized by keratinization of the tissue surrounding the infected nail.
    [89] One of the advantages of plaster described here is that plaster is only replaced once a week, not once per day. Therefore, an excess of antifungal medication is used to ensure that a sufficient amount of antifungal agent is still present in the plaster's adherent layer after a week. The amount of antifungal drug remaining in the plaster is preventive and can prevent the development of infection and reduce the risk of third party infection by the patient.
    [90] Plasters 2 to 6 according to Examples 2 to 6 show similar results.
    [91] The duration of treatment can last one year or more in a separate case. Typically, the treatment period will take from one month to several months under conditions where the plaster is replaced weekly.
    [92] Example 2.
    [93] Plaster 2. Composition for the preparation of 1.0 cm 2 plaster
    [94] No.Furtherancecontent OneClotrimazole1-2mg 2Durotak 87-2852 solution (36.1%)22.2mg 3Ethyl alcohol (96%)2mg
    [95] The composition will be weighed and mixed until homogeneous. The mixture can be applied to a siliconized polyester sheet (thickness 75 μm, Loparex, Apeldorn, NL). The wet thickness of the glue film reaches 400 mu m. Following 15 minutes drying at 60 ° C. in a subsequent drying cabinet and storage for 12 hours at 25 ° C., the glue layer will be covered with a 50 μm thick polyolefin film (Cotran No. 9722, from 3M-Medica, Borken, Germany). )
    [96] Finally, a self-adhesive plaster of the size of a nail or toenail may be punched out of the sheet.
    [97] Example 3.
    [98] Plaster 3: composition for the production of 1.0 cm 2 plaster
    [99] No.Furtherancecontent OneClotrimazole1.8mg 2Durotak 36-6172 solution (57.1%)14mg 3n-heptane2mg
    [100] The composition will be weighed and mixed until homogeneous. The mixture can be applied to a siliconized polyester sheet (thickness 75 μm, Loparex, Apeldorn, NL). The wet thickness of the glue film reaches 400 mu m. Following 15 minutes drying at 60 ° C. in a subsequent drying cabinet and storage for 12 hours at 25 ° C., the glue layer will be covered with a 50 μm thick polyolefin film (Cotran No. 9722, from 3M-Medica, Borken, Germany). )
    [101] Finally, a self-adhesive plaster of the size of a nail or toenail may be punched out of the sheet.
    [102] Example 4.
    [103] Plaster 4: composition for the production of 1.0 cm 2 plaster
    [104] No.Furtherancecontent OneTerbinafine1.5mg 2Durotak 87-2100 solution (52.9%)15.1mg 3Ethyl alcohol (96%)3mg
    [105] The composition will be weighed and mixed until homogeneous. The mixture can be applied to a siliconized polyester sheet (thickness 75 μm, Loparex, Apeldorn, NL). The wet thickness of the glue film reaches 400 mu m. Following 15 minutes drying at 60 ° C. in a subsequent drying cabinet and storage for 12 hours at 25 ° C., the glue layer will be covered with a 50 μm thick polyolefin film (Cotran No. 9722, from 3M-Medica, Borken, Germany). )
    [106] Finally, a self-adhesive plaster of the size of a nail or toenail may be punched out of the sheet.
    [107] Example 5.
    [108] Plaster 5: composition for the production of 1.0 cm 2 plaster
    [109] No.Furtherancecontent OneAmorphine1.7mg 2Durotak 387-2516 solution (42.5%)18.8mg 3Ethyl alcohol (96%)3mg
    [110] The composition will be weighed and mixed until homogeneous. The mixture can be applied to a siliconized polyester sheet (thickness 75 μm, Loparex, Apeldorn, NL). The wet thickness of the glue film reaches 400 mu m. Following 15 minutes drying at 60 ° C. in a subsequent drying cabinet and storage for 12 hours at 25 ° C., the glue layer will be covered with a 50 μm thick polyolefin film (Cotran No. 9722, from 3M-Medica, Borken, Germany). )
    [111] Finally, a self-adhesive plaster of the size of a nail or toenail may be punched out of the sheet.
    [112] Example 6.
    [113] Plaster 6. Composition of contact layer for 1.0 cm 2 plaster
    [114] No.ingredientConcentration OneEUDRAGIT E10042.2 g 2Fluconazole17.1 g 3Dibutyl Sebacate19.0 g 4Susanic acid3.8 g 5Acetone21.0 g 6Isopropanol2.3g 7ethanol11.7 g
    [115] equipment
    [116] The solution is made in a high speed agitation tank. The stirrer may be a dissolution disc and may, for example, ensure complete agitation even at elevated viscosities. At the laboratory scale, coating and drying can be carried out in laboratory coating equipment with an integrated dryer (LTS / LTS by W. Mathis AG, Switzerland).
    [117] Instructions for processing
    [118] Acetone, isopropanol and ethanol are in the stirred tank. And EUDRAGIT E 100 is added in small portions for 90 minutes. Stirrer EUDRAGIT It is set at a speed that melts the E 100 and prevents the formation of deposits. Dibutyl sebacate is added immediately and stirring continues for the next 20 minutes. Then fluconazole is added with vigorous stirring and susnic acid is added little by little into the polymer solution. After complete addition of the sonic acid, the polymer solution is further stirred for 20 minutes.
    [119] Coating is carried out with the last polymer solution under the following conditions.
    [120] Coating: About 100 g of the polymer solution is applied to a support layer foil (15 μm thick, Revatrans MN, Tricon GmbH Freiburg) by means of a rotary doctor blade in a nip of 200 μm.
    [121] Drying: The drying proceeds at 60 ° C. for 10 minutes. Circulated air: 1500m 3 / h, exhaust air: 80m 3 / h.
    [122] The present invention has the effect of providing a plaster for the prevention or treatment of nails, nail structure, nail growth and dysfunction or disease, not due to nail fungus. And this effect can be obtained through the use of the plaster of the independent claim, the claim of the treatment method and the plaster.
    权利要求:
    Claims (33)
    [1" claim-type="Currently amended] A layer designed to adhere to the nail and, optionally, the surrounding skin, the layer comprising:
    a) adhesive;
    b) at least one skin or nail permeation enhancer;
    c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    d) A plaster for the prevention or treatment of a dysfunction or disease of the nail, comprising at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants.
    [2" claim-type="Currently amended] a) support layer; And
    b) the contact layer comprises a contact layer attached to the support layer and designed to be in close contact with the nail and, optionally, the surrounding skin,
    The contact layer is
    aa) an adhesive;
    bb) at least one skin or nail permeation enhancer;
    cc) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    dd) A plaster for the prevention or treatment of a dysfunction or disease of the nail comprising at least one additive selected from the group consisting of a binder, a crosslinking agent, a softener, a solvent, a filler and an antioxidant.
    [3" claim-type="Currently amended] 3. The plaster of claim 2 wherein said support layer is a closed support layer.
    [4" claim-type="Currently amended] The method of claim 1, wherein the skin or nail permeation enhancer is fatty acid, fatty acid ester, fatty acid amide, fatty alcohol, 2- (2-ethoxyethoxy) -ethanol [2- (2- ethoxyethoxy) -ethanol], esters of glycerol, glycerol monolaurate, propylene glycol, polyethylene glycol, unsaturated polyglycolide glycerides, saturated polyglycerides, partial glycerides of ricinoleic acid, α-hydroxy acids, dimethyl sulfoxide Side, decylmethylsulfoxide, pyrrolidones, salicylic acid, lactic acid, myristyl, isopropyl myristate, dimethylformamide, dimethylacetamide, sodium dodecyl sulfate, phospholipides and proteolytic enzymes A plaster selected from the group consisting of.
    [5" claim-type="Currently amended] The plaster according to any one of claims 1 to 4, wherein the skin or nail permeation enhancer is contained in the contact layer in an amount of 0.7% to 6% by weight of the contact layer.
    [6" claim-type="Currently amended] 6. A plaster according to any one of claims 1 to 5, wherein the additive is contained in the contact layer in an amount of 15% to 20% by weight of the contact layer.
    [7" claim-type="Currently amended] The method according to any one of claims 1 to 6, wherein the pharmaceutically active agent is fluconazole (Diflucan ), Butoconazole, enylconazole, penticonazole, sulfonazole, naphthypidine, clioquinol, iodo Quinol, limoprogin, griseofulvin, terbinafine (Lamisil ® ), clotrimazole, itraconazole (Sempera ® ), thioconazole, myconazole, tolnaftate, pyrogallol, echonazol, isoconazole, ter to Kona sol, oxy nose sol, voriconazole, amphotericin B, you statins, tolyl Sickle rate, alcohol bentin, ketoconazole, ciclopirox (Batrafen ), amorphous rolpin, before-najol, sodium pyrithione, salicylic acid and A plaster selected from the group consisting of salts of these drugs.
    [8" claim-type="Currently amended] The plaster according to any one of claims 1 to 7, wherein the pharmaceutically active drug is contained in the adhesive in an amount of 0.01 mg to 5 mg per cm 2 plaster.
    [9" claim-type="Currently amended] The plaster of claim 1, wherein the adhesive is selected from the group consisting of acrylic adhesives, rubber adhesives and silicone adhesives.
    [10" claim-type="Currently amended] 10. A plaster according to any one of claims 1 to 9, wherein the adhesive is contained in the plaster in an amount of 80% to 90% by weight of the layer.
    [11" claim-type="Currently amended] Combination therapy in which plaster is used in combination with systemic treatment of dysfunctions and diseases of nail or nail growth.
    [12" claim-type="Currently amended] A layer designed to adhere to the nail and optionally to the surrounding skin, the layer comprising:
    a) glue
    b) at least one skin or nail permeation enhancer;
    c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    d) at least one additive selected from the group consisting of binders, crosslinking agents, emollients, solvents, fillers and antioxidants, comprising a sticky adhesive to protect the nails and optionally the surrounding skin of the nails and thereby the function of nail or nail growth Use of plaster for the prevention or treatment of percutaneous or hard palpation of disorders or diseases.
    [13" claim-type="Currently amended] a) support layer; And
    b) a contact layer attached to the support layer and designed to be in close contact with the nail and, optionally, the surrounding skin;
    The contact layer,
    aa) an adhesive;
    bb) at least one skin or nail permeation enhancer;
    cc) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    dd) at least one additive selected from the group consisting of binders, crosslinking agents, emollients, solvents, fillers and antioxidants, and is adherent to sticking to protect the nails and optionally the surrounding skin of the nails, thereby avoiding nail dysfunction or disease Use of plaster for the prevention or treatment of sexual or hypersensitivity.
    [14" claim-type="Currently amended] Use of a plaster according to claim 13, wherein said support layer is a closed support layer.
    [15" claim-type="Currently amended] The method of claim 12, wherein the skin or nail permeation enhancer is fatty acid, fatty acid ester, fatty acid amide, fatty alcohol, 2- (2-ethoxyethoxy) -ethanol [2- (2- ethoxyethoxy) -ethanol], esters of glycerol, glycerol monolaurate, propylene glycol, polyethylene glycol, unsaturated polyglycolide glycerides, saturated polyglycerides, partial glycerides of ricinoleic acid, α-hydroxy acids, dimethyl sulfoxide Side, decylmethylsulfoxide, pyrrolidones, salicylic acid, lactic acid, myristyl, isopropyl myristate, dimethylformamide, dimethylacetamide, sodium dodecyl sulfate, phospholipides and proteolytic enzymes Use of a plaster selected from the group consisting of.
    [16" claim-type="Currently amended] Use of a plaster according to any one of claims 12 to 15, wherein the skin or nail permeation enhancer is contained in the contact layer in an amount of 0.7% to 6% by weight of the contact layer.
    [17" claim-type="Currently amended] 17. Use of a plaster according to any one of claims 12 to 16, wherein the additive is contained in the contact layer in an amount of 15% to 20% by weight of the contact layer.
    [18" claim-type="Currently amended] Of claim 12 to 17 Compounds according to any one of the preceding, the active drug over the drug is fluconazole (Diflucan ), Unit Toko najol, enyl to Kona sol, pen Tycho najol, liquor to Kona sol, naphthyl typhimurium Dean, clo quinol, EO also Quinol, limoprogin, griseofulvin, terbinafine (Lamisil ® ), clotrimazole, itraconazole (Sempera ® ), thioconazole, myconazole, tolnaftate, pyrogallol, echonazol, isoconazole, ter to Kona sol, oxy nose sol, voriconazole, amphotericin B, you statins, tolyl Sickle rate, alcohol bentin, ketoconazole, ciclopirox (Batrafen ), amorphous rolpin, before-najol, sodium pyrithione, salicylic acid and Use of a plaster selected from the group consisting of salts of such drugs.
    [19" claim-type="Currently amended] Use according to any one of claims 12 to 18, wherein the pharmaceutically active drug is contained in the adhesive in an amount of 0.01 mg to 5 mg per cm 2 plaster.
    [20" claim-type="Currently amended] 20. The use of a plaster according to any one of claims 12 to 19, wherein said adhesive is selected from the group consisting of acrylic adhesives, rubber adhesives and silicone adhesives.
    [21" claim-type="Currently amended] 21. Use of a plaster according to any one of claims 12 to 20, wherein said adhesive is contained in the plaster in an amount of 80% to 90% by weight of the contact layer.
    [22" claim-type="Currently amended] 22. The method according to any one of claims 12 to 21, wherein the dysfunction or disease of the nail or nail growth, in particular nail fungus, nail depression, nail dry scleroderma, black nail striation, ringworm, eczema, chronic Use of plaster in combination with other forms of systemic treatment of no nail, nail discoloration, thick nail disease and nail dystrophy.
    [23" claim-type="Currently amended] A layer designed to adhere to the nail and, optionally, the surrounding skin, the layer comprising:
    a) adhesive;
    b) at least one skin or nail permeation enhancer;
    c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    d) dysfunction of nail or nail growth, comprising at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants, and sticking securely to protect the surrounding skin of the nail and optionally the nail B) methods of preventing or treating percutaneous or hard palpation of the disease.
    [24" claim-type="Currently amended] a) support layer; And
    b) the contact layer comprises a contact layer attached to the support layer and designed to be in close contact with the nail and, optionally, the surrounding skin,
    The contact layer,
    aa) an adhesive;
    bb) at least one skin or nail permeation enhancer;
    c) a therapeutically effective amount of at least one pharmaceutically active agent contained in said layer; And
    dd) a dysfunction of nail or nail growth, comprising at least one additive selected from the group consisting of binders, crosslinkers, emollients, solvents, fillers and antioxidants, and sticking together to protect the surrounding skin of the nail and optionally the nail (B) prevention or treatment of percutaneous or hyperparaplegic disease.
    [25" claim-type="Currently amended] The method of claim 24, wherein the support layer is an occlusive support layer.
    [26" claim-type="Currently amended] The skin or nail permeation enhancer according to any one of claims 23 to 25, wherein the skin or nail permeation enhancer is fatty acid, fatty acid ester, fatty acid amide, fatty alcohol, 2- (2-ethoxyethoxy) -ethanol [2- (2- ethoxyethoxy) -ethanol], esters of glycerol, glycerol monolaurate, propylene glycol, polyethylene glycol, unsaturated polyglycolide glycerides, saturated polyglycerides, partial glycerides of ricinoleic acid, α-hydroxy acids, dimethyl sulfoxide Side, decylmethylsulfoxide, pyrrolidones, salicylic acid, lactic acid, myristyl, isopropyl myristate, dimethylformamide, dimethylacetamide, sodium dodecyl sulfate, phospholipides and proteolytic enzymes A prophylactic or therapeutic method selected from the group consisting of.
    [27" claim-type="Currently amended] 27. The method of any one of claims 23 to 26, wherein the skin or nail permeation enhancer contains from 0.7% to 6% by weight of the contact layer in the contact layer.
    [28" claim-type="Currently amended] 28. The method of any one of claims 23 to 27, wherein the additive contains 15% to 20% by weight of the contact layer in the contact layer.
    [29" claim-type="Currently amended] Of claim 23 to claim 28, Compounds according to any one of the preceding, the active drug over the drug is fluconazole (Diflucan ), Unit Toko najol, enyl to Kona sol, pen Tycho najol, liquor to Kona sol, naphthyl typhimurium Dean, clo quinol, EO also quinol, remote procedure long, so Seo pulbin, terbinafine (Lamisil , Novartis Pharma), clotrimazole, itraconazole (Sempera ), thio to Kona sol, M. najol, toll-naphthyl lactate, pyrogallol, echo najol, iso to Kona sol, Terre to Kona sol, oxy nose sol, voriconazole, amphotericin B, you statins, tolyl Sickle rate, alcohol bentin, ketoconazole, ciclopirox (Batrafen ), amorphous rolpin, before-najol, sodium pyrithione, salicylate Preventing or treating selected from the group consisting of silicic acid and salts of such drugs.
    [30" claim-type="Currently amended] 30. The method of any one of claims 23 to 29, wherein the pharmaceutically active drug is contained in the adhesive in an amount of 0.01 mg to 5 mg per cm 2 plaster.
    [31" claim-type="Currently amended] 31. The method of any one of claims 23-30, wherein the adhesive is selected from the group consisting of acrylic adhesives, rubber adhesives and silicone adhesives.
    [32" claim-type="Currently amended] 32. The method of any one of claims 23 to 31 wherein the adhesive contains 80% to 90% by weight of the contact layer in the plaster.
    [33" claim-type="Currently amended] 33. The method according to any one of claims 23 to 32, wherein the dysfunction and disease of nail or nail growth, in particular nail fungus, nail depression, nail dry scleroderma, black nail striation, ringworm, eczema, chronic nails A prophylactic or therapeutic method in combination with other forms of systemic treatment of noness, nail discoloration, thick nail disease and nail dystrophy.
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    同族专利:
    公开号 | 公开日
    RU2004106780A|2005-04-20|
    DE60223694D1|2008-01-03|
    WO2003020250A1|2003-03-13|
    EP1423102B1|2007-11-21|
    BR0212304A|2004-10-13|
    DE60223694T2|2008-10-30|
    CA2459483A1|2003-03-13|
    US20040265362A1|2004-12-30|
    JP4806162B2|2011-11-02|
    MXPA04001833A|2004-07-08|
    IL160550A|2010-11-30|
    CY1107284T1|2012-11-21|
    EP1423102A1|2004-06-02|
    ES2299630T3|2008-06-01|
    CZ301310B6|2010-01-13|
    AU2002361825B2|2007-01-25|
    CA2459483C|2009-06-23|
    PL205576B1|2010-05-31|
    CZ2004317A3|2004-10-13|
    PL367513A1|2005-02-21|
    KR100757611B1|2007-09-10|
    DK1423102T3|2008-04-14|
    NO20040936L|2004-06-04|
    PT1423102E|2008-02-25|
    ZA200401445B|2005-03-10|
    NZ531406A|2006-03-31|
    IL160550D0|2004-07-25|
    RU2302857C2|2007-07-20|
    CN1703206A|2005-11-30|
    JP2005501885A|2005-01-20|
    NO20040936D0|2004-03-03|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-09-04|Priority to EP01121202
    2001-09-04|Priority to EP01121202.4
    2002-09-04|Application filed by 트롬스도르프 게엠베하 운트 코. 카게 알츠나이미텔
    2002-09-04|Priority to PCT/EP2002/009912
    2004-04-09|Publication of KR20040031046A
    2007-09-10|Application granted
    2007-09-10|Publication of KR100757611B1
    优先权:
    申请号 | 申请日 | 专利标题
    EP01121202|2001-09-04|
    EP01121202.4|2001-09-04|
    PCT/EP2002/009912|WO2003020250A1|2001-09-04|2002-09-04|Plaster for the treatment of dysfunctions and disorders of nail growth|
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