WO2017026386A1 - 貼付剤 - Google Patents
貼付剤 Download PDFInfo
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- WO2017026386A1 WO2017026386A1 PCT/JP2016/073068 JP2016073068W WO2017026386A1 WO 2017026386 A1 WO2017026386 A1 WO 2017026386A1 JP 2016073068 W JP2016073068 W JP 2016073068W WO 2017026386 A1 WO2017026386 A1 WO 2017026386A1
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- styrene
- weight
- isoprene
- block copolymer
- mixture
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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
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
- A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
Definitions
- the present invention relates to a patch that can be used for local anesthesia.
- a local anesthetic preparation which is a kind of transdermal absorption preparation, is widely used for the purpose of reducing pain caused during medical procedures such as venous needle puncture and minor skin surgery.
- a lidocaine tape (Penless (registered trademark)) is commercially available in Japan.
- This tape preparation is a preparation (60% concentration) containing lidocaine crystals in an acrylic adhesive, and according to the attached document of this tape preparation, when used for pain relief at the time of puncture of an indwelling needle, It is described that it is applied to the site for about 30 minutes.
- an application time of 100 minutes is required on average (Non-patent Document 1). Due to problems, there is a demand for shortening the onset time of the anesthetic effect.
- a percutaneous absorption preparation for local anesthesia a mixture containing two kinds of local anesthetics such as a mixture of lidocaine and prilocaine and a mixture of lidocaine and tetracaine has been proposed and administered as a single agent. It is known that it exhibits an excellent local anesthetic effect compared with the case where it was done.
- a cream preparation (Emra cream) obtained by emulsifying a mixture of lidocaine and prilocaine in an oil-in-water type is commercially available, and a higher anesthetic action has been confirmed than a cream preparation containing lidocaine alone or prilocaine alone (patented) Reference 1).
- Patent Document 2 discloses a prescription using a cross-linked acrylic pressure-sensitive adhesive, and an immediate effect of anesthesia is recognized as compared with a prior lidocaine tape (Penless (registered trademark)).
- Patent Document 2 discloses a prescription using a cross-linked acrylic pressure-sensitive adhesive, and an immediate effect of anesthesia is recognized as compared with a prior lidocaine tape (Penless (registered trademark)).
- the skin permeability (in ⁇ ⁇ vitro test) of a drug that is an index of drug efficacy does not reach that of the previous cream, and is about twice that of Penless (registered trademark). It became clear that.
- Patent Document 3 a water-soluble patch composed of a mixture of lidocaine and prilocaine, a mixture of lidocaine and tetracaine, etc. has been proposed (Patent Document 3).
- Patent Document 3 There are problems such as low stickiness compared to water-insoluble tapes and easy removal from the skin.
- Shingles is a disease accompanied by pain caused by the eruption caused by chickenpox and herpes zoster virus infection, which occurs along the skin segment of the nerve control area. Most herpes zoster patients lose their pain as the rash is healed, but some patients transition to postherpetic neuralgia where the pain remains even after the rash has healed. Postherpetic neuralgia is caused by damage or degeneration of peripheral nerve fibers caused by infected chickenpox and herpes zoster virus, and is classified as neuropathic pain. Since unbearable pain symptoms such as electric shock and allodynia that are rarely experienced in daily life occur continuously, the QOL of postherpetic neuralgia patients is significantly reduced.
- Liderderm Lidocaine 5% Pap formulation, Endo Pharmaceuticals, Inc.
- the therapeutic effect of Lidoderm is not necessarily high (nonpatent literature 2), the patch which has a higher post-herpetic neuralgia therapeutic effect is calculated
- An object of the present invention is to provide a patch having a practical adhesive force and a cohesive force as a pharmaceutical product and exhibiting a fast-acting anesthetic action.
- the present inventors have included, as a drug, "lidocaine and other local anesthetics" in a rubber-based adhesive layer having a tackifier of 10% by weight or less. It was clarified that a patch with extremely excellent drug skin permeability could be realized. Usually, when a rubber-based pressure-sensitive adhesive is used, it is difficult to realize a preparation having sufficient adhesive strength as a pharmaceutical if the content of the tackifier is small. Surprisingly, however, the present inventors have found that "mixture of lidocaine and other local anesthetics" contributes to maintaining and improving the adhesive strength, and thereby the adhesive strength and cohesive strength of the preparation are sufficiently high. A fast-acting local anesthetic preparation was completed. That is, the gist of the invention is as follows.
- a patch containing and containing 10% by weight or less of a tackifier in the adhesive layer (2) The patch according to (1), wherein the liquid paraffin is 0.5 to 2.6 times the weight of the rubber adhesive.
- the patch according to (1), wherein the liquid paraffin is 0.6 to 2.0 times by weight with respect to the rubber-based adhesive.
- the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 15% by weight or more and 60% by weight or less. Patch.
- the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 20% by weight or more and 50% by weight or less. Patch.
- the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 60% by weight or more and 95% by weight or less. Patch.
- the content of the styrene-isoprene-styrene copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer is 70% by weight or more and 90% by weight or less. Patch.
- the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block.
- the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block.
- the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, the weight of liquid paraffin relative to the weight of the rubber adhesive is y, and the styrene-isoprene-styrene block. 0.48e 0.022x ⁇ y ⁇ e 0.021x , where x is the weight percent of the styrene-isoprene-styrene copolymer in the mixture of the copolymer and styrene-isoprene block copolymer and x is the base of the natural logarithm.
- the patch according to (1) which is represented by an exponential function of
- a method for local anesthesia comprising the step of applying the patch according to any one of (1) to (29) to an affected area of a patient requiring local anesthesia.
- a method for analgesia or pain treatment comprising the step of applying the patch according to any one of (1) to (29) to an affected area of a patient in need of analgesia or pain treatment.
- the method according to (31), wherein the pain is neuropathic pain.
- the method according to (31), wherein the pain is postherpetic neuralgia.
- FIG. 1 shows the measurement results of the cumulative drug skin permeation amount in the evaluation of in vitro rat skin permeability.
- FIG. 2 shows the measurement results of the drug skin permeation rate in the evaluation of in vitro rat skin permeability.
- the patch of the present invention preferably has a support and at least one pressure-sensitive adhesive layer provided on the support.
- the pressure-sensitive adhesive layer in the present invention contains (a) a mixture of lidocaine and another local anesthetic as a drug, and further contains (b) a rubber-based pressure-sensitive adhesive and (c) liquid paraffin.
- the lidocaine that can be used in the present invention may be free lidocaine or a pharmaceutically acceptable salt of lidocaine.
- the pharmaceutically acceptable salt is not particularly limited, and may be an inorganic salt or an organic salt.
- inorganic salts of lidocaine include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.
- organic acid salts include formate, acetate, trifluoroacetate, propionic acid. Salt, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, methanesulfonate and the like can be mentioned.
- free lidocaine or lidocaine hydrochloride is preferably used, and from the viewpoint of dispersibility in the pressure-sensitive adhesive, it is particularly preferable to use free lidocaine.
- Other local anesthetics that can be used in the present invention have a basic skeleton composed of an aromatic ring, an alkyl chain, and an amino group, and have a structure in which the aromatic ring and the alkyl chain are connected by an ester bond or an amide bond. If it is, it will not specifically limit.
- Examples of such other local anesthetics include prilocaine, tetracaine, benzocaine, bupivacaine, mepivacaine and the like.
- the other local anesthetics described above exist in a solid state at room temperature, but a local anesthetic agent that decreases in melting point and is liquefied at room temperature when mixed with solid lidocaine can be preferably used.
- Preferred as a mixture of lidocaine and other local anesthetics is a mixture of lidocaine-prilocaine, a mixture of lidocaine-tetracaine, a mixture of lidocaine-benzocaine, more preferably a mixture of lidocaine-prilocaine, a mixture of lidocaine-tetracaine. is there.
- the lidocaine content in the mixture of lidocaine and other local anesthetics is preferably 30% by weight to 70% by weight, more preferably 40% by weight to 60% by weight, and even more preferably 45% by weight to 55% by weight. Most preferably, the weight ratio of the mixture of lidocaine and other local anesthetic is 50/50.
- the lidocaine content in the lidocaine-prilocaine mixture is preferably 30% by weight to 70% by weight, more preferably 40% by weight to 60% by weight, and even more preferably 45% by weight to 55% by weight.
- the prilocaine that can be used in the present invention may be a free prilocaine or a pharmaceutically acceptable prilocaine salt.
- the pharmaceutically acceptable salt is not particularly limited, and examples thereof include the salts described for lidocaine. From the viewpoint of easy availability, it is preferable to use free-form prilocaine or prilocaine hydrochloride, and from the viewpoint of dispersibility in the pressure-sensitive adhesive, it is particularly preferable to use free-form prilocaine.
- the tetracaine that can be used in the present invention may be free tetracaine or a pharmaceutically acceptable tetracaine salt.
- the pharmaceutically acceptable salt is not particularly limited, and examples thereof include the salts described for lidocaine. From the viewpoint of easy availability, it is preferable to use free tetracaine or tetracaine hydrochloride, and it is particularly preferable to use free tetracaine from the viewpoint of dispersibility in the pressure-sensitive adhesive.
- the benzocaine that can be used in the present invention may be a free benzocaine or a pharmaceutically acceptable salt of benzocaine.
- the pharmaceutically acceptable salt is not particularly limited, and examples thereof include the salts described for lidocaine. From the viewpoint of easy availability, it is preferable to use free benzocaine or benzocaine hydrochloride, and it is particularly preferable to use free benzocaine from the viewpoint of dispersibility in an adhesive.
- the blending amount of lidocaine and other local anesthetics is preferably 5% by weight or more based on the total amount of the pressure-sensitive adhesive component in order to obtain sufficient medicinal effects. More preferably, it is 7 weight% or more.
- the upper limit is preferably less than 20% by weight. More preferably, it is less than 15 weight%, More preferably, it is less than 12 weight%, Most preferably, it is 10 weight% or less.
- adheresive component means a component constituting the adhesive layer.
- the total amount of the pressure-sensitive adhesive component refers to the whole preparation excluding the support and the liner.
- the blending amount of lidocaine and another local anesthetic is preferably 5% by weight or more and less than 20% by weight, more preferably 5% by weight or more and less than 15% by weight, and particularly preferably 5% by weight.
- % By weight or more and less than 12% by weight, most preferably 7% by weight or more and less than 12% by weight.
- Rubber-based adhesive The rubber-based adhesive that can be used in the patch of the present invention is not particularly limited, and examples thereof include styrene-based block copolymers, polyisobutylene, natural rubber, butyl rubber, polyisoprene, and polybutene. Can be mentioned.
- a styrene block copolymer is particularly preferable from the viewpoint of satisfying sufficient drug release properties, cohesiveness and adhesiveness, which are the objects of the present invention.
- Specific examples of styrene block copolymers include styrene-butadiene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene block copolymers, styrene-isoprene-styrene block copolymers, and styrene.
- ethylene / butylene represents a copolymer block of ethylene and butylene
- ethylene / propylene represents a copolymer block of ethylene and propylene
- styrene block copolymers one or two selected from the group consisting of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are preferably used from the viewpoint of availability. Particularly preferred is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.
- the adhesiveness to the skin tends to decrease, and when it is high, the shape maintaining property of the adhesive layer is decreased. In some cases, such as a tendency to become.
- the upper limit of the styrene-isoprene-styrene block copolymer is preferably 95% by weight or less, and 90% by weight. % Or less, 80% by weight or less, 60% by weight or less, or 50% by weight or less.
- the lower limit is preferably 10% by weight or more, 15% by weight or more, 20% by weight or more, 50% by weight or more, 60% by weight or more, or 70% by weight or more.
- the content of the styrene-isoprene-styrene block copolymer in the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene copolymer is 10% by weight or more and 90% by weight or less. More preferably 15 to 60% by weight, most preferably 20 to 50% by weight.
- the styrene-isoprene-styrene block copolymer content in the mixture of styrene-isoprene-styrene block copolymer and styrene-isoprene copolymer is preferably 50 wt% or more and 95 wt%. Or less, more preferably 60% by weight or more and 95% by weight or less, and most preferably 70% by weight or more and 90% by weight or less.
- the styrene content in the styrene-isoprene-styrene block copolymer and styrene-isoprene copolymer is not particularly limited, but the lower limit of the styrene content is preferably 5% by weight or more, particularly preferably 10% by weight or more.
- the upper limit of the styrene content is preferably 50% by weight or less, more preferably 30% by weight or less, and most preferably 20% by weight or less.
- the styrene content in the styrene-isoprene-styrene block copolymer and styrene-isoprene copolymer is preferably 5% by weight to 50% by weight, more preferably 10% by weight to 30% by weight, among the above. Or less, and most preferably 10 wt% or more and 20 wt% or less.
- styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer a copolymer produced by a known method can be used, respectively, or a commercially available product satisfying the above characteristics can be used. wear. Also, a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer is commercially available.
- the content of the rubber-based pressure-sensitive adhesive is not particularly limited as long as it does not impair the sufficient drug release property, cohesiveness, and pressure-sensitive adhesiveness, which are the objects of the present invention.
- the lower limit of the rubber-based pressure-sensitive adhesive is preferably 15% by weight or more, more preferably 25% by weight or more, particularly preferably 30% by weight or more, based on the total amount of the pressure-sensitive adhesive component. Most preferably, it is 35 weight% or more.
- the upper limit of the rubber-based pressure-sensitive adhesive is preferably 60% by weight or less, more preferably 55% by weight or less, and most preferably 50% by weight or less based on the total amount of the pressure-sensitive adhesive component.
- the content of the rubber-based pressure-sensitive adhesive is preferably in the range of 30% by weight to 55% by weight, and more preferably in the range of 35% by weight to 50% by weight.
- the liquid paraffin content used in the present invention is not particularly limited as long as it does not impair the effects of the present invention such as the pressure-sensitive adhesive and drug release properties. It is preferably 0.5 times or more, 0.6 times or more, 0.7 times or more, 0.8 times or more, 0.9 times or more, or 1. It may be 0 times or more, 1.5 times or more, 2.0 or more times, 2.3 or more times, or 2.6 or more times.
- the upper limit of the liquid paraffin is preferably 7.0 times by weight or less, 6.0 times by weight or less, 5.5 times by weight or less, and 5.0 weight by weight with respect to the rubber-based adhesive. 2 times or less, 3.0 times by weight or less, 2.6 times by weight or less, 2.0 times by weight or less, 1.7 times by weight or less, 1.6 times by weight or less, It may be 1.5 times or less.
- the liquid paraffin content is preferably 0.5 to 2.6 times by weight, more preferably 0.6 to 2.0 times by weight with respect to the rubber-based pressure-sensitive adhesive. Or less, more preferably 0.7 to 1.7 times, particularly preferably 0.7 to 1.6 times, most preferably 0.7 to 1 times. .5 weight times or less.
- the liquid paraffin content is preferably 2.0 times by weight or more and 6.0 times by weight or less, more preferably 2.3 times by weight or more and 5.5 times by weight with respect to the rubber-based pressure-sensitive adhesive.
- the weight is not more than twice the weight, and more preferably not less than 2.6 times and not more than 5.0 times.
- the lower limit of the liquid paraffin content relative to the total amount of the pressure-sensitive adhesive component is preferably 30% by weight or more, more preferably 35% by weight or more, and most preferably It is 40% by weight or more.
- the upper limit of the liquid paraffin content with respect to the total amount of the pressure-sensitive adhesive component is preferably 70% by weight or less, more preferably 65% by weight or less, and particularly preferably 60% by weight or less with respect to the total amount of the pressure-sensitive adhesive component. Yes, most preferably 55% by weight or less.
- the liquid paraffin content relative to the total amount of the pressure-sensitive adhesive component is preferably 30% by weight to 65% by weight, more preferably 35% by weight to 60% by weight, and most preferably 40%. % By weight or more and 55% by weight or less.
- the rubber adhesive is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer
- the weight of liquid paraffin relative to the weight of the rubber adhesive is y
- the styrene-isoprene-styrene block is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer
- 0.48e 0.022x -0.4 ⁇ y ⁇ e 0.021x +0.4 is preferably represented by an exponential function, more preferably 0.48e 0.022x ⁇ 0.2 ⁇ y ⁇ e 0.021x +0.2. More preferably, it is represented by an exponential function of 48e 0.022x ⁇ y ⁇ e 0.021x .
- the patches of Examples 1 to 17 described later satisfy an exponential function of 0.48e 0.022x ⁇ y ⁇ e 0.021x .
- Tackifier A tackifier may be added to the pressure-sensitive adhesive layer.
- “Tackifier” is a tackifier that is generally used in the field of patches. For example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene-phenol resin, alicyclic saturation A hydrocarbon resin etc. are mentioned. Since the release of the drug decreases when a large amount of the tackifier is added, the content of the tackifier is preferably 10% by weight or less, more preferably 5% by weight or less, more preferably 5% by weight or less. Most preferably not.
- (E) Other components
- (e1) surfactant, (e2) esters, (e3) alcohols, (e4) antioxidant, (e5) filler, etc. Can be included.
- surfactant examples include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.
- Nonionic surfactants include, for example, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, glycerol monooleate, glycerol monostearate, decaglyceryl monolaurate, hexaglycerin polyricinoleate, polyoxyethylene (9) Lauryl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene (4,2) lauryl ether, polyoxyethylene (5) nonylphenyl ether, polyoxyethylene (7,5) nonylphenyl ether, polyoxy Ethylene (10) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether, polyoxyethylene (10) octylphenyl ether, polyoxyethylene (10) oleylamine, Riokishi (5) oleylamine, polyoxy (5) oleic acid amide, polyoxyethylene (2) monolaurate, monoglyceride stearate, polyoxyethylene castor
- anionic surfactant examples include sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, sodium cetyl sulfate, sodium lauroyl sarcosine, di-2-ethylhexyl sodium sulfosuccinate, polyoxyethylene (10) lauryl ether phosphorus
- examples thereof include sodium acid, polyoxyethylene (4) sodium lauryl ether phosphate, polyoxyethylene (5) sodium cetyl ether phosphate, polyoxyethylene (6) sodium ether oil phosphate and the like.
- cationic surfactant examples include stearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride and the like.
- amphoteric surfactant examples include lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, and the like.
- lauroyl diethanolamide can also be used.
- nonionic surfactants are preferable, and sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, glycerol monooleate, and glycerol monostearate are more preferable.
- Surfactants may be used alone or in combination of two or more.
- the content of the surfactant is not particularly limited, and the surfactant can be contained within a range in which high skin permeability and sufficient cohesive force and adhesive strength as a patch can be maintained. Preferably it is 5 weight% or less with respect to the adhesive agent whole quantity, More preferably, it is 3 weight% or less.
- a surfactant When a surfactant is used, it can be replaced with a rubber adhesive and / or liquid paraffin constituting the adhesive layer.
- esters examples include isopropyl isostearate, methyl stearate, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl olive oleate, myristyl myristate, cetyl isoctanate, myristine Fatty acids such as octyldodecyl acid, diisopropyl adipate, cetyl palmitate, retinol palmitate, methyl laurate, methyl myristate, methyl caproate, methyl palmitate, isopropyl myristate, isopropyl palmitate, diethyl sebacate, diethyl adipate Monohydric alcohol esters such as glyceryl monooleate, glyceryl monocaprate, glyceryl dioleate, propylene glycol monostearate And fatty acid
- Esters may be used alone or in combination of two or more.
- the ester content is not particularly limited, and the ester can be contained in a range where high skin permeability and sufficient cohesive force and adhesive strength can be maintained as a patch.
- the amount is preferably 55% by weight or less, more preferably 45% by weight or less, still more preferably 35% by weight or less, particularly preferably 25% by weight or less, and most preferably 15% by weight or less based on the total amount of the pressure-sensitive adhesive component. % By weight or less.
- esters When esters are used, they can be substituted for the rubber-based pressure-sensitive adhesive and / or liquid paraffin constituting the pressure-sensitive adhesive layer. From the viewpoint of ensuring the cohesiveness of the preparation, it is preferable to replace it with liquid paraffin. All of the liquid paraffin may be replaced with esters, or a part thereof may be replaced.
- Alcohols examples include aliphatic alcohols such as ethanol, isopropanol, lauryl alcohol, 2-octyldodecanol, 2-hexyldecanol, ethylene glycol, propylene glycol, 1,3-butanediol, and glycerin, such as salicylic acid.
- Aromatic alcohols such as glycol and benzyl alcohol can be mentioned.
- Preferred are aliphatic alcohols, and more preferred are lauryl alcohol, 2-octyldodecanol, 2-hexyldecanol, propylene glycol, 1,3-butanediol and the like. Alcohols may be used alone or in combination of two or more.
- the content of alcohols is not particularly limited, and can be contained within a range in which high skin permeability and sufficient cohesive force and adhesive strength as a patch can be maintained.
- the amount is preferably 55% by weight or less, more preferably 45% by weight or less, still more preferably 35% by weight or less, particularly preferably 25% by weight or less, and most preferably 15% by weight or less based on the total amount of the pressure-sensitive adhesive component. % By weight or less.
- antioxidants examples include dibutylhydroxyl toluene, 4-dioxyphenol, EDTA-2Na and the like. Of these, dibutylhydroxyl toluene is preferable. Antioxidants may be used alone or in admixture of two or more.
- the content of the antioxidant is not particularly limited, and can be contained within a range where high skin permeability and sufficient cohesive force and adhesive strength can be maintained as a patch.
- the amount is preferably 10% by weight or less, more preferably 5% by weight or less, and most preferably 2% by weight or less based on the total amount of the pressure-sensitive adhesive component.
- an antioxidant When used, it can be replaced with a rubber-based pressure-sensitive adhesive and / or liquid paraffin constituting the pressure-sensitive adhesive layer.
- a filler In order to control the softness
- the filler include kaolin, titanium oxide, talc, calcium carbonate, magnesium carbonate, silicate, silicic acid, aluminum hydrate, barium sulfate, and calcium sulfate.
- the fillers may be used alone or in combination of two or more.
- the content of the filler is not particularly limited, and can be contained within a range where high skin permeability and sufficient cohesive force and adhesive strength as a patch can be maintained. Among them, the amount is preferably 10% by weight or less, more preferably 5% by weight or less, and most preferably 2% by weight or less based on the total amount of the pressure-sensitive adhesive component.
- the support used in the present invention is not particularly limited, and those generally used can be used.
- a support made of a polyester material is preferable.
- Nonwoven fabrics, woven fabrics, and knitted fabrics are preferable in terms of stretchability, and transparent films are preferable in terms of usability.
- the patch of the present invention can be prepared using the pressure-sensitive adhesive composition described below.
- the pressure-sensitive adhesive composition can be prepared by mixing and stirring the components of the pressure-sensitive adhesive. That is, a pressure-sensitive adhesive composition can be obtained by mixing and stirring (a) lidocaine and other local anesthetics, (b) a rubber-based pressure-sensitive adhesive, and (c) liquid paraffin. For example, (a) to (c) may be sequentially added, or (b) and (c) may be mixed in advance, and then (a) may be mixed.
- the heating temperature is preferably 50 ° C. or higher, more preferably 70 ° C. or higher, and most preferably 90 ° C. or higher.
- the upper limit of the temperature is preferably 170 ° C. or lower, and more preferably 150 ° C. or lower.
- the heating temperature is preferably 40 ° C. or higher and 170 ° C. or lower, more preferably 70 ° C. or higher and 170 ° C. or lower, particularly preferably 70 ° C. or higher and 150 ° C. or lower, and most preferably 90 ° C. or higher and 150 ° C. or lower. It is as follows.
- a solvent can be further added to the pressure-sensitive adhesive component to prepare a pressure-sensitive adhesive solution, which can be used for preparation of a patch.
- the solvent that can be used in the present invention is not particularly limited as long as it can dissolve the adhesive component, but toluene, hexane, heptane, ethyl acetate, isopropyl acetate, n-propyl acetate and N-methyl-
- An organic solvent such as 2-pyrrolidone can be preferably used.
- toluene, hexane, heptane, ethyl acetate, and isopropyl acetate can be preferably used, and toluene is particularly preferable.
- uniform mixing can be performed without any particular heating, but heating may be performed in order to achieve uniform and rapid mixing.
- the heating temperature is preferably 30 ° C or higher, more preferably 40 ° C or higher. If the temperature is too high, the solvent tends to volatilize, and therefore, the temperature is preferably 120 ° C. or lower, more preferably 100 ° C. or lower, and most preferably 90 ° C. or lower.
- the heating temperature is preferably 30 ° C. or higher and 120 ° C. or lower among the above, more preferably 40 ° C. or higher and 100 ° C. or lower, and most preferably 40 ° C. or higher and 90 ° C. or lower.
- a method for producing the patch of the present invention a method similar to that of the pressure-sensitive adhesive tape can be employed.
- a hot-melt coating method in which the pressure-sensitive adhesive composition is heated and melted and coated on a support, or a pressure-sensitive adhesive composition.
- a solvent coating method in which a pressure-sensitive adhesive solution obtained by dissolving a product in an organic solvent is coated on a support and dried.
- the pressure-sensitive adhesive composition is once coated on the release paper, and then peeled off from the release paper and transferred and adhered to the support, or the coated surface without peeling is supported on the support. It is also possible to use a method of transferring and adhering to the substrate.
- the release paper is used for the purpose of protecting the pressure-sensitive adhesive layer, and can be appropriately selected according to the purpose in consideration of easy release from the pressure-sensitive adhesive layer, air permeability, water permeability and flexibility.
- a film made of a polymer material such as polyethylene, polypropylene and polyester is used, and the film surface can be treated with silicon or fluorocarbon in order to enhance the peelability.
- the pressure-sensitive adhesive layer may be a single layer or a multilayer of two or more layers.
- at least one layer contains a mixture of lidocaine and other local anesthetics. It only has to be.
- the thickness of the pressure-sensitive adhesive layer is preferably 20 ⁇ m or more and 2000 ⁇ m or less, more preferably 50 ⁇ m or more and 1500 ⁇ m or less, particularly preferably 100 ⁇ m or more and 1000 ⁇ m or less, and most preferably 120 ⁇ m or more and 600 ⁇ m or less.
- the patch of the present invention can be used as a transdermally absorbable preparation. Since the patch of the present invention contains lidocaine and other local anesthetics, it can be used as a local anesthetic. Further, since the patch of the present invention contains lidocaine and other local anesthetics, it can also be used as an analgesic or pain therapeutic agent, preferably as a neuropathic pain therapeutic agent, for example, It can be used as a therapeutic agent for neuralgia after herpes zoster.
- lidocaine and prilocaine that permeated the rat skin in the buffer were quantified by HPLC.
- the total permeation amount of lidocaine and prilocaine is defined as the permeation amount of drug. How many times the permeation amount of the drug when using the existing lidocaine patch (manufactured by Yutoku Yakuhin Kogyo Co., Ltd., product name: Yupatch (R) tape) The amount was evaluated.
- Cohesive force The cohesive force of the patch was evaluated from the following viewpoints. ⁇ : No adhesive residue was observed. ⁇ : Slightly insufficient cohesion, but no problem. X: Adhesive residue, loss of shape, etc. were observed, and lack of cohesive strength was remarkable.
- Adhesiveness The adhesiveness of the patch was evaluated from the following viewpoints. ⁇ : High adhesiveness compared to the existing local anesthetic patch (lidocaine tape). ⁇ : Adhesiveness slightly lower than that of the existing local anesthetic patch (lidocaine tape). X: Peeling was remarkable.
- lidocaine and 0.75 g of prilocaine were sequentially added and mixed and stirred at the same temperature for 15 hours or more to obtain a uniform pressure-sensitive adhesive solution.
- the pressure-sensitive adhesive solution was applied to an 80 ⁇ m-thick polyethylene terephthalate (PET) film whose surface was silicon-treated using an applicator, and toluene was removed by drying in a hot air oven at 60 ° C. for 120 minutes or more. After forming an adhesive layer having a thickness of ⁇ 450 ⁇ m, a PET film having a thickness of 60 ⁇ m was laminated on the surface of the adhesive layer to prepare a desired patch (transdermal absorption preparation). The components of the adhesive and the weight ratio (%) are shown in Table 1.
- Example 2 A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed at the ratio shown in Table 1.
- a tackifier 0.20 g of lidocaine and 0.20 g of prilocaine were sequentially added and mixed and stirred at the same temperature for 15 hours or more to obtain a uniform adhesive solution.
- the pressure-sensitive adhesive solution was applied to an 80 ⁇ m-thick polyethylene terephthalate (PET) film whose surface was silicon-treated using an applicator, and toluene was removed by drying in a hot air oven at 60 ° C. for 120 minutes or more. After forming an adhesive layer having a thickness of ⁇ 450 ⁇ m, a PET film having a thickness of 60 ⁇ m was laminated on the surface of the adhesive layer to prepare a target patch.
- the components of the adhesive and the weight ratio (%) are shown in Table 1.
- SIS-E Weight mixing ratio of styrene-isoprene-styrene block copolymer / s
- All of the patches of Examples 1 to 4 showed good cohesive strength and adhesiveness.
- the skin permeability of the patches of Examples 1 to 4 was extremely high, 3.4 to 8.6 times the skin permeability of the existing lidocaine tape.
- a PET film having a thickness of 60 ⁇ m was laminated on the surface of the adhesive layer to prepare a target patch.
- the components of the pressure-sensitive adhesive and the weight ratio (%) are shown in Table 4.
- Example 5 A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 5.
- Examples 7 to 17 A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 6.
- Example 18 A patch was prepared in the same manner as in Example 1 except that lidocaine, prilocaine, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 7.
- Example 20 A patch was prepared in the same manner as in Example 1 except that the drug substance, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 8.
- the patches of Examples 20 and 21 in which the type of the drug substance was changed showed cohesive strength and adhesiveness that had no practical problems, and had sufficiently high skin permeability.
- Example 22 A patch was prepared in the same manner as in Example 1 except that the drug substance, SIS copolymer, and liquid paraffin were mixed in the types and ratios shown in Table 9.
- the patches of Examples 22 and 23 in which the mixing ratio of the drug substance was changed showed good cohesive strength and adhesiveness and sufficiently high skin permeability.
- Example 1 Evaluation of in vitro rat skin permeability
- the patch prepared in Example 2 and the existing lidocaine patch Liderderm (manufactured by Teikoku Pharmaceutical Co., Ltd.) were punched into a circle with a diameter of 1.3 cm, and HWY / Slc It was affixed on the abdominal extract skin of a male male hairless rat (5 weeks old).
- the skin was set in a vertical diffusion cell, and the test was started with a transdermal absorption test automatic sampling device (manufactured by Cosmedy).
- the analgesic action was evaluated using the Chung model which is a neuropathic pain model.
- the rat Chung model was prepared according to the method of Kim and Chung (Pain 50 (3), 355-363 (1992)). Specifically, 6-week-old Crl: CD (SD) male rats (8 rats per group) were used to expose the L5 and L6 spinal nerves under isoflurane anesthesia, and the central side was silk thread (5-0). ) Strongly ligated.
- the pain threshold value of the patch application group of Example 2 was significantly higher than that of the Lidoderm administration group immediately after peeling the patch for 12 hours and after 2 hours of peeling. Furthermore, it was revealed that the analgesic action lasts for a longer time than Lidoderm. That is, in the treatment of postherpetic neuralgia, the patch of the present invention has a significantly higher therapeutic effect than Lidoderm, and thus is useful as a preparation for treating superficial and localized neuropathic pain. I understood that.
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Abstract
Description
(2) 流動パラフィンがゴム系粘着剤に対して0.5重量倍以上2.6重量倍以下である(1)に記載の貼付剤。
(3) 流動パラフィンがゴム系粘着剤に対して0.6重量倍以上2.0重量倍以下である(1)に記載の貼付剤。
(4) 流動パラフィンがゴム系粘着剤に対して0.7重量倍以上1.5重量倍以下である(1)に記載の貼付剤。
(5) ゴム系粘着剤が、スチレン系ブロック共重合体である(1)~(4)のいずれか一に記載の貼付剤。
(6) ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物である(5)に記載の貼付剤。
(7) スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が15重量%以上60重量%以下である(6)に記載の貼付剤。
(8) スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が20重量%以上50重量%以下である(6)に記載の貼付剤。
(10) 流動パラフィンがゴム系粘着剤に対して2.3重量倍以上5.5重量倍以下である(1)に記載の貼付剤。
(11) 流動パラフィンがゴム系粘着剤に対して2.6重量倍以上5.0重量倍以下である(1)に記載の貼付剤。
(12) ゴム系粘着剤が、スチレン系ブロック共重合体である(9)~(11)の何れか一に記載の貼付剤。
(13) ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物である(12)に記載の貼付剤。
(14) スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が60重量%以上95重量%以下である(13)に記載の貼付剤。
(15) スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が70重量%以上90重量%以下である(13)に記載の貼付剤。
(17) ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物であり、ゴム系粘着剤の重量に対する流動パラフィンの重量をy、スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の重量%をx、自然対数の底をeとした時、0.48e0.022x-0.2≦y≦e0.021x+0.2の指数関数で表される(1)に記載の貼付剤。
(18) ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物であり、ゴム系粘着剤の重量に対する流動パラフィンの重量をy、スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の重量%をx、自然対数の底をeとした時、0.48e0.022x≦y≦e0.021xの指数関数で表される(1)に記載の貼付剤。
(20) リドカインと他の局所麻酔薬の混合物中のリドカイン含量が30重量%以上70重量%以下である(19)記載の貼付剤。
(21) リドカインと他の局所麻酔薬の混合物中のリドカイン含量が40重量%以上60重量%以下である(19)記載の貼付剤。
(22) リドカインと他の局所麻酔薬の混合物中のリドカイン含量が45重量%以上55重量%以下である(19)記載の貼付剤。
(23) リドカインと他の局所麻酔薬の混合物の重量比が50/50である(19)に記載の貼付剤。
(24) リドカインと他の局所麻酔薬の混合物の含有量が、粘着剤成分全量に対して5重量%以上15%重量未満である(19)~(23)のいずれか一に記載の貼付剤。
(25) 粘着層中に粘着付与剤を含まない(1)~(24)のいずれか一に記載の貼付剤。
(27) 鎮痛剤又は疼痛治療剤として使用する、(1)~(26)のいずれか一に記載の貼付剤。
(28) 神経障害性疼痛治療剤として使用する、(27)に記載の貼付剤。
(29) 帯状疱疹後神経痛治療剤として使用する、(27)に記載の貼付剤。
(31) (1)~(29)のいずれか一に記載の貼付剤を、鎮痛又は疼痛治療を必要とする患者の患部に貼り付ける工程を含む、鎮痛又は疼痛治療のための方法。
(32) 疼痛が、神経障害性疼痛である、(31)に記載の方法。
(33) 疼痛が、帯状疱疹後神経痛である、(31)に記載の方法。
(35) 鎮痛剤又は疼痛治療剤の製造のための、(1)~(29)のいずれか一に記載の貼付剤の使用。
(36) 疼痛治療剤が、神経障害性疼痛治療剤である、(35)に記載の使用。
(37) 疼痛治療剤が、帯状疱疹後神経痛治療剤である、(35)に記載の使用。
本発明に用いることのできるリドカインは、フリー体のリドカインであっても、薬学的に許容されるリドカインの塩であってもよい。薬学的に許容される塩は特に限定されず、無機塩であっても有機塩であってもよい。リドカインの無機塩としては、例えば、塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩などが挙げられ、有機酸塩としては、ギ酸塩、酢酸塩、トリフルオロ酢酸塩、プロピオン酸塩、乳酸塩、酒石酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、クエン酸塩、マロン酸塩、メタンスルホン酸塩等が挙げられる。入手のしやすさの観点から、フリー体のリドカイン又はリドカイン塩酸塩を用いるのが好ましく、粘着剤への分散性の観点から、フリー体のリドカインを用いることが特に好ましい。
本発明の貼付剤に用いることができるゴム系粘着剤は特に限定されないが、例えば、スチレン系ブロック共重合体、ポリイソブチレン、天然ゴム、ブチルゴム、ポリイソプレン及びポリブテン等が挙げられる。
本発明で用いることのできる流動パラフィンは、特に限定されないが、市販のものを好適に用いることができる。
なお、後記する実施例1~17の貼付剤は、0.48e0.022x≦y≦e0.021xの指数関数を充足する。
上記粘着剤層中には粘着付与剤を添加しても良い。「粘着付与剤」とは、通常貼付剤の分野で汎用される粘着付与剤であり、例えばロジン系樹脂、ポリテルペン系樹脂、クマロン-インデン樹脂、石油系樹脂、テルペン-フェノール樹脂、脂環族飽和炭化水素樹脂等が挙げられる。粘着付与剤を大量に添加すると薬物の放出性が低下することから、粘着付与剤の含量は粘着剤成分全量に対し10重量%以下が好ましく、5重量%以下がさらに好ましく、粘着付与剤を全く含まないのが最も好ましい。
本発明の貼付剤には、必要に応じて、(e1)界面活性剤、(e2)エステル類、(e3)アルコール類、(e4)抗酸化剤、(e5)充填剤等を含有させることが出きる。
界面活性剤としては、非イオン系界面活性剤、アニオン系界面活性剤、カチオン系界面活性剤、両性界面活性剤を挙げることができる。
エステル類としては、例えば、イソステアリン酸イソプロピル、ステアリン酸メチル、ステアリン酸ブチル、ミリスチン酸ブチル、リノール酸エチル、リノール酸イソプロピル、オリーブオレイン酸エチル、ミリスチン酸ミリスチル、イソクタン酸セチル、ミリスチン酸オクチルドデシル、アジピン酸ジイソプロピル、パルミチン酸セチル、パルミチン酸レチノール、ラウリン酸メチル、ミリスチン酸メチル、カプロン酸メチル、パルミチン酸メチル、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、セバシン酸ジエチル、アジピン酸ジエチル等の脂肪酸一価アルコールエステル、例えば、モノオレイン酸グリセリン、モノカプリン酸グリセリン、ジオレイン酸グリセリン、モノステアリン酸プロピレングリコール、デカオレイン酸デカグリセリン等の脂肪酸多価アルコールエステル、例えば、モノステアリン酸ソルビタン、モノラウリン酸ソルビタン、モノオレイン酸ソルビタン、トリオレイン酸ソルビタン、パルミチン酸アスコルビル等の脂肪酸環状多価アルコールエステル、例えば、乳酸セチル、乳酸ミリスチル等の乳酸エステル、例えば、炭酸プロピレン等の炭酸エステル、例えばN-メチル-2-ピロリドン等のピロリドン誘導体である。
エステル類の含有量は特に限定されず、高い皮膚透過性および貼付剤として十分な凝集力、粘着力が維持できる範囲で含有させることができる。中でも好ましくは粘着剤成分全量に対し55重量%以下であり、より好ましくは45重量%以下であり、さらに好ましくは35重量%以下であり、特に好ましくは25重量%以下であり、最も好ましくは15重量%以下である。
アルコール類としては、例えばエタノール、イソプロパノール、ラウリルアルコール、2-オクチルドデカノール、2-ヘキシルデカノール、エチレングリコール、プロピレングリコール、1,3-ブタンジオール、グリセリン等の脂肪族アルコール、例えばサリチル酸グリコール、ベンジルアルコール等の芳香族アルコールを挙げることができる。好ましいものとしては、脂肪族アルコールであり、さらに好ましくは、ラウリルアルコール、2-オクチルドデカノール、2-ヘキシルデカノール、プロピレングリコール、1,3-ブタンジオール等を挙げることができる。アルコール類は、単独でも2種以上混合して使用してもよい。
抗酸化剤としては、例えばジブチルヒドロキシルトルエン、4-ジオキシフェノール、EDTA-2Na等が挙げることができる。中でも好ましくはジブチルヒドロキシルトルエンである。抗酸化剤は、単独でも2種以上混合して使用してもよい。
粘着剤層の柔軟性を制御するために充填剤を含有させることができる。
充填剤としては、例えば、カオリン、酸化チタン、タルク、炭酸カルシウム、炭酸マグネシウム、珪酸塩、珪酸、アルミニウム水和物、硫酸バリウム、硫酸カルシウム等が挙げられる。充填剤は、単独でも2種以上混合して使用してもよい。
本発明で用いる支持体とは、特に限定されるものではなく一般的に用いられるものが使用できる。例えば、ポリエステルフィルム、ポリエチレンフィルム、ポリプロピレンフィルム、ポリ塩化ビニルフィルム、ポリカーボネートフィルム、ポリウレタンフィルム及びセロハンフィルムなどのプラスチックフィルム、発泡体、ポリエステル繊維、ポリエチレン繊維及びポリプロピレン繊維などからなる不織布、織布及び編布などの布基剤、これらの積層体などが挙げられる。これらの中でもポリエステルからなる材質の支持体が好ましく、伸縮性の点では不織布、織布及び編布が、使用性の面では透明性を有するフィルムが好ましい。
本発明の貼付剤は、下記に説明する粘着剤組成物を用いて調製することができる。粘着剤組成物は、粘着剤の成分を混合撹拌することにより調製することができる。即ち、(a)リドカイン及び他の局所麻酔薬、(b)ゴム系粘着剤、(c)流動パラフィンを混合撹拌することにより粘着剤組成物を得ることができる。混合する順序は、例えば前記(a)~前記(c)を逐次投入してもよいし、前記(b)と前記(c)をあらかじめ混合した後、前記(a)を混合してもよい。
本発明の貼付剤の作製方法は、粘着剤層を支持体上に塗工する方法を好適に用いることができる。
本発明の貼付剤は、経皮吸収製剤として使用することができる。
本発明の貼付剤は、リドカインと他の局所麻酔薬を含有することから、局所麻酔剤として使用することができる。
また本発明の貼付剤は、リドカインと他の局所麻酔薬を含有することから、鎮痛剤又は疼痛治療剤として使用することもでき、好ましくは神経障害性疼痛治療剤として使用することができ、例えば、帯状疱疹後神経痛治療剤として使用することができる。
除毛した雄性Wister系ラット(5週齢)の腹部抽出皮膚を縦型フランツ拡散セル(ビードレックス社製、型番:TP-8s)に装着し、実施例および比較例で作製した貼付剤を直径1.3cmの円形に打ち抜き、フランツ拡散セルのラット皮膚上に貼付した。バッファーとして5%エタノール含有0.01mol/Lリン酸緩衝生理食塩水(pH 7.2~7.4)を用い、バッファー温度32℃で試験を行った。試験開始後、1時間後にバッファーの一部を抜き取り、バッファー中のラット皮膚を透過してきたリドカイン量およびプリロカイン量をHPLCにより定量した。リドカインとプリロカインの透過量の和を薬物透過量とし、既存のリドカイン貼付剤(祐徳薬品工業株式会社製、品名:ユーパッチ(R)テープ)を用いた場合の薬物透過量に対し、何倍の透過量であるかを評価した。
以下の視点で、貼付剤の凝集力を評価した。
○:糊残りは認められなかった。
△:やや凝集力が不足しているが、問題のない範囲であった。
×:糊残り、型崩れ等が認められ、凝集力不足が顕著であった。
以下の視点で、貼付剤の粘着性を評価した。
○:既存の局所麻酔貼付剤(リドカインテープ剤)と比較して高い粘着性を示した。
△:既存の局所麻酔貼付剤(リドカインテープ剤)よりやや低い粘着性であった。
×:剥がれが顕著であった。
5.40gのスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレン共重合体の混合物(スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=50/50)と、8.10gの流動パラフィンに9.45gのトルエンを投入し混合した後、内温50℃で120分間加熱撹拌して完全に溶解させて、20~30℃に冷却した。次に、0.75gのリドカインと0.75gのプリロカインを順次添加し、同温で15時間以上混合攪拌し、均一な粘着剤溶液を得た。粘着剤溶液を、表面をシリコン処理された80μm厚のポリエチレンテレフタラート(PET)フィルムにアプリケーターを用いて塗工し、トルエンを熱風オーブンで60℃で120分以上乾燥除去し、乾燥後厚みが350~450μm厚の粘着剤層を形成した後、粘着剤層の表面に、60μm厚のPETフィルムをラミネートし、目的の貼付剤(経皮吸収製剤)を作製した。粘着剤の成分とその重量比(%)を表1に示した。
リドカイン、プリロカイン、SIS共重合体、流動パラフィンを、表1に示した比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
1.60gのスチレン-イソプレン-スチレンブロック共重合体(スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=50/50)と、1.60gの流動パラフィンに2.24gのトルエンを投入し混合した後、内温50℃で120分間加熱撹拌して完全に溶解させて、20~30℃に冷却した。次に、0.40gの粘着付与剤、0.20gのリドカインと0.20gのプリロカインを順次添加し、同温で15時間以上混合攪拌し、均一な粘着剤溶液を得た。粘着剤溶液を、表面をシリコン処理された80μm厚のポリエチレンテレフタラート(PET)フィルムにアプリケーターを用いて塗工し、トルエンを熱風オーブンで60℃で120分以上乾燥除去し、乾燥後厚みが350~450μm厚の粘着剤層を形成した後、粘着剤層の表面に、60μm厚のPETフィルムをラミネートし、目的の貼付剤を作製した。粘着剤の成分とその重量比(%)を表1に示した。
SIS-A:スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=80/20
SIS-B:スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=50/50
SIS-C:スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=22/78
SIS-D:スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=88/12
SIS-E:スチレン-イソプレン-スチレンブロック共重合体/スチレン-イソプレン共重合体の重量混合比=74/26
リドカイン、SIS共重合体、流動パラフィンを、表2に示した比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
リドカイン、プリロカイン、SIS共重合体、流動パラフィンを、表3に示した比率で混合した以外は、実施例4と同様の方法で貼付剤を作製した。
7.76gの架橋型アクリル系共重合体(Durotak87-901A、44wt%溶液)に対して、0.20gのリドカインと0.20gのプリロカインを順次添加し、室温にて15時間混合攪拌し、均一な粘着剤溶液を得た。粘着剤溶液を、表面をシリコン処理された80μm厚のポリエチレンテレフタラート(PET)フィルムにアプリケーターを用いて塗工し、トルエンを熱風オーブンで60℃で120分以上乾燥除去し、乾燥後厚みが350~450μm厚の粘着剤層を形成した後、粘着剤層の表面に、60μm厚のPETフィルムをラミネートし、目的の貼付剤を作製した。粘着剤の成分とその重量比(%)を表4に示した。
リドカイン、プリロカイン、SIS共重合体、流動パラフィンを、表5に示した種類及び比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
リドカイン、プリロカイン、SIS共重合体、流動パラフィンを、表6に示した種類及び比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
リドカイン、プリロカイン、SIS共重合体、流動パラフィンを、表7に示した種類及び比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
原薬、SIS共重合体、流動パラフィンを、表8に示した種類及び比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
原薬、SIS共重合体、流動パラフィンを、表9に示した種類及び比率で混合した以外は、実施例1と同様の方法で貼付剤を作製した。
(試験例1)in vitroラット皮膚透過性の評価
実施例2で作製した貼付剤および既存のリドカイン貼付剤であるLidoderm(帝國製薬株式会社製)を直径1.3cmの円形に打ち抜き、HWY/Slc系雄性ヘアレスラット(5週齢)の腹部抽出皮膚上に貼付した。その皮膚を垂直型拡散セルにセットし、経皮吸収試験自動サンプリング装置(コスメディ社製)にて試験を開始した。バッファーとして0.01mol/Lリン酸緩衝生理食塩水(pH 7.2~7.4)を用い、バッファー温度32℃とした。試験開始後、3、6、9、12、18、24時間後にバッファーの一部を抜き取り、バッファー中のラット皮膚を透過してきたリドカイン量およびプリロカイン量をHPLCにより定量した。リドカインとプリロカインの透過量の和を薬物透過量とし、Lidodermを用いた場合の薬物透過量に対し、何倍の透過量であるかを評価した。累積薬物皮膚透過量の測定結果を図1に示し、薬物皮膚透過速度の測定結果を図2に示す。
神経障害性疼痛モデルであるChungモデルを用いて、鎮痛作用の評価を行った。ラットChungモデルは、Kim及びChungの方法(Pain 50(3),355-363(1992))に準じて作製した。具体的には、6週齢のCrl:CD(SD)系雄性ラット(1群8匹)を用い、イソフルラン麻酔下にてL5及びL6脊髄神経を露出させ、その中枢側を絹糸(5-0)で強く結紮した。傷口を縫合して1週間飼育した後、対照製剤として既存のリドカイン貼付剤であるLidoderm、被験物質として実施例2の貼付剤の疼痛閾値をダイナミックプランター・エステシオメーター(ウゴバジル社製)を用いて測定した。貼付剤は左肢足裏に12時間貼付し、測定時間は製剤剥離直後(0時間)及び2時間後とした。疼痛閾値は各群平均値±標準誤差で表し、試験結果を表10に示す。なお、有意差の検定はLidoderm投与群と実施例2製剤投与群との多群間比較においてDunnettの多重比較検定を用いて行い、P<0.05で有意差ありとした(表10中の*はP<0.05)。
Claims (28)
- リドカインと他の局所麻酔薬の混合物を5重量%以上20重量%未満で含有する粘着層から形成された貼付剤であって、前記粘着層中に少なくともゴム系粘着剤および流動パラフィンを含有し、且つ前記粘着層中の粘着付与剤の含量が10重量%以下である貼付剤。
- 流動パラフィンがゴム系粘着剤に対して0.5重量倍以上2.6重量倍以下である請求項1に記載の貼付剤。
- 流動パラフィンがゴム系粘着剤に対して0.6重量倍以上2.0重量倍以下である請求項1に記載の貼付剤。
- 流動パラフィンがゴム系粘着剤に対して0.7重量倍以上1.5重量倍以下である請求項1に記載の貼付剤。
- ゴム系粘着剤が、スチレン系ブロック共重合体である請求項1~4のいずれか一項に記載の貼付剤。
- ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物である請求項5に記載の貼付剤。
- スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が15重量%以上60重量%以下である請求項6に記載の貼付剤。
- スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が20重量%以上50重量%以下である請求項6に記載の貼付剤。
- 流動パラフィンがゴム系粘着剤に対して2.0重量倍以上6.0重量倍以下である請求項1に記載の貼付剤。
- 流動パラフィンがゴム系粘着剤に対して2.3重量倍以上5.5重量倍以下である請求項1に記載の貼付剤。
- 流動パラフィンがゴム系粘着剤に対して2.6重量倍以上5.0重量倍以下である請求項1に記載の貼付剤。
- ゴム系粘着剤が、スチレン系ブロック共重合体である請求項9~11の何れか一項に記載の貼付剤。
- ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物である請求項12に記載の貼付剤。
- スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が60重量%以上95重量%以下である請求項13に記載の貼付剤。
- スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の含量が70重量%以上90重量%以下である請求項13に記載の貼付剤。
- ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物であり、ゴム系粘着剤の重量に対する流動パラフィンの重量をy、スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の重量%をx、自然対数の底をeとした時、0.48e0.022x-0.4≦y≦e0.021x+0.4の指数関数で表される請求項1に記載の貼付剤。
- ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物であり、ゴム系粘着剤の重量に対する流動パラフィンの重量をy、スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の重量%をx、自然対数の底をeとした時、0.48e0.022x-0.2≦y≦e0.021x+0.2の指数関数で表される請求項1に記載の貼付剤。
- ゴム系粘着剤がスチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物であり、ゴム系粘着剤の重量に対する流動パラフィンの重量をy、スチレン-イソプレン-スチレンブロック共重合体とスチレン-イソプレンブロック共重合体の混合物中のスチレン-イソプレン-スチレン共重合体の重量%をx、自然対数の底をeとした時、0.48e0.022x≦y≦e0.021xの指数関数で表される請求項1に記載の貼付剤。
- 他の局所麻酔薬がプリロカイン、テトラカインまたはベンゾカインである、請求項1~18の何れか一項に記載の貼付剤。
- リドカインと他の局所麻酔薬の混合物中のリドカイン含量が30重量%以上70重量%以下である請求項19記載の貼付剤。
- リドカインと他の局所麻酔薬の混合物中のリドカイン含量が40重量%以上60重量%以下である請求項19記載の貼付剤。
- リドカインと他の局所麻酔薬の混合物中のリドカイン含量が45重量%以上55重量%以下である請求項19記載の貼付剤。
- リドカインと他の局所麻酔薬の混合物の重量比が50/50である請求項19に記載の貼付剤。
- リドカインと他の局所麻酔薬の混合物の含有量が、粘着剤成分全量に対して5重量%以上15%重量未満である請求項19~23のいずれか一項に記載の貼付剤。
- 粘着層中に粘着付与剤を含まない請求項1~24のいずれか一項に記載の貼付剤。
- 局所麻酔剤として使用する、請求項1~25のいずれか一項に記載の貼付剤。
- 鎮痛剤又は疼痛治療剤として使用する、請求項1~26のいずれか一項に記載の貼付剤。
- 神経障害性疼痛治療剤として使用する、請求項27に記載の貼付剤。
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Also Published As
Publication number | Publication date |
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EP3332776A1 (en) | 2018-06-13 |
CN107921007A (zh) | 2018-04-17 |
US10525014B2 (en) | 2020-01-07 |
CN107921007B (zh) | 2021-09-24 |
US20180235902A1 (en) | 2018-08-23 |
EP3332776A4 (en) | 2019-03-20 |
JP6808628B2 (ja) | 2021-01-06 |
JPWO2017026386A1 (ja) | 2018-05-31 |
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