Title of Invention: RILUZOLE-CONT AINING TRANSDERMAL

PATCH

Technical Field

[0001] This invention relates to a transdermal patch comprising a backing layer, a drug- containing layer and a release liner, and containing riluzole in the drug-containing layer as an active ingredient. Background Art

[0002] Amyotrophic lateral sclerosis, hereinafter referred to as ALS, is a disease of ventral horn motor neuron and cortex neuron which provides afferent inputs, and is known as the fatal disease by causing pneumonia or respiratory insufficiency to many patients in two to three years. The currently available and sole cure for ALS is an oral drug under the name of "Rilutek (registered trademark) tablet" containing riluzole as an active ingredient.

[0003] Since swallowing disturbance and respiratory difficulty are caused in the patients suffered from the advanced ALS symptom, the oral administration to such patients is difficult. Further, rapid increase of the plasma concentration is observed in a short time of period after oral administration of the drug, and more than necessary concentration of the drug is attained temporarily. Due to the excess increase of the plasma concentration of the drug, the occurrence of adverse effects such as symptoms of neuron (helplessness or dizziness) or digestive symptoms (nausea, vomiting or diarrhea) have become problem.

[0004] Patent Literature 1 discloses a composition containing riluzole such as cream for the production of a drug for the treatment of the diseases characterized by the hyperpro- liferation of keratinocytes, particularly psoriasis and atopic dermatitis. This Patent Literature 1 discloses that the cream is a transdermal formulation for the topical administration of riluzole on the skin and the like, and is useful for the treatment and/or prevention of other diseases such as ALS where high plasma concentration is necessary. Though it is needed that an appropriate amount of riluzole should be trans- dermally administered in consideration of the occurrence of the adverse effects in case that the drugs are administered to the ALS patients for the treatment of ALS, the control of the dose and the plasma concentration by the cream are difficult. While the dosage forms other than the cream are also exemplified in the Patent Literature 1, the patent literature does not disclose the detailed composition and the effectiveness for the ALS treatment. Therefore, the development of the novel transdermal formulation containing riluzole which is useful for ALS treatment has been desired. Citation List

Patent Literature

[0005] PTL 1 : WO2004/096216

Summary of Invention Technical Problem

[0006] The object of the present invention is to provide a new transdermal formulation containing riluzole which is capable of the administration to the patients who have difficulties with the oral administration, and is able to inhibit the adverse effects caused by the oral administration and to improve the difficulty of the control of the dose and the plasma concentration caused by the cream described in Patent Literature 1. Furthermore, the another object of the present invention is to provide the transdermal formulation by which high transdermal absorption of riluzole can be achieved and the compliance and quality of life (QOL) of the patients can be improved. Solution to Problem

[0007] As a result of the repeated intensive investigations to solve the above-mentioned problems, the present inventors have found that providing the transdermal patch containing riluzole can solve the above-mentioned problems and have completed the present invention.

[0008] Namely, the present invention relates to the transdermal patch comprising a backing layer, a drug-containing layer and a release liner, and containing riluzole in the drug- containing layer as the active ingredient.

Advantageous Effects of Invention

[0009] According to the present invention, transdermal patches are adopted as the dosage form of riluzole and these patches are adhered on the skin of the ALS patients, and thereby the transdermal administration of riluzole can be achieved to the ALS patients who have difficulties taking the drug orally. Further, the advantage of the transdermal patches of the present invention can be illustrated that the administration amount of riluzole and the plasma concentration can be controlled, and moreover when the undesired effects have occurred, the administration can be immediately discontinued by removing the patches. Consequently, the transdermal patches of the present invention are superior in view of the safety. Brief Description of Drawings

[0010] [fig.1] Fig. 1 is a graph exhibiting the human plasma concentration profiles of riluzole of the patches of Examples 1, 2 and 4 which are calculated by using SKIN-CAD (registered trademark), simulation software for the transdermal system. [fig.2]Fig. 2 is a graph exhibiting the human plasma concentration profiles of riluzole of the patches of Examplesl3, 16 and 17 which are calculated by using SKIN-CAD (registered trademark), simulation software for the transdermal system. Description of Embodiments

[0011] The transdermal patches of the present invention comprise of the drug-containing layer on the backing layer and the drug-containing layer contains riluzole as the active ingredient. Further, a release liner is coated on the drug-containing layer for the purpose of the protection of the drug-containing layer till it uses.

[0012] It is important that the transdermal patches of the present invention contain a high concentration of riluzole in the drug-containing layer in order that the effective amount of riluzole for the treatment of ALS is administered transdermally to ALS patients.

[0013] In the specification of the present invention, it is meant that the transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of drug through the skin and into the bloodstream.

[0014] The amount of riluzole of the transdermal patches of the present invention ranges from 20 to 60% by weight based on the drug-containing layer, preferably from 30 to 60% by weight. The case that the amount is less than 20% by weight is not preferable because the effective plasma concentration is not achieved, and the case that the amount is more than 60% by weight is not preferable because the physical or mechanical properties of the patches difficultly maintain satisfactory.

[0015] Riluzole which is contained in the transdermal patches of the present invention can be used as a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of riluzole include acid addition salts with inorganic acids or organic acids, and are exemplified, but not limited to, hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, ascorbate, benzoate, cinnamate, citrate, formate, fumarate, glutamate, lactate, maleate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, succinate, tartarate, propionate, butyrate, pamoate, p- toluenesulfonate (tosylate) and the like. In performing the present invention, it is preferable to use riluzole in the free form.

[0016] The area of the transdermal patches of the present invention may ranges from 15 to 60 cm ² . The case when the area is less than 15 cm ² is not preferable because the effective plasma concentration is not attained and the case when the area is more than 60 cm ² is not preferable since the patients feel uncomfortably during the administration and the compliance of the patients is lowered.

[0017] The transdermal patches of the present invention comprise the backing layer, the drug-containing layer and the release liner. The release-control membranes to control the transdermal absorption of riluzole or the adhesive layers to adhere to the skin can be added, if desired. Furthermore, the reservoir-type patches can be adopted. [0018] In the transdermal patches of the present invention, the drug-containing layer preferably is a matrix-type adhesive layer containing riluzole and an adhesive agent as a base agent. By providing the patches of the present invention as the matrix-type patches, the patches can be easily designed and the additional layer such as the adhesive layers is not needed so that the cost for manufacturing the patches can be reduced.

[0019] The adhesive agents contained in the drug-containing layers of the transdermal patches of the present invention are preferably the non-aqueous adhesive agents, and are inclusive of rubber adhesive agents, acryl polymers and silicone polymers.

[0020] The rubber adhesive agents are inclusive of one or not less than two agents selected from styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-butadiene rubber, polyisobutylene, polybutene, butyl rubber, natural rubber and isoprene rubber and can be used in the present invention.

[0021] The acryl polymers include, but not limited to, the polymers or copolymers containing at least one kind of the (meth)acrylate represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like as a monomer unit, for example, adhesive polymers such as acrylic acid-octyl acetate copolymer, 2-ethylhexyl acrylate-N-vinyl-2-pyrrolidone-l,6-hexaneglycolyl dimethacrylate copolymer, 2-ethylhexyl acrylate- vinyl acetate copolymer, 2-ethylhexyl acrylate- vinyl acetate-acrylic acid copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, methyl methacrylate-2-ethylhexyl acrylate copolymerization resin emulsion, acryl polymer contained in acryl resin- alkanolamine solution can be used and the commercially available DURO-TAK (registered trademark) acrylate adhesive agents series (provided by Henkle Japan Ltd.), GELVA (registered trademark) acrylate adhesive agents series (provided by Monsanto Co.), SK-DYNE MATRIDERM (provided by Soken Chemical and Engineering Co., Ltd) or EUDRAGIT (registered trademark) series (provided by Higuchi Inc.) and can be used in the present invention.

[0022] The silicone polymers include derivatives of polysiloxane (for example, silicone polymer such as polydimethylsiloxane and amine-resistant polydimethylsiloxane).

[0023] The amount of the adhesive agents added in the drug-containing layer ranges from 20 to 80% by weight, preferably from 35 to 75% by weight in consideration of the formation of the drug-containing layer and the sufficient drug flux. The case when the amount is less than 20% by weight is not preferable because the physical and mechanical properties are hardly maintained well and the case when the amount is more than 80% by weight is not preferable because the effective plasma concentration of riluzole can not be obtained.

[0024] One kind, or two or more kinds in combination selected from the above-mentioned rubber adhesive agents, acryl polymers and silicone polymers can be used as the adhesive agents which are contained in the drug-containing layer of the transdermal patches of the present invention. The acryl polymer can be preferably used in view that riluzole can be contained in a high concentration, and further the high concentration of riluzole can exist in a dissolved state in the drug-containing layer. A non-dissolved riluzole, namely crystalline riluzole which is contained or formed in the drug- containing layer is not preferable because it may cause many troubles such as a drop of the flux of riluzole and an increased formation of the crystalline riluzole with a passage of time.

[0025] Furthermore, in order to improve the transdermal permeability of riluzole, a skin- penetration enhancer can be added, if necessary. The skin-penetration enhancers are inclusive of any agents exhibiting skin-penetration enhancing effects which are conventionally used, and are exemplified an alkanolamine such as diisopropanolamine and triisopropanolamine; a fatty acid or an ester thereof such as lauric acid, oleic acid, isopropyl myristate, octyldodecyl myristate, glycerin monooleate and hexadecyl isostearate; an alcohol, an ester thereof or an ether thereof such as oleyl alcohol, propy- leneglycol and polyethyleneglycol monooleate; a sorbitan ester or ether such as sorbitan monolaurate and sorbitan monooleate; a phenol ether such as polyoxyethylene nonylphenyl ether or polyoxyethylene octylphenyl ether; castor oil or hydrogenated castor oil; an ionic surfactant such as oleoylsarcosine, lauryldimethylaminoacetic acid betaine and sodium laurylsulfate; a non-ionic surfactant such as polyoxyethylene oleyl ether, polyoxyethylene lauryl ether and dimethyllaurylamine oxide; an alkylmethyl- sulf oxide such as dimethylsulf oxide and decylmethylsulf oxide; a pyrrolidone such as 2-pyrrolidone and l-methyl-2-pyrrolidone; an azacycloalkane such as l-dodecylazacycloheptan-2-one and l-geranylazacycloheptan-2-one; or a terpene such as menthol, camphor and limonene. Among them, an alkanolamine such as diisopropanolamine and triisopropanolamine; a myristic acid ester such as isopropyl myristate, octyldodecyl myristate or hexadecyl isostearate; propyleneglycol; polyoxyethylene lauryl ether or polyoxyethylene oleyl ether are preferable.

[0026] In case that the skin-penetration enhancer is added to the transdermal patches of the present invention, the amount of the skin-penetration enhancer may ranges from 0.1 to 10% by weight, preferably from 1 to 5% by weight based on the drug-containing layer. Moreover, the contents which exceed 10% by weight are not preferable since the skin irritation caused by the skin-penetration enhancers is used to develop and further the physical properties of the patches are lowered and sticky sense is generated.

[0027] An additional agent such as a plasticizer, an antioxidant, a cross-linker, a colorant, an ultraviolet ray absorbent, or a tackifier and the like can be blended to the transdermal patches of the present invention, if necessary. [0028] The plasticizers include a petroleum oil such as paraffinic process oil, naphthenic process oil and aromatic process oil; a liquid fatty acid ester such as isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate and isopropyl linoleate; a plant oil such as olive oil, camellia oil, castor oil, tall oil and peanut oil; glycerin; chlorobutanol; polyvinyl acetate; dimethylpolysiloxane-silicon dioxide mixture; d- sorbitol; medium chain fatty acid triglyceride; triacetin; 2-pyrrolidone; phytosterol; propylene glycol; polyethylene glycol; polysorbate 80 (registered trademark); and glyceryl monostearate.

[0029] The antioxidants include ascorbic acid, sodium bisulfite, sodium pyrosulfite, disodium edetate, citric acid, potassium dichloroisocyanurate, dibutylhydroxytoluene, soybean lecithin, thymol, tocopherol or ester thereof, ascorbic acid palmitate, butylhy- droxyanisol, 1,3-butylene glycol, benzotriazole, pentaerythrityl-tetrakis[3-(3,5- di- t-butyl-4-hydroxyphenyl)propionate], monothioglycerol, and propyl gallate.

[0030] The cross-linkers include amino resin; phenolic resin; epoxy resin; alkyd resin; a thermosetting resin such as unsaturated polyester; isocyanate compound; organic cross-linker; and an inorganic cross-linker such as metal or metal compound.

[0031] The colorants include indigocarmine, yellow oxide of iron, yellow ferric oxide, carbon black, caramel, photosensitizer 201, sasa albo-marginata extract, black iron oxide, kekketsu, zinc oxide, titanium oxide, red ferric oxide, amaranth, sodium hydroxide, talc, sodium copper chlorophyllin, rye green leaf juice powder, d-borneol, 2-octyldodecyl myristate, methylrosanilinium chloride, methylene blue, ammonium manganese phosphate, and rose oil.

[0032] The ultraviolet ray absorbents include an amino acid compound such as urocanic acid; a benzophenone compound such as 2,4-dihydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone; a cinnamic acid derivative such as cinoxate and diethanolamine-p-methoxycinnamate; a cyanoacrylate derivative such as 2-ethylhexyl-2-cyano-3,3-diphenylacrylate; an aminobenzoic acid derivative such as ethyl p-aminobenzoate and propyl p-aminobenzoate; an anthranilic acid derivative such as anthranilic acid and menthyl anthranilate; a salicylate derivative such as phenyl salicylate and p-octylphenyl salicylate; and a coumarin derivative such as 7-ethylamino-4-methylcoumarin and 7,8-dihydroxy coumarin.

[0033] The tackifiers include a rosin derivative such as rosin, glycerol ester of rosin, hy- drogenated rosin and glycerol ester of hydrogenated rosin; alicyclic saturated hydrocarbon resin; alicyclic hydrocarbon resin; terpene resin; aliphatic saturated hydrocarbon resin; aliphatic hydrocarbon resin; maleic acid resin; carnauba wax; carmellose sodium; xanthan gum; chitosan; glycerin; aluminum magnesium silicate; light anhydrous silicic acid; benzyl acetate; talc; hydroxyethylcellulose; hydroxypropy- lcellulose; hypromellose; polyacrylic acid; sodium polyacrylate; partially neutralized polyacrylate; and polyvinyl alcohol.

[0034] The drug-impermeable elastic or non-elastic backing can be used as the backing of the transdermal patches of the present invention. Such backings include, for example, synthetic resin film or sheet such as polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (e.g. polyethylene terephthalate), nylon, polyurethane, or laminates thereof, porous materials and foam thereof, paper, textiles and nonwovens and the like.

[0035] As the release liner of the transdermal patches of the present invention, the drug- impermeable release liner can be used. Such liners are, for example, inclusive of films made of polymer such as polyethylene, polypropylene and polyester and the like, aluminum evaporated film, silicone oil and the like applied paper and the like. Among them, polyester film is preferable and polyethylene terephthalate (PET) film is more preferable in view of impermeability of the drug, processability and low cost and the like. Furthermore, laminate films laminated by multiple materials can be used as such release liner.

[0036] The transdermal patches of the present invention can be prepared, but not limited to, by the known methods. The preferable known methods for preparing the transdermal patches of the present invention include, for example, the method for obtaining the transdermal patches by dissolving the agents such as riluzole and the adhesive polymers and, if necessary, the skin-penetration enhancer to be added to the drug- containing layer into an organic solvent such as ethyl acetate, hexane, toluene or a mixture thereof, spreading these dissolved materials on the release liner or the backing, and evaporating the solvent in the dissolved materials to form the drug-containing layer and thereafter coating on the backing or the release liner, or the method for obtaining the transdermal patches by heating and melting the agents such as riluzole and the adhesive polymers and, if necessary, the skin-penetration enhancer to be added to the drug-containing layer, spreading the melted materials on the release liner or the backing to form the drug-containing layer and thereafter coating on the backing or the release liner. Examples

[0037] The present invention is explained in more detail by the following examples and it is construed that the present invention is not limited thereto.

[0038] Example 1

According to the ratio of blend described in Table 1, to an acrylic polymer (DURO-TACK (registered trademark) 87-4098, available from Henkle Japan Ltd.) riluzole was added, and mixed with stirring to obtain the homogeneous dissolved mixture. Then the homogeneous dissolved mixture was spreaded on a release liner (silicone-treated PET film, available from Fujimori Kogyo Co., Ltd.) to make the thickness after distilling off the solvent of 100 μm by using a doctor blade coater, and the solvent was distilled off to form the drug-containing layer and then the backing was coated. Then, the transdermal patches were obtained by cutting into an appropriate size. [0039] Example 2

According to the ratio of blend described in Table 1, to an acrylic polymer (DURO-TACK (registered trademark) 87-4098), riluzole and diisopropanolamine were added, and mixed with stirring to obtain the homogeneous dissolved mixture. Then the homogeneous dissolved mixture was spreaded on a release liner (silicone-treated PET film, available from Fujimori Kogyo Co., Ltd.) to make 100 μm of the thickness of the drug- containing material after distilling off the solvent by using a doctor blade coater, and the solvent was distilled off to form the drug-containing layer and then the backing was coated. Then, the transdermal patches were obtained by cutting into an appropriate size. [0040] Example 3

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that triisopropanolamine in place of diisopropanolamine was used. [0041] Example 4

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that propyleneglycol in place of diisopropanolamine was used. [0042] Example 5

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that isopropyl myristate in place of diisopropanolamine was used. [0043] Example 6

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that octyldodecyl myristate in place of diisopropanolamine was used. [0044] Example 7

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that polyoxyethylene lauryl ether in place of diisopropanolamine was used. [0045] Example 8

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that polyoxyethylene oleyl ether in place of diisopropanolamine was used. [0046] Example 9

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that DURO-TACK (registered trademark) 87-202A (available from Henkle Japan Ltd.) in place of DURO-TACK (registered trademark) 87-4098 was used. [0047] Example 10

According to the ratio of blend described in Table 1, the transdermal patches were obtained by a similar manner as Example 2 except that DURO-TACK (registered trademark) 87-2100 (available from Henkle Japan Ltd.) in place of DURO-TACK (registered trademark) 87-4098 was used. [0048] Example 11

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 2 except that DURO-TACK (registered trademark) 87-2516 (available from Henkle Japan Ltd.) in place of DURO-TACK (registered trademark) 87-4098 was used. [0049] Example 12

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 1 except that DURO-TACK (registered trademark) 87-2516 in place of DURO-TACK (registered trademark) 87-4098 was used. [0050] Example 13

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 9 except that isopropyl myristate was added and the amount of DURO-TACK (registered trademark) 87-202A was changed. [0051] Example 14

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 9 except that hexadecyl isostearate was added and the amount of DURO-TACK (registered trademark) 87-202A was changed. [0052] Example 15

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 9 except that dimethylhexadecylamine in place of diisopropanolamine was used. [0053] Example 16

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 15 except that isopropyl myristate was added and the amounts of riluzole and DURO-TACK (registered trademark) 87-202A were changed.

[0054] Example 17

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 2 except that the amounts of riluzole and DURO-TACK (registered trademark) 87-4098 were changed.

[0055] Example 18

According to the ratio of blend described in Table 2, the transdermal patches were obtained by a similar manner as Example 9 except that the amounts of riluzole and DURO-TACK (registered trademark) 87-202A were changed.

[0056] [Table 1]

[0057]

[Table 2]

O by weight) Experimental Example 1

Experiments on skin permeability of the drug:

The skin permeability of riluzole from the transdermal patches of Examples 1 to 18 prepared by the above-mentioned formulations and methods was examined by using the cell for the membrane permeation. Skins (intact skins) isolated from the back of hairless mice (n=4 to 6, Hr-/Kud, Kyudo Co., Ltd.) were attached to the cell for the membrane permeation, the patches of each examples were applied on the side of stratum corneum of the skins, and then applied to an in-vitro membrane-permeation test instruments. An aqueous solution of 40% polyethyleneglycol 400 was used as a receptor solution, and the amounts of riluzole transferred to the receptor solution were determined by HPLC. The fluxes were calculated from the slopes of the regression lines obtained by least-squares method based on the cumulative amounts of permeated riluzole obtained from the experimental results and sampling times. Further, as to the patches of Example 1, Example 2, Example 4, Example 13, Example 16 and Example 17, the delay times were calculated from the time intercepts of the regression lines in order to calculate the plasma concentrations in human by employing a SKIN-CAD (registered trademark, Professional Edition ver. 5.2 available from i-HIVE Communication, Inc.), a simulation software for the transdermal system, and also the similar experiments were performed by using the exfoliated skins(strip skins) from the stratum corneums of the isolated skins from the back of hairless mice with cellophane tape. The results are summarized in Table 3. [0059] [Table 3]

In this Table 3, "-" means "not-tested".

[0060] As shown in Table 3, the fluxes of the patches of Examples 1 to 18 were 60 to

300 μm/cmfyhour. Further the patches of Example 2j Example 3, Example 4, Example 6,

Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 13, Example 14 and Example 15 exhibited increased skin-permeabilities by the skin- penetration enhancers.

[0061] Experimental Example 2

Human plasma concentrations by the continuous administration at the interval of 24 hours were calculated by employing a SKIN-CAD (registered trademark, Professional Edition ver. 5.2 available from i-HIVE Communication, Inc.), the simulation software for the transdermal system based on the pharmacokinetic parameters of riluzole in human and the parameters (Table 3) obtained from the results of skin-permeability experiments by employing hairless mice for the patches of Example 1, Example 2, Example 4, Example 13, Example 16 and Example 17. The results were summarized in Figures 1 and 2. The areas of the patches of Example 1, Example 2, Example 4, Example 13 and Example 16 were set to 60 cm ² , and the area of the patch of Example 17 was set to 15 cm ² .

[0062] Based on that the plasma concentrations at the steady state by the repeated administration of the oral preparation of 50 mg of riluzole is about 40 (minimum) to about 300 (maximum) ng/mL (cf. "Journal of Clinical Therapeutics & Medicine", vol. 12, No. 5, pp. 809(61)-827(79), 1996; especially Fig. 5 and Table 6), the effective plasma concentrations required for the patches of the present invention were set to be 40 to 300 ng/mL. As shown in Figures 1 and 2, all of patches of Example 1, Example 2, Example 4, Example 13, Example 16 and Example 17 exhibited the plasma concentrations of 40 to 300 ng/mL. These results demonstrated that the riluzole-containing transdermal patches which maintain the stably effective plasma concentration could be obtained by containing 20 to 60 %, preferably 30 to 60% by weight of riluzole based on the drug-containing layer and setting the area of 15 to 60 cm ² . Industrial Applicability

[0063] As mentioned above, the transdermal patches of the present invention are novel patches containing high concentration of riluzole and being able to administer trans- dermally and quantitatively the drug. According to the transdermal patches of the present invention, the therapeutically effective amount of riluzole can be transdermally and easily administered to the ALS patients having difficulties taking the drug orally. Furthermore, the transdermal patches of the present invention can prevent the occurrence of adverse effects which have become trouble in the oral administration, and the compliance and quality of life (QOL) of the patients can be improved and various problems can be solved, then the transdermal patches of the present invention are useful for the treatment of ALS.