WO2019026844A1 - 貼付剤 - Google Patents
貼付剤 Download PDFInfo
- Publication number
- WO2019026844A1 WO2019026844A1 PCT/JP2018/028460 JP2018028460W WO2019026844A1 WO 2019026844 A1 WO2019026844 A1 WO 2019026844A1 JP 2018028460 W JP2018028460 W JP 2018028460W WO 2019026844 A1 WO2019026844 A1 WO 2019026844A1
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- WIPO (PCT)
- Prior art keywords
- oxybutynin
- acid
- patch
- skin
- mass
- Prior art date
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Classifications
-
- 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
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/7061—Polyacrylates
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the present invention relates to a patch.
- Oxybutynin hydrochloride is known as one of the anticholinergics, and is known to be effective for the treatment of overactive bladder having symptoms such as urgency and frequent urination.
- Overactive bladder has a symptom in which the acetylcholine nervous system is activated by some cause, and even if urine does not collect in the bladder, bladder smooth muscle contracts to make it feel urinary.
- Oxybutynin can suppress contraction of bladder smooth muscle and alleviate symptoms of overactive bladder by its anticholinergic action.
- oral preparations are known as oxybutynin-containing preparations.
- oxybutynin When oxybutynin is orally administered, it is susceptible to metabolism by the liver (first pass effect) after being absorbed in the digestive tract, and produces metabolites such as N-desethyl oxybutynin. It is known that these metabolites are more likely to cause side effects such as dry mouth, constipation and fogging as compared to oxybutynin itself.
- the oxybutynin-containing patch developed anew is capable of avoiding the first-pass effect because oxybutynin is absorbed from the skin, and the occurrence of the above-mentioned side effects can be reduced (see Patent Documents 1 to 4). .
- an object of the present invention is to provide a patch which contains oxybutynin or a salt thereof and which has reduced skin irritation due to oxybutynin as compared with a conventional patch.
- the present invention provides the following [1] to [4].
- a patch comprising a support and an adhesive layer on the support, wherein the adhesive layer is at least one drug selected from the group consisting of oxybutynin and a pharmaceutically acceptable salt thereof. And an adhesive base and diflucortrone valerate ester, and the content of the above diflucortrone valerate ester is 0.0007% to 0.05% by mass on the basis of the total mass of the pressure sensitive adhesive layer.
- the patch according to [1] wherein the mass ratio of the drug to the diflucortorone valerate is 180: 1 to 20000: 1.
- the patch which reduced the skin irritation property by oxybutynin compared with the conventional patch can be provided, without reducing content of oxybutynin.
- skin atrophy may be observed, but according to the patch of the present invention, skin atrophy is less likely to occur.
- skin irritation refers to skin irritation that occurs at the site of application when a patch containing oxybutynin or a pharmacologically acceptable salt thereof is applied to the skin, specifically, Show skin symptoms such as itching, erythema, rash, pain, eczema and dermatitis. Also, the presence or absence of skin irritation may be evaluated, for example, by scoring the degree of erythema and edema as a standard.
- skin atrophy means that when a steroid is applied to the skin, the epidermis at the application site becomes thinner compared to the normal epidermis (the thickness of the epidermis in a state not affected by the steroid). Means a symptom.
- the presence or absence of skin atrophy may be evaluated, for example, on the basis of whether the thickness of the epidermis after applying the patch to the skin is 50% or less as compared to the thickness of the normal epidermis.
- a patch according to an embodiment of the present invention is a patch comprising a support and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer comprises oxybutynin and a pharmaceutically acceptable salt thereof. It is an adhesive patch containing at least 1 sort (s) of drug
- the support is a layer that physically supports the pressure-sensitive adhesive layer.
- the material of the support is not limited as long as it is generally used for patches.
- Examples of the material of the support include polyolefins such as polyethylene, polypropylene and polybutadiene; polyesters such as polyethylene terephthalate, polybutylene terephthalate and polyethylene naphthalate; and ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, Synthetic resins such as polyvinyl chloride, polyamide, nylon, cellulose derivatives, polyurethane and the like can be mentioned.
- the properties of the support may be a film, a sheet, a sheet-like porous body, a sheet-like foam, a woven fabric, a knitted fabric, a non-woven fabric, or a laminate thereof.
- a knitted fabric is preferable from the viewpoint of adhesion to the skin because it is excellent in stretchability.
- the adhesive layer contains at least one drug selected from the group consisting of oxybutynin and its pharmaceutically acceptable salts, an adhesive base, and diflucortorone valerate.
- the drug may be oxybutynin, a pharmaceutically acceptable salt of oxybutynin, or a mixture thereof.
- Oxybutynin is also referred to as ⁇ -phenylcyclohexane glycolate 4- (diethylamino) -2-butynyl.
- Oxybutynin can alleviate the symptoms of overactive bladder such as urinary urgency and frequent urination by relaxing bladder smooth muscle by competitively inhibiting muscarinic receptors.
- the pharmaceutically acceptable salt of oxybutynin may be a mineral acid salt or an organic acid salt.
- the inorganic acid that forms the inorganic acid salt of oxybutynin include hydrochloric acid, hydrobromic acid, silicic acid and phosphoric acid.
- the organic acid salt which forms the organic acid salt of oxybutynin include acetic acid, citric acid, fumaric acid and maleic acid. Among them, oxybutynin hydrochloride or oxybutynin acetate is preferable.
- the content of oxybutynin or a pharmaceutically acceptable salt thereof may be an amount capable of securing an effective blood concentration of oxybutynin.
- the content of oxybutynin or a pharmaceutically acceptable salt thereof is, for example, preferably 4 to 50% by mass based on the total mass of the pressure-sensitive adhesive layer when converted to the mass of oxybutynin, and is preferably 6 to 30 More preferably, it is 9% by mass, and more preferably 9 to 14% by mass.
- the content of oxybutynin is 4% by mass or more, it tends to be an amount sufficient for the pharmacological action of oxybutynin to be more stably exhibited.
- the content of oxybutynin is 50% by mass or less, it is difficult for skin irritation due to oxybutynin to occur.
- the mass of oxybutynin or a pharmaceutically acceptable salt thereof is converted to the mass of oxybutynin, it may be calculated based on the molecular weight.
- the adhesive base may be one generally used in patches, and examples thereof include rubber-based adhesive bases, acrylic adhesive bases and silicone-based adhesive bases.
- the preferred adhesive base is a rubber adhesive base or an acrylic adhesive base.
- the rubber-based adhesive base may be a polymer based on natural or synthetic rubber, for example, polyisoprene, polyisobutylene, polybutadiene, styrene-isoprene-styrene block copolymer (SIS block copolymer), styrene Butadiene-styrene block copolymers, styrene-butadiene rubbers, or styrene-isoprene rubbers.
- polyisoprene polyisobutylene, polybutadiene
- SIS block copolymer styrene-isoprene-styrene block copolymer
- SIS block copolymer styrene Butadiene-styrene block copolymers
- styrene-butadiene rubbers styrene-butadiene rubbers
- styrene-isoprene rubbers for example
- (meth) acrylic acid alkyl ester means acrylic acid alkyl ester and methacrylic acid alkyl ester.
- (meth) acrylic acid alkyl esters include butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and Methyl) decyl acrylate is mentioned.
- the (meth) acrylic acid alkyl esters may be used alone or in combination of two or more.
- Comonomers include, for example, hydroxyalkyl (meth) acrylate, ethylene, propylene, styrene, vinyl acetate, N-vinylpyrrolidone, and (meth) acrylic acid amide.
- the comonomers may be used alone or in combination of two or more.
- the acrylic adhesive base is a co-solvent containing at least two selected from butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, methacrylic acid, hydroxyethyl acrylate, glycidyl methacrylate, methoxyethyl acrylate, and acrylic acid.
- Polymers are mentioned, and more specifically, DURO-TAK 87-2097, 87-2194, 87-2196, 87-2287, 87-2516, and 87-2852 (trade names, Henkel), and Examples include Nissetsu KP-77 and AS-370 (trade names, Nippon Carbide Industries, Ltd.).
- silicone type adhesive bases organopolysiloxanes, such as a condensation reaction product of dimethylpolysiloxane and dimethylpolysiloxane and silicate resin, are mentioned, for example.
- Specific examples of the silicone-based adhesive base include BIO-PSA X7-4201, BIO-PSA Q7-4501, 360 Medical Fluid 1000CS, and MDX4-4210 (trade name, Dow Corning).
- the content of the adhesive base is, for example, preferably 5 to 90% by mass, more preferably 10 to 50% by mass, and 10 to 30% by mass, based on the total mass of the adhesive layer. Is more preferred.
- Diflucortorone valerate is also referred to as 6 ⁇ , 9-difluoro-11 ⁇ -hydroxy-21-valeryloxy-16 ⁇ -methyl-1,4-pregnadiene-3,20-dione.
- Diflucortorone valerate is a kind of steroid having synthetic adrenocortical hormone action, and has anti-inflammatory action like other steroids. According to the atopic dermatitis medical care guideline 2016 in Japan, diflucortorone valerate belongs to Class II (Very strong) out of 5 classes of steroids.
- it is 0.0007-0.05 mass%, and it is more preferable that it is 0.0009-0.03 mass%, based on the total mass of an adhesive layer, as for content of the diflucortrone valerate ester. Preferably, it is more preferably 0.001 to 0.01% by mass. If the content of diflucortrone valerate is 0.0007% by mass or more, skin irritation by oxybutynin tends to be more easily reduced. When the content of diflucortrone valerate is 0.05% by mass or less, skin atrophy at the application site becomes more difficult to occur.
- the mass ratio of oxybutynin to diflucortrone valerate contained in the pressure-sensitive adhesive layer may be 150: 1 to 25000: 1, preferably 180: 1 to 20000: 1, and 300: It is more preferably 1 to 140000: 9 (that is, 15555: 1), and particularly preferably 900: 1 to 14000: 1.
- the adhesive layer contains a pharmaceutically acceptable salt of oxybutynin as a drug
- the mass of the pharmaceutically acceptable salt of oxybutynin is calculated in terms of the mass of oxybutynin.
- the mass ratio of oxybutynin to diflucortrone valerate is 25000 or less (that is, the mass of oxybutynin is an amount of 25000 times or less of the mass of diflucortrone valerate), skin irritation by oxybutynin It can reduce more effectively.
- the pressure-sensitive adhesive layer may further contain other components (a tackifier, a plasticizer, a filler, a stabilizer, a percutaneous absorption enhancer for a drug, a fragrance, a colorant, and the like).
- a tackifier e.g., a plasticizer, a filler, a stabilizer, a percutaneous absorption enhancer for a drug, a fragrance, a colorant, and the like.
- tackifiers include terpene resins, terpene phenol resins, rosin ester resins, hydrogenated rosin ester resins, alicyclic saturated hydrocarbon resins, and petroleum resins.
- the terpene resin is preferably a hydrogenated terpene resin.
- the terpene resin includes, for example, ⁇ -pinene resin, ⁇ -pinene resin, aromatic modified terpene resin, and terpene phenol resin.
- plasticizer for example, paraffin oil (liquid paraffin, etc.), squalane, squalene, vegetable oils (olive oil, camellia oil, castor oil, tall oil, peanut oil, spearmint oil, eucalyptus oil, jojoba oil, camphor white oil, sunflower oil, Orange oil etc., fats and oils (dibutyl phthalate, dioctyl phthalate etc.), and liquid rubbers (liquid polybutene, liquid isoprene rubber etc).
- paraffin oil liquid paraffin, etc.
- squalane squalene
- vegetable oils oil, camellia oil, castor oil, tall oil, peanut oil, spearmint oil, eucalyptus oil, jojoba oil, camphor white oil, sunflower oil, Orange oil etc.
- fats and oils dibutyl phthalate, dioctyl phthalate etc.
- liquid rubbers liquid polybutene, liquid isoprene rubber etc.
- metal compounds aluminum oxide, aluminum hydroxide, zinc oxide, titanium oxide, calcium carbonate etc.
- ceramics talc, clay, kaolin, silica, hydroxyapatite, synthetic aluminum silicate, metasilicate aluminate
- Short fibers of powders or resins containing these, such as magnesium) or organic compounds cellulose powder, stearate etc.
- the percutaneous absorption enhancer may be any compound conventionally known to have a percutaneous absorption promoting effect on the skin.
- organic acids and salts thereof for example, aliphatic carboxylic acids having 6 to 20 carbon atoms (hereinafter, also referred to as “fatty acids”) and salts thereof, cinnamic acid and salts thereof
- Organic acid ester eg, fatty acid ester, cinnamic acid ester
- organic acid amide eg, fatty acid amide
- fatty alcohol polyhydric alcohol
- ether eg, fatty ether, polyoxyethylene alkyl ether
- the percutaneous absorption enhancer may have unsaturated bonds, and may have a cyclic, linear or branched chemical structure.
- the percutaneous absorption enhancer may be a monoterpene compound, a sesquiterpene compound, and a vegetable oil (for example, olive oil).
- One of these percutaneous absorption enhancers may be used alone, or two or more thereof may be used in combination.
- Such organic acids include aliphatic (mono, di or tri) carboxylic acids (eg, acetic acid, propionic acid, citric acid (including citric anhydride), isobutyric acid, caproic acid, caprylic acid, fatty acids, lactic acid, maleic acid , Pyruvic acid, oxalic acid, succinic acid, tartaric acid, etc., aromatic carboxylic acids (eg, phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid etc.), cinnamic acid, alkanesulfonic acids (eg, methanesulfonic acid, ethanesulfone, etc.) Acid, propanesulfonic acid, butanesulfonic acid), alkylsulfonic acid derivatives (eg, polyoxyethylene alkyl ether sulfonic acid, N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid), cholic acid
- fatty acids examples include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid and linolenic acid.
- organic acid ester examples include ethyl acetate, propyl acetate, cetyl lactate, lauryl lactate, methyl salicylate, ethylene glycol salicylate, methyl cinnamic acid and fatty acid ester.
- fatty acid esters include methyl laurate, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate.
- the fatty acid ester may be glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyethylene glycol sorbitan fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, or polyoxyethylene hydrogenated castor oil.
- fatty acid esters include glycerin monocaprylate, glycerin mono caprate, glycerin mono laurate, glycerin mono oleate, sorbitan mono laurate, sucrose mono laurate, polysorbate 20 (trade name), propylene glycol mono laur , Polyethylene glycol monolaurate, polyethylene glycol monostearate, Span 20, Span 40, Span 60, Span 80, Span 120 (trade name), Tween 20, Tween 21, Tween 40, Tween 60, Tween 80 (trade name), NIKKOL HCO-60 (trade name) Can be mentioned.
- organic acid amides examples include fatty acid amides (eg, lauric acid diethanolamide), hexahydro-1-dodecyl-2H-azepine-2-one (also referred to as Azone) and derivatives thereof, and pyrothiodecane.
- fatty acid amides eg, lauric acid diethanolamide
- hexahydro-1-dodecyl-2H-azepine-2-one also referred to as Azone
- derivatives thereof examples include pyrothiodecane.
- fatty alcohol is meant aliphatic alcohols having 6 to 20 carbon atoms.
- fatty alcohols include lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol and cetyl alcohol.
- polyhydric alcohols include propylene glycol.
- polyoxyethylene alkyl ether polyoxyethylene lauryl ether is mentioned, for example.
- Examples of the monoterpene compounds include geraniol, thymol, eugenol, terpineol, l-menthol, borneolol, d-limonene, isoeugenol, isoborneol, nerol and dl-camphor.
- Fatty acids are preferred and oleic acid is particularly preferred.
- the pressure-sensitive adhesive layer may be provided with a release liner on the side facing the skin opposite to the support.
- the release liner is a liner that is removed when using the patch, and is not limited as long as it is generally used for a patch.
- Examples of the material of the release liner include polyester (polyethylene terephthalate (PET) or the like), polyolefin (polypropylene, polyethylene or the like), and cellulose compound (paper or the like).
- PET polyethylene terephthalate
- the release liner may be a sheet made of a laminate of the above materials.
- the surface of the release liner is preferably release-treated with silicone or fluorinated polyolefin or the like.
- the patch according to the present embodiment can be produced, for example, by the following method. 1) Weigh the components of the pressure-sensitive adhesive layer, and if necessary, perform heating and solvent addition, mix and homogenize. 2) The obtained pressure-sensitive adhesive composition is applied to a release surface of a release liner with a certain thickness, and dried as required to remove solvent components, thereby forming a pressure-sensitive adhesive layer. 3) laminating a support on the pressure-sensitive adhesive layer; 4) It is cut into a predetermined shape (for example, a rectangle having a short side of 3 cm to 14 cm and a long side of 7 cm to 20 cm, or a circle having a diameter of 1 cm to 10 cm).
- a predetermined shape for example, a rectangle having a short side of 3 cm to 14 cm and a long side of 7 cm to 20 cm, or a circle having a diameter of 1 cm to 10 cm.
- Example 1 Evaluation of Skin Stimulation and Skin Atrophy According to the descriptions in Table 1 and Table 2, patches of Example 1 and Comparative Examples 1 to 8 were respectively prepared. In Tables 1 and 2, unless otherwise specified, numerical values mean% by mass.
- HWY Slc rats (6 to 7 weeks old, female) were purchased and allowed to acclimate for 6 days or more. During the habituation period, the back of the rat was subjected to a cutting and shaving treatment. Out of all the rats, rats with good general condition and skin condition were selected, and grouping was carried out so as to equalize the weight. For each group of rats, any one patch and the patch of Comparative Example 1 were applied as a control.
- the application site (approximately 1.5 cm ⁇ 1.5 cm) was set on the back skin (shaving area) of the rat on the day of application, and the four corners were marked.
- the patches obtained above were applied to the marked application sites.
- a mesh-like adhesive bandage was applied so as to cover the application site, and a lint cloth was further placed thereon and fixed with an adhesive stretchable bandage.
- Twenty-four hours after application the lint cloth, the adhesive bandage and the patch were peeled off, and the degree of skin irritation in each group of rats was evaluated.
- the skin at the application site was removed, a skin slice preparation was prepared, and the degree of skin atrophy was evaluated.
- Draize et al. For evaluation of skin irritation, refer to the criteria of Draize et al. (Reference: Draize JH et al., J. Pharmacol. Exp. Ther. 1944: 82: 377-390) 0.5 hours after peeling the patch. It carried out. Specifically, by observing the skin of the application site 0.5 hours after peeling, it is scored according to the following criteria in terms of (1) erythema and scab formation, and (2) edema formation. And the average value was calculated for each group. And the average score of the Example with respect to the average score of a corresponding comparative example was computed as a relative value.
- the image of the sample taken with a microscope was analyzed using image analysis software (trade name: WinROOF ver 7.3, manufactured by Mitani Corporation), and the thickness of the epidermis was measured.
- the thickness of the epidermis was measured at 5 points for each epidermal section, and the average value was calculated.
- the case where the thickness of the epidermis of the sticking site exceeds 50% of the thickness of the epidermis of the non-sticking site (normal skin) was evaluated as "A", and the case of 50% or less was evaluated as "B".
- Example 1 The evaluation of the skin irritation of Example 1 and Comparative Examples 2 to 8 is a relative value to the average score of Comparative Example 1.
- patches containing diflucortrone valerate, clobetasol propionate, amcinonide, mometasone furan carboxylate, fluocinonide, dexamethasone propionate, beclomethasone propionate, or fluocinolone acetonide diflucortoronekine Only patches containing herbal esters (Example 1) reduced skin irritation due to oxybutynin hydrochloride and did not show skin atrophy.
- topical steroids for topical use are classified into 5 stages (class I: Strongest, class II: Very strong, class III: Strong, IV) based on their anti-inflammatory and vasoconstrictive effects. Class: Mild, Class V: Weak). According to Tables 1 and 2, the patch of Example 1 containing diflucortorone valerate (class II) reduced the skin irritation caused by oxybutynin and did not exhibit skin atrophy.
- the patches of Comparative Examples 3 to 5 containing amcinonide (class II), mometasone furan carboxylic acid ester (class II) or fluocinonide (class II) can reduce skin irritation caused by oxybutynin, but the skin atrophy Also indicated.
- Test Example 2 Concentration of Diflucortorone Valerate According to the description in Table 3, the patches of Examples 1 to 5 and Comparative Examples 9 and 10 were respectively prepared. In Table 3, unless otherwise stated, numerical values mean% by mass.
- HWY Slc rats (6 to 7 weeks old, female) were purchased and allowed to acclimate for 6 days or more. During the habituation period, the back of the rat was subjected to a cutting and shaving treatment. Out of all the rats, rats with good general condition and skin condition were selected, and grouping was carried out so as to equalize the weight. For each group of rats, any one patch and the patch of Comparative Example 1 were applied as a control.
- Test Example 3 Skin Permeability of Oxybutynin For the patches of Examples 1 and 6 and Comparative Example 1, the skin permeation of oxybutynin was measured over time using a hairless mouse (7 weeks old, male). Three patches of each patch were applied to the removed hairless mouse skin. The skin was set in a vertical flow-through cell, the inside of the cell was filled with saline, and a tube was connected with a roller pump and fraction collector. Next, the circulation phase of the cell and a thermostatic circulation tank set to 32 ° C. were connected by a tube, and the receiver liquid was collected every four hours while being stirred by a multi stirrer. The test was repeated six times for each patch. The results of the average cumulative skin permeation of oxybutynin in each patch are shown in Table 4.
- the cumulative skin permeation of oxybutynin was measured up to 24 hours after application, and the average value of 2 animals was calculated.
- the cumulative skin permeation amount of oxybutynin at 24 hours after application was not significantly different. Therefore, it was revealed that the reduction in skin permeation of oxybutynin did not reduce skin irritation.
- Test Example 4 Stability of Diflucortorone Valerate As described in the Japanese Pharmacopoeia, the adhesive patch of Example 3 is contained in the adhesive layer after storage at 40 ° C. for one month or six months. The content of diflucortorone valerate was measured by high performance liquid chromatography. The content of diflucortorone valerate in the patch after storage under each condition was calculated relative to the content (initial value) of diflucortorone valerate in the patch at the time of preparation, and is shown in Table 5.
- Test Example 5 Evaluation of Skin Stimulation and Skin Atrophy
- the patches of Example 7 and Comparative Examples 11 to 13 were prepared in the same manner as in Test Example 1, and skin irritation and skin atrophy were evaluated.
- Example 7 The evaluation of the skin irritation of Example 7 and Comparative Examples 11 to 13 is a relative value to the average score of Comparative Example 1.
- the patch of Example 7 not only reduced skin irritation due to oxybutynin hydrochloride, but also showed no skin atrophy.
- Test Example 6 Evaluation of skin irritation According to the description in Table 7, patches of Comparative Example 14 and Examples 8 and 9 were prepared, and evaluation of skin irritation was performed in the same manner as in Test Example 1. In Table 7, unless otherwise stated, numerical values mean% by mass. The evaluation of skin irritation in Examples 8 and 9 is a relative value to the average score in Comparative Example 14.
- Test Example 7 Evaluation of skin irritation (continuous administration) According to the description of Table 8, patches of Comparative Example 15 and Example 10 were prepared. In Table 8, unless otherwise stated, numerical values mean% by mass. The skin irritation was evaluated when the patches of Examples 3, 8 and 10 and Comparative Examples 1, 14 and 15 were continuously administered twice. Specifically, the application site (approximately 1.5 cm ⁇ 1.5 cm) was set on the back skin (shaving area) of the rat, and the four corners were marked. The rats were divided into a comparative example application group and an example application group such that the number of rats in each group was 6-8. The patches obtained above were each affixed to the marked application site (first administration).
- a mesh-like adhesive bandage was applied so as to cover the application site, and a lint cloth was further placed thereon and fixed with an adhesive stretchable bandage. After 24 hours of application, the lint cloth, adhesive bandage and patch were peeled off. 0.5 hours after peeling, the second patch was applied to the same site (second administration). After the second patch was applied for 24 hours, it was peeled off, and after 0.5 hour, skin irritation was evaluated in the same manner as in Test Example 1.
- the results are shown in Table 9.
- the skin irritation evaluations of Examples 3, 8 and 10 are relative to the average scores of Comparative Examples 1, 14 and 15, respectively.
- the patch of the example had a lower degree of skin irritation than the patch of the comparative example.
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Abstract
Description
[1]支持体及び上記支持体上に粘着剤層を備える貼付剤であって、上記粘着剤層が、オキシブチニン及びその薬学的に許容される塩からなる群から選択される少なくとも1種の薬物と、粘着基剤と、ジフルコルトロン吉草酸エステルと、を含有し、上記ジフルコルトロン吉草酸エステルの含有量が、上記粘着剤層の全質量基準で0.0007~0.05質量%である、貼付剤。
[2]上記薬物と上記ジフルコルトロン吉草酸エステルの質量比が、180:1~20000:1である、[1]に記載の貼付剤。
[3]上記粘着基剤が、ゴム系粘着基剤及びアクリル系粘着基剤からなる群から選択される少なくとも1種の粘着基剤を含む、[1]又は[2]に記載の貼付剤。
[4]支持体及び上記支持体上に粘着剤層を備える貼付剤の製造方法であって、オキシブチニン及びその薬学的に許容される塩からなる群から選択される少なくとも1種の薬物、粘着基剤、並びにジフルコルトロン吉草酸エステルを含有する粘着剤組成物を、剥離ライナー上に展延して粘着剤層を形成する工程と、形成された上記粘着剤層の上に支持体を積層する工程と、を含み、上記ジフルコルトロン吉草酸エステルの含有量が、上記粘着剤層の全質量基準で0.0007~0.05質量%である、方法。
1)粘着剤層の成分を秤り取り、必要に応じて加温及び溶媒添加を行い、混合し、均一化する。
2)得られた粘着剤組成物を、剥離ライナーの離型面に一定の厚さで塗布し、必要に応じて乾燥して溶媒成分を除去し、粘着剤層を形成する。
3)粘着剤層の上に支持体を積層する。
4)所定の形状(例えば、短辺が3cm~14cmかつ長辺が7cm~20cmの矩形、又は直径が1cm~10cmの円形)に裁断する。
表1及び表2の記載にしたがい、実施例1及び比較例1~8の貼付剤をそれぞれ調製した。なお、表1及び2中、特記しない限り、数値は質量%を意味する。
HWY:Slcラット(6~7週齢、雌性)を購入し、6日以上馴化させた。馴化期間中にラット背部に刈毛及び剃毛処置を施した。全ラットの中から一般状態及び皮膚状態の良好なラットを選抜し、体重が均等になるように群分けを実施した。各群のラットに対して、いずれか1つの貼付剤と、対照として比較例1の貼付剤とを適用した。具体的には、貼付日にラットの背部皮膚(剃毛領域)に貼付部位(約1.5cm×1.5cm)を設定し、その四隅にマーキングした。上記で得られた貼付剤を、マーキングした貼付部位にそれぞれ貼付した。貼付後、貼付部位を覆うようにメッシュ状粘着包帯を貼付し、さらにリント布を被せて粘着性伸縮包帯で固定した。貼付から24時間後、リント布、粘着包帯及び貼付剤を剥離し、各群のラットにおける皮膚刺激の程度を評価した。また、皮膚刺激の程度を評価した後、貼付部位の皮膚を摘出して、皮膚切片標本を調製し、皮膚萎縮の程度を評価した。
<Draizeらの判定基準>
(1)紅斑及び痂皮形成
0:紅斑なし
1:非常に軽微な紅斑(かろうじて識別できる程度)
2:はっきりした紅斑
3:中等度ないし高度紅斑
4:高度紅斑(beet redness)からわずかな痂皮の形成(深部損傷)まで
(2)浮腫形成
0:浮腫なし
1:非常に軽微な浮腫(かろうじて識別できる程度)
2:軽度浮腫(はっきりとした膨隆による明確な縁が識別できる程度)
3:中等度浮腫(約1mmの膨隆)
4:高度浮腫(1mm以上の膨隆と暴露範囲を超えた広がり)
表3の記載にしたがい、実施例1~5及び比較例9、10の貼付剤をそれぞれ調製した。なお、表3中、特記しない限り、数値は質量%を意味する。
HWY:Slcラット(6~7週齢、雌性)を購入し、6日以上馴化させた。馴化期間中にラット背部に刈毛及び剃毛処置を施した。全ラットの中から一般状態及び皮膚状態の良好なラットを選抜し、体重が均等になるように群分けを実施した。各群のラットに対して、いずれか1つの貼付剤と、対照として比較例1の貼付剤とを適用した。すなわち、得られた貼付剤を、ラットの背部に24時間適用した後、貼付剤を剥離した。その後、試験例1と同様にして、各群のラットにおける皮膚刺激及び皮膚萎縮の程度を評価した。実施例1~5及び比較例9、10の皮膚刺激の評価は、比較例1の平均スコアに対する相対値である。
実施例1、6及び比較例1の貼付剤について、ヘアレスマウス(7週齢、雄性)を用いて、オキシブチニンの皮膚透過量を経時的に測定した。摘出したヘアレスマウス皮膚に、各貼付剤を3枚ずつ貼付した。この皮膚を縦型のフロースルー型セルにセットし、セル内を生理食塩水で満たしてローラーポンプ及びフラクションコレクターとチューブにより接続した。次にセルの循環相と32℃に設定した恒温循環槽をチューブで接続し、マルチスターラーで撹拌しながら4時間毎にレシーバー液の回収を行った。試験は、各貼付剤につき、6回繰り返した。各貼付剤におけるオキシブチニンの平均累積皮膚透過量の結果を表4に示す。
日本薬局方の記載に準じて、実施例3の貼付剤を40℃にて1か月間又は6か月間保管した後、粘着剤層に含まれるジフルコルトロン吉草酸エステルの含有量を高速液体クロマトグラフ法にて測定した。調製時の貼付剤におけるジフルコルトロン吉草酸エステルの含有量(初期値)に対する、各条件で保管後の貼付剤におけるジフルコルトロン吉草酸エステルの含有量を算出し、表5に示した。
表7の記載にしたがい、比較例14、実施例8、9の貼付剤を調製し、試験例1と同様にして、皮膚刺激の評価を行った。表7中、特記しない限り、数値は質量%を意味する。実施例8、9の皮膚刺激の評価は、比較例14の平均スコアに対する相対値である。
表8の記載にしたがい、比較例15及び実施例10の貼付剤を調製した。表8中、特記しない限り、数値は質量%を意味する。実施例3、8及び10、比較例1、14及び15の貼付剤を2回連続投与した場合の皮膚刺激を評価した。具体的には、ラットの背部皮膚(剃毛領域)に貼付部位(約1.5cm×1.5cm)を設定し、その四隅にマーキングした。各群のラットの数が6~8となるように、ラットを比較例適用群と実施例適用群に群分けした。上記で得られた貼付剤を、マーキングした貼付部位にそれぞれ貼付した(初回投与)。貼付後、貼付部位を覆うようにメッシュ状粘着包帯を貼付し、さらにリント布を被せて粘着性伸縮包帯で固定した。貼付から24時間後、リント布、粘着包帯及び貼付剤を剥離した。剥離から0.5時間後、2枚目の貼付剤を同じ部位に貼付した(2回目投与)。2枚目の貼付剤を24時間貼付した後、剥離し、さらに0.5時間後に、試験例1と同様にして、皮膚刺激を評価した。
Claims (3)
- 支持体及び前記支持体上に粘着剤層を備える貼付剤であって、
前記粘着剤層が、オキシブチニン及びその薬学的に許容される塩からなる群から選択される少なくとも1種の薬物と、粘着基剤と、ジフルコルトロン吉草酸エステルと、を含有し、
前記ジフルコルトロン吉草酸エステルの含有量が、前記粘着剤層の全質量基準で0.0007~0.05質量%である、貼付剤。 - 前記オキシブチニンと前記ジフルコルトロン吉草酸エステルの質量比が、180:1~20000:1である、請求項1に記載の貼付剤。
- 前記粘着基剤が、ゴム系粘着基剤及びアクリル系粘着基剤からなる群から選択される少なくとも1種の粘着基剤を含む、請求項1又は2に記載の貼付剤。
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EP18841780.2A EP3662905B1 (en) | 2017-08-01 | 2018-07-30 | Adhesive patch |
CN201880043287.2A CN110891563B (zh) | 2017-08-01 | 2018-07-30 | 贴剂 |
KR1020197036116A KR102201003B1 (ko) | 2017-08-01 | 2018-07-30 | 첩부제 |
US16/610,955 US11033511B2 (en) | 2017-08-01 | 2018-07-30 | Pharmaceutical patch |
JP2018567314A JP6748237B2 (ja) | 2017-08-01 | 2018-07-30 | 貼付剤 |
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WO2020158879A1 (ja) * | 2019-01-31 | 2020-08-06 | 久光製薬株式会社 | 貼付剤 |
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JPH0853354A (ja) * | 1994-08-11 | 1996-02-27 | Hisamitsu Pharmaceut Co Inc | 皮膚疾患用水性貼付剤 |
WO2001007018A1 (fr) | 1999-07-27 | 2001-02-01 | Hisamitsu Pharmaceutical Co., Inc. | Bandes adhesives a usage externe |
WO2002069942A1 (fr) | 2001-03-07 | 2002-09-12 | Hisamitsu Pharmaceutical Co., Inc. | Timbre adhesif |
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WO2013061969A1 (ja) | 2011-10-26 | 2013-05-02 | 久光製薬株式会社 | オキシブチニン含有経皮吸収製剤 |
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AU3618795A (en) | 1994-10-05 | 1996-05-02 | Hisamitsu Pharmaceutical Co., Inc. | Drug compounding ingredients comprising n-substituted-o-toluidine derivative and percutaneously absorbable preparation |
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