JP6827403B2 - Patch - Google Patents

Description

The present invention relates to a patch.

Emedastine fumarate has a strong and selective antihistamine effect, and has been shown to have a clear antiallergic effect, an inhibitory effect on nasal respiratory resistance, and an eosinophil infiltration inhibitory effect on the nasal mucosa in an experimental allergy model. .. Further, emedastine fumarate, release inhibiting action of histamine from mast cells by substance P stimulation in vitro, also has migration inhibitory action of eosinophils by platelet activating factor and leukotrienes B _4.

Since the oral preparation of emedastine fumarate has a large fluctuation range in blood concentration, there are problems that side effects such as drowsiness may occur and sufficient pharmacological effects may not be obtained. Therefore, in recent years, attempts have been made to develop various preparations containing emedastine (Patent Documents 1 to 3). Patent Document 2 discloses a composition for transdermal administration comprising emedastin and an aliphatic monocarboxylic acid lower alkyl ester or an aliphatic dicarboxylic acid dilower alkyl ester, specifically, an oily ointment or a gel agent. , Creams, lotions, and sprays. Further, Patent Document 3 discloses an adhesive patch in which an acrylic adhesive base, a silicone adhesive base, or an adhesive layer composed of a rubber adhesive base and emedastine is laminated on one side of a support layer. Has been done. Further, Patent Document 4 discloses an emedastine patch preparation having a pressure-sensitive adhesive layer containing an acrylic polymer and emedastine that substantially does not contain an acid residue.

Japanese Unexamined Patent Publication No. 3-83924 Japanese Unexamined Patent Publication No. 7-33665 Japanese Unexamined Patent Publication No. 8-193030 JP-A-2007-186500

However, Darren Capsules (trade name), which is an oral preparation of emedastine fumarate, increases the blood concentration of emedastine after administration and is effective in treating allergic symptoms, but has a problem that the duration of pharmacological effect is very short. was there. On the other hand, Patent Documents 1 to 3 only show transdermal absorbability data using the skins of rats, rabbits or snakes, and when an emedastine fumarate-containing patch is actually applied to humans. The result of was not present.

Therefore, an object of the present invention is to provide a drug that suppresses the occurrence of side effects caused by emedastine in humans and treats or alleviates allergic symptoms.

The present invention is based on the findings of the present inventors obtained by administering emedastine fumarate to humans, and provides the following [1] to [46].
[1] A patch for treating or alleviating allergic symptoms, which comprises a pressure-sensitive adhesive layer on a support and the pressure-sensitive adhesive layer contains emedastine fumarate for 16 to 26 hours for humans. A patch that is used for transdermal administration of emedastine fumarate and has an emedastine fumarate content of 0.06 to 0.20 mg per kg of human body weight.
[2] The patch according to [1], wherein the allergic symptom is allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo.
[3] It is used so that the maximum blood concentration C _{max of the} above-mentioned emedastine is 0.3 to 4 ng / mL and the maximum blood concentration arrival time T _max is 8 to 32 hours. The patch according to [1] or [2].
[4] The moisture permeability of the adhesive patch is 1~200g ^/ m 2 · 24hr, patch according to any one of [1] to [3].
[5] The patch according to any one of [1] to [4], which is applied to the chest, upper arm, back or abdomen of the human.
[6] The patch according to any one of [1] to [5], wherein the area of the surface of the patch in contact with the skin is 8 to 24 cm ² .
[7] The patch according to any one of [1] to [6], wherein the pressure-sensitive adhesive layer contains a styrene-isoprene-styrene copolymer.
[8] A set of a plurality of patches, wherein the patch according to any one of [1] to [7] is replaced once every 16 to 26 hours, and the patch is continuously transdermal for 7 days or more. A set of patches used to be administered.
[9] A patch having a pressure-sensitive adhesive layer on a support, wherein the pressure-sensitive adhesive layer contains 4 to 12 mg of emedastine fumarate for treating or alleviating allergic symptoms in humans.
[10] The patch according to [9], which is used to be applied to the human for 16 to 26 hours.
[11] The patch according to [9] or [10], wherein the allergic symptom is allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo.
[12] The above-mentioned emedastine is attached so that the maximum blood concentration C _max is 0.3 to 4 ng / mL and the maximum blood concentration arrival time T _max is 8 to 32 hours, [9] to The patch according to any one of [11].
[13] The moisture permeability of the adhesive patch is 1~200g ^/ m 2 · 24hr, patch according to any one of [9] to [12].
[14] The patch according to any one of [9] to [13], which is applied to the chest, upper arm, back or abdomen of the human.
[15] The patch according to any one of [9] to [14], wherein the area of the surface of the patch in contact with the skin is 8 to 24 cm ² .
[16] The patch according to any one of [9] to [15], wherein the pressure-sensitive adhesive layer further contains a styrene-isoprene-styrene copolymer.
[17] The patch according to any one of [9] to [16], wherein the content of the styrene-isoprene-styrene copolymer is 10 to 60 mg.
[18] A set of a plurality of patches, the patch according to any one of [9] to [17] is replaced once every 16 to 26 hours, and continuously transdermally administered for 7 days or more. A set of patches used as a patch.
[19] A therapeutic agent for allergic symptoms containing emedastine fumarate, which is used to be administered transdermally to humans for 16 to 26 hours.
[20] The therapeutic agent according to [19], wherein the transdermal administration is performed by a patch having an adhesive layer containing 0.06 to 0.20 mg of emedastine fumarate per 1 kg of human body weight.
[21] The therapeutic agent according to [19] or [20], wherein the human is a patient who exhibits allergic symptoms.
[22] The therapeutic agent according to [21], wherein the allergic symptom is allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo.
[23] Any of [19] to [22], wherein the maximum blood concentration C _{max of the} above-mentioned emedastine is 0.3 to 4 ng / mL, and the time to reach the maximum blood concentration T _max is 8 to 32 hours. The therapeutic agent described in Crab.
[24] The moisture permeability of the adhesive patch is 1~200g ^/ m 2 · 24hr, therapeutic agent according to any one of [19] - [23].
[25] The therapeutic agent according to any one of [19] to [24], which is applied to the skin of the chest, upper arm, back or abdomen of the human.
[26] The therapeutic agent according to any one of [19] to [25], wherein the area of the surface of the patch in contact with the skin is 8 to 24 cm ² .
[27] The therapeutic agent according to any one of [19] to [26], wherein the pressure-sensitive adhesive layer further contains a styrene-isoprene-styrene copolymer.
[28] The treatment according to any one of [23] to [27], which is used so that the patch is replaced once every 16 to 26 hours and continuously transdermally administered for 7 days or more. Agent.
[29] A patch having an adhesive layer on a support and the adhesive layer containing 0.06 to 0.20 mg / kg body weight of emedastine fumarate is applied to humans for 16 to 26 hours. A method of treating or alleviating allergic symptoms, including doing so.
[30] The method according to [29], wherein the human is a patient who exhibits allergic symptoms.
[31] The method according to [29] or [30], wherein the allergic symptom is allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo.
[32] Attach so that the maximum blood concentration C _max of emedastine is 0.3 to 4 ng / mL and the time to reach the maximum blood concentration T _max is 8 to 32 hours, [29] to [31]. ] The method described in any of.
[33] The moisture permeability of the adhesive patch is 1~200g ^/ m 2 · 24hr, method according to any one of [29] - [32].
[34] The method according to any one of [29] to [33], wherein the patch is applied to a human chest, upper arm, back or abdomen.
[35] The method according to any one of [29] to [34], wherein the area of the surface of the patch in contact with the skin is 8 to 24 cm ² .
[36] The method according to any one of [29] to [35], wherein the pressure-sensitive adhesive layer contains a styrene-isoprene-styrene copolymer.
[37] The method according to any one of [29] to [36], wherein the patch is replaced once every 16 to 26 hours and continuously transdermally administered for 7 days or more.
[38] A patch having an adhesive layer on a support and the adhesive layer containing 0.06 to 0.20 mg / kg body weight of emedastine fumarate is applied to humans for 16 to 26 hours. Emedastine fumarate, which is used to treat or alleviate allergic symptoms.
[39] The emedastine fumarate according to [38], wherein the human is a patient who exhibits allergic symptoms.
[40] The emedastine fumarate according to [38] or [39], wherein the allergic symptom is allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo.
[41] Attach so that the maximum blood concentration C _max of the above emedastine is 0.3 to 4 ng / mL and the maximum blood concentration arrival time T _max is 8 to 32 hours, [38] to [ 40]. Emedastine fumarate according to any one of.
[42] The moisture permeability of the adhesive patch is ^{1~200g / m 2 · 24hr, [} 38] fumarate emedastine according to any one of - [41].
[43] The emedastine fumarate according to any one of [38] to [42], wherein the patch is applied to a human chest, upper arm, back or abdomen.
[44] The emedastine fumarate according to any one of [38] to [43], wherein the area of the surface of the patch in contact with the skin is 8 to 24 cm ² .
[45] The emedastine fumarate according to any one of [38] to [44], wherein the pressure-sensitive adhesive layer contains a styrene-isoprene-styrene copolymer.
[46] The emedastine fumarate according to any one of [38] to [45], wherein the patch is replaced once every 16 to 26 hours and continuously transdermally administered for 7 days or more.

According to the present invention, it is possible to provide a drug that suppresses the occurrence of side effects caused by emedastine in humans and treats or alleviates allergic symptoms.

According to the present invention, transdermal administration of emedastine fumarate at a lower dose as compared with the content of emedastine in the patches described in Patent Documents 1 to 4 is effective in treating or alleviating allergic symptoms. , The side effects of emedastine can be suppressed. In addition, the present invention can maintain the pharmacological action of emedastine for a long period of time by exhibiting excellent transdermal absorbability and sustained release.

The first embodiment of the present invention is a patch for treating or alleviating allergic symptoms, which comprises a pressure-sensitive adhesive layer on a support and the pressure-sensitive adhesive layer contains emedastine fumarate. , A patch that is used for transdermal administration of emedastine fumarate over 16 to 26 hours and has an emedastine fumarate content of 0.06 to 0.20 mg per kg of human body weight.

The support is not particularly limited as long as it is suitable for supporting the pressure-sensitive adhesive layer, and stretchable or non-stretchable ones can be used. As the material of the support, films such as polyethylene (PE), polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, polyacrylonitrile (PAN), sheets, laminates thereof, and porous materials are used. Body, foam, cloth and non-woven fabric, and laminated products thereof can be used. The preferred support material is polyethylene terephthalate (PET) or polyethylene. Specific examples of preferable supports include the Scotchpac series such as Scotchpak (registered trademark, 3M Ltd.) 9723, 9732.

The surface of the support in contact with the pressure-sensitive adhesive layer may be sand-matted. By applying sand mat treatment to the support, the anchoring property is further improved. As a method of sand mat treatment, a method well known to those skilled in the art can be used.

The patch according to the present embodiment contains emedastine fumarate in the pressure-sensitive adhesive layer.

Emedastine is also called 1- (2-ethoxyethyl) -2- (4-methyl-1,4-diazepan-1-yl) -1H-benzimidazole and has a molecular weight of 302.41. Emedastine fumarate is emedastine 2 fumarate represented by the following chemical formula (1).

The content of emedastine fumarate may be an amount capable of transdermally administering 0.06 to 0.20 mg / kg body weight of emedastine fumarate to humans over 16 to 26 hours. The content of emedastine fumarate is, for example, preferably 4 to 12 mg, more preferably 6 to 12 mg, and even more preferably 4 mg or 8 mg. By applying a patch containing 4 mg or more of emedastine fumarate to human skin, it becomes easier to maintain the blood concentration of emedastine higher than the effective blood concentration during the application of the patch. It becomes easy to maintain a sufficient treatment or alleviation effect of allergic symptoms. In addition, by applying a patch containing 12 mg or less of emedastine fumarate to human skin, the occurrence of side effects such as drowsiness can be further suppressed.

In the present specification, "0.06 to 0.20 mg / kg body weight of emedastine fumaric acid" means fumaric acid when the human being to be administered is an adult (assuming that the body weight of an adult is 60 kg). The amount of emedastine is 4 to 12 mg, which means that when the human being to be administered is a child (assuming the weight of the child is 15 kg), the amount of emedastine fumarate is 1 to 3 mg. That is, the patch according to the present embodiment is a patch having a pressure-sensitive adhesive layer on a support, the pressure-sensitive adhesive layer contains emedastine fumarate, and the content of emedastine fumarate is 4 to 12 mg. There is also an aspect of a patch for treating or alleviating allergic symptoms in humans.

The content of emedastine fumarate may be 1 to 7% by mass, 2 to 7% by mass, or 3 to 7% by mass based on the total mass of the pressure-sensitive adhesive layer.

The pressure-sensitive adhesive layer may further contain a styrene-isoprene-styrene copolymer. The content of the styrene-isoprene-styrene copolymer is preferably 10 to 60 mg, more preferably 10 to 50 mg.

The content of the styrene-isoprene-styrene copolymer may be 10 to 95% by mass, 10 to 80% by mass, or 10 to 60% by mass based on the total mass of the pressure-sensitive adhesive layer.

The pressure-sensitive adhesive layer further contains other components other than the styrene-isoprene-styrene copolymer, such as rubber-based pressure-sensitive adhesives, tackifier resins, plasticizers, transdermal absorption promoters, stabilizers, fillers, and fragrances. You may.

Other rubber-based pressure-sensitive adhesives other than styrene-isoprene-styrene copolymer are isoprene rubber, polyisobutylene (PIB), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), and polysiloxane. And so on. These rubber-based pressure-sensitive adhesives may be used alone or in combination of two or more. Preferred rubber-based pressure-sensitive adhesives include SIS and PIB. Specific examples of the rubber adhesive include Opanol B12, B15, B50, B80, B100, B120, B150, B220 (trade name, manufactured by BASF), JSR Butyl 065, 268, 365 (trade name, manufactured by JSR). , Vistanex LM-MS, MH, H, MML-80, 100, 120, 140 (trade name, manufactured by Exxon Chemical), HYCAR (trade name, manufactured by Goodrich), SIBSTAR T102 (trade name, manufactured by Kaneka). Made) and the like.

The content of the other rubber-based pressure-sensitive adhesive is preferably 10 to 95% by mass, more preferably 10 to 80% by mass, based on the total mass of the pressure-sensitive adhesive layer.

Examples of the tackifying resin include rosin, rosin derivatives such as rosin glycerin ester, hydrocarbon rosin, hydrocarbon rosin glycerin ester and rosin pentaeristol ester, and fats such as Archon P100 (trade name, Arakawa Chemical Industry). Examples include a ring-type saturated hydrocarbon resin, an aliphatic hydrocarbon resin such as Quinton B170 (trade name, Nippon Zeon), a terpene resin such as Clearon P-125 (trade name, Yasuhara Chemical), and a maleate resin. Among these, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin and terpene resin are particularly preferable. These tackifier resins may be used alone or in combination of two or more. By including the tackifier resin, the adhesiveness of the pressure-sensitive adhesive layer can be improved and other physical properties can be stably maintained.

The content of the tackifier resin is preferably 0 to 80% by mass, more preferably 10 to 70% by mass, based on the total mass of the pressure-sensitive adhesive layer.

Plasticizers include petroleum oils such as paraffin process oils, naphthenic process oils and aromatic process oils; squalane; squalane; olive oils, camellia oils, castor oils, tall oils and lacquer oils; silicon oils. Dibasic acid esters such as dibutylphthalate and dioctylphthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate; diethylene glycol; polyethylene glycol; Examples thereof include glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamitone. Among these, liquid paraffin, liquid polybutene, isopropyl myristate, diethyl sebacate and hexyl laurate are preferable as the plasticizer, and liquid polybutene, isopropyl myristate and liquid paraffin are particularly preferable. Two or more of these plasticizers may be mixed and used.

The content of the plasticizer is preferably 0 to 30% by mass, more preferably 0 to 20% by mass, based on the total mass of the pressure-sensitive adhesive layer.

The transdermal absorption promoter may be any compound conventionally known to have a transdermal absorption promoting action on the skin. Examples of the transdermal absorption promoter include organic acids and salts thereof (for example, aliphatic carboxylic acids having 6 to 20 carbon atoms (hereinafter, also referred to as “fatty acids”) and salts thereof, silicic acid and salts thereof). , Organic acid esters (eg, fatty acid esters, silicic acid esters), organic acid amides (eg, fatty acid amides), fatty alcohols, polyhydric alcohols, ethers (eg, aliphatic ethers, polyoxyethylene alkyl ethers) and the like. .. These absorption enhancers may have unsaturated bonds and may have a cyclic, linear or branched chemical structure. Further, the transdermal absorption accelerator may be a monoterpene compound, a sesquiterpene compound, and a vegetable oil (for example, olive oil). One of these transdermal absorption promoters may be used alone, or two or more thereof may be used in combination.

Examples of such organic acids include aliphatic (mono, di or tri) carboxylic acids (for example, acetic acid, propionic acid, sulfonic acid (including anhydrous citrate), isobutyric acid, caproic acid, capric acid, fatty acid, lactic acid and maleic acid. , Pyruvate, oxalic acid, succinic acid, tartaric acid, etc.), aromatic carboxylic acids (eg, phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid, etc.), silicic acid, alkanesulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.) Acids, propane sulfonic acids, butane sulfonic acids), alkyl sulfonic acid derivatives (eg, polyoxyethylene alkyl ether sulfonic acids, N-2-hydroxyethylpiperazin-N'-2-ethane sulfonic acids), coli acid derivatives (eg, for example. Dehydrosulfonic acid, etc.). These organic acids may be alkali metal salts such as sodium salts. Of these, aliphatic carboxylic acids, aromatic carboxylic acids or salts thereof are preferable, and acetic acid, sodium acetate or citric acid are particularly preferable.

Examples of fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linolenic acid, and linolenic acid.

Examples of the organic acid ester include ethyl acetate, propyl acetate, cetyl lactate, lauryl lactate, methyl salicylate, ethylene glycol salicylate, methyl cinnamate, and fatty acid ester. Examples of the fatty acid ester include methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, and cetyl palmitate. The fatty acid ester may be glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyethylene glycol sorbitan fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, or polyoxyethylene hydrogenated castor oil. Specific examples of the fatty acid ester include glycerin monocaprelate, glycerin monocaplate, glycerin monolaurate, glycerin monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20 (trade name), and propylene glycol monolaurate. Rate, polyethylene glycol monolaurate, polyethylene glycol monostearate, Span20, Span40, Span60, Span80, Span120 (trade name), Tween20, Tween21, Tween40, Tween60, Tween80 (trade name), NIKKOL HCO-60 (trade name, Nikko Chemicals Co., Ltd.).

Examples of the organic acid amide include fatty acid amide (for example, lauric acid diethanolamide), hexahydro-1-dodecyl-2H-azepin-2-one (also referred to as Azone), a derivative thereof, and pyrothiodecane.

The fatty alcohol means an aliphatic alcohol having 6 to 20 carbon atoms. Examples of fatty alcohols include lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol. Examples of the polyhydric alcohol include propylene glycol.

Examples of the polyoxyethylene alkyl ether include polyoxyethylene lauryl ether.

Examples of monoterpene compounds include geraniol, thymol, eugenol, terpineol, l-menthol, borneolol, d-limonene, isoeugenol, isobornol, nerol, and dl-camfur.

Oleyl alcohol, lauryl alcohol, isostearyl alcohol, lauric acid diethanolamide, glycerin monocaprilate, glycerin monocaplate, glycerin monooleate, sorbitan monolaurate, propylene glycol monolaurate, polyoxyethylene lauryl ether or pyrothiodecane preferable. Fatty acids are preferred, and oleic acid is particularly preferred.

The content of the transdermal absorption accelerator is preferably 0 to 20% by mass, more preferably 0 to 10% by mass, based on the total mass of the pressure-sensitive adhesive layer.

Stabilizers are antioxidants (tocopherol derivative, ascorbic acid derivative, erythorbic acid derivative, nordihydroguayaletinic acid, gallic acid derivative, dibutylhydroxytoluene (BHT), butylhydroxyanisole, sodium pyrosulfate, sodium sulfite, etc.) , Ultraviolet absorbers (imidazole derivatives, benzotriazole derivatives, p-aminobenzoic acid derivatives, anthranyl acid derivatives, salicylic acid derivatives, silicic acid derivatives, benzophenone derivatives, coumarin acid derivatives, camphor derivatives, etc.) and the like.

The content of the stabilizer is preferably 0 to 5% by mass, more preferably 0 to 2% by mass, based on the total mass of the pressure-sensitive adhesive layer.

Fillers include metal oxides (zinc oxide, titanium oxide, etc.), metal salts (calcium carbonate, magnesium carbonate, zinc stearate, etc.), silicic acid compounds (kaolin, talc, bentonite, aerodil, hydrous silica, aluminum silicate, etc.) Magnesium silicate, magnesium aluminometasilicate, etc.), metal hydroxides (aluminum hydroxide, etc.) and the like can be mentioned.

The content of the filler is preferably 0 to 10% by mass, more preferably 0 to 5% by mass, based on the total mass of the pressure-sensitive adhesive layer.

The pressure-sensitive adhesive layer may contain a solvent. Examples of the solvent include methanol, ethanol, acetone, ethyl acetate, toluene, tetrahydrofuran, acetonitrile and the like.

As used herein, the term "allergic symptom" means allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo. In addition, "treatment or alleviation of allergic symptoms" and similar expressions mean that the subjective symptoms of the above allergic symptoms (for example, sneezing, nasal juice, nasal congestion) are not observed, or the frequency of the subjective symptoms is reduced. Means that.

The patch according to the present embodiment is used to be applied to humans for 16 to 26 hours, preferably 20 to 26 hours, and more preferably 22 to 26 hours. When the patch according to the present embodiment is applied to a human, the blood concentration of emedastine reaches its maximum value C _max 8 to 32 hours after application, and the same blood concentration is maintained for about 10 hours. The maximum blood concentration C _max of emedastine is preferably 0.3 to 4 ng / mL. When the blood concentration is 0.3 ng / mL or more, the therapeutic or allergic effect of emedastine on allergic symptoms can be more sufficiently ensured. When the blood concentration is 4 ng / mL or less, side effects such as drowsiness due to emedastine are less likely to occur. By applying the patch according to the present embodiment for 16 to 26 hours, the blood concentration suitable for treating or alleviating allergic symptoms can be maintained for a longer period of time while suppressing the occurrence of side effects of emedastine. It can be maintained stably.

The part to be affixed is not particularly limited as long as it is a part expected in the actual usage of the affix. As the part to be attached, the human chest, upper arm, back, lumbar region or abdomen is preferable, and the human chest, upper arm, back or abdomen is more preferable. Applying the patch to the chest, upper arm, back or abdomen makes it easier to maintain higher blood levels of emedastine.

The area of the surface in contact with the skin of the patch may be a 8～24Cm ^2, may be 8~16cm ^2. When the area is 8 cm ² or more, emedastine fumarate contained in the pressure-sensitive adhesive layer tends to be more efficiently percutaneously absorbed, and it becomes easier to exert a more sufficient treatment or alleviation effect for allergic symptoms. The duration also tends to be longer. When the area is 24 cm ² or less, the occurrence of side effects such as drowsiness associated with an increase in the blood concentration of emedastine can be further suppressed. That is, when the application area is within the above range, the blood concentration of emedastine can be maintained at the same level as the effective blood concentration for a longer period of time, and the treatment or alleviation effect of allergic symptoms can be more efficiently performed. It will be possible to demonstrate it.

Moisture permeability of the patch ^{is, 1~200g / m 2 · 24hr,} 1~150g / m 2 · 24hr, 1~100g / m 2 · 24hr, 1~50g / m 2 · 24hr, 1~20g / m 2 · 24 hr or, or is preferably 1~10g ^/ m 2 · 24hr. Moisture permeability is a physical property that indicates the degree to which moisture permeates through the pressure-sensitive adhesive layer and / or support of the patch. When the moisture permeability is in the above range, the stratum corneum of the skin is moistened by appropriately blocking the moisture evaporated from the skin (occlusive state), and it becomes easier to improve the percutaneous absorption of emedastine (ODT). Effect: Occlusive Dressing Technique). If the moisture permeability is less than 1g / m 2 ^· 24hr, upon sticking the patch for a long time, for moisture transpiration from the skin accumulates between the patch and skin, tends to occur stuffiness, resulting in skin irritation In some cases. In addition, the water accumulated between the patch and the skin may reduce the adhesive strength of the patch. Furthermore, when the moisture permeability is higher than 200g ^/ m 2 · 24hr, sometimes sufficient ODT effect can not be obtained.

The patch according to the present embodiment may further include a release film for coating and protecting the pressure-sensitive adhesive layer.

As the material of the release film, a film such as polyester (polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), polyolefin (polyethylene, polypropylene, etc.), paper, etc. can be used, and the surface that comes into contact with the adhesive layer can be used. A silicone, Teflon (registered trademark) or the like coated and subjected to a mold release treatment is preferable, and a polyethylene terephthalate film treated with silicone is particularly preferably used.

The thickness of the pressure-sensitive adhesive layer is preferably 10 to 200 μm, more preferably 10 to 150 μm, and even more preferably 30 to 140 μm. If the pressure-sensitive adhesive layer is within the above range, it will not easily come off when putting on and taking off clothes.

The patch of the present embodiment is preferably stored in a packaging bag until use. For example, 1 to 7 patches are enclosed in one packaging bag. The packaging bag preferably has a multi-layer structure, and particularly preferably the material of the innermost layer is polyacrylonitrile (PAN), polyethylene terephthalate (PET), cyclic olefin, or ethylene-vinyl alcohol copolymer. When the material of the innermost layer is the above, it is difficult to cause the adsorption of emedastine. A particularly preferable material for the innermost layer is a heat-sealable PET film.

The patch according to this embodiment is used to be applied to humans for 16 to 26 hours. Conventionally, in the study of patches containing emedastine fumarate, no experimental results of administration to humans have been shown, and only data on transdermal absorbability in animal models using rats and rabbits have been discussed. According to the present invention, the occurrence of side effects caused by emedastine can be suppressed, and the pharmacological action of emedastine can be exerted for a long period of time.

When the patch according to the present embodiment is applied to a human, the blood concentration of emedastine reaches the maximum value C _max 8 to 32 hours after application (Tmax), and the same blood concentration is maintained for about 10 hours. Will be done. The maximum blood concentration C _max of emedastine is 0.3 to 4 ng / mL. When the blood concentration is 0.3 ng / mL or more, the therapeutic or allergic effect of emedastine on allergic symptoms can be more sufficiently ensured. When the blood concentration is 4 ng / mL or less, side effects such as drowsiness due to emedastine are less likely to occur. By applying the patch according to the present embodiment for 16 to 26 hours, the blood concentration suitable for treating or alleviating allergic symptoms can be maintained for a longer period of time while suppressing the occurrence of side effects caused by emedastine. It can be maintained stably.

Further, a plurality of patches of the present embodiment may be combined to form a set of patches. Specifically, such a set is a set in which seven or more of the above-mentioned patches are combined. After sticking one patch for 16 to 26 hours, it is used by replacing it with another patch. The set of patches facilitates the steady state of emedastine fumarate at high blood levels. Furthermore, according to the set of patches, daily replacement for 7 days or more, 10 days or more, or 14 days or more is more effective in treating or alleviating allergic symptoms during sleep or chronic allergic symptoms. ..

The patch according to the present embodiment also has an aspect of being a therapeutic agent for allergic symptoms containing emedastine fumarate, which is used for transdermal administration to humans for 16 to 26 hours. Further, in the present embodiment, a patch having an adhesive layer on a support and the adhesive layer containing emedastine fumarate having a body weight of 0.06 to 0.20 mg / kg is applied to humans 16 There is also an aspect of a method of treating or alleviating allergic symptoms, including application over ~ 26 hours. Further, in the present embodiment, a patch having a pressure-sensitive adhesive layer on a support and the pressure-sensitive adhesive layer containing emedastine fumarate having a body weight of 0.06 to 0.20 mg / kg is applied to humans 16 There is also an aspect of emedastine fumarate, which is applied for ~ 26 hours and is used to treat or alleviate allergic symptoms. Preferred embodiments in these aspects are as described above.

A second embodiment of the present invention is emedastine fumarate, which is used to transdermally administer 4 to 12 mg of emedastine fumarate over 16 to 26 hours to humans.

The emedastine fumarate according to the present embodiment is used to transdermally administer 4 to 12 mg of emedastine fumarate to humans over 16 to 26 hours. The human is preferably a patient who exhibits allergic symptoms or is suspected of exhibiting allergic symptoms. The allergic symptoms are preferably allergic rhinitis, urticaria, eczema, dermatitis, pruritus dermatitis or prurigo.

The transdermal administration is not particularly limited as long as it is administered by a preparation known in the art as a preparation for transdermal administration. Examples of the method of transdermal administration include patches, gels, creams, ointments, sprays, lotions and the like.

Percutaneous administration is preferably administered so that the maximum blood concentration C _max of emedastine is 0.3 to 4 ng / mL and the time to reach the maximum blood concentration T _max is 8 to 32 hours.

A preferred transdermal formulation is a patch with a pressure-sensitive adhesive layer containing 4-12 mg of emedastine fumarate. The pressure-sensitive adhesive layer preferably further contains a styrene-isoprene-styrene copolymer. When the pressure-sensitive adhesive layer further contains a styrene-isoprene-styrene copolymer, it becomes easy to adjust the maximum blood concentration C _max and the maximum blood concentration arrival time T _max of emedastine within the above ranges.

The pressure-sensitive adhesive layer further contains other components other than the styrene-isoprene-styrene copolymer, such as rubber-based pressure-sensitive adhesives, tackifier resins, plasticizers, transdermal absorption promoters, stabilizers, fillers, and fragrances. You may. As these components, the components described in the first embodiment can be used.

The part to be applied is preferably a human chest, upper arm, back, lumbar region or abdomen, and more preferably a human chest, upper arm, back or abdomen. Applying the patch to the chest, upper arm, back or abdomen makes it easier to maintain higher blood levels of emedastine.

The area of the surface in contact with the skin of the patch may be a 8～24Cm ^2, may be 8~16cm ^2. When the area is 8 cm ² or more, emedastine fumarate contained in the pressure-sensitive adhesive layer tends to be more efficiently percutaneously absorbed, and it becomes easier to exert a more sufficient treatment or alleviation effect for allergic symptoms. The duration also tends to be longer. When the area is 24 cm ² or less, the occurrence of side effects such as drowsiness associated with an increase in the blood concentration of emedastine can be further suppressed. That is, when the application area is within the above range, the blood concentration of emedastine can be maintained at the same level as the effective blood concentration for a longer period of time, and the treatment or alleviation effect of allergic symptoms can be more efficiently performed. It will be possible to demonstrate it.

Moisture permeability of the patch ^{is, 1~200g / m 2 · 24hr,} 1~150g / m 2 · 24hr, 1~100g / m 2 · 24hr, 1~50g / m 2 · 24hr, 1~20g / m 2 · 24 hr or, or is preferably 1~10g ^/ m 2 · 24hr. When the moisture permeability is in the above range, the moisture vaporized from the skin is blocked and the skin is closed, so that the stratum corneum of the skin is moistened and the transdermal absorbability of emedastine is more easily improved (ODT effect). ). When the moisture permeability is low, when the patch is applied for a long time, the moisture evaporated from the skin accumulates between the patch and the skin, so that stuffiness is likely to occur, which may cause skin irritation. In addition, the water accumulated between the patch and the skin may reduce the adhesive strength of the patch.

The patch according to this embodiment can be produced, for example, by the following method.
1) Emedastine fumarate, optionally a styrene-isoprene-styrene copolymer and other components are weighed, warmed and solvent added as necessary and mixed to obtain a uniform pressure-sensitive adhesive composition. ..
2) The obtained pressure-sensitive adhesive composition is applied to the release surface of the release liner to a certain thickness, and if necessary, dried to remove the solvent component to form a pressure-sensitive adhesive layer.
3) The support is laminated on the pressure-sensitive adhesive layer.
4) Cut into a predetermined shape (for example, a rectangle having a short side of 3 to 14 cm and a long side of 5 to 20 cm, or a circle having a diameter of 1 to 8 cm).

Hereinafter, the patch of the present invention will be described in more detail with reference to Examples and Comparative Examples. Unless otherwise specified, the thickness of the pressure-sensitive adhesive layer was adjusted to 100 μm with respect to Examples and Comparative Examples.

Test Example 1: Single administration The patches of Examples 1 and 2 and Comparative Examples 1 and 2 were prepared according to the description in Table 1. Unless otherwise specified, the numerical values in Table 1 mean mass (unit: mg).

The obtained patches were applied to the chests of 12 healthy adult men, and immediately before and after application, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 48, After 72 hours, blood was collected and the blood concentration of emedastine at each time point was measured. Based on the obtained values of blood concentration, the maximum blood concentration C _{max of emedastine} and the time to reach the maximum blood concentration T _max were calculated for each patch. In addition, a graph was created by plotting the blood concentration on the vertical axis and time on the horizontal axis, and the area under the curve AUC _0-∞ of the time-blood concentration curve was calculated. Furthermore, the percentage of people who felt drowsy while applying each patch was calculated.

Similarly, in place of the patch, an oral preparation containing emedastine fumarate "Dallen Capsule" (trade name) was orally administered to 12 healthy adult men, and the blood concentration was measured.

The results are shown in Table 2. In Table 2, Comparative Example 3 is the result of oral administration of Darren capsules. In Comparative Example 1, the values of C _max and AUC _0-∞ were lower than those of Comparative Example 3, and the pharmacological action of emedastine was not sufficiently exhibited. Further, in Comparative Example 2, the blood concentration of emedastine was high, and the symptom of somnolence (side effect due to emedastine) was exhibited. The patches of Examples 1 and 2 reached the maximum blood concentration over about 20 hours without developing the symptoms of somnolence. On the other hand, the capsule of Comparative Example 3 reached the maximum blood concentration 4 hours after administration, and also developed symptoms of somnolence.

Test Example 2: Repeated administration The patches of Examples 3 and 4 were prepared according to the description in Table 3. Unless otherwise specified, the numerical values in Table 3 mean mass (unit: mg). In addition, patches having the same composition as in Examples 3 and 4, except that they did not contain emedastine fumarate, were prepared in Comparative Examples 4 and 5, respectively.

The obtained patches of Examples 3 and 4 and Comparative Examples 4 and 5 were applied to the chests of 96 patients with seasonal allergic rhinitis, respectively, and replaced with new patches every 24 hours. Repeated until the day. Blood was collected at the time of reattachment of the patch, and the blood concentration of emedastine at each time point was measured. Based on the obtained blood concentration values, the maximum blood concentration value (peak value) and the minimum blood concentration value (trough value) when the steady state was reached by repeated administration of each patch were calculated. .. In addition, a graph was created by plotting the blood concentration on the vertical axis and time on the horizontal axis, and the area under the curve AUC _0-∞ of the time-blood concentration curve was calculated.

Table 4 shows the values (peak / trough ratio) obtained by dividing the obtained peak value by the trough value for each patch. The peak / trough ratio at the 7th dose was 1.2, and the fluctuation range of the blood concentration in the steady state was small. Considering that when emedastine fumarate is orally administered, C _max is reached 4 hours after administration and the blood concentration decreases immediately, even if emedastine fumarate is orally administered twice a day, The fluctuation range of the blood concentration is larger than that of the patch of the present invention. That is, according to the patch of the present invention, the occurrence of side effects due to emedastine can be suppressed and sufficient pharmacological action can be expected as compared with the oral preparation.

Table 5 shows the average value of AUC _0-∞ for each patch. Since Comparative Example 4 is a patch that does not contain emedastine fumarate, the AUC _0-∞ when Comparative Example 4 is pasted is not calculated. It was found that the AUC gradually increased as the number of administrations increased, and reached a steady state at about the 7th administration. That is, it can be said that the amount of newly absorbed emedastine and the amount of metabolized or excreted emedastine are in equilibrium. Reaching a steady state makes it easier to maintain high levels of emedastine in the blood, even 26 hours after application.

Test Example 3: Repeated administration The obtained patches of Examples 2 to 4 and Comparative Example 4 were applied to the chests of 96 patients with seasonal allergic rhinitis, respectively, and replaced with new patches every 24 hours. This work was repeated until the 15th day. On the 15th day, each patient scored three endpoints of allergic symptoms, sneezing attack, runny nose, and nasal congestion, according to the following evaluation criteria based on his / her own subjectivity, and scored the scores before administration. The amount of change was calculated by comparing with the score.
<Evaluation criteria for allergic symptoms>
0: No symptom 1: Mild 2: Slightly severe 3: Severe 4: Very severe

The least squares average value of the amount of change in the obtained score was calculated and shown in Table 6. Patients who received emedastine fumarate transdermally for 14 days using the patches of Examples 2 to 4 had a marked improvement in allergic rhinitis. In addition, the score was significantly reduced as compared with the amount of change in the score when Comparative Example 4 containing no emedastine fumarate was attached.

Further, each patch after peeling was collected, and the amount of emedastine fumarate contained in the pressure-sensitive adhesive layer was measured by high performance liquid chromatography (detection wavelength: 280 nm). The results are shown in Table 7. In all of the patches of Examples 2 to 4, the release rate of emedastine fumarate was about 65%.

Test Example 4: Repeated administration The patches of Examples 3 and 4 and Comparative Examples 4 and 5 were applied to the chest, upper arm, back or abdomen of 1276 patients with seasonal allergic rhinitis, and the evaluation criteria shown in Table 8 were applied. Based on this, on day 15, the nasal congestion scores of allergic symptoms of each patient were compared.

The results are shown in Table 9. Even if the number of subjects was increased, the same results as in Test Example 3 were obtained.

Test Example 5: Evaluation of allergic symptoms The obtained patches of Examples 3 and 4 were applied to the chest, upper arm, back or abdomen of 247 patients with seasonal allergic rhinitis, respectively, and new patches were applied every 24 hours. It was replaced with an agent, and this work was repeated for 12 weeks (84 days), and in some cases 52 weeks (364 days). On the day following repeated administration, nasal congestion score was recorded for allergic symptoms (sneezing attack, runny nose, nasal congestion) of each patient in the same manner as in Test Example 4. The average value of the scores was compared with the scores of each patient before administration, and the amount of change was calculated.

The results are shown in Table 10. In the group to which Examples 3 and 4 were applied, the total score of the above allergic symptoms decreased at the latest 1 week after application, and the decreased score was maintained until 52 weeks later.

Test Example 6: Examination of application site 20 healthy adults were divided into 5 groups, and the application of Example 4 was applied to any one of the chest, upper arm, back, lumbar region and abdomen of healthy adults in each group. Was pasted. Blood was collected immediately before the application and 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 48, 72 hours after the application, and the blood concentration of emedastine was measured. In addition, after a certain period of time (drug holiday) had elapsed after blood collection, the mixture was attached to another part of the chest, upper arm, back, lumbar region and abdomen, and the blood concentration of emedastine was measured in the same manner. This was repeated 5 times in total, and the test was conducted at 5 sites for the same subject.

The blood concentration data were classified according to the application site, and the highest value was recorded as the maximum blood concentration C _max from the obtained blood concentration values, which is shown in Table 11. Of the five sites tested, the emedastine absorption rate was highest when the patch was applied to the back, and the emedastine absorption rate (unit: ng / mL) was the lowest when the patch was applied to the lumbar region.

Test Example 7: Examination of Moisture Permeability With respect to the patch of Example 4, the moisture permeability was measured according to the method described in JIS Z-0280: 1976 (cup method). The test was carried out three times, and the average value was calculated.

Moisture permeability of the adhesive patch of Example 4 is 6.15~6.68g ^/ m 2 · 24hr, the average value was 6.45g ^/ m 2 · 24hr.

Test Example 8: Examination of Support A patch (sticking area: 3.0 cm ² ) of Examples 5 and 6 was prepared by using a polyester film or a knitted cloth as a support in the same adhesive layer as in Example 4. ..

Moisture permeability test and skin permeability test were carried out for the patches of Examples 5 and 6. The moisture permeability test was carried out in the same manner as in Test Example 7. The skin permeation test was performed as follows.
The skin on the back of the hairless mouse was peeled off, the dermis side was directed toward the receptor layer, and the mouse was attached to a flow-through cell in which warm water at 32 ° C. was circulated around the outer periphery. The patch of Example 5 or 6 was applied to the stratum corneum side, and sampling was performed at a rate of 2.0 mL / hour every 4 hours from the time of application to 24 hours later. In this test, phosphate buffered saline (pH 7.4) was used as the receptor layer. The concentration of emedastine in the receptor layer was measured over time, and the cumulative skin permeation amount (μg / cm ² ) of emedastine (as a free form) from the time of application to 24 hours later was calculated.

The results are shown in Table 12. The patches of Examples 5 and 6 had excellent skin permeability of emedastine in a test using mouse skin. In particular, the patch of Example 5 had a higher value of emedastine permeating the skin.

Claims (7)

A patch for treating or alleviating allergic symptoms, wherein the pressure-sensitive adhesive layer is provided on a support and the pressure-sensitive adhesive layer contains emedastine fumarate.
Used to transdermally administer emedastine fumarate to humans for 16-26 hours
A patch having an emedastine fumarate content of 0.06 to 0.20 mg per kg of the human body weight. The patch according to claim 1, wherein the allergic symptom is allergic rhinitis, urticaria, eczema, dermatitis, prurigo dermatitis or prurigo. It is used so that the maximum blood concentration C _max of emedastine is 0.3 to 4 ng / mL and the time to reach the maximum blood concentration T _max is 8 to 32 hours. The patch according to 2. Moisture permeability of the adhesive patch, JIS Z-0280: when measured in accordance with a cup method as described in 1976, is a 1~200g ^/ m 2 · 24hr, pasting according to any one of claims 1 to 3 Agent. The patch according to any one of claims 1 to 4, which is applied to the chest, upper arm, back or abdomen of a human. The patch according to any one of claims 1 to 5, wherein the area of the surface of the patch in contact with the skin is 8 to 24 cm ² . The patch according to any one of claims 1 to 6, wherein the pressure-sensitive adhesive layer contains a styrene-isoprene-styrene copolymer.