WO2017006974A1 - Patch de type à absorption transdermique - Google Patents

Patch de type à absorption transdermique Download PDF

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Publication number
WO2017006974A1
WO2017006974A1 PCT/JP2016/070062 JP2016070062W WO2017006974A1 WO 2017006974 A1 WO2017006974 A1 WO 2017006974A1 JP 2016070062 W JP2016070062 W JP 2016070062W WO 2017006974 A1 WO2017006974 A1 WO 2017006974A1
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Prior art keywords
drug
solifenacin
containing layer
transdermal
patch
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PCT/JP2016/070062
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English (en)
Japanese (ja)
Inventor
古賀　徹
山根　教郎
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王子ホールディングス株式会社
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Priority to JP2017527485A priority Critical patent/JP6729584B2/ja
Publication of WO2017006974A1 publication Critical patent/WO2017006974A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to a transdermal patch containing a pharmaceutically acceptable salt of solifenacin as an active ingredient.
  • transdermal patches have the advantages of reducing the number of administrations, improving compliance, ease of administration and discontinuation, in addition to solving problems in oral administration, especially elderly and pediatric patients It is expected to be a useful drug administration method in the treatment of cancer.
  • Solifenacin (R) -quinuclidin-3-yl (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate) is a muscarin with high affinity for the muscarinic M3 receptor. It is a receptor antagonist (Patent Document 1) and is currently used as a therapeutic agent for overactive bladder in clinical settings.
  • the preparations currently in practical use are solifenacin succinate tablets and orally disintegrating tablets, which are prescribed to patients with overactive bladder as an oral preparation under the trade name “Vesicare®”.
  • Overactive bladder patients are known to refrain from drinking water on a daily basis, and solifenacin is a drug that is often taken by elderly people with reduced swallowing function. Rather, transdermal patches are suitable.
  • oxybutynin hydrochloride is a product name of “Neoxy (registered trademark) tape” and is currently used clinically as a transdermal absorption patch. Erythema is frequently observed (Non-Patent Document 1), and from the viewpoint of patient safety, development of a preparation with less odor and skin irritation is desired.
  • Solifenacin is known to degrade over time in the general formulation method, solifenacin, the main drug in the formulation, and various stabilization methods are available to suppress the formation of degradation products in the formulation. It has been proposed (Patent Documents 2, 3, 4 and 5). However, these documents do not describe the stability of solifenacin in transdermal patches.
  • Patent Document 6 proposes a transdermal absorption patch (tape) containing a solifenacin-free body and fatty acid esters as a transdermal absorption accelerator. There is no description regarding the temporal stability of this patch.
  • Patent Document 7 also includes a thermoplastic elastomer, a liquid component in excess of 300 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, and an overactive bladder therapeutic agent having anticholinergic action (solifenacin, darifenacin, etc.). Skin-absorbing patches have been proposed. However, Patent Document 7 does not describe the temporal stability of this patch.
  • the present inventor evaluated the storage stability of solifenacin-free body by a severe test, and it was confirmed that the decomposition products increased with time (see Test Example 1). From this, it was found that the solifenacin-free body decomposes with time in the usual storage method. Therefore, when a percutaneous absorption type patch is prepared using solifenacin-free drug substance as a drug substance, the degradation product contained in the drug substance itself is mixed at the time of preparation of the patch, and the content of the resulting patch product is contained. The amount could exceed 0.5%.
  • a pharmaceutically acceptable salt such as solifenacin succinate
  • stability over time was improved, and it was confirmed that there was almost no degradation in a normal storage method (see Test Example 1). Therefore, in preparing a transdermal absorption patch, it is preferable to use a pharmaceutically acceptable salt of solifenacin as a drug substance.
  • solifenacin was degraded over time.
  • the percentage of the decomposition product may exceed 0.5%. Therefore, a patch with excellent storage stability that can suppress the degradation of solifenacin over time has been desired.
  • transdermal absorption patch it is necessary to have desirable solifenacin skin permeability and low irritation to the skin.
  • the present invention is a transdermal patch containing a pharmaceutically acceptable salt of solifenacin as at least one active ingredient, maintaining good skin permeability of solifenacin, and degradation of solifenacin over time.
  • An object of the present invention is to provide a preparation that suppresses skin irritation and has low skin irritation.
  • transdermal patch containing a pharmaceutically acceptable salt of solifenacin and an inorganic base in a drug-containing layer has a transdermal absorbability and It was found that the storage stability was excellent and the skin irritation was small. Based on this knowledge, further studies have been made and the present invention has been completed.
  • the present invention is as follows.
  • [1] A transdermal absorption patch having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin and an inorganic base. .
  • [2] The transdermal system according to [1], wherein the drug-containing layer further contains an adhesive, and the adhesive contains at least one selected from the group consisting of a rubber-based resin and an acrylic resin as a main component.
  • Absorbent patch [3] The transdermal patch according to [2], wherein the rubber resin is a styrene-isoprene-styrene block copolymer.
  • the tackifier is an alicyclic saturated hydrocarbon resin.
  • the inorganic base is at least one selected from the group consisting of potassium hydroxide and sodium hydroxide.
  • the drug-containing layer further contains an absorption enhancer, and the absorption enhancer is at least one selected from the group consisting of alcohols and esters.
  • transdermal patch according to any one of the above [1] to [9] for use as a therapeutic agent for overactive bladder.
  • solifenacin by containing a pharmaceutically acceptable salt of solifenacin and an inorganic base in the drug-containing layer, high skin permeability can be obtained, and solifenacin is not decomposed over time, and thus preserved. It is possible to provide a transdermal absorption patch having excellent stability and little skin irritation.
  • a pharmaceutically acceptable salt of solifenacin as a transdermal absorption patch improves administration convenience for patients with dysphagia and overactive bladder patients who refrain from drinking.
  • an improvement in medication adherence can be expected.
  • the transdermal patch of the present invention can achieve a blood concentration of solifenacin effective for the treatment of overactive bladder.
  • solifenacin since solifenacin is percutaneously absorbed, a desired plasma concentration can be maintained over a long period of time.
  • the transdermal patch is a parenteral preparation which is used by being affixed to the skin, and the active ingredient is absorbed through the skin and delivered to the bloodstream.
  • the transdermal patch of the present invention is a patch having a support and a drug-containing layer, and examples thereof include a tape, a poultice, and a plaster.
  • the transdermal patch of the present invention may be a matrix-type patch preparation containing an adhesive in the drug-containing layer, and a release-controlling membrane for adjusting the transdermal absorption of the drug on the skin-pasted side of the drug-containing layer and It may be a reservoir-type patch preparation further having an adhesive layer for sticking to the skin. With such a structure, solifenacin can be efficiently transdermally absorbed.
  • a matrix-type patch is preferable.
  • the matrix type patch will be described as an example, but the present invention is not limited thereto.
  • the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin as an active ingredient.
  • Pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; and organic acid salts such as formate, acetate, Trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate, sorbate , Lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, isostearate Succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate), etc. Absent.
  • inorganic acid salts such as hydrochloride, hydro
  • solifenacin succinate that has already been established to be useful for oral administration as a muscarinic receptor antagonist.
  • the content of the pharmaceutically acceptable salt of solifenacin in the transdermal absorption patch of the present invention is an effective amount for the treatment of overactive bladder.
  • the effective amount is an amount that can achieve the blood concentration of solifenacin effective for treating overactive bladder when the transdermal absorption patch of the present invention is applied to the skin of a living body.
  • Such content can be appropriately adjusted based on information on pharmacokinetics of oral administration, and may vary depending on the administration subject, disease, symptoms, and the like.
  • the content is preferably 0.2 to 50% by mass, more preferably 0.5 to 35% by mass, and more preferably 0.5 to 25% by mass with respect to the drug-containing layer (that is, based on the total mass of the drug-containing layer; More preferred is mass%.
  • the blood concentration of solifenacin effective for the treatment of overactive bladder can be comparable to that of an oral pharmaceutically acceptable salt of solifenacin.
  • a blood concentration effective for treating overactive bladder can be achieved by adjusting the skin permeation rate of solifenacin.
  • the skin permeation rate can be adjusted by any means such as adjusting the content and administration area of the pharmaceutically acceptable salt of solifenacin in the drug-containing layer.
  • the skin permeation rate of a pharmaceutically acceptable salt of solifenacin means a value measured by an in vitro skin permeability test described in Examples described later.
  • Skin permeation rate of solifenacin is preferably 5 ⁇ 40 ⁇ g / cm 2 / time value converted to warpage phenacyl down free form, and more preferably 5 ⁇ 35 ⁇ g / cm 2 / hour. If the skin permeation rate is 5 ⁇ g / cm 2 / hour or more, a sufficient blood concentration can be obtained. A skin permeation rate of 40 ⁇ g / cm 2 / hour or less is preferable from the viewpoint of safety because skin irritation such as erythema of the applied skin hardly occurs.
  • the drug-containing layer contains an inorganic base.
  • alkali metal hydroxides potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and the like are preferable, and sodium hydroxide and potassium hydroxide are more preferable.
  • Such inorganic bases can be used alone or in admixture of two or more.
  • the content of the inorganic base is preferably 0.5 to 3 equivalents, and preferably 0.5 to 2 equivalents, relative to the equivalent of the pharmaceutically acceptable salt of solifenacin (particularly the acid addition salt). More preferred.
  • the content of the inorganic base is preferably 0.1 to 35% by mass, more preferably 1 to 30% by mass, and further preferably 1 to 20% by mass with respect to the drug-containing layer. preferable.
  • the inorganic base acts on a pharmaceutically acceptable salt (especially an acid addition salt) of solifenacin, and the skin permeability of solifenacin is improved.
  • the effect of improving skin permeability becomes more remarkable as compared with the case where the content is outside the above range.
  • decomposition disassembly of solifenacin in a drug content layer can be suppressed by using an inorganic base. This effect is remarkably superior especially when an organic base is used.
  • the adhesive drug-containing layer can further contain an adhesive.
  • Examples of the pressure-sensitive adhesive contained in the drug-containing layer include those containing rubber resins, acrylic resins, silicone resins, and the like.
  • the pressure-sensitive adhesive preferably contains at least one selected from the group consisting of acrylic resins, rubber resins and silicone resins as a main component, and at least selected from the group consisting of acrylic resins and rubber resins. What contains 1 type as a main component is more preferable.
  • the “main component” means usually 70% by mass or more, further 80% by mass or more, further 90% by mass or more, and particularly 100% by mass with respect to the total mass of the pressure-sensitive adhesive.
  • rubber resins examples include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, and polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, preferably SIS.
  • SIS styrene-isoprene-styrene block copolymer
  • SBS styrene-butadiene-styrene block copolymer
  • SBR styrene-butadiene rubber
  • PIB polyisobutylene
  • Rubber-based resins such as Kraton D polymer series (manufactured by Kraton Polymer Japan), JSR SIS / TR series (manufactured by JSR Life Sciences), and quintack series (manufactured by Nippon Zeon) may also be used.
  • acrylic resins include (meth) acrylic acid esters represented by monomer units such as 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, and the like. Examples thereof include a polymer or copolymer containing at least one kind.
  • acrylic acid / octyl acrylate copolymer 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-Hexane glycol copolymer, acrylic acid ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid
  • examples thereof include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic resin alkanolamine solution.
  • DURO-TAK (registered trademark) acrylic adhesive series (DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 387-2510, DURO-TAK 87-2510, DURO -TAK 387-2287, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 387-2516, DURO-TAK 87-2516, DURO-TAK 87-2074, DURO-TAK 387-235A, DURO- TAK 387-2353, DURO-TAK 87-2353, DURO-TAK 87-2852, DURO-TAK 387-2051, DURO-TAK 87-2051, DURO-TAK 387-2052, DURO-TAK 387-2052, DURO-TAK 387-2054, DURO-TAK 87-2054, DURO-
  • silicone resins include polymers having an organopolysiloxane skeleton and derivatives thereof, and specific examples include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane.
  • a commercially available silicone resin such as BIO-PSA series (manufactured by Dow Corning) may also be used.
  • one of the above rubber resins, acrylic resins, and silicone resins may be used alone or in combination of two or more. Can be used. More preferably, acrylic or rubber resin is used, and rubber resin is more preferably used.
  • the amount of the adhesive contained in the drug-containing layer of the transdermal patch of the present invention is determined in consideration of the formation of the drug-containing layer, sufficient skin permeability of a pharmaceutically acceptable salt of solifenacin, and the like. Adjusted.
  • the content of the pressure-sensitive adhesive is usually 10 to 90% by mass, preferably 10 to 80% by mass with respect to the drug-containing layer.
  • the content of the rubber-based resin is a total for the drug-containing layer in consideration of sufficient cohesion as a patch. Is preferably 10 to 70% by mass, more preferably 10 to 60% by mass, and still more preferably 10 to 50% by mass.
  • the acrylic resin content is determined relative to the drug-containing layer in consideration of sufficient cohesive strength and adhesive strength as a patch.
  • the total amount is preferably 20 to 90% by weight, more preferably 20 to 80% by weight.
  • the silicone resin content is determined relative to the drug-containing layer in consideration of sufficient cohesion and adhesive strength as a patch.
  • the total amount is preferably 20 to 90% by weight, more preferably 20 to 80% by weight.
  • the drug-containing layer may further contain a tackifier to improve the adhesive strength.
  • the tackifier include rosin derivatives such as rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic Saturated hydrocarbon resin, aliphatic hydrocarbon resin, maleic resin, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose , Polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like.
  • tackifier commercially available products such as Alcon series (Arakawa Chemical Co., Ltd.), Pine Crystal series (Arakawa Chemical Co., Ltd.), Clearon series (Yasuhara Chemical Co., Ltd.), YS Resin Series (Yasuhara Chemical Co., Ltd.), etc. You may use suitably.
  • the rubber-based resin is used as an adhesive, it is preferable to use a glycerin ester of hydrogenated rosin, an alicyclic saturated hydrocarbon resin, a terpene resin, or an aliphatic saturated hydrocarbon resin as a tackifier.
  • a tackifier can be used individually by 1 type or in combination of 2 or more types.
  • the content of the tackifier is preferably 5 to 70% by mass in total with respect to the drug-containing layer when a rubber-based resin is used as the adhesive. 60% by mass is more preferable, and 20 to 50% by mass is more preferable.
  • the total amount is preferably 1 to 40% by mass, more preferably 5 to 30% by mass, and still more preferably 5 to 20% by mass with respect to the drug-containing layer.
  • a silicone resin is used as the adhesive, it is preferably 1 to 40% by mass, more preferably 5 to 30% by mass, and still more preferably 5 to 20% by mass with respect to the drug-containing layer.
  • Plasticizer The drug-containing layer may further contain a plasticizer.
  • Plasticizers include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, liquid paraffin, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), diethylene glycol, polyethylene glycol, salicylic acid glycol, triacetin, citric acid Examples include triethyl and crotamiton.
  • plasticizer you may use suitably what is marketed, such as a high coal series (made by Kaneda Co., Ltd.).
  • a high coal series made by Kaneda Co., Ltd.
  • liquid paraffin is preferably used as a plasticizer.
  • a plasticizer can be used individually by 1 type or in combination of 2 or more types.
  • the content of the plasticizer is adjusted in consideration of sufficient permeability of solifenacin and maintenance of sufficient cohesion as a patch.
  • the total amount is preferably 1 to 70% by mass, more preferably 1 to 60% by mass, and still more preferably 1 to 50% by mass with respect to the drug-containing layer.
  • the total amount is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and still more preferably 1 to 30% by mass with respect to the drug-containing layer.
  • silicone resins are used as the pressure-sensitive adhesive, the total amount is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and still more preferably 1 to 30% by mass with respect to the drug-containing layer.
  • the absorption enhancer drug-containing layer may further contain an absorption enhancer for improving the skin permeability of solifenacin.
  • the absorption enhancer may be any compound that has been shown to promote skin permeation through transdermal administration, such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oleic acid, linol.
  • Fatty acids or esters thereof such as acid, linolenic acid, isopropyl myristate, oleyl oleate, glyceryl tri (capryl / caprate), isopropyl palmitate, octyldodecyl myristate, glycerol oleate monoester, hexadecyl isostearate; lactic acid, Acetic acid, malic acid, citric acid, tartaric acid, oxalic acid, fumaric acid, succinic acid, glutaric acid, glycolic acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, salicylic acid, nicotinic acid, methanesulfonic acid, benzenesulfonic acid, Toluene sul Acids, organic acids such as saccharin or salts thereof; polycarboxylic esters such as diisopropyl adipate, diethyl sebacate,
  • alcohols and esters are preferred.
  • examples of alcohols include polyhydric alcohols having 3 to 8 carbon atoms such as propylene glycol, dipropylene glycol, and 1,3-butanediol; aliphatic alcohols such as oleyl alcohol and isostearyl alcohol.
  • esters for example, polyvalent carboxylic acid esters and fatty acid esters are preferable.
  • the polyvalent carboxylic acid ester include divalent aliphatic carboxylic acid esters such as diisopropyl adipate, diethyl sebacate, and diisopropyl sebacate.
  • fatty acid esters examples include isopropyl myristate, isopropyl palmitate, oleyl oleate, hexyl laurate, propylene glycol monocaprylate, propylene glycol dicaprylate, and tri (caprylic / capric acid) glycerin. More preferred are propylene glycol, dipropylene glycol, isopropyl myristate, isopropyl palmitate, hexyl laurate, and propylene glycol dicaprylate.
  • An absorption accelerator can be used individually by 1 type or in combination of 2 or more types.
  • the content of the absorption promoter can be appropriately adjusted according to the type of pharmaceutically acceptable salt of solifenacin, but is usually 30% by mass or less and 25% by mass or less based on the drug-containing layer. preferable.
  • an absorption accelerator is included, it is preferably 0.1 to 30% by mass, more preferably 0.5 to 25% by mass, and further preferably 1 to 25% by mass.
  • the drug-containing layer further contains known additives such as a pH adjuster, a crosslinking agent, an antioxidant, a colorant, an ultraviolet absorber, a filler, or an antiseptic, as necessary. May be.
  • the pH adjuster is used in the drug-containing layer for the purpose of improving the solubility, stability and skin permeability of pharmaceutically acceptable salts of solifenacin or solvates thereof, and improving the safety to the skin.
  • the pH adjuster may be any compound as long as it is an acid or base or a salt thereof that is usually used for pH adjustment in the pharmaceutical field.
  • crosslinking agents include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. Is mentioned. Among these, an isocyanate compound or a blocked isocyanate compound is preferable.
  • antioxidants examples include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.
  • colorants include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water
  • colorants include sodium oxide, talc, copper chlorophyllin sodium, green leaf extract powder, d-borneol, octyldodecyl myristate, methylene blue, ammonium manganese phosphate, and rose oil.
  • ultraviolet absorbers examples include amino acid compounds, benzophenone compounds, cinnamic acid derivatives, cyanoacrylate derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, and the like. Can be mentioned.
  • Fillers include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium bicarbonate, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium), magnesium hydroxide, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.
  • silicate eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium
  • magnesium hydroxide eg, magnesium hydroxide, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.
  • preservatives examples include ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.
  • the total content of other optional components is usually 10% by mass or less, preferably 5% by mass or less, based on the drug-containing layer.
  • the content is preferably 0.05 to 10% by mass, more preferably 0.1 to 5% by mass.
  • the area of the drug-containing layer in the transdermal patch of the present invention can be appropriately adjusted according to the content of the pharmaceutically acceptable salt of solifenacin and / or the skin permeation rate. Is in the range of 2 to 140 cm 2 , preferably 2 to 100 cm 2 , more preferably 2 to 50 cm 2 .
  • the shape is not particularly limited, and may be a square, a rectangle, a circle, an ellipse, or the like.
  • the thickness of the drug-containing layer in the transdermal patch of the present invention can be appropriately adjusted according to the type of adhesive, the content of pharmaceutically acceptable salt of solifenacin, and / or the skin permeation rate. Although not particularly limited, it is typically in the range of 20 to 300 ⁇ m, preferably 25 to 150 ⁇ m, and more preferably 25 ⁇ m to 100 ⁇ m.
  • the drug-containing layer in the transdermal absorption patch of the present invention contains a pharmaceutically acceptable salt of solifenacin and an inorganic base as essential components.
  • the pharmaceutically acceptable salt of solifenacin is preferably an organic acid salt (particularly succinate), and its content is preferably 0.5 to 25% by mass with respect to the drug-containing layer.
  • alkali metal hydroxides particularly potassium hydroxide and sodium hydroxide
  • the content thereof is preferably 1 to 20% by mass with respect to the drug-containing layer.
  • the adhesive is preferably a rubber resin (particularly SIS) or an acrylic resin.
  • the content is preferably 10 to 50% by mass with respect to the drug-containing layer.
  • the pressure-sensitive adhesive is an acrylic resin, the content thereof is preferably 20 to 80% by mass with respect to the drug-containing layer.
  • the tackifier is preferably an alicyclic saturated hydrocarbon resin.
  • the content of the tackifier is preferably 20 to 50% by mass with respect to the drug-containing layer.
  • the content of the tackifier is The content is preferably 5 to 20% by mass with respect to the drug-containing layer.
  • the absorption enhancer is preferably isopropyl myristate.
  • the content of the absorption accelerator is preferably 1 to 25% by mass with respect to the drug-containing layer.
  • a drug-impermeable, stretchable or non-stretchable support can be used.
  • a support is not particularly limited as long as it is usually used in the field of pharmaceuticals.
  • polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.) examples thereof include synthetic resin films or sheets such as nylon and polyurethane, laminates thereof, porous bodies, foams, films obtained by vapor-depositing aluminum, paper, woven fabrics, and nonwoven fabrics.
  • the transdermal absorption patch of the present invention may further have a release liner.
  • the release liner is laminated on the surface of the drug-containing layer laminated on the support opposite to the surface in contact with the support, and the drug-containing layer is applied until the transdermal absorption patch is applied to the skin. Can be protected.
  • the release liner is not particularly limited as long as it is impervious to at least solifenacin in the drug-containing layer.
  • a film made of a polymer material such as polyethylene, polypropylene, polyester, polyethylene terephthalate, and aluminum is deposited on the film. And those obtained by applying silicone oil or the like on paper.
  • the transdermal patch of the present invention can be produced according to a known method.
  • a mixture containing a pharmaceutically acceptable salt of solifenacin, an inorganic base, and, if necessary, the above optional components is prepared, and this mixture is applied (spread) onto a release liner to form a drug-containing layer. It can be produced by attaching a support to the drug-containing layer.
  • a pharmaceutically acceptable salt of solifenacin for example, a pharmaceutically acceptable salt of solifenacin, an inorganic base, and, if necessary, a pressure-sensitive adhesive, a tackifier, a plasticizer, an absorption enhancer, and / or other additives, It adds to an organic solvent so that it may become quantity, and mixes and stirs and prepares a coating liquid.
  • a mixing method for example, stirring, in-line mixing, ultrasonic treatment, or the like can be used.
  • organic solvent ethyl acetate, hexane, pentane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used.
  • the content of the organic solvent in the coating liquid is not particularly limited and is, for example, 30 to 90% by mass, preferably 40 to 80% by mass with respect to the entire coating liquid.
  • this coating liquid is spread on a release liner, and after evaporating the solvent in the coating liquid to form a drug-containing layer, a support is attached to obtain a transdermal absorption type patch.
  • a transdermal absorption patch can be obtained by spreading the coating liquid on a support, evaporating the solvent in the coating liquid to form a drug-containing layer, and then bonding a release liner. it can.
  • a method of spreading a coating solution on a release liner, evaporating the solvent in the coating solution to form a drug-containing layer, and then laminating the support is preferable.
  • the coating solution can be applied using a knife coater, comma coater, reverse coater, or die coater. Although an example of a manufacturing flow is shown in FIG. 1, it is not limited to this.
  • transdermal patch of the present invention a pharmaceutically acceptable salt of solifenacin, an inorganic base, and other optional components as necessary are heated and melted, and this melt is applied onto a release liner. And after the drug-containing layer is formed, the transdermal patch can be produced by pasting the support.
  • a transdermal patch may be produced by applying (spreading) a melt on a support to form a drug-containing layer and then bonding a release liner.
  • Treatment of overactive bladder with the transdermal absorption patch of the present invention can be performed by directly applying the transdermal absorption patch of the present invention to the target skin and administering solifenacin transdermally.
  • the subject in the present invention is a mammal such as a human, preferably a human.
  • treatment of overactive bladder can be performed by applying (applying) the patch to the skin of a patient requiring treatment of overactive bladder.
  • the content of solifenacin in the drug-containing layer and / or the skin permeation rate so as to achieve a blood concentration effective for treatment of overactive bladder. Then, after appropriately adjusting the area of the drug-containing layer and / or the thickness of the drug-containing layer, the transdermal patch of the present invention is applied to the skin.
  • the transdermal absorption patch of the present invention may be applied to the skin of any part of the body as long as it can be applied.
  • the upper arm, abdomen, chest, neck, waist back, buttocks or legs Can be affixed to.
  • the transdermal administration of the transdermal patch of the present invention to a subject may be combined with the administration of a pharmaceutical composition containing a pharmaceutical ingredient other than the pharmaceutically acceptable salt of solifenacin as necessary.
  • the administration form may be simultaneous administration or administration with a time difference, and the pharmaceutical composition may be intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. It can be administered by various routes including:
  • a pharmaceutical composition containing a pharmaceutical ingredient other than a pharmaceutically acceptable salt of solifenacin is administered to a subject by an administration route usually used for the pharmaceutical ingredient.
  • Pharmaceutical components other than pharmaceutically acceptable salts of solifenacin include, but are not limited to, ⁇ 1 adrenergic receptor antagonists, ⁇ 3 adrenergic receptor agonists, and the like.
  • Example 1 Preparation of rubber-based resin composition
  • Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries) , Liquid paraffin (Hicoll M-352, manufactured by Kaneda Co., Ltd.) having the following composition: Styrene-isoprene-styrene block copolymer 35.0% Alicyclic saturated hydrocarbon resin 50.0% Liquid paraffin 15.0% Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (1).
  • the rubber-type resin composition (1) was added to the solifenacin succinate weighed beforehand, and it stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below; Rubber resin composition (1) 75.5% Potassium hydroxide 4.5% Solifenacin succinate 20.0% A coating solution having
  • the obtained coating solution was applied onto a polyethylene terephthalate release film (Film Binner 75E-0010 BD, manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent was about 50 ⁇ m, and dried.
  • a 25 ⁇ m polyester film (Lumirror T-60, manufactured by Toray Industries, Inc.) was bonded as a support to obtain a transdermal absorption patch.
  • Example 2 The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below; Rubber resin composition (1) 65.5% Isopropyl myristate 10.0% Potassium hydroxide 4.5% Solifenacin succinate 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Example 3 The rubber-based resin composition (1) and isopropyl myristate are added to the solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of sodium hydroxide and stirred, the composition shown below: Rubber resin composition (1) 66.8% Isopropyl myristate 10.0% Sodium hydroxide 3.2% Solifenacin succinate 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Rubber-based resin composition (1) and isopropyl myristate are added to solifenacin succinate weighed in advance, and the mixture is stirred uniformly and shown below: Rubber-based resin composition (1) 70.0% Isopropyl myristate 10.0% Solifenacin succinate 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Test Example 1 Drug substance stability test Solifenacin succinate and solifenacin free body were each placed in a brown screw vial and stored at 60 ° C. The solifenacin succinate sampled over time and the solifenacin free form were each dissolved in a pH 3.5 phosphate buffer / acetonitrile mixture and analyzed by the HPLC method. From the peak area of solifenacin and the decomposition product in the sample, the amount (%) of the decomposition product was calculated by the following formula. The obtained results are shown in Table 1.
  • Decomposition product amount (%) (Peak area of decomposition product) / (Peak area of solifenacin) ⁇ 100 ⁇ HPLC conditions>
  • HPLC system ACQUITY UPLC H-Class system (Waters) Column: Inertsil ODS-3 (2 ⁇ m, 2.1 ⁇ 100 mm, manufactured by GL Science) Column oven: constant temperature around 40 ° C.
  • Mobile phase pH 3.5 phosphate buffer / acetonitrile mixture Flow rate: 0.5 mL / min Measurement wavelength: 210 nm
  • solifenacin succinate did not decompose over time, while solifenacin free body increased the degradation products over time.
  • Example 4 The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below; Rubber resin composition (1) 77.7% Isopropyl myristate 10.0% Potassium hydroxide 2.3% Solifenacin succinate 10.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Example 5 The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of sodium hydroxide and stirred, the composition shown below: Rubber-based resin composition (1) 78.4% Isopropyl myristate 10.0% Sodium hydroxide 1.6% Solifenacin succinate 10.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Example 6 The rubber-based resin composition (1) and propylene glycol (SR Propylene Glychol, manufactured by Croda) were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below; Rubber resin composition (1) 65.5% Propylene glycol 10.0% Potassium hydroxide 4.5% Solifenacin succinate 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • SR Propylene Glychol manufactured by Croda
  • Example 7 Preparation of rubber-based resin composition (2)
  • Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon Co., Ltd.), hydrogenated rosin glycerin ester (Pine Crystal KE-311, manufactured by Arakawa Chemical Industries), Liquid paraffin (Hicoll M-352, manufactured by Kaneda Co.) has the following composition; Styrene-isoprene-styrene block copolymer 35.0% Hydrogenated rosin glycerin ester 50.0% Liquid paraffin 15.0% Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (2).
  • Example 8 Acrylic resin (Duro-Tak 387-2287, manufactured by Henkel) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below; Acrylic resin (Duro-Tak 387-2287) 65.5% Isopropyl myristate 10.0% Potassium hydroxide 4.5% Solifenacin succinate 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Rubber-based resin composition (1) was added to solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of diisopropanolamine and stirred, the composition shown below: Rubber-based resin composition (1) 69.5% Diisopropanolamine 10.5% Solifenacin succinate 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Rubber-based resin composition (1) and isopropyl myristate are added to a pre-weighed solifenacin-free body, and the mixture is stirred uniformly and shown below: Rubber-based resin composition (1) 70.0% Isopropyl myristate 10.0% Solifenacin free body 20.0% A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
  • Test Example 2 In vitro skin permeability test Using the obtained transdermal absorption patch, an in vitro skin permeability test was performed according to the following procedure.
  • Test Example 3 Stability test The transdermal patch prepared in each Example and Comparative Example was heat sealed on a bag of composite film (PET 12 ⁇ m / PE 15 ⁇ m / Al 9 ⁇ m / PE 30 ⁇ m) based on aluminum foil. Sealed and stored at 60 ° C.
  • the transdermal patch after being stored at 60 ° C. for 4 weeks was peeled off the release liner and extracted with 2 mL of tetrahydrofuran for 30 minutes. After adding 8 mL of a pH 3.5 phosphate buffer / acetonitrile mixture to this solution, the solution was filtered through a 0.2 ⁇ m membrane filter and analyzed by the HPLC method. From the peak area of solifenacin and the decomposition product in the sample, the amount (%) of the decomposition product was calculated by the following formula. The obtained results are shown in Tables 2 and 3.
  • Decomposition product amount (%) (Peak area of decomposition product) / (Peak area of solifenacin) ⁇ 100
  • the amount of degradation products in the preparation is preferably 0.5% or less.
  • Tables 2 and 3 as a result of Test Example 3, the preparations of Examples 1 to 8 using an inorganic base as the base were used. Even under severe conditions at 60 ° C. for 4 weeks, the amount of decomposed product was 0.5% or less, and it had sufficient aging stability and skin permeability.
  • Examples 9-15 A transdermal patch was obtained in the same manner as in Example 2 except that the isopropyl myristate in Example 2 was replaced with the esters shown in Table 4.
  • Example 16 Preparation of rubber-based resin composition (3)
  • Styrene-isoprene-styrene block copolymer Quintac 3570C, manufactured by Nippon Zeon
  • alicyclic saturated hydrocarbon resin Alcon P-100, manufactured by Arakawa Chemical Industries
  • Polybutene polybutene HV-300, manufactured by JX Nippon Oil & Energy Corporation
  • Styrene-isoprene-styrene block copolymer 30.0% Alicyclic saturated hydrocarbon resin 50.0% Polybutene 20.0% was dissolved in toluene so that the solid content concentration would be 50% to obtain a rubber-based resin composition (3).
  • Example 16 Using the transdermal absorption patch obtained in Example 16, an in vitro skin permeability test was conducted in the same manner as in Test Example 2. The skin permeation rate was 25.9 ⁇ g / cm 2 / h. Using the transdermal absorption patch obtained in Example 16, a stability test was conducted in the same manner as in Test Example 3. The amount of decomposition products was 0.20% (60 ° C. for 4 weeks).
  • Reference example 1 A “neoxy (registered trademark) tape” for the treatment of overactive bladder, which is currently in clinical use, was used.
  • Test Example 4 Guinea Pig Skin Primary Irritation Test A 6-week-old Hartley male guinea pig was used. On the day before administration, the left and right torso parts of the guinea pig are shaved and shaved to a size of about 4 ⁇ 8 cm. On the next day of hair cutting, the patches (15 mm ⁇ ) of Example 2, Example 3, Example 5, Example 16, Comparative Example 4, and Reference Example 1 were applied to the left and right body parts, and the foam pad M with adhesive ( 3M Healthcare Co., Ltd.) and a polyethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.) is wound around the body and then fixed with Silky Tech (ALCARE No. 5).
  • 3M Healthcare Co., Ltd. 3M Healthcare Co., Ltd.
  • a polyethylene film tape Keeppore A, manufactured by Nichiban Co., Ltd.
  • Example 2 the transdermal patches of Example 2, Example 3, Example 5 and Example 16 are mildly irritants, and the transdermal patches of Comparative Example 4 and Reference Example 1 were used. Compared with skin irritation.
  • the percutaneously absorbable preparation of Example 16 content of solifenacin succinate per preparation: about 5 mg / sheet) cut into a size of 10 cm 2 (3.16 cm ⁇ 3.16 cm) on the back of the rat Affixed, wrapped in member (white cross), Tegaderm Roll (manufactured by 3M Healthcare), and non-woven adhesive bandage (silky tech, manufactured by ALCARE) and administered for 24 hours.
  • the administration solution was adjusted so that the dosage was 0.3 and 1 mg / kg relative to the body weight of the rat, and the administration solution was administered so that the dosage was 1 mL / kg.
  • blood was collected from the subclavian vein under isoflurane inhalation anesthesia (about 0.3 mL), and centrifuged (4 ° C., 2000 G, 15 minutes) to obtain plasma.
  • Example 17 Preparation of rubber-based resin composition (4)
  • Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon Co., Ltd.), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries, Ltd.) , Liquid paraffin (Hicoll M-352, manufactured by Kaneda Co., Ltd.) having the following composition: Styrene-isoprene-styrene block copolymer 30.0% Alicyclic saturated hydrocarbon resin 50.0% Liquid paraffin 20.0% Was dissolved in toluene so that the solid content concentration would be 50% to obtain a rubber-based resin composition (4).
  • Example 17 Using the transdermal absorption patch obtained in Example 17, an in vitro skin permeability test was conducted in the same manner as in Test Example 2. The skin permeation rate was 18.7 ⁇ g / cm 2 / h. Moreover, as a result of conducting a stability test in the same manner as in Test Example 3, the amount of the decomposition product was 0.15% (60 ° C., 4 weeks).
  • transdermal absorption patch containing a pharmaceutically acceptable salt of solifenacin having excellent transdermal absorbability, storage stability and safety is provided.
  • the transdermal patch of the present invention can more effectively treat overactive bladder.

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Abstract

La présente invention concerne un patch de type à absorption transdermique contenant un sel pharmacologiquement acceptable de solifénacine et présentant des propriétés d'absorption transdermique, une stabilité au stockage et une sécurité exceptionnelles. La présente invention se rapporte à un patch de type à absorption transdermique comprenant un support et une couche contenant un médicament, la couche contenant un médicament du patch de type à absorption transdermique contenant un sel pharmacologiquement acceptable de solifénacine et une base inorganique.
PCT/JP2016/070062 2015-07-08 2016-07-07 Patch de type à absorption transdermique WO2017006974A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021522187A (ja) * 2018-04-17 2021-08-30 エルテーエス ローマン テラピー−ジステーメ アーゲー ソリフェナシンの経皮投与のための経皮治療システム
CN113476459A (zh) * 2021-08-16 2021-10-08 浙江鼎泰药业股份有限公司 一种高活性缓释止痛贴及其制备工艺
US12121616B2 (en) 2018-04-17 2024-10-22 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for the transdermal administration of solifenacin

Citations (6)

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Publication number Priority date Publication date Assignee Title
JPH02174716A (ja) * 1988-09-05 1990-07-06 Takeda Chem Ind Ltd 経皮用製剤
WO2005077364A1 (fr) * 2004-02-18 2005-08-25 Yamanouchi Pharmaceutical Co., Ltd. Préparation transdermique de solifénacine et procédé d'amélioration de la perméabilité transdermique de celle-ci
JP2009013171A (ja) * 2007-06-07 2009-01-22 Hisamitsu Pharmaceut Co Inc メマンチン含有経皮吸収製剤
WO2009145177A1 (fr) * 2008-05-30 2009-12-03 日東電工株式会社 Préparation de patch contenant du donézépil et conditionnement
WO2013081014A1 (fr) * 2011-11-28 2013-06-06 株式会社 ケイ・エム トランスダーム Timbre cutané adhésif
JP2015010066A (ja) * 2013-06-28 2015-01-19 久光製薬株式会社 貼付剤の製造方法、貼付剤及び包装体

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Publication number Priority date Publication date Assignee Title
JPH02174716A (ja) * 1988-09-05 1990-07-06 Takeda Chem Ind Ltd 経皮用製剤
WO2005077364A1 (fr) * 2004-02-18 2005-08-25 Yamanouchi Pharmaceutical Co., Ltd. Préparation transdermique de solifénacine et procédé d'amélioration de la perméabilité transdermique de celle-ci
JP2009013171A (ja) * 2007-06-07 2009-01-22 Hisamitsu Pharmaceut Co Inc メマンチン含有経皮吸収製剤
WO2009145177A1 (fr) * 2008-05-30 2009-12-03 日東電工株式会社 Préparation de patch contenant du donézépil et conditionnement
WO2013081014A1 (fr) * 2011-11-28 2013-06-06 株式会社 ケイ・エム トランスダーム Timbre cutané adhésif
JP2015010066A (ja) * 2013-06-28 2015-01-19 久光製薬株式会社 貼付剤の製造方法、貼付剤及び包装体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021522187A (ja) * 2018-04-17 2021-08-30 エルテーエス ローマン テラピー−ジステーメ アーゲー ソリフェナシンの経皮投与のための経皮治療システム
US12121616B2 (en) 2018-04-17 2024-10-22 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for the transdermal administration of solifenacin
CN113476459A (zh) * 2021-08-16 2021-10-08 浙江鼎泰药业股份有限公司 一种高活性缓释止痛贴及其制备工艺

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