WO2015093503A1 - 含水型貼付剤 - Google Patents
含水型貼付剤 Download PDFInfo
- Publication number
- WO2015093503A1 WO2015093503A1 PCT/JP2014/083335 JP2014083335W WO2015093503A1 WO 2015093503 A1 WO2015093503 A1 WO 2015093503A1 JP 2014083335 W JP2014083335 W JP 2014083335W WO 2015093503 A1 WO2015093503 A1 WO 2015093503A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- water
- patch
- dexmedetomidine
- salt
- fatty acid
- Prior art date
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- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- KXGHESPKMFRICD-UHFFFAOYSA-N n-ethenylacetamide;sodium Chemical compound [Na].CC(=O)NC=C KXGHESPKMFRICD-UHFFFAOYSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940116422 propylene glycol dicaprate Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- 235000019830 sodium polyphosphate Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229920003170 water-soluble synthetic polymer Polymers 0.000 description 1
Classifications
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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
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F13/00051—Accessories for dressings
- A61F13/00063—Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F13/02—Adhesive bandages or dressings
- A61F13/0246—Adhesive bandages or dressings characterised by the skin-adhering layer
- A61F13/0253—Adhesive bandages or dressings characterised by the skin-adhering layer characterized by the adhesive material
-
- 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
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
- A61K9/7069—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
Definitions
- the present invention relates to a patch containing dexmedetomidine or a salt thereof useful as a sedative.
- Dexmedetomidine or a salt thereof is an agonist of ⁇ 2 adrenergic receptor, has sedative action, analgesic action, and sympathetic nerve inhibitory action, and is used as a sedative.
- a sedative Currently, it is used in Japan for sedation during artificial respiration and after withdrawal in intensive care, but is widely used overseas as a sedative and analgesic.
- As the administration form of dexmedetomidine only intravenous administration is used.
- Patent Document 1 non-aqueous patches
- Patent Document 2 reservoir-type patches
- cyclodextrin derivatives composed of a backing layer / fixed adhesive layer / porous intermediate layer / contact adhesive layer / release liner
- Patent Document 3 a patch that uses dexamete
- Patent Document 4 a patch that contains dexmedetomidine as a salt with carboxylic acid.
- an object of the present invention is to provide a patch with sufficiently high dexmedetomidine absorbability and less skin irritation.
- the present inventor has produced dexmedetomidine-containing patches using various bases and studied their transdermal absorbability, and surprisingly combined dexmedetomidine or a salt thereof with a water-soluble polymer. As a result, it was found that if a water-containing patch containing a large amount of water was obtained, a patch having excellent transdermal absorbability of dexmedetomidine and less skin irritation was obtained, and the present invention was completed.
- the present invention provides the following [1] to [8].
- a water-containing patch containing dexmedetomidine or a salt thereof and a water-soluble polymer [2] The water-containing type patch according to [1], wherein the content of the water-soluble polymer is 5 to 25% by mass in the plaster and the content of water is 25 to 70% by mass in the plaster. [3] The water-containing patch according to [1] or [2], wherein the water-soluble polymer contains polyacrylic acid or a salt thereof and carboxymethylcellulose or a salt thereof. [4] The water-containing patch according to any one of [1] to [3], wherein the pH of the paste is 6 to 7.
- the patch of the present invention is excellent in transdermal absorbability of dexmedetomidine and has little skin irritation, so that the effect of dexmedetomidine as a sedative can be stably obtained for a long time.
- the active ingredient of the patch of the present invention is dexmedetomidine or a salt thereof.
- Dexmedetomidine has the chemical name (+)-(S) -4- [1- (2,3-dimethylphenyl) ethyl] -1H-imidazole and is an agonist of the central ⁇ 2 adrenergic receptor.
- Examples of the salt of dexmedetomidine include acid addition salts, and inorganic acid addition salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid are preferable, and hydrochloride is particularly preferable.
- the content of dexmedetomidine or a salt thereof is 0.1 to 10% by mass, and further 0.1 to 7% by mass in the plaster of the patch from the viewpoint of transdermal absorbability, skin irritation, and formulation stability. Preferably there is.
- water-soluble polymer used in the patch of the present invention examples include water-soluble natural polymers such as gelatin, starch and agar; water-soluble polymers such as carboxymethyl cellulose or a salt thereof, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and ethylcellulose.
- water-soluble synthetic polymers such as copolymers.
- gelatin polyacrylic acid, polyacrylic acid salt, partially neutralized polyacrylic acid, cross-linked polyacrylic acid, carboxyvinyl polymer, carboxymethylcellulose or a salt thereof, hydroxypropylcellulose, and hydroxypropylmethylcellulose are preferable.
- water-soluble polymers can be used alone or in combination of two or more.
- polyacrylic acid or a salt thereof and carboxymethylcellulose or a salt thereof are used in combination from the viewpoint of transdermal absorbability, skin irritation and formulation stability of dexmedetomidine or a salt thereof. Further preferred.
- polyacrylic acid or a salt thereof and carboxymethylcellulose or a salt thereof a combination of a partially neutralized polyacrylic acid, sodium polyacrylate and sodium carboxymethylcellulose is more preferable.
- the content mass ratio (PA: CMC) of polyacrylic acid or its salt (PA) to carboxymethylcellulose or its salt (CMC) is preferably 1: 5 to 5: 1, and 1: 3 to 3: 1. Is more preferable, and 1: 2 to 2: 1 is even more preferable.
- PA polyacrylic acid partially neutralized product
- PANa sodium polyacrylate
- CMCNa sodium carboxymethylcellulose
- the content of the water-soluble polymer is preferably 5 to 25% by mass and more preferably 5 to 20% by mass in the plaster of the patch from the viewpoint of transdermal absorbability, skin irritation and formulation stability.
- the patch of the present invention is a hydrous patch, and it is important to contain a relatively large amount of water from the viewpoint of transdermal absorbability and skin irritation of dexmedetomidine or a salt thereof.
- the water content is 25 to 70% by mass, further 30 to 60% by mass, and further 30 to 55% by mass in the plaster of the patch from the viewpoint of transdermal absorbability, skin irritation and formulation stability. Is preferred.
- the patch of the present invention preferably contains one or more selected from polyhydric alcohols and fatty acid ester absorption accelerators from the viewpoint of improving the transdermal absorbability of dexmedetomidine or a salt thereof.
- polyhydric alcohol examples include glycols such as ethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol (molecular weight 1000 or less), polypropylene glycol (molecular weight 1000 or less); glycerin, diglycerin, polyglycerin Glycerins such as sugar alcohols such as sorbitol and maltitol. These polyhydric alcohols can be used alone or in combination of two or more. Of these, propylene glycol, glycerin and sugar alcohol are preferred. In particular, propylene glycol is preferably added in terms of preventing crystallization of dexmedetomidine or a salt thereof in the plaster.
- glycols such as ethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol (molecular weight 1000 or less), polypropylene glycol (molecular weight 1000 or less); glycerin, diglycerin,
- the content of the polyhydric alcohol is 10 to 60% by mass, further 20 to 55% by mass, and further 25 to 55% by mass in the plaster in the patch from the viewpoint of transdermal absorbability and skin irritation. preferable.
- Fatty acid ester-based absorption accelerators include higher fatty acid alkyl esters such as isopropyl myristate, isopropyl palmitate, butyl stearate, butyl myristate (preferably C 8 -C 24 fatty acid C 1 -C 6 alkyl ester); sebacic acid Dibasic fatty acid dialkyl esters (preferably dibasic acid di-C 1 -C 6 alkyl esters) such as diisopropyl, diethyl sebacate, and diisopropyl adipate; propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, monocapryl Examples thereof include polyhydric alcohol fatty acid esters (preferably polyhydric alcohol C 8 -C 24 fatty acid esters) such as glyceryl acid, tetraglyceryl monocaprylate, and sorbitan hexacaprylate.
- higher fatty acid alkyl esters such as iso
- higher fatty acid alkyl esters, polyhydric alcohol fatty acid esters, and dibasic fatty acid dialkyl esters are preferable, and higher fatty acid alkyl esters and polyhydric alcohol fatty acid esters are particularly preferable.
- a desired analgesic level is maintained.
- isopropyl myristate and propylene glycol monocaprylate are preferable.
- These fatty acid ester absorption promoters may not be added, but are 0.01 to 15% by mass, further 0.1 to 10% by mass, and further 0.1 to 5% by mass in the plaster of the patch. It is preferable to contain.
- polyhydric alcohols and the above-mentioned absorption promoters it is preferable to use one or two or more selected from propylene glycol, glycerin, sugar alcohol, higher fatty acid alkyl ester and polyhydric alcohol fatty acid ester.
- Glycerin, sugar alcohol, isopropyl myristate and propylene glycol monocaprylate are preferably used alone or in combination.
- glycerin sugar alcohol, higher fatty acid alkyl ester, polyhydric alcohol fatty acid ester, and propylene glycol in combination.
- sorbitol is particularly preferable as the sugar alcohol.
- higher fatty acid alkyl ester isopropyl myristate is particularly preferable.
- polyhydric alcohol fatty acid ester propylene glycol monocaprylate is particularly preferable.
- the long-term storage stability of the patch is improved.
- examples thereof include C 8 to C 18 higher alcohols such as alcohols; polyoxyethylene alkyl ethers, alkyl sulfates, N-methyl-2-pyrrolidone and the like.
- the patch of the present invention may contain a crosslinking agent, a pH adjuster, a chelating agent, a surfactant, and other additives.
- the crosslinking agent is a component that forms a gel by crosslinking a water-soluble polymer, and an aluminum compound is preferable.
- the aluminum compound include aluminum hydroxide, aluminum chloride, synthetic aluminum silicate, dry aluminum hydroxide gel, alumina magnesium hydroxide, aluminum sulfate, and dihydroxyaluminum aminoacetate.
- the content of the cross-linking agent is preferably 0.001 to 1% by mass, more preferably 0.01 to 1% by mass in the plaster of the patch from the viewpoint of transdermal absorbability and formulation stability.
- the pH adjuster lactic acid, tartaric acid, citric acid, acetic acid and salts thereof are used.
- the content of the pH adjuster is preferably 0.001 to 1% by mass, more preferably 0.01 to 1% by mass in the plaster of the patch.
- the paste pH of the hydrous patch is 6-7.
- chelating agents examples include sodium polyphosphate such as sodium edetate (EDTA), glucono delta lactone, and sodium metaphosphate.
- the content of the chelating agent is preferably 0.001 to 1% by mass, more preferably 0.01 to 1% by mass in the plaster of the patch.
- surfactant examples include polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether and the like. These surfactants need not be added, but are preferably contained in the plaster of the patch at 0.01 to 5% by mass, and more preferably 0.01 to 3% by mass.
- additives include acrylic copolymers (methacrylic acid / acrylic acid / n-butyl copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer), preservatives, antioxidants, stabilizers, excipients (Kaolin, silicic anhydride, titanium oxide, talc, etc.), flavoring agents, coloring agents, oil components (crotamiton, castor oil) and the like.
- acrylic copolymers methacrylic acid / acrylic acid / n-butyl copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer
- preservatives antioxidants
- stabilizers excipients
- excipients Keratibility, silicic anhydride, titanium oxide, talc, etc.
- flavoring agents coloring agents
- oil components crotamiton, castor oil
- the water-containing type patch of the present invention is usually produced by applying a paste containing the above-mentioned components on a support and attaching a coating film (release sheet) to the surface of the paste.
- a water-impermeable support is preferable, and a nonwoven fabric laminated on a polyolefin film such as polyethylene terephthalate, polyethylene, or polypropylene is preferable.
- a polyolefin film such as a polyethylene film and a polypropylene film, and a polyester film are used. These films may be subjected to silicon peeling treatment, discharge corona treatment and embossing treatment.
- the coating amount of the plaster is preferably 40 to 400 g / m 2, more preferably 50 to 300 g / m 2 .
- the patch of the present invention has a size of 10 to 100 cm 2 and is preferably a square, a circle, an ellipse or the like.
- the water-containing type patch of the present invention is a patch, a certain amount of dexmedetomidine or a salt thereof can be easily administered without smearing hands during the application.
- it contains an effective amount of dexmedetomidine or a salt thereof, has low skin irritation and good transdermal absorbability, so it can be continuously applied by reapplying it 1 to 3 times a day without intravenous administration. Effects can be expected, the desired sedation level can be reached quickly, and a stable sedation can be obtained.
- the stable sedation means that a sedation level with a score of 0 to -2 can be obtained when evaluated according to RASS (Richmond Agitation-Sedation Scale).
- the percutaneous absorption rate of the hydrous patch of the present invention is such that the skin permeation rate of dexmedetomidine hydrochloride is 3.40 ⁇ g / h cm 2 / hr or more, and preferably further 4.45 ⁇ g / cm 2 / hr or more. Further, the percutaneous absorption rate in humans is preferably 0.2 ⁇ g / kg / hr or more.
- Test Example 1 ⁇ Skin Permeation Test> Test Method Abdominal excised skin of a hairless mouse (7 weeks old, male) was attached to a horizontal diffusion cell with a water jacket. A predetermined patch was applied to the stratum corneum side, and 2.5 mL of pH 6.8 phosphate buffer was applied to the receiver side. The water jacket was kept at a constant temperature by circulating hot water of 32 ° C. While stirring the receiver-side solution with a stirrer, 0.5 mL of the receiver-side solution was collected over time to obtain a sample solution. Immediately after collecting the receiver solution, 0.5 mL of a new phosphate buffer solution was added.
- the amount of dexmedetomidine hydrochloride in the sample solution was quantified by high performance liquid chromatography (HPLC), and the cumulative permeation amount of dexmedetomidine hydrochloride from the preparation to the receiver side was determined. Further, the permeation rate of dexmedetomidine hydrochloride 6 to 9 hours after the start of the test was calculated from the change over time in the cumulative permeation amount of dexmedetomidine hydrochloride. The results are shown in Tables 4-6. Furthermore, Tables 4 to 6 list the pH of each preparation. The pH of the preparation was measured with a pH meter after 1 part by weight of the plaster was dissolved in 9 parts by weight of purified water by heating and the solution reached 20-25 ° C.
- dexmedetomidine or a salt thereof improves percutaneous absorbability by incorporating a water-soluble polymer into a water-containing patch with a high water content.
- transdermal absorbability is improved by blending polyhydric alcohol (propylene glycol, glycerin, sorbitol) and / or higher fatty acid alkyl ester (isopropyl myristate). It was also confirmed that the patches of Examples 1 to 10 had no skin irritation and were stable.
- Test Example 2 Skin penetration rate and long-term stability
- the hydrous patches of Examples 1, 6, 8, 9, and 10 were produced and evaluated for long-term storage stability (presence of crystal precipitation and stability of dexmedetomidine hydrochloride).
- the water-containing patch of Example 1 was also subjected to a skin permeation test after long-term storage in the same manner as in Test Example 1.
- Crystal confirmation method After the preparation (10 cm 2 ) is packaged in an aluminum bag and stored at room temperature for 8 months, the presence or absence of dexmedetomidine hydrochloride crystals in the preparation is visually confirmed and evaluated according to the following score.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
Description
従って、本発明の課題は、デクスメデトミジンの吸収性が十分に高く、かつ皮膚刺激性の少ない貼付剤を提供することにある。
〔2〕水溶性高分子の含有量が膏体中に5~25質量%であり、水の含有量が膏体中に25~70質量%である〔1〕記載の含水型貼付剤。
〔3〕水溶性高分子が、ポリアクリル酸又はその塩とカルボキシメチルセルロース又はその塩とを含むものである〔1〕又は〔2〕記載の含水型貼付剤。
〔4〕膏体のpHが6~7である、〔1〕~〔3〕のいずれかに記載の含水型貼付剤。
〔5〕さらに、多価アルコール及び脂肪酸エステル系吸収促進剤から選ばれる1種又は2種以上を含有する〔1〕~〔4〕のいずれかに記載の含水型貼付剤。
〔6〕さらに、多価アルコール、高級脂肪酸アルキルエステル、二塩基酸ジアルキルエステル及び多価アルコール脂肪酸エステルから選ばれる1種又は2種以上を含有する〔1〕~〔4〕のいずれかに記載の含水型貼付剤。
〔7〕さらに、プロピレングリコール、グリセリン、糖アルコール、ミリスチン酸イソプロピル及びモノカプリル酸プロピレングリコールから選ばれる1種又は2種以上を含有する〔1〕~〔4〕のいずれかに記載の含水型貼付剤。
〔8〕該貼付剤が鎮静剤である、〔1〕~〔7〕のいずれかに記載の含水型貼付剤。
多価アルコールの含有量は、経皮吸収性、皮膚刺激性の点から、貼付剤中の膏体に10~60質量%、さらに20~55質量%、さらに25~55質量%含有するのが好ましい。
このうち、高級脂肪酸アルキルエステル、多価アルコール脂肪酸エステル、二塩基脂肪酸ジアルキルエステルが好ましく、特に高級脂肪酸アルキルエステル、多価アルコール脂肪酸エステルが好ましく、さらに高い吸収促進効果に加えて所望の鎮痛レベルを維持しやすい点でミリスチン酸イソプロピル、モノカプリル酸プロピレングリコールが好ましい。
これらの脂肪酸エステル系吸収促進剤は、添加しなくても良いが、貼付剤の膏体中に0.01~15質量%、さらに0.1~10質量%、さらに0.1~5質量%含有するのが好ましい。
具体的には、グリセリンと糖アルコールを組み合わせるのが好ましく、さらに、グリセリン、糖アルコール、高級脂肪酸アルキルエステルを組み合わせるのが好ましく、さらにグリセリン、糖アルコール、高級脂肪酸アルキルエステル、プロピレングリコールを組み合わせて用いるのが好ましく、さらにグリセリン、糖アルコール、高級脂肪酸アルキルエステル、多価アルコール脂肪酸エステル、プロピレングリコールを組み合わせて用いるのが好ましい。ここで糖アルコールとしては、ソルビトールが特に好ましい。また、高級脂肪酸アルキルエステルとしては、ミリスチン酸イソプロピルが特に好ましい。多価アルコール脂肪酸エステルとしては、モノカプリル酸プロピレングリコールが特に好ましい。ここで多価アルコール脂肪酸エステルを配合すると、貼付剤の長期保存安定性が向上する。
架橋剤の含有量は、経皮吸収性及び製剤安定性の点から、貼付剤の膏体中に0.001~1質量%、さらに0.01~1質量%含有するのが好ましい。
尚、安定した鎮静作用は、RASS(Richmond Agitation-Sedation Scale)に準じて評価するとき、スコア0~-2の鎮静レベルを得ることが出来ることをいう。
安定した鎮静効果を速やかに得るために、本発明の含水型貼付剤の経皮吸収速度は、ヘアレスマウス腹部摘出皮膚を用いて評価するとき、デクスメデトミジン塩酸塩の皮膚透過速度が3.40μg/cm2/hr以上、さらに4.45μg/cm2/hr以上であるのが好ましい。また、ヒトでの経皮吸収速度は0.2μg/kg/hr以上であるのが好ましい。
表1~表3の処方に従い、含水型貼付剤を製造した。
(2)膏体を支持体上に、膏体の塗布量が160g/m2となるように展延し、さらに粘着面をシリコン剥離処理したポリエステルフィルムで覆った後、所定の大きさに裁断し、デクスメデトミジンの含水型貼付剤を得た。
(3)支持体にはポリエステルフィルムにポリエステル不織布を積層したものを用いた。
試験方法
ヘアレスマウス(7週齢、オス)の腹部摘出皮膚を、ウォータージャケット付き横型拡散セルに装着した。角質層側には所定の貼付剤を適用し、レシーバー側にはpH6.8のリン酸緩衝液2.5mLを適用した。ウォータージャケットには32℃の温水を循環させ一定温度に保った。レシーバー側溶液を、攪拌子で攪拌しながら経時的にレシーバー側の液0.5mLを採取し試料溶液とした。尚、レシーバー液採取後直ちに、新しいリン酸緩衝液0.5mL補液をした。試料溶液中のデクスメデトミジン塩酸塩の量は高速液体クロマトグラフィー(HPLC)で定量し、製剤からレシーバー側へのデクスメデトミジン塩酸塩の累積透過量を求めた。また、デクスメデトミジン塩酸塩の累積透過量の経時変化から、試験開始後6~9時間目のデクスメデトミジン塩酸塩の透過速度を計算した。結果を表4~表6に示す。
さらに、表4~表6には、各製剤のpHを記載した。製剤のpHは膏体1質量部を精製水9質量部に加温溶解し、溶解液が20~25℃になった後pHメーターを用いて測定した。
実施例1、6、8、9及び10の含水型貼付剤を製造し、長期保存安定性(結晶の析出の有無及びデクスメデトミジン塩酸塩の安定性)を評価した。また、実施例1の含水型貼付剤については、試験例1と同様にして長期保存後の皮膚透過試験も行った。
製剤(10cm2)をアルミ袋に包装し、室温で8ヶ月保管した後の、製剤中のデクスメデトミジン塩酸塩の結晶の有無を目視確認し、下記のスコアにしたがって評価する。
製剤1枚(10cm2、デクスメデトミジン塩酸塩として160mg)をアルミ袋に包装し、60℃で3週間保管した。保管後の製剤中のデクスメデトミジン塩酸塩をメタノールで加熱還流抽出した。抽出液中のデクスメデトミジン塩酸塩の量を高速液体クロマトグラフィー(HPLC)で定量し、イニシャル値に対する、保管後のデクスメデトミジン塩酸塩の残存率(%)を求めた。
Claims (8)
- デクスメデトミジン又はその塩及び水溶性高分子を含有する含水型貼付剤。
- 水溶性高分子の含有量が膏体中に5~25質量%であり、水の含有量が膏体中に25~70質量%である請求項1記載の含水型貼付剤。
- 水溶性高分子が、ポリアクリル酸又はその塩とカルボキシメチルセルロース又はその塩とを含むものである請求項1又は2記載の含水型貼付剤。
- 膏体のpHが6~7である、請求項1~3のいずれか1項に記載の含水型貼付剤。
- さらに、多価アルコール及び脂肪酸エステル系吸収促進剤から選ばれる1種又は2種以上を含有する請求項1~4のいずれか1項に記載の含水型貼付剤。
- さらに、多価アルコール、高級脂肪酸アルキルエステル、二塩基酸ジアルキルエステル及び多価アルコール脂肪酸エステルから選ばれる1種又は2種以上を含有する請求項1~4のいずれか1項に記載の含水型貼付剤。
- さらに、プロピレングリコール、グリセリン、糖アルコール、ミリスチン酸イソプロピル及びモノカプリル酸プロピレングリコールから選ばれる1種又は2種以上を含有する請求項1~4のいずれか1項に記載の含水型貼付剤。
- 該貼付剤が鎮静剤である、請求項1~7のいずれか1項に記載の含水型貼付剤。
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JP2019534288A (ja) * | 2016-10-31 | 2019-11-28 | テイコク ファーマ ユーエスエー インコーポレーテッド | デクスメデトミジン経皮送達デバイスを用いた疼痛管理の方法 |
JP2020066592A (ja) * | 2018-10-24 | 2020-04-30 | 帝國製薬株式会社 | 水性貼付剤 |
US10772871B2 (en) | 2013-10-07 | 2020-09-15 | Teikoku Pharma Usa, Inc. | Dexmedetomidine transdermal delivery devices and methods for using the same |
JPWO2020241605A1 (ja) * | 2019-05-27 | 2020-12-03 | ||
US10874642B2 (en) | 2013-10-07 | 2020-12-29 | Teikoku Pharma Usa, Inc. | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
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TW201609200A (zh) | 2016-03-16 |
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JP6469587B2 (ja) | 2019-02-13 |
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