WO2006082888A1 - 経皮吸収型製剤 - Google Patents
経皮吸収型製剤 Download PDFInfo
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- WO2006082888A1 WO2006082888A1 PCT/JP2006/301759 JP2006301759W WO2006082888A1 WO 2006082888 A1 WO2006082888 A1 WO 2006082888A1 JP 2006301759 W JP2006301759 W JP 2006301759W WO 2006082888 A1 WO2006082888 A1 WO 2006082888A1
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- crotamiton
- rosin
- adhesive
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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
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
-
- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- 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
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to a percutaneous absorption-type preparation containing as an active ingredient 4 (2-methyl-1imidazolyl) -2,2 diphenylbutyramide (hereinafter abbreviated as imidazolacin).
- an active ingredient 4 (2-methyl-1imidazolyl) -2,2 diphenylbutyramide (hereinafter abbreviated as imidazolacin).
- Imidafenacin is a compound having a selective M3 muscarinic receptor antagonistic action (Japanese Patent Publication No. 7-215943; Patent Document 1), and is promising as a therapeutic drug for frequent urinary incontinence and urinary incontinence associated with overactive bladder ( Bioorg. Med. Chem., 1999, VII, 1151-1116; Non-patent document 1).
- an oral solid preparation containing imidafinacin has been proposed as well as a dosage form of a frequent urinary incontinence / urinary incontinence drug already on the market (WO 01Z34147; Patent Reference 2).
- Urinary incontinence is mainly classified into urinary incontinence, stress urinary incontinence, functional urinary incontinence, and overflow urinary incontinence.
- urinary incontinence increases with age.
- an increase in the number of patients with frequent urination / urinary incontinence and changes in patient demographics are expected.
- frequent urinary incontinence occurs in patients with long-term bedridden patients after cerebrovascular disorders such as cerebral infarction and cerebral hemorrhage, cerebrospinal trauma, or various tumor operations.
- these elderly people often have difficulty swallowing, and oral medications taken at regular intervals are often difficult to administer.
- Oral administration increases the amount of drug exposure to the liver and increases the maximum blood concentration, thus increasing the incidence of side effects. Therefore, from the viewpoint of improving the quality of life of patients who are difficult to administer orally, parenteral preparations with higher patient orientation are desired.
- a drug delivery system aimed at optimizing treatment
- a drug delivery system drug Delivery System
- a function that is different from conventional external preparations that is, sustained drug effect.
- percutaneous absorption-type preparations that have functions to reduce the side effects and reduce side effects.
- non-oral administration routes particularly transdermal drug delivery systems typified by ointments and patches, have attracted attention as effective drug administration routes.
- Transdermal absorbents also have problems such as drug stability, durability, efficacy, safety (adverse effects), adhesion, discomfort, skin irritation (erythema, edema, pruritus, rash, pigmentation, etc.) There are many points
- Patent Document 1 Japanese Patent Laid-Open No. 7-215943
- Patent Document 2 Pamphlet of International Publication No. 01Z34147
- Non-Patent Literature l Bioorg. Med. Chem., 1999, VII, 1151-1116 Disclosure of the Invention
- Oral muscarinic receptor antagonists are often used as side urinary urinary incontinence medications, and generally have side effects such as roar, residual urine, difficulty urinating, constipation, diarrhea, urinary retention, stomach Discomfort, abdominal pain, abnormal eye feeling (mydriasis), dizziness, etc. are manifested as clinical problems.
- imidafenacin a selective M3 muscarinic receptor antagonist, has been found and is being investigated for frequent urination and urinary incontinence in patients with overactive bladder.
- transdermal absorption-type drug that can be stopped immediately by peeling off is easier to obtain stable blood dynamics.
- imidafenacin has a very low absorption of skin power, and it has been difficult to secure a sufficient blood concentration for a long time due to absorption from the skin.
- An object of the present invention is to solve the above-mentioned problems, and provides a transdermal absorption preparation capable of increasing the skin permeation amount of imidafenacin and allowing imidafenacin to be absorbed from the skin for a long time. It is.
- the active ingredient content in one preparation or in a single dose is about 0.1 mg to about 10 mg,
- the size is from about lcm 2 to about 300 cm 2 ;
- the present inventors have found that a percutaneous absorption preparation satisfying at least one of these conditions can achieve this purpose, and completed the present invention.
- the present invention relates to a transdermal preparation having the following constitution.
- the active ingredient content in one preparation or in a single dose is about 0.1 mg to about 10 mg,
- the size is about lcm 2 to about 300 cm 2 .
- External preparation base is (0 styrene 'isoprene' styrene block copolymer, silicone resin, polyisobutylene rubber, rosin resin, acrylic copolymer, and alicyclic saturated hydrocarbon 2.
- the preparation according to 1 above which comprises at least one adhesive selected from rosin and a GO amphiphilic dissolution aid, a transdermal penetration enhancer, and Z or a skin irritation alleviator.
- the external preparation base is selected from (0 styrene 'isoprene' styrene block copolymer, silicone-based resin, polyisobutylene rubber, rosin-based resin, and alicyclic saturated hydrocarbon resin 1 From more than one adhesive, GO amphiphilic dissolution aid, and (iii) transdermal penetration enhancer. 3.
- Adhesive is styrene 'isoprene' styrene block copolymer, silicone resin, acrylic copolymer, polyisobutylene rubber, rosin resin and alicyclic saturated hydrocarbon resin (Ii) N-methyl-2-pyrrolidone, isopropyl myristate, propylene glycol, triacetin, benzyl alcohol, oleyl alcohol, oleic acid, jetyl sebacate , One or more selected from diisopropyl adipate, liquid paraffin, and cetyl lactate, and the percutaneous penetration enhancer is selected from triacetin, crotamiton, cetyl lactate, diisopropyl adipate, oleic acid, and oleyl alcohol. 3. The preparation according to 2 above, wherein the preparation is at least a species and the skin irritation relieving agent is crotamiton.
- Adhesive strength (0 Styrene 'isoprene' styrene block copolymer and rosin-based resin, GO silicone-based resin, GiO silicone-based resin and rosin-based resin, Gv) Silicone-based A combination of rosin, rosin-based and alicyclic saturated hydrocarbons, (V) acrylic copolymers, (vi) combinations of acrylic and silicone resins, or (vii) styrene '' 5.
- the preparation according to the above item 4 which is a combination of isoprene / styrene block copolymer, polyisobutylene rubber, rosin-based resin and alicyclic saturated hydrocarbon resin.
- adhesive is a combination of styrene 'isoprene' styrene block copolymer and rosin-based rosin
- G 1) Amphiphilic solubilizer is N-methyl-2-pyrrolidone, propylene glycol, Triacetin, oleyl alcohol, oleic acid, or cetyl lactate, or G) 2) Force that transdermal penetration enhancer is triacetin, crotamiton, cetyl lactate, oleic acid, or oleyl alcohol, or (ii-3) 3.
- an amphiphilic dissolution aid and a transdermal penetration enhancer is oleic acid and crotamiton, oleyl alcohol and crotamiton, cetyl lactate and crotamiton, or triacetin and crotamiton.
- adhesive is silicone-based resin
- amphiphilic solubilizer is N-methyl-2-pyrrolidone, isopropyl myristate, propylene glycol, triacetin, oleyl alcohol, oleic acid, Or (ii-2) the ability of the transdermal penetration enhancer to be triacetin, crotamiton, cetyl lactate, oleic acid, or oleyl alcohol; Or (ii-3) The preparation according to 2 above, wherein the combination of the amphiphilic dissolution aid and the transdermal penetration enhancer is oleic acid and crotamiton, or oleyl alcohol and crotamiton.
- adhesive is styrene 'isoprene' styrene block copolymer, polyisobutylene rubber
- a combination of rosin-based and alicyclic saturated hydrocarbon resins, and the GO amphiphilic solubilizer is N-methyl-2-pyrrolidone, isopropyl myristate, propylene glycol, triacetin, oleyl alcohol, olein Acid, liquid paraffin, and lactic acid lactate are one or more selected, and transdermal penetration enhancers are triacetin, crotamiton, lactic acid cetyl, oleic acid, and oleyl alcohol. 3.
- the active ingredient is about 25 parts by weight to about 350 parts by weight with respect to 1 part by weight of the active ingredient (0 amphiphilic dissolution aid and Z or transdermal penetration enhancer is about 2 parts by weight About 400 parts by weight, or about 2 parts by weight to about 200 parts by weight of GO amphiphilic dissolution aid and Z or transdermal penetration enhancer and about 0.1 parts by weight to about 10 parts by weight of skin irritation relieving agent
- amphiphilic dissolution aid and Z or transdermal penetration enhancer is about 2 parts by weight About 400 parts by weight, or about 2 parts by weight to about 200 parts by weight of GO amphiphilic dissolution aid and Z or transdermal penetration enhancer and about 0.1 parts by weight to about 10 parts by weight of skin irritation relieving agent
- the active ingredient is about 25 parts by weight to about 350 parts by weight with respect to 1 part by weight of the active ingredient, and the amphiphilic dissolution aid is about 2 parts by weight to about 400 parts by weight.
- any one of 2 to 11 above comprising about 0.01 part by weight to about 10 parts by weight of dibutyl hydroxytoluene or DL-a-tocopherol with respect to 1 part by weight of the active ingredient Formulation.
- the active ingredient content in one preparation or in a single dose is about 0.1 mg to about 2 mg,
- the size is about lcm 2 to about 40 cm 2 .
- the thickness of the adhesive paste is about 20 ⁇ m to about 200 ⁇ m.
- imidaf nacin which has low skin absorbability, can be absorbed from the skin stably and efficiently into the body.
- the imidafenacin which is an active ingredient of the transdermally absorbable preparation of the present invention is 4-1- (2-methyl-1-1-imidazolyl) -2,2-diphenylbutyramide.
- 4- (2-Methyl-11-imidazolyl) 2,2 diphenylbutyramide can be produced, for example, by the method described in Example 11 of JP-A-7-215943.
- imidafinacin can be used together with its free form or a medically acceptable salt thereof.
- Medically acceptable salts include inorganic acids (for example, hydrochloric acid, sulfuric acid, or hydrobromic acid).
- the percutaneous absorption-type preparation of the present invention can also be used as a percutaneous absorption-type preparation such as tolterodine, darifenacin, and solifenacin, which are selective M3 muscular phosphorus antagonists.
- an amphiphilic dissolution aid As an external preparation base for the percutaneous absorption preparation used in the present invention, an amphiphilic dissolution aid, a suspension base, a softener, an emulsifier, a buffer, a transdermal penetration enhancer, an adhesive,
- a base selected from the group consisting of an adhesion enhancer, an adhesive, a skin irritation relieving agent and an additive can be used alone or in combination of two or more.
- adhesives amphiphilic solubilizers, suspending bases, softeners, emulsifiers, buffers, transdermal penetration enhancers, adhesion enhancers, adhesives, skin irritation mitigants and additives.
- a base selected from the group consisting of a single species or a combination of two or more species.
- Examples of the adhesive or adhesion enhancer include natural rubber, raw rubber, high molecular weight rubber, RS SNo. 1 raw rubber, styrene isoprene rubber, styrene butadiene rubber (SBR), cis polyisoprene rubber, polyisobutylene rubber (high molecular weight).
- Amphiphilic solubilizers include, for example, ⁇ ⁇ ⁇ -methyl 2 pyrrolidone, L-menthol, methyl ethyl ketone, methyl isobutyl ketone, higher fatty acid esters (isopyristyl myristate ( ⁇ ), isopropyl palmitate, oleyl oleate, etc.) , Lauric acid ethanolamide, triethyl taenoate, dimethylimidazolidinone, glycerin fatty acid ester (lipophilic glyceryl monooleate, etc.), polyglycerin fatty acid ester, sorbitan fatty acid ester (sorbitan monooleate, sorbitan trioleate, sesquioleate Rubitan, etc.), polyoxyethylene sorbitan ester, polyoxyethylene sorbite fatty acid ester (polysorbate 20, polysorbate 60, polysorbate 80, polyoxyethylene sorbita Monolaurate),
- Suspending bases include, for example, ethanol, stearyl alcohol, cetanol, polyhydric alcohols (ethylene glycol, propylene glycol, butanediol, triethylene glycol nore, polyethylene glycol nore (macro gonore 200, macro gonore 300, macro gool 400, macro gol).
- polyhydric alcohols ethylene glycol, propylene glycol, butanediol, triethylene glycol nore, polyethylene glycol nore (macro gonore 200, macro gonore 300, macro gool 400, macro gol).
- softener examples include allantoin, almond oil, olive oil, rapeseed oil, castor oil, cottonseed oil and soybean oil mixture, process oil, beef tallow, propylene glycol, polybutene, glycerin, liquid paraffin, light liquid paraffin, Crystalline cellulose, macrogol 1500, squalane, squalene, purified lanolin, medium-chain fatty acid triglyceride, glycerin monostearate, isopropyl myristate, raw rubber, lactyl ethyl, cetyl lactate, octyldodecyl lactate, nor-acid ⁇ ⁇ -rilamide, high Cis polyisoprene rubber may be mentioned.
- emulsifier examples include glycerin fatty acid esters (glyceryl monooleate, glyceryl monooleate, glyceryl monostearate, glyceryl monostearate, glyceryl monostearate, self-emulsifying glyceryl monostearate, polyoxystearate triisostearate).
- glycerin fatty acid esters glyceryl monooleate, glyceryl monooleate, glyceryl monostearate, glyceryl monostearate, glyceryl monostearate, self-emulsifying glyceryl monostearate, polyoxystearate triisostearate.
- Examples of the buffer include succinic acid, anhydrous succinic acid, sodium succinate, tartaric acid, succinic acid, dl-malic acid, fumaric acid, maleic acid, lactic acid, sodium lactate solution, boric acid, borax, Acetic acid, glacial acetic acid, sodium acetate, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, anhydrous sodium phosphate-sodium hydrogen phosphate, anhydrous sodium dihydrogen phosphate, benzoic acid, sodium benzoate Primary, secondary or tertiary phosphates (primary sodium phosphate, dibasic sodium phosphate, anhydrous trisodium phosphate, trisodium phosphate, etc.), sodium metaphosphate, ⁇ -aminocaproic acid, water Sodium oxide, sodium carbonate, sodium bicarbonate, ammonium chloride, sodium chloride, benzalkonium chloride, amino acids or amino acids thereof Salts (
- Examples of the percutaneous penetration enhancer include triacetin (glyceryl triacetate), crotamiton, urea, ethanol, decylmethyl sulfoxide, natural essential oil, terpene oil (Nokakka oil, orange oil, turpentine oil, L-menthol, d—limonene, menthone, pinene, piperiton, terbinene, terpinolene, terpinol, carbeol, etc.), fatty acid esters (glyceryl monolaurate, glyceryl monooleate, cetyl lactate, octyldodecyl lactate, glycerono remonolau) Glycerol, glycerol monomonolate, propylene glycol monooleate, propylene glycol monooleate, sorbitan monolaurate, sonolebitan monolate, etc.), dibasic acid diesters (jetyl sebac
- Examples of the skin irritation mitigating agent include glycerin, crotamiton, allantoin, antihistamines (diphenhydramine, etc.), anti-inflammatory agents (darlicylretinoic acid, etc.), and steroids.
- Further additives include, for example, mudizing agents (gelatin, etc.); powder excipients (kaolin, bentonite, zinc oxide, etc.); petroleum resins (quinton, alkone, etc.); D-sorbitol; D- Sorbitol solution; Sucrose; Surfactant (Polyoxyethylene hydrogenated castor oil 20, Polyoxyethylene hydrogenated castor oil 60, Polyoxyethylene sorbite fatty acid ester (Polysorbate 20, Polysonolate 60, Polysonolate 80, Poly Oxyethylene sorbitan monolaurate, etc.), polyoxyethylene fatty acid esters (polyoxyl 40 stearate, etc.), sorbitan fatty acid esters (sorbitan monooleate, sorbitan trioleate, sorbitan monolaurate, sorbitan sesquioleate, etc.), self-emulsifying type Dali Serine monostearate, monos Glycerin acrylate, sorbitan monostearate, sucrose
- an external preparation base for example, a water-soluble polymer compound (polyacrylic acid and its derivatives, cellulose derivatives, polybutyl alcohol, gelatin, casein, polyethylene glycol, gum arabic, methylvinyl ether Z maleic anhydride copolymer, Natural polysaccharides), fat-soluble polymer compounds (natural rubber, isoprene rubber, butyl rubber, styrene isobutylene block copolymer, styrene butadiene copolymer, silicone, lanolin, ⁇ serine, plastic base, beeswax, whale candy, Solid paraffin, etc.), fatty acids and derivatives thereof (fatty acids having 3 to 40 carbon atoms, fatty acid esters thereof, or fatty acid alkali metal salts thereof), animal and vegetable oils (olive oil, hearth oil, soybean oil, cottonseed oil, corn oil) Oil, castor oil, castor oil, sesame oil, almond oil Camellia oil, persic oil,
- Examples of the easily peelable adsorbent include a crosslinked acrylic pressure-sensitive adhesive polymer, an ethylene acetate butyl copolymer, or an ethylene ethyl acrylate copolymer.
- a crosslinked acrylic pressure-sensitive adhesive polymer an ethylene acetate butyl copolymer, or an ethylene ethyl acrylate copolymer.
- SIS styrene 'isoprene' styrene block copolymer
- natural rubber type natural rubber type, synthetic rubber type, acrylic type, silicone type, butyl ether type, etc.
- Adhesion may be adjusted using a liquid component, and a mineral oil as a softening agent and a fatty acid ester or the like may be added.
- the plaster is about 50 g to about 800 g in the adhesive bandage adhesive test method using an instron type tensile tester shown in the Japanese Pharmacopoeia. More preferably, it is about 50 g to about 400 g.
- the transdermal absorption preparation is preferably a patch, for example, a blaster agent (for example, an adhesive monolayer percutaneous absorption preparation, a reservoir type transdermal absorption preparation, etc.), And poultices.
- a plaster agent particularly an adhesive single layer type transdermal Absorption formulations are preferred.
- Adhesive single-layer percutaneous absorption preparations are adhesive “adhesive plaster bodies” and “support bodies” formed by combining imidafenacin, an active ingredient, with a base selected from the above-mentioned external preparation bases. And a percutaneously absorbable preparation structure forming body comprising a “release liner” for protecting the adhesive plaster body.
- the thickness of the adhesive plaster of the adhesive single-layer transdermal preparation is about 10 m to about 2000 m.
- the thickness of the adhesive plaster is about 10 ⁇ m to about 500 ⁇ m for plaster because it can withstand long-time application to the skin and hardly causes adhesive residue on the skin surface during peeling and removal.
- About 10 ⁇ m to about 200 ⁇ m is more preferable, and about 20 ⁇ m to about 200 ⁇ m is particularly preferable.
- about 300 ⁇ m to about 2000 ⁇ m force ⁇ is preferred ⁇ , about 500 ⁇ m to about 1500 ⁇ m force ⁇ more preferred! / ⁇ .
- Emulsifiers buffers, transdermal penetration enhancers, adhesion enhancers, and / or skin irritation mitigators.
- Examples of the adhesive include styrene 'isoprene' styrene block copolymer, silicone-based resin, acrylic copolymer, polyisobutylene rubber, rosin-based resin, and alicyclic saturated hydrocarbon resin.
- styrene 'isoprene' styrene block copolymer and rosin-based resin GO silicone-based resin
- silicone-based resin and rosin-based resin i
- the styrene 'isoprene' styrene block copolymer is not particularly limited, but SIS-5009 and SIS-5229 manufactured by Nippon Synthetic Rubber Co. are preferably used.
- the silicone-based resin is not particularly limited, but BIO-PSA Q7-4501 manufactured by Dow Co., Ltd. is preferably used.
- the polyisobutylene rubber is not particularly limited, but high molecular weight polyisobutylene (preferably, Vistanex MML-100 manufactured by Ettasony Gakki) and Z or low molecular weight polyisobutylene is preferable. Ren (preferably, Opanol B12SPN manufactured by BASF Japan Ltd.) is preferably used.
- the rosin-based rosin is not particularly limited, but ultra-light rosin ester (ester gum) KE311 manufactured by Arakawa Chemical Industries, Ltd. is preferably used.
- the alicyclic saturated hydrocarbon resin is not particularly limited, but Alcon P-100 manufactured by Arakawa Chemical Industries, Ltd. is preferably used.
- the adhesive is used in the mass of the adhesive paste! It is more preferably about 30% by mass to about 97% by mass, more preferably about 20% by mass to about 99.9% by mass.
- Adhesive plaster mass in the case of plaster more preferably preferably tool about lOgZm 2 ⁇ about 500GZm 2 about 20gZm 2 ⁇ about 200gZm 2.
- tool about lOOgZm 2 ⁇ about 2000 g Zm 2 is about 500gZm 2 ⁇ about 1500gZm 2.
- imidafenacin used in the present invention is poor in absorbability from the skin when only an adhesive is used, it is preferable to add an amphiphilic dissolution aid, a percutaneous penetration enhancer and / or a skin irritation relieving agent. . In particular, it is preferable to add an amphiphilic dissolution aid and a transdermal penetration enhancer.
- Amphiphilic dissolution aids include higher fatty acid esters (isopropyl myristate, isopropyl normitate, oleyl oleate, etc.), higher alcohols (lauryl alcohol, isopropanol, isostearyl alcohol, otatildodecanol, oleyl alcohol).
- Fatty acids (strength puric acid, adipic acid, sebacic acid, myristic acid, oleic acid, etc.), dibasic acid diesters (such as decyl sebacate, diisopropyl sebacate, diisopropyl adipate), triacetin, benzyl alcohol, Cetyl lactate, octyl lactate dodecyl and Z or liquid paraffin power 1 or more selected are preferred Especially isopropyl myristate, oleyl alcohol, oleic acid, jetyl sebacate, diisopropyl adipate Toriasechin, benzyl alcohol or liquid paraffin are preferable.
- Preferred amphiphilic solubilizers are N-methyl-2-pyrrolidone, propylene glycol, or a mixture of N-methyl-2-pyrrolidone and propylene glycol! / ⁇
- the amphiphilic solubilizer it is more preferable to use (0 liquid paraffin and G0N-methyl-2-pyrrolidone, propylene glycol, or a mixture of N-methyl-2-pyrrolidone and propylene glycol.
- the amount of the amphiphilic solubilizer added is preferably about 2 parts by weight to about 100 parts by weight, more preferably about 2 parts by weight to about 400 parts by weight with respect to 1 part by weight of imidafenacin.
- the amount of liquid paraffin added as an amphiphilic solubilizer is preferably about 10 to about 400 parts by weight, preferably about 20 to about 80 parts by weight, based on 1 part by weight of imidafenacin. More preferred.
- the amount of N-methyl-2-pyrrolidone as an amphiphilic solubilizing agent is preferably about 3 parts by mass to about 100 parts by mass with respect to 1 part by mass of imidafenacin. More preferably, about 20 parts by weight are added.
- the amount of propylene glycol added as an amphiphilic solubilizer is preferably about 2 to about 100 parts by weight, preferably about 3 to about 20 parts by weight, based on 1 part by weight of imidafenacin. More preferred.
- N-methyl-2-pyrrolidone and propylene glycol as an amphiphilic solubilizer. It is more preferable to add about 3 parts by weight to about 20 parts by weight.
- the ratio of N-methyl-2-pyrrolidone to propylene glycol is preferably about 1: 1 to about 1:10. 1: 3 is more preferable.
- Percutaneous penetration enhancers include triacetin, fatty acids or fatty alcohols (oleic acid, lauric acid, myristic acid, oleyl alcohol, isopropanol, lauryl alcohol, etc.), fatty acid esters (glyceryl monolaurate, glyceryl monophenol). Preferred are acrylate, cetyl lactate, octyldodecyl lactate, glycerol monolaurate, glycerol monooleate, propylene glycolenolemonolaurate, propyleneglycolenomonomonolate, sorbitan monolaurate, sorbitan monooleate). In particular, oleic acid, oleyl alcohol, triacetin, and cetyl lactate are preferred. Especially preferred is oleic acid Yes.
- the amount of the transdermal penetration enhancer is preferably about 2 parts by mass to about 200 parts by mass with respect to 1 part by mass of imidafenacin.
- the amount of oleic acid added as a transdermal permeation enhancer is preferably about 3 parts by weight to about 10 parts by weight, preferably about 2 parts by weight to about 50 parts by weight with respect to 1 part by weight of imidafenacin. More preferred.
- crotamiton and steroids are preferred.
- the adhesive is about 25 parts by mass to about 350 parts by mass with respect to 1 part by mass of imidafenacin, amphiphilic dissolution aid and Z or transdermal.
- About 2 parts by weight to about 400 parts by weight of a penetration enhancer, or about 2 parts by weight to about 200 parts by weight of an amphiphilic dissolution aid and Z or transdermal penetration enhancer, and mitigating skin irritation It is preferable that about 0.1 parts by weight to about 10 parts by weight of the agent is blended.
- the preparation of the present invention may contain a preservative and Z or an anti-oxidation agent.
- a preservative and Z or antioxidants dibutylhydroxytoluene (BHT) or DL-a tocopherol is preferred, and the amount is about 0.01 to about 10 parts by weight per 1 part by weight of imidafenacin. preferable.
- an external preparation base for a patch (A) (i) a combination of a styrene 'isoprene' styrene block copolymer and a rosin-based resin, GO silicone-based resin, (iii) Combination of silicone resin and rosin resin, Gv) Combination of silicone resin, rosin resin and alicyclic saturated hydrocarbon resin, (V) Acrylic copolymer, (vi) Acryl A combination of copolymer and silicone resin, or (vii) a combination of styrene 'isoprene' styrene block copolymer, polyisobutylene rubber, rosin resin and alicyclic saturated hydrocarbon resin, and (B) Isopropyl myristate, diethyl sebacate, diisopropyl adipate, liquid paraffin, oleic acid, oleyl alcohol, triacetin, benzyl alcohol, N
- One or two or more selected bases, or a combination of (C) crotamiton, BHT or DL-a-tocophenol is preferred.
- A Silicone fats
- B Forces that are oleic acid and crotamiton, oleic acid and crotamiton, oleyl alcohol and crotamiton, cetyl lactate and crotamiton, N-methyl-2-pyrrolidone, propylene glycol, crotamiton, or triacetin and crotamiton Isopropyl myristate, jetyl sebac
- the one or more combinations are liquid paraffin, isopropyl myristate, oleic acid, oleyl alcohol, cetyl lactate, triacetin, liquid paraffin and isopropyl myristate, liquid paraffin and oleic acid, liquid paraffin and oleyl alcohol.
- the external preparation base is (0 (A) a combination of an adhesive strength styrene 'isoprene' styrene block copolymer and a rosin-based resin, and (B) a biparent.
- Soluble dissolution aid, transdermal penetration enhancer and Z or skin irritation relieving agent are oleic acid, cetyl lactate, triacetin, N-methyl-2-pyrrolidone, propylene glycol, crotamiton, oleic acid and crotamiton, oleyl alcohol and crotamiton , Cetyl lactate and crotamiton, power of triacetin and crotamiton, GO (A) the adhesive is a silicone-based oil, and (B) amphiphilic dissolution aid, transdermal penetration enhancer and / or skin irritation The relaxation agent Force of being oleic acid, oleyl alcohol, N-methyl-2-pyrrolidone, propylene glycol, crotamiton, oleic acid and crotamiton, or oleyl alcohol and crotamiton or (iii) (A) Adhesive is styrene 'isoprene' s
- Amphiphilic dissolution aid, transdermal penetration enhancer and / or skin irritation relieving agent are preferably liquid paraffin, isopropyl myristate, oleic acid, oleyl alcohol, cetyl lactate, triacetin , Crotamiton, liquid paraffin and isopropyl myristate, liquid paraffin and oleic acid, liquid paraffin and oleyl alcohol, liquid paraffin and cetyl lactate, liquid paraffin and triacetin, liquid paraffin and crotamiton, liquid paraffin and isopropyl myristate and crotamiton, liquid Baraphine and oleic acid and crotamiton, liquid paraffin and oleyl alcohol and crotamiton, liquid paraffin and cetyl lactate and crotamiton, N-methyl-2-pyrrolidone, propylene glycol, N-methyl-2-pyrrolidone and pro Pyrene glycol, liquid paraffin and
- the support constituting the structure-forming body of the adhesive single-layer percutaneous absorption preparation is not particularly limited.
- a plastic film that is flexible enough not to cause a sense of incongruity when applied to the skin surface is preferable.
- Polyethylene, polyethylene terephthalate, polyurethane, polyethylene, ethylene butyl acetate, polypropylene, polyester, polyvinyl acetate, ethylene vinyl acetate copolymer, etc.), metal foil (aluminum foil, etc.), non-woven cloth, cotton cloth, woven cloth, knitting Single layer films such as cloth and paper, and laminated films of these can be used.
- the release liner is not particularly limited as long as it can be easily peeled off when the preparation is used, and can maintain the adhesive paste before covering the release liner.
- paper or plastic film polyethylene, Ethylene terephthalate, polyurethane, polyethylene, ethylene vinylate acetate, polypropylene, polyester, poly (butyl acetate), ethylene vinyl acetate copolymer, etc.
- paper or plastic film polyethylene, Ethylene terephthalate, polyurethane, polyethylene, ethylene vinylate acetate, polypropylene, polyester, poly (butyl acetate), ethylene vinyl acetate copolymer, etc.
- a preferable administration method of the present invention is a method of applying twice a day, once a day, or once a time between 2 to 7 days, or a method of applying before bedtime or a necessary situation. More preferably, it is a method of pasting once a day or once every 2 to 4 days, or a method of pasting before going to bed or before a necessary situation.
- the application site is not particularly limited, but for example, behind the ear, arm, abdomen (preferably lower abdomen, etc.), chest, back, waist, buttocks or leg (preferably thigh inner side, calf) Etc.) 1) or 2-4 sheets are affixed to the same or different sites.
- the position is not particularly limited, but it is preferable to attach them at a symmetrical position. To avoid skin irritation, it is preferable not to apply it continuously in the same location.
- Frequent urination associated with overactive bladder (OAB) 'Prevention of urinary incontinence or chronic obstructive pulmonary disease (COPD) The effective human blood concentration can be extrapolated to the results of animal experiments.
- the blood concentration near the ID value which suppresses airway contraction during choline stimulation
- the imidafenacin-containing transdermal absorption preparation shown in the present invention is about lOpgZ in humans. It is a preparation that can maintain a blood concentration of mL to about lOngZmL.
- the effective blood concentration in humans is preferably about lOpgZmL to about 3 ngZmL, more preferably about lOOpgZmL to about 3 ngZmL, and still more preferably about lOOpgZmL to about 500 pgZmL.
- the imidafenacin blood concentration range is an optimal range that exhibits the intended effect and does not exhibit side effects.
- the period for maintaining the effective blood concentration in humans is preferably about 0.5 days to about 7 days, more preferably about 0.5 days to about 4 days, and even more preferably about 0.5 days to about 2 days. is there.
- the amount of imidafenacin blended in the percutaneous absorption preparation for maintaining the effective blood concentration in humans depends on the administration time, the external preparation base used, the blending amount thereof, and the like. It is preferable that about O.Olmg to about 10 mg is blended in a single dose when different force is in one preparation. In particular, in the case of a transdermal preparation to be applied for 24 hours, it is preferable to add about 0.1 mg to about 1 mg in one preparation or in a single dose, about 0.2 mg, about 0.3 mg, More preferred is about 0.5 mg and about 1 mg.
- the amount of imidafenacin is preferably about 0.005% by mass to about 30% by mass of the entire adhesive plaster, about 0.05% by mass to about 10% by mass. It is more preferable that
- the size is about lcm 2 ⁇ about 300 cm 2 instrument More preferred is about 1.5 cm 2 to about 280 cm 2 . If a plaster agent is about lcm 2 ⁇ about 140c m 2 is preferred instrument especially about 1.5 cm 2 ⁇ about 40 cm 2 is preferred. If a NOP agent, 140c m 2 ⁇ about 280 cm 2 is preferred.
- the shape may be any shape, but is preferably square, rectangular, round or oval.
- Imidafenacin which is an active ingredient in the present invention, maintains stability and safety regardless of whether it is formulated in a dissolved form or a mixed form of a dissolved form and an insoluble form, and the active ingredient is efficiently used. It is not limited as long as the skin can be permeated quickly and continuously. Concrete Is formulated with a force having substantially only dissolved imidafenacin as an active ingredient, or mixed and non-dissolved mixed imidafenacin as an active ingredient.
- a drug in an insoluble state does not participate in percutaneous absorption, but the higher the content of the soluble drug in the adhesive plaster, the higher the amount of drug absorbed percutaneously. It is possible to maintain the time medicinal effect. In other words, the duration of the pharmacological action is limited by the saturated solubility of the drug in the external preparation base. However, in the case of an external preparation base with low drug solubility, the duration of the drug or the stable effective blood concentration may not be sufficient.
- use a highly soluble adhesive plaster increase the thickness of the adhesive plaster in which the drug is dissolved, increase the drug content, or adhere to the skin surface. Increase the dose by means such as force to increase the area of the plaster.
- these methods have many problems in discomfort, adhesion, skin irritation, economy and the like.
- the silicone resin is further added to the adhesive layer.
- a two-layered adhesive plaster layer coated with coalescence or the like is used.
- the concentration of the dissolved drug in the adhesive plaster directly affects the percutaneous absorption rate and decreases by being absorbed into the skin. Excess drug exceeding the saturation solubility in the adhesive paste used is dispersed in the adhesive paste as a non-dissolvable drug, so the amount of the dissolved drug contained in the adhesive paste is the external preparation used. Determined by the base.
- the non-dissolving drug has a function of supplying and supplementing the dissolving drug, which is reduced by absorption of the drug dissolved in the adhesive paste into the skin.
- a high percutaneous absorption rate is maintained for a long time, and the effective blood concentration is maintained for a long time.
- a pressure-sensitive adhesive paste having a high saturated solubility of a drug is selected, and a preparation containing substantially only dissolved imidafenacin as an active ingredient is prepared, or if the absorption rate is fast, imidafenacin Coated with a non-adhesive adhesive to produce a two-layer formulation, or a formulation containing dissolved and non-dissolved mixed imidafenacin as an active ingredient.
- dissolved imidafenacin means that imidafenacin is present in the adhesive plaster in a completely dissolved state.
- imidafenacin crystals are visually or optically observed in the adhesive plaster. It is not observed with a microscope and the adhesive paste is uniform.
- the drug can be held in a state completely dissolved in the adhesive plaster body in which the drug does not precipitate even at a high concentration.
- an additive may be further used.
- the additive is not limited as long as it has excellent compatibility with the pressure-sensitive adhesive, sufficiently dissolves imidafenacin, and does not separate from the pressure-sensitive adhesive and the additive over time. As a result, the percutaneous absorption rate is excellent at the initial stage of administration, and the effective blood concentration can be maintained for a long time.
- dissolved and non-dissolved mixed imidafenacin refers to imidafenacin dissolved and non-dissolved, more specifically in the dissolved and crystalline or amorphous state in the adhesive paste. It is to be mixed. Re-dissolution of non-dissolvable imidafenacin that quickly compensates for the decrease in imidafenacin in the adhesive paste due to rapid absorption by the dissolved form, and sustained drug efficacy is maintained by absorption of the dissolved imidafenacin.
- the ratio of the disappearance rate of undissolved imidafenacin to the disappearance rate of total imidafenacin in the adhesive paste is preferably about 0.1 or more. When the ratio of disappearance rate is small, the re-dissolution of the non-dissolved drug with respect to the decrease of the dissolved drug becomes insufficient, so that the sustained efficacy is not good.
- the patch can be produced by a general production method.
- a general production method for example, (1) solvent method, (2) heating method (hot melt method), or (3) calendar method.
- the solvent method is to dissolve the active ingredient and external preparation base in solvents such as hexane, rubber volatile oil, ethyl acetate, alcohols, xylene, chloroform, water, etc. Is the method. Preferably, it is dried at about 20 ° C to about 60 ° C for about 30 seconds to about 60 minutes.
- the heating method is a method in which an active ingredient and a base for external use are dissolved and mixed with high heat, spread and cooled.
- the calendar method is a method in which an active ingredient and a base for external use are mixed with a mixer and spread with a calendar roll. If the viscosity is relatively low, the active ingredient and the base for external use are mixed with an ordinary mixer and spread.
- the production method of the preparation of the present invention is not limited to the above method, and may be produced by other efficient methods.
- the transdermally absorbable preparation of the present invention is a muscarinic receptor for smooth muscle such as bladder, trachea and digestive tract. Because of selective antagonism of M3 and Ml, asthma and chronic obstructive pulmonary (COPD) as well as frequent urinary incontinence associated with overactive bladder (OAB) It is also useful for prevention and Z or treatment of Disease No, Irritable Bowel byndome (IBS), etc. Therefore, the transdermally absorbable preparation of the present invention is used in the case of oral preparations and injections.
- the percutaneously absorbable preparation of the present invention is aged. Overactivity that improves the quality of life for the elderly and patients who have difficulty with oral administration It is very useful as a drug for sustained prevention and Z or treatment of frequent urination, urinary incontinence, asthma, COPD or IBS associated with the bladder (OAB), especially in the prevention and Z or treatment of COPD.
- OAB IBS associated with the bladder
- the skin-absorbable preparations can effectively reach the peripheral tissues of the vascular side force alveoli, and the respiratory function that makes it difficult to administer inhalants to the periphery is reduced. It is also a useful formulation for patients who are currently living.
- Imidafenacin (2 Omg), oleyl alcohol (200 mg) and crotamiton (200 mg) were dispersed in silicone-based rosin (Q7-4501, manufactured by Dow Coung) (1.975 g) to prepare an adhesive paste.
- the adhesive plaster was spread on a release liner (Scotch Pack 9742, manufactured by 3EM Healthcare) using an applicator so that the thickness was about 125 m.
- the adhesive plaster surface was dried with hot air (about 50 to 60 ° C.) for 20 minutes.
- the dried adhesive plaster surface was covered with a release liner and cut into a 15 mm diameter (1.766 cm 2 ) circle to prepare a preparation (main component content: lm g / lOcm 2 ).
- Silicone resin (Q7-4501, manufactured by Dow Co., Ltd.) (1.975g) and imidafenacin (2 Omg), oleic acid (200 mg) and crotamiton (200 mg) were dispersed to prepare an adhesive paste.
- the adhesive paste was spread on a release liner (Scotch Pack 9742, manufactured by 3EM Healthcare) using an applicator so that the thickness was (about 125 m).
- the surface of the adhesive plaster was dried with hot air (about 50 to 60 ° C.) for 20 minutes.
- the dried adhesive plaster surface was covered with a release liner and cut into a 15 mm diameter (1.766 cm 2 ) circle to prepare a preparation (main component content: lmg / 10 cm 2 ).
- Example 2 Using imidafenacin (20 mg), the adhesive shown in Table 1 below, and other external preparation bases, the same procedure as in Example 1 was used (however, SIS and ultra-light rosin ester (ester gum) were used) In this case, black mouth form (7.5 g) was used as an organic solvent.) A 15 mm diameter (1.766 cm 2 ) circular preparation (main component content: lmgZlOcm 2 ) was prepared.
- High molecular weight polyisobutylene (Vistanex MML-100, manufactured by Exxon Chemical) (3g), low molecular weight polyisobutylene (Opanol B12SPN, manufactured by BASF Japan) (7g), styrene'isoprene'styrene block copolymer (SIS5229, Japan) (Manufactured by Synthetic Rubber) (20g), esthetic Lugum (KE-311, Arakawa Chemical Industries, Ltd.) (10 g), Alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical Industries, Ltd.) (20 g), Liquid paraffin (Cristol 352, Kaneda Corporation) (34 g), isopropyl myristate (manufactured by NOF Corporation) (5 g), and imidafenacin (lg) were mixed and dissolved in hexane to prepare an adhesive paste.
- the adhesive paste was spread on a silicone-treated liner (PET 75 ⁇ m) to a thickness of about 100 ⁇ m after drying, and dried with hot air at about 50 ° C for 5 minutes to volatilize the hexane. It was.
- the dried adhesive plaster body surface covered with the support (Poriu urethane 50 mu m), was cut into a square of 3.2 X 3.2mm (10cm 2), the formulation (the main component content: lmg / lOcm 2) was prepared.
- High molecular weight polyisobutylene (Vistanex MML-100, manufactured by Exxon Chemical) (3g), low molecular weight polyisobutylene (Opanol B12SPN, manufactured by BASF Japan) (7g), styrene'isoprene'styrene block copolymer (SIS5229, Japan) Synthetic Rubber Co., Ltd.
- the dried adhesive plaster body surface covered with the support (pET15 m), was cut into a square of 3.2 X 3.2mm (10cm 2), the formulation (the main component content: lmg / lOcm 2) was prepared.
- High molecular weight polyisobutylene (Vistanex MML-100, manufactured by Exxon Chemical) (3g), low molecular weight polyisobutylene (Opanol B12SPN, manufactured by BASF Japan) (7g), styrene'isoprene'styrene block copolymer (SIS5229, Japan) Synthetic Rubber Co., Ltd.
- the dried adhesive plaster body surface support covered with ( ⁇ 4 ⁇ 20 ⁇ ⁇ ), was cut into a square of 3.2 X 3.2mm (10cm 2), the formulation (the main component content: lmg / lOcm 2) was prepared.
- Silicone-based fat (Q7-4501, manufactured by Dow Co., Ltd.) (74 g), ester gum (KE-311, manufactured by Arakawa Chemical Industries, Ltd.) (20 g), isopropyl myristate (manufactured by NOF Corporation) (2.5 g), crotamiton
- An adhesive paste was prepared by mixing and dissolving (manufactured by Kongo Chemical Co., Ltd.) (2.5 g) and imidafenacin (lg). The adhesive paste was spread on a silicone-treated liner (PE 80 m) so that the thickness after drying was about 100 m, and dried with hot air at about 50 ° C.
- Silicone resin (Q7-4501, manufactured by Dow Co., Ltd.) (74g), Ester gum (KE-311, manufactured by Arakawa Chemical Industries) (10g), Alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical) Kogyo Kogyo Co., Ltd. (10 g), oleyl alcohol (Nippon Yushi Co., Ltd.) (2.5 g), crotamiton (Kongo Kagaku Co., Ltd.) (2.5 g), and imidafenacin (lg) were mixed and prepared. did .
- the adhesive paste was spread on a silicone-treated liner (quality paper 100 m) so that the thickness after drying was about 100 m, and dried with hot air at about 50 ° C.
- High molecular weight polyisobutylene (Vistanex MML-100, manufactured by Exxon Chemical) (3g), low Molecular weight polyisobutylene (Opanol B12SPN, manufactured by BASF Japan) (6g), styrene'isoprene'styrene block copolymer (SIS5229, manufactured by Nippon Synthetic Rubber) (20g), ester gum (KE-311, manufactured by Arakawa Chemical Industries) ) (7 g), alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical Industries) (21 g) and liquid paraffin (Cristol 352, Kaneda) (37 g) An approximately equal weight of hexane was added and dissolved by stirring (solution A).
- Imidafenacin (lg) and isopropyl myristate (5 g) were mixed and stirred at 90 ° C. for about 10 minutes (Liquid B). After the liquid B was cooled to 30 ° C, it was added to the liquid A to prepare a paste liquid.
- the plaster liquid is automatically coated on a silicone-treated liner (PET 75 ⁇ m, manufactured by Toray Film Co., Ltd.) so that the thickness after drying is about 100 ⁇ m. It was spread using an apparatus (manufactured by Tester Sangyo Co., Ltd.) and dried naturally.
- the dried adhesive plaster body surface covered with the support (PET / nonwoven) was cut into a square of 3.2 X 3.2 mm (10 cm 2), the formulation (the main component content: lmg / lOcm 2) was prepared.
- Example 6 (1) Using the components shown in Table 4 instead of isopropyl myristate, the same procedure as in Example 6 (1) was performed to prepare a preparation (main component content: lmg / lOcm 2 ).
- High molecular weight polyisobutylene (Vistanex MML-100, manufactured by Exxon Chemical) (3g), low molecular weight polyisobutylene (Opanol B12SPN, manufactured by BASF Japan) (4g), styrene'isoprene'styrene block copolymer (SIS5229, Japan) (Manufactured by Synthetic Rubber) (20g), esthetic Lugum (KE-311, Arakawa Chemical Industries) (2g), alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical Industries) (26g) and liquid paraffin (Cristol 352, Kaneda) ) (38.5 g), approximately equal weight of hexane was added to these base components and dissolved by stirring (solution A).
- Imidafenacin (lg), N-methyl-2-pyrrolidone (3 g) and propylene glycol (2.5 g) were mixed and stirred at 75 ° C. for about 10 minutes (liquid B). After the liquid B was cooled to 30 ° C, it was added to the liquid A to prepare a paste liquid.
- To make the plaster weight lOOgZm 2 it is automatically coated on the liner (PET 75 ⁇ m, manufactured by Toray Film Co., Ltd.) with the plaster liquid so that the thickness after drying is about 100 m. It was spread using an apparatus (manufactured by Tester Sangyo Co., Ltd.) and dried naturally. The dried adhesive plaster body surface covered with the support (Petz nonwoven), was cut into a square of 3.2 X 3.2mm (10c m 2) , the formulation (the main component content: lmgZlOcm 2) was prepared.
- Example 7 (1) Using the solutions A and B described in Table 5 and Table 6, the same procedure as in Example 7 (1) was performed to prepare a preparation (main component content: 0.1 to: Lmg / lOcm 2 ). did.
- High molecular weight polyisobutylene Vistanex MML-100, manufactured by Exxon Chemical Co., Ltd.
- Low molecular weight polyisobutylene Opanol B12SPN, manufactured by BASF Japan
- SIS Styrene 'isoprene' styrene block copolymer (SIS5229, manufactured by Nippon Synthetic Rubber Co., Ltd. Ester gum: KE-311, manufactured by Arakawa Chemical Industries, Ltd.
- Alicyclic saturated hydrocarbon resin Alcon P-100, manufactured by Arakawa Chemical Industries
- Liquid paraffin Christol 352, manufactured by Kaneda
- High molecular weight polyisobutylene Vistanex MML-100, manufactured by Exxon Chemical
- SIS Styrene 'isoprene' styrene block copolymer (SIS5229, manufactured by Nippon Synthetic Rubber Co., Ltd. Ester gum: KE-311, manufactured by Arakawa Chemical Industries, Ltd.
- Alicyclic saturated hydrocarbon resin Alcon P-100, manufactured by Arakawa Chemical Industries
- Liquid paraffin Christol 352, manufactured by Kaneda Purified oleic acid: manufactured by NOF Corporation
- Silicone resin (Q7-4501, manufactured by Dow Co., Ltd.) (74g), Ester gum (KE-311, manufactured by Arakawa Chemical Industries) (10g), Alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa Chemical) (7g), purified oleic acid (manufactured by NOF Corporation, 3g), N-methyl-2-pyrrolidone (2g), propylene glycol (3.5g) and imidafenacin (0.5g) An adhesive paste was prepared.
- the adhesive plaster was spread on a silicone-treated liner (fine paper 100 m) so that the thickness after drying was about 100 / zm, and then naturally dried to volatilize the solvent. ⁇ covering the dried adhesive plaster body surface a support (PET5 ⁇ mZ20g nonwoven), was cut into a square of 3.2 X 3.2mm (10 cm 2) , the formulation (the main component content: 0. 5mg / 10cm 2) was prepared .
- Example 9 (1) Using the components shown in Table 8 instead of the purified oleic acid, the same operation as in Example 9 (1) was performed to prepare a preparation (main component content: 0.5 mgZlOcm 2 ). However, when DL-a-tocopherol was added, the amount of alicyclic saturated hydrocarbon resin was 6.8 g.
- Example 3 (12) in which the external preparation base consists only of SIL
- Example 3 (13) in which the external preparation base is ⁇ and oleyl alcohol.
- a high cumulative permeation amount was obtained for the other preparations for which the adhesive was manufactured using SISS or SIL.
- the preparation of the present invention obtained a sufficient cumulative permeation amount even in minipigs.
- the average cumulative permeation amount of the preparation of Example 2 was 10.27 gZcm 2 .
- the cumulative permeation amount using the minipig percutaneous and the permeation amount using the hairless rat percutaneous of the preparations produced in Reference Example 1, Example 3 (11) and Example 2 described later are shown in FIG. As shown, a good correlation was obtained.
- Imidafenacin 25mg
- styrene 'isoprene' styrene block copolymer (0.9875g, SIS-5002, made by Nippon Synthetic Rubber) and ultra-light rosin ester (ester gum) (1.2375g, KE-311, Arakawa Chemical Industries, Ltd.
- isopropyl myristate 125 mg were dispersed in black mouth form (9.375 g) to prepare an adhesive paste.
- the adhesive plaster was spread on a release liner (Scotch Pack 9742, manufactured by 3EM Healthcare) using an applicator so that the thickness was about 125 m.
- the adhesive plaster surface was dried with hot air (about 50-60 ° C) for 20 minutes.
- the dried adhesive plaster surface was covered with a release liner and cut into a 15 mm diameter (1.766 cm 2 ) circle to prepare a preparation (main component content: lmg / lOcm 2 ).
- the abdominal skin of male hairless rats (10 weeks old, HWYZSlc, n 6) was shaved with an electric clipper.
- the preparation prepared in the above Example was affixed to the abdomen, wound with a non-woven adhesive bandage (Mesh Pore, manufactured by Ciba) and closed for 48 hours. The formulation was removed after 48 hours.
- blood was collected (approximately 0.3 mL) using a disposable syringe made of polypropylene that had been parinized into the jugular vein force without anesthesia, and the plasma was treated with polypropylene. Made Transferred to a container. The obtained plasma was immediately ice-cooled and stored frozen.
- Example 4 (11) in which the external preparation base was only an adhesive, was hardly absorbed into the blood and had a powerful force that did not achieve this purpose.
- the other preparations of the present invention were applied for 48 hours. During this period, it was confirmed that it was absorbed into the blood continuously and maintained at a certain level or higher.
- the preparation produced in Example 4 (3) showed a continuous blood concentration in the range of 0.152 ⁇ 0.049 ng ZmL to 0.766 ⁇ 0.594 ng ZmL for 48 hours after application.
- the preparations produced in Examples 7 (15), 7 (21), 7 (24) and 7 (27) to 7 (31) showed a continuous blood concentration within the range shown in Table 10.
- the preparation obtained by the above production method was 2 ⁇ 2 mm (4 cm 2 ). A rectangular cut was used for evaluation.
- the 10 cm 2 preparation was applied as it was and evaluated.
- Test Example 4 Evaluation of primary irritation of hairless rat skin
- Test Example 3 the preparation produced in the above example was applied to the male abdominal rat abdomen at 48 hours. After interstitial application, the skin reaction was observed at the time of removal of the preparation (0 hour), 24 hours after removal, 48 hours after removal, and 72 hours after removal, and P ⁇ I. was calculated. Evaluation was performed according to the evaluation criteria [see J. Pharmacol. Exp. Ther., 83, 377-390, (1944)].
- Safety category G) P ⁇ I. No irritation when 0, (ii) weak irritation when greater than 0 and less than 2, (iii) moderate when greater than 2 and less than 5 (Iv) When it exceeds 5, it was considered a strong stimulant. If the safety category is 0 or more than 0 and 2 or less, it can be judged that there is no problem with irritation.
- Test Example 5 Evaluation of primary irritating properties of rabbit skin
- Example 1 Male rabbits (10 weeks old, body weight 2.00-3.50 kg) were used. On the day before application (24 hours before), the hair on the back was removed with an electric clipper to create 6 application sites. Of these, 3 sites were normal skin, and the remaining 3 sites were damaged skin by scratching the stratum corneum with an injection needle.
- Example The preparations prepared in 4 (2), 4 (3) and 4 (4) and the negative control preparation were applied to normal skin and damaged skin, respectively, and then fixed with -chiban adhesive bandage. The application time was 24 hours. After removing the preparation, the remaining drug and the like were lightly wiped with absorbent cotton moistened with slightly warm water.
- Test Example 6 Adhesive strength test
- Measurement was performed using an Instron type tensile tester (AUTOGRAPH AGS-1KND; manufactured by Shimadzu Corporation). Place the long edge of the auxiliary paper (width 25 mm, length 100 mm) on the area of 10 mm from the side of the preparation of the present invention (20 mm X 20 mm), and strain it for 30 minutes at room temperature. Attach the remaining adhesive surface of this preparation to the center of a test strip made of resin (width 25mm, length 125mm, thickness 5mm) so that the long sides of the test plate and auxiliary paper are in the same direction. A rubber ring (850 g) was passed over the preparation twice at a speed of 300 mm for 1 minute.
- AUTOGRAPH AGS-1KND Instron type tensile tester
- the free end of the auxiliary paper attached to the test plate is folded back to 180 °, and the tensile tester is used to keep the free end of the preparation at the top and the test plate at the bottom. It was pinched with gold, peeled off continuously at a speed of 100 mm for 1 minute, and four loads were measured at approximately lmm intervals. For example, the average value of the preparation of Example 4 (2) was 240 g.
- Test Example 7 Measurement of effective blood concentration in guinea pigs
- mice Male Std: Hartley guinea pigs (Japan SLC, Inc., age of use: 6 weeks of age, weight 340.6-488.0 g) were anesthetized with urethane. After a midline incision in the abdomen, the ureters on both sides were ligated to prevent urine from flowing from the kidneys to the bladder. Bladder apex after ligation of bladder neck A catheter for measuring intravesical pressure was inserted from the part and fixed by ligation. Thereafter, in order to measure the intravesical pressure, 1 mL of physiological saline was injected into the bladder. Next, a catheter was placed in the left jugular vein.
- the intravesical pressure was measured via a strain pressure amplifier (Nihon Kohden, CARRI ER ANPLIFIER AP-601G) by connecting the intravesical pressure measuring catheter to a pressure transducer (Nihon Kohden, Life Kit DX-100).
- a catheter was inserted into the jugular vein, and imidafenacin was continuously administered intravenously (100 / z LZkgZ).
- methacholine ⁇ / z gZkg was intravenously administered to induce bladder contraction. Inhibition of bladder contraction was evaluated using the peak height of bladder contraction induced by methacholine as an index.
- imidafenacin had a dose-dependent inhibitory action at 0.03, 0.1 and 0.3 gZkgZ, and the ID value was 0.064 g / kg / min. Also, near this ID value
- the blood concentration was approximately IngZmL.
- the blood concentration was measured with LCZMSZMS using plasma.
- Guinea pigs were artificially breathed at a ventilation rate of 4mL / animal and the number of aspirations 70 times Z minutes, and the change in ventilation pressure was measured with a transducer (UGO BASILE, BRONCHOSPASM TRANSDU CER 7020) connected to the side of trachea-yure. .
- a catheter was inserted into the jugular vein, and imidaf-nacin was administered intravenously continuously (100 / z LZkgZ).
- methacholine (10 / z gZkg) was intravenously administered to induce airway contraction. Inhibition of airway contraction was evaluated using the peak height of airway contraction induced by methacholine as an index.
- imidafenacin showed a suppressive action depending on the dose at 0.03, 0.1, and 0.3 gZkgZ, and the ID value was 0.061 ⁇ g / kg / min. Also, near this ID value
- the blood concentration was approximately IngZmL.
- the blood concentration was measured with LCZMSZMS using plasma.
- imidafenacin patch is a preparation that can maintain the same blood concentration. It was also confirmed that it is useful for COPD that uses only OAB.
- Test Example 8 Airway contraction inhibitory effect
- An adhesive paste was prepared by dispersing imidafenacin (20 mg), SIS (790 mg) and ultra-light rosin ester (ester gum) (990 mg) and isopropyl myristate (200 mg) in black mouth form (7.5 g).
- the adhesive paste was spread on a release liner (Scotch Pack 9742, manufactured by 3EM Healthcare) using an applicator so that the thickness was (about 125 / zm).
- the adhesive plaster surface was dried with hot air (about 50 to 60 ° C.) for 20 minutes.
- the dried adhesive plaster body surface covered with a release liner, and cut into a square of 3.2cm X 3.2cm (10cm 2), to prepare the pressure-sensitive single-layer type transdermal formulation (lmgZlOcm 2).
- the adhesive single-layer transdermal preparation prepared above was affixed to the abdomen and fixed with surgical tape.
- the guinea pigs in the untreated group and the patch group were anesthetized with sodium pentobarbital and the force was also incised, and a polyethylene tubule was attached to the trachea as tracheal force-Yure.
- the tracheal force-Yule was connected to a quantitative respirator (Model SN-480-7, manufactured by Shinano Seisakusho) and ventilated (4 mL) and ventilated at 70 minutes Z min.
- a polyethylene tube filled with physiological saline was inserted into the left jugular vein. Airway contraction was measured by the Konzett & Rossler method. The change in aeration pressure was measured by a transducer (BRONCHOSPASM TRANSDUCE R, Cat No. 7020, UGO BASILE) connected to the auxiliary side passage of the artificial respiration circuit, and recorded on a recorder (LINEARCORDER, WR3320, manufactured by Graphtec).
- BRONCHOSPASM TRANSDUCE R Cat No. 7020, UGO BASILE
- the percutaneous absorption-type preparation used in the present invention is a preparation having an excellent sustained release property that significantly improves the low skin permeability of imidafinacin and has very weak skin irritation. That happened. Sarakuko, the transdermally absorbable preparation of the present invention It has also been confirmed that it has a phosphorus-induced airway contraction and bladder contraction inhibitory action, and its effect is strong.
- Test Example 9 Stability test
- the preparation examples of the present invention were stored as (1) 6 months at room temperature, or (2) 6 months at 40 ° C. and 75% relative humidity for use as test samples.
- test specimen excluding the liner was placed in a test tube, and jethyl ether (18 mL) and an internal standard solution were added and shaken for 15 minutes. 10 mL of this solution was taken and the solvent was distilled off under reduced pressure. Heptane (10 mL) was added to the residue and shaken for 15 minutes. To this solution was added 'acetonitryl phosphate mixture (7: 3, lOmL) and shaken for 15 minutes. This mixture was centrifuged (250 Orpm, 10 minutes), and the lower layer was collected. To the remaining liquid, phosphoric acid / acetonitrile mixed solution (7: 3, 10 mL) was added again and shaken for 15 minutes.
- the mixture was centrifuged (2500 rpm, 10 minutes), the lower layer was collected, combined with the lower layer described above, and the phosphate solution mixed with acetonitrile (7: 3) was added to make exactly 25 mL to obtain a sample solution.
- a 50 L sample solution was analyzed by liquid chromatography, and the amount of imidafenacin calculated from the peak area of imidafenacin relative to the peak area of the internal standard was also calculated according to the calibration curve.
- the preparation of the present invention is a stable preparation. For example, even when the preparation produced in Example 7 (3) was stored under the conditions (1) and (2), the content of imidafenacin over time was not recognized.
- a transdermal absorption-type preparation that has low skin power absorbability and imidafunacin that has low irritation and can be absorbed into the body continuously and efficiently. Therefore, the percutaneous absorption preparation has sustained effects, avoids side effects, and improves the convenience of administration compared to oral administration, and it is effective for chronic obstructive pulmonary disease (COPD) that is not limited to overactive bladder (OAB). Is also useful.
- COPD chronic obstructive pulmonary disease
- OAB overactive bladder
- FIG. 1 Male hairless rat skin of the preparations prepared in Examples 1, 2 and 3 (1) to 3 (13) It is a result of a penetration test.
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Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020137006703A KR20130069764A (ko) | 2005-02-03 | 2006-02-02 | 경피 흡수형 제제 |
JP2007501615A JP5020061B2 (ja) | 2005-02-03 | 2006-02-02 | 経皮吸収型製剤 |
KR1020077020031A KR101312814B1 (ko) | 2005-02-03 | 2006-02-02 | 경피 흡수형 제제 |
EP06712902A EP1844773A4 (en) | 2005-02-03 | 2006-02-02 | PREPARATION FOR PERCUTANEOUS ABSORPTION |
US11/815,499 US20110071204A1 (en) | 2005-02-03 | 2006-02-02 | Percutaneous absorption preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2005027826 | 2005-02-03 | ||
JP2005-027826 | 2005-02-03 |
Publications (1)
Publication Number | Publication Date |
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WO2006082888A1 true WO2006082888A1 (ja) | 2006-08-10 |
Family
ID=36777270
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2006/301759 WO2006082888A1 (ja) | 2005-02-03 | 2006-02-02 | 経皮吸収型製剤 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20110071204A1 (ja) |
EP (1) | EP1844773A4 (ja) |
JP (2) | JP5020061B2 (ja) |
KR (2) | KR20130069764A (ja) |
WO (1) | WO2006082888A1 (ja) |
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WO2009096560A1 (ja) | 2008-01-31 | 2009-08-06 | Kyorin Pharmaceutical Co., Ltd. | イミダフェナシン含有口腔内速崩壊性錠剤 |
WO2009096559A1 (ja) | 2008-01-31 | 2009-08-06 | Kyorin Pharmaceutical Co., Ltd. | イミダフェナシンを有効成分とする口腔内速崩錠の製造方法 |
JP2011032183A (ja) * | 2009-07-30 | 2011-02-17 | Kyorin Pharmaceutical Co Ltd | イミダフェナシン含有口腔内速崩錠 |
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CN110554104B (zh) * | 2019-07-26 | 2022-05-13 | 南京海纳医药科技股份有限公司 | 一种hplc-ms/ms联用检测人血浆中咪达那新的方法 |
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US20100137429A1 (en) * | 2007-06-21 | 2010-06-03 | Fujimoto Co., Ltd. | Composition for transdermal or transmucosal administration |
WO2008156160A1 (ja) | 2007-06-21 | 2008-12-24 | Fujimoto Co., Ltd. | 経皮または経粘膜投与用組成物 |
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JP5740300B2 (ja) * | 2009-02-27 | 2015-06-24 | 久光製薬株式会社 | 経皮投与製剤 |
JP2011032183A (ja) * | 2009-07-30 | 2011-02-17 | Kyorin Pharmaceutical Co Ltd | イミダフェナシン含有口腔内速崩錠 |
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JP5654006B2 (ja) * | 2010-04-28 | 2015-01-14 | 久光製薬株式会社 | 皮膚刺激抑制剤及び経皮吸収製剤 |
WO2012057212A1 (ja) * | 2010-10-28 | 2012-05-03 | 久光製薬株式会社 | 経皮吸収型製剤 |
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US9254325B2 (en) | 2010-10-28 | 2016-02-09 | Hisamitsu Pharmaceutical Co., Inc. | Percutaneously absorbed preparation |
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JPWO2013061588A1 (ja) * | 2011-10-26 | 2015-04-02 | 杏林製薬株式会社 | 経皮吸収型製剤 |
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US9457012B2 (en) | 2012-03-22 | 2016-10-04 | Teikoku Seiyaku Co., Ltd. | Transdermal absorption preparation |
JPWO2013140799A1 (ja) * | 2012-03-22 | 2015-08-03 | 杏林製薬株式会社 | 経皮吸収型製剤 |
KR20140138925A (ko) | 2012-03-22 | 2014-12-04 | 교린 세이야꾸 가부시키 가이샤 | 경피 흡수형 제제 |
WO2013140799A1 (ja) | 2012-03-22 | 2013-09-26 | 杏林製薬株式会社 | 経皮吸収型製剤 |
JP2014172885A (ja) * | 2013-03-11 | 2014-09-22 | Nitto Denko Corp | 経皮吸収促進用組成物および貼付製剤 |
JP2014214109A (ja) * | 2013-04-24 | 2014-11-17 | 杏林製薬株式会社 | 貼付剤 |
JP2016037608A (ja) * | 2014-08-08 | 2016-03-22 | ヨハン リ | 偽まつげ粘着部材及び偽まつげキット |
JP2015108026A (ja) * | 2015-03-10 | 2015-06-11 | 杏林製薬株式会社 | イミダフェナシン含有口腔内速崩錠 |
JP2016117768A (ja) * | 2016-03-24 | 2016-06-30 | 杏林製薬株式会社 | イミダフェナシン含有口腔内速崩錠 |
JP2017082012A (ja) * | 2017-02-14 | 2017-05-18 | 杏林製薬株式会社 | イミダフェナシン含有口腔内速崩錠 |
JP2017088618A (ja) * | 2017-02-14 | 2017-05-25 | 杏林製薬株式会社 | イミダフェナシン含有口腔内速崩錠 |
WO2020250840A1 (ja) * | 2019-06-14 | 2020-12-17 | 久光製薬株式会社 | ロチゴチン含有貼付剤 |
JP6872675B1 (ja) * | 2019-06-14 | 2021-05-19 | 久光製薬株式会社 | ロチゴチン含有貼付剤 |
KR20210137247A (ko) * | 2019-06-14 | 2021-11-17 | 히사미쓰 세이야꾸 가부시키가이샤 | 로티고틴 함유 첩부제 |
CN113950356A (zh) * | 2019-06-14 | 2022-01-18 | 久光制药株式会社 | 含罗替戈汀的贴附剂 |
KR102401412B1 (ko) | 2019-06-14 | 2022-05-23 | 히사미쓰 세이야꾸 가부시키가이샤 | 로티고틴 함유 첩부제 |
Also Published As
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EP1844773A4 (en) | 2010-04-28 |
KR101312814B1 (ko) | 2013-09-27 |
KR20070100834A (ko) | 2007-10-11 |
KR20130069764A (ko) | 2013-06-26 |
JP5020061B2 (ja) | 2012-09-05 |
JPWO2006082888A1 (ja) | 2008-06-26 |
EP1844773A1 (en) | 2007-10-17 |
US20110071204A1 (en) | 2011-03-24 |
JP2012126739A (ja) | 2012-07-05 |
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