WO2009119673A1 - 経皮吸収製剤 - Google Patents
経皮吸収製剤 Download PDFInfo
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- WO2009119673A1 WO2009119673A1 PCT/JP2009/055965 JP2009055965W WO2009119673A1 WO 2009119673 A1 WO2009119673 A1 WO 2009119673A1 JP 2009055965 W JP2009055965 W JP 2009055965W WO 2009119673 A1 WO2009119673 A1 WO 2009119673A1
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- drug
- layer
- skin
- transdermally absorbable
- absorbable preparation
- Prior art date
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- 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
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a percutaneous absorption preparation capable of administering a drug to a living body efficiently and stably for a long period of time.
- percutaneous absorption preparations have attracted attention as preparations for administering drugs in vivo from the viewpoint of convenience of handling and management of dosage.
- a main dosage form of a transdermal absorption preparation a reservoir type percutaneous absorption preparation and a matrix type transdermal absorption preparation can be mentioned.
- Reservoir type percutaneous absorption preparation is a preparation comprising an adhesive layer, a release controlling membrane and a drug-containing layer in order from the skin side.
- Japanese Patent Application Laid-Open No. 2003-63955 discloses that drug release from an adhesive layer is improved by uniformly dispersing a fine inorganic salt or a water-soluble polymer in the adhesive layer of a reservoir-type transdermal absorption preparation. It has been reported. However, it is necessary for the reservoir type transdermal preparation to optimize the constitution of the adhesive layer in consideration of the nature of the drug, the release period, etc., and it takes time and labor. In addition, in the case of long-term administration, components such as drugs migrate to the adhesive layer over time and change the physical properties of the adhesive layer, significantly reducing the ability to adhere to the skin and release the drug. Is a problem.
- matrix-type transdermal absorption preparations are known as preparations having an adhesive layer containing a drug.
- the matrix-type transdermal absorption preparation is simpler to produce than the reservoir type.
- drug crystals are precipitated from the adhesive layer during the period of use, and as a result, the ability to adhere to the skin is impaired and the drug release ability is reduced It has been reported to do.
- the use amount of components such as drugs and absorption enhancers is limited in order to maintain the ability to adhere to the skin.
- transdermally absorbable preparation capable of administering a drug to a living body efficiently and stably for a long period is still desired.
- an object of the present invention is to provide a novel transdermally absorbable preparation capable of administering a drug to a living body efficiently and stably for a long period of time.
- the percutaneous absorption preparation in order from the skin side, a laminate comprising an outer membrane, a drug-containing layer, and a support layer;
- a transdermally absorbable preparation comprising a fixing means capable of fixing the laminate on the skin,
- the outer membrane is a drug-permeable polymer membrane that can control the release of the drug to the skin, and is characterized by being disposed on the skin contact surface of the laminate.
- a drug can be administered to a living body efficiently and stably for a long period of time.
- a to G are rear views of a preferred embodiment of the transdermally absorbable agent according to the present invention.
- A is a cross-sectional view of another preferred embodiment of the transdermally absorbable preparation according to the present invention in the production process.
- B is a rear view showing another preferred embodiment of the transdermally absorbable preparation according to the present invention.
- C is a cross-sectional view of another preferred embodiment of the transdermally absorbable preparation according to the present invention on the skin. It is a graph which shows the result of the in-vitro human skin permeation test using the transdermal absorption agent by this invention. It is a graph which shows the result of the sticking test using the transdermal absorption agent by this invention. It is a graph which shows the result of the elution test of the percutaneous absorption agent by this invention before and behind 40 degreeC and the storage period of 1 month.
- Transdermal absorption preparation is characterized in that, as described above, a drug-permeable polymer membrane is disposed on the skin contact surface drug.
- a transdermally absorbable preparation according to the present invention is excellent in drug retention stability and adhesion stability on the skin, can easily control the drug release rate, and can efficiently and stably administer the drug to a living body for a long period of time. Can be advantageously used.
- FIG. 1 is a cross-sectional view showing an embodiment of a transdermally absorbable preparation according to the present invention.
- the percutaneously absorbable preparation 1 has a laminate 6 including an outer membrane 3, a drug-containing layer 4, and a support layer 5 in order from the skin 2 side, and fixes the laminate 6 on the skin 2.
- Fixing means 7 that can be used.
- the outer membrane 3 is composed of a drug-permeable polymer membrane that can control the release of the drug to the skin 2, and is disposed on the skin contact surface 8 of the laminate 6.
- the fixing means 7 includes an adhesive layer 10 and a cover layer 9 in order from the skin side, and covers a portion other than the skin contact surface 8 of the laminate 6.
- the adhesive layer 10 adheres to the skin 2 at the peripheral edge / end of the skin contact surface 8 of the laminate 6 and fixes the transdermal absorption preparation 1 on the skin 2.
- Such an adhesive layer arrangement prevents the drug or other constituents from moving from the drug-containing layer to the adhesive layer and changes the physical properties of the adhesive layer over time. It is advantageous in securing the property.
- the back surface (skin contact surface) in the transdermally absorbable preparation is composed of an outer membrane 3 and an adhesive layer 10 disposed on the peripheral edge / end of the outer membrane 3, and the outer membrane 3 is arranged so as to be in direct contact with the skin 2.
- the adhesive layer is disposed not on the entire surface but on the peripheral edge / end of the outer membrane, and the skin irritation at the time of peeling of the percutaneous absorption preparation This is advantageous in reducing.
- the adhesive adhesive 11 may be applied to the skin contact surface of the outer membrane 3 as desired in order to assist the adhesion between the skin and the transdermally absorbable preparation.
- the arrangement of the auxiliary adhesive 11 can be appropriately changed as long as the outer membrane 3 can be in direct contact with the skin 2.
- Use of the auxiliary pressure-sensitive adhesive 13 in this manner is advantageous in further improving the stability of the transdermally absorbable preparation on the skin.
- a honeycomb-like structure in which the outer membrane 3 and the auxiliary adhesive 13 are alternately arranged on one side of the skin side of the transdermally absorbable preparation can be taken.
- Such embodiments are also encompassed.
- FIG. 3A to 3C schematically illustrate another preferred embodiment of the transdermally absorbable preparation according to the present invention, which has excellent adhesion stability to the skin and drug retention stability.
- FIG. 3A shows a state in which each layer is laminated in the production process of the transdermal absorption preparation according to the present invention.
- the transdermal absorption preparation 1 further includes an inner layer 12 between the laminate 6 and the fixing means 7.
- One characteristic is that The inner layer 12 extends outward from the peripheral edge of the support layer 5 on the fixing means 7.
- the inner layer 12 is configured in a ring shape and has an inner hole 13.
- FIG. 3B is a rear view (skin contact surface) of the transdermal absorption preparation 1 having the inner layer 12.
- FIG. 3C is a cross-sectional view on the skin of the transdermally absorbable preparation 1 having the inner layer 12.
- the inner layer 12 separates the drug-containing layer 4 and the adhesive layer 10.
- the adhesive layer 10 is in direct contact with the support layer 5 surrounded by the inner layer 12 through the hole 13 inside the inner layer 12, and fixes the laminate 6 from the inside. Such a configuration is advantageous for stably fixing the laminate on the skin during the application period.
- the support layer and the inner layer may be formed integrally or separately, but are preferably formed separately. From our experiments, configuring the support layer and the inner layer as separate bodies prevents the contact between the adhesive layer and the drug-containing layer, and the migration of the components of the drug-containing layer to the adhesive layer, It has been revealed that it is particularly advantageous in improving the storage stability of the drug and stabilizing the skin absorption of the drug during application.
- the drug content in the drug-containing layer can be set without considering the adhesion to the skin, unlike conventional reservoir-type preparations and matrix-type preparations.
- Such drug content is preferably set to a high dose in consideration of long-term administration.
- the amount of drug in the drug-containing layer is preferably 15% by weight or more, more preferably 15 to 50% by weight.
- the drug in the present invention can be appropriately determined in consideration of the target disease / patient condition and the like.
- the drug may be a free form or a salt.
- Specific examples of drugs include local anesthetics (bupivacaine hydrochloride, mepivacaine hydrochloride, etc.), antiepileptic drugs (sodium valproate, etc.), analgesics (morphine hydrochloride, fentanyl citrate, buprenorphine hydrochloride, etc.), antipyretic analgesics (sulpyrine, Antipyrine, acetaminophen), antipsychotic drugs (chlorpromazine hydrochloride, levomepromazine hydrochloride, clocapramine hydrochloride, etc.), depression drugs (imipramine hydrochloride, trazodone hydrochloride, fluvoxamine maleate, etc.), anxiolytic drugs (diazepam, alprazolam, tandospirone citrate
- the drug-containing layer can contain other materials such as a base in consideration of drug retention in addition to the drug.
- the base in the drug-containing layer can be appropriately determined according to the nature and content of the drug, but preferably a dialkylaminoalkyl (meth) acrylate, an alkyl (meth) acrylate, a hydroxyalkyl (meth) acrylate copolymer , (Meth) acrylic acid ester / vinyl ester copolymer, polyacrylate, polydimethylsiloxane, polyisobutylene, styrene / isoprene / styrene block copolymer, polyisoprene or a combination thereof, more preferably (meth) acrylic acid Dialkylaminoalkyl, alkyl (meth) acrylate, hydroxyalkyl (meth) acrylate, copolymer, (meth) acrylate, vinyl ester, or combinations thereof, more preferably (meth) Di-C
- the drug-containing layer may further contain an absorption enhancer.
- absorption enhancer can be appropriately selected depending on the nature of the drug, desired skin acceleration, etc., but is preferably alcohol, organic acid, organic acid ester, or a combination thereof, more preferably higher alcohol, A monohydric alcohol, a divalent to tetravalent carboxylic acid, a fatty acid, a fatty acid ester, or a combination thereof, more preferably a C8-18 higher alcohol, a divalent to trivalent alcohol, a C6 to 10 divalent to trivalent carboxylic acid, a C7 -19 fatty acids, sorbitan C7-19 fatty acid esters, C7-19 fatty acid C2-8 alkyl esters, or combinations thereof.
- the drug-permeable polymer membrane constituting the outer membrane is disposed directly on the skin, so that the properties of the adhesive layer and the like are considered unlike conventional reservoir-type preparations and matrix preparations.
- the drug release rate can be easily controlled by the type of the drug-permeable polymer membrane.
- the drug-permeable polymer membrane is not particularly limited as long as the release of the drug to the skin can be controlled, but is preferably a microporous membrane having pores that can permeate the drug.
- the pore diameter and pore density in the microporous membrane can be appropriately determined in consideration of the desired drug skin permeation rate and the like. For example, the average pore diameter of the pores is 0.03 to 0.25 ⁇ m.
- the area of one side of the skin of the drug permeable membrane can be appropriately determined in consideration of the desired drug release rate, the site of application, and the like.
- preferred examples of the material constituting the drug-permeable polymer membrane include EVA (ethylene-vinyl acetate copolymer), polyethylene, polypropylene, polyacrylonitrile, polymethyl methacrylate, or combinations thereof.
- EVA ethylene-vinyl acetate copolymer
- polyethylene polyethylene
- polypropylene polypropylene
- polyacrylonitrile polymethyl methacrylate
- the inner layer is suitably used to separate the adhesive layer of the fixing means from the drug-containing layer.
- an inner layer material is preferably a drug-impermeable material, and specifically includes polyethylene terephthalate, polyester, polyethylene, polyurethane, polyamide, polypropylene, and an ethylene-vinyl acetate copolymer. It is done.
- a support body layer can be comprised using the material similar to an inner layer.
- the constituent material of the cover layer may be stretchable or non-stretchable, but is preferably a drug-impermeable material.
- Specific examples of the material constituting the cover layer include woven fabric, non-woven fabric, PET (polyethylene terephthalate), polyurethane, polyester, polyethylene, or a composite material thereof.
- the adhesive layer is not particularly limited as long as it is a biocompatible material capable of bonding the skin and the transdermally absorbable preparation, but is preferably a pressure-sensitive adhesive, and more preferably polyacrylate, polydimethylsiloxane, polyisobutylene or A combination thereof. Furthermore, for example, a known tackifier may be appropriately added to the constituent material of the adhesive layer. The above-mentioned material can also be used as an auxiliary pressure-sensitive adhesive added to the surface of the drug-permeable membrane.
- the contact area of the adhesive layer with the skin can be appropriately determined in consideration of the area of the drug-permeable membrane, the administration period, the application site, and the like.
- a preferred production method of the transdermally absorbable preparation according to the present invention is as follows. First, a plaster solution obtained by mixing the materials constituting the drug-containing layer is applied onto the liner. Next, the plaster solution is dried at about 60 to 120 ° C. to obtain a drug-containing layer, and a support layer is laminated thereon. Next, the liner is peeled from the drug-containing layer, and the outer membrane is laminated on one side of the drug-containing layer on which the liner has been disposed, to obtain a laminate. Next, a cover layer having an adhesive layer disposed on one side is prepared. Under the present circumstances, you may arrange
- a layer other than the skin contact surface of the laminate is covered with a cover layer to obtain a transdermal absorption preparation.
- the position and size of a fixing means are preset so that an adhesion layer may be arrange
- the inner layer extends between the support layer and the adhesive layer from the periphery of the support layer toward the outside, and at the time of application, the adhesive layer and the drug-containing layer are combined. It sets beforehand so that it may space apart.
- examples of the solvent used in preparing the drug-containing layer and the adhesive layer include ethyl acetate, butyl acetate, toluene, n-hexane, n-heptane, tetrahydrofuran, dimethylformamide, methanol, ethanol, and the like. Can be mentioned.
- the transdermally absorbable preparation according to the present invention is preferably used for diseases requiring long-term drug administration because the drug can be stably and efficiently administered to a living body.
- the application period of the transdermally absorbable preparation can be set to a long period even if it is a single administration, and is preferably 3 to 7 days, more preferably about 1 week.
- a specific administration plan is appropriately determined by those skilled in the art according to the type of drug, the symptoms of the patient, the administration period, the size of the preparation, and the like.
- examples of the living body to which the transdermally absorbable preparation according to the present invention is applied include rabbits, dogs, and humans, and humans are preferable.
- Example 1 Preparation of transdermally absorbable preparation (without inner layer)
- Preparation of laminate Preparation of laminate : Drug-containing layer
- Bisoprolol fumarate (Palm Chem Asia), aminoalkyl methacrylate copolymer E (Degussa), triethyl citrate (Wako Pure Chemical Industries), isopropyl myristate (Nikko Chemicals) and oleyl alcohol (higher alcohol industry) These were mixed and stirred in an appropriate amount of ethyl acetate.
- Duro-Tak (trademark) 387-2516 (manufactured by National Starch & Chemical) was added to the resulting mixture at the ratio of the above formulation to obtain a plaster solution.
- the plaster solution was applied onto a polyethylene terephthalate liner and dried at 70 ° C. for 15 minutes to obtain a drug-containing layer.
- the weight of the drug-containing layer after drying was adjusted to 100 g / m 2 .
- a support layer (Scotchpak TM 9732, manufactured by 3M) was laminated on one side of the drug-containing layer opposite to the liner. Thereafter, the liner was peeled from the drug-containing layer, and the drug-containing layer and a microporous polypropylene film (outer film) were bonded together to obtain a laminate.
- a polyethylene terephthalate liner is bonded to the surface formed by the adhesive layer and the microporous polypropylene film, the skin contact surface is prepared, cut, and a percutaneous absorption preparation (shape: square, 65 ⁇ 65 mm) is prepared. Obtained.
- Example 2 Preparation of transdermally absorbable preparation (no inner layer) Preparation of laminate : Drug-containing layer
- Bisoprolol fumarate (Palm Chem Asia Co., Ltd.), aminoalkyl methacrylate copolymer E, triethyl citrate and isopropyl myristate were prepared in the proportions described above, and these were mixed and stirred in an appropriate amount of ethyl acetate.
- Duro-Tak (trademark) 387-2516 (manufactured by National Starch & Chemical) was added to the resulting mixture at the ratio of the above formulation to obtain a plaster solution.
- This plaster solution was applied onto a polyethylene terephthalate liner and dried at 70 ° C. for 15 minutes to obtain a drug-containing layer. The weight of the drug-containing layer after drying was adjusted to 100 g / m 2 .
- a support layer (Scotchpak TM 9732, manufactured by 3M) was laminated on one side of the drug-containing layer opposite to the liner. Thereafter, the liner on one side of the drug-containing layer was peeled off, and the drug-containing layer and the microporous polypropylene film (outer film) were laminated to obtain a laminate (10 cm 2 ). Next, in the same manner as in Example 1, a fixing means was prepared and placed on the laminate to obtain a transdermal absorption preparation.
- Example 3 Preparation of transdermal absorption preparation (without inner layer) Preparation of laminate : Drug-containing layer
- Flurbiprofen, isopropyl myristate, glycerin and sorbitan monolaurate were mixed in the above-mentioned proportions and dispersed uniformly.
- Duro-Tak (trademark) 87-2194 manufactured by National Starch & Chemical was added to the obtained mixed solution so as to have a ratio of the above-mentioned formulation to obtain a plaster solution.
- the plaster solution was applied onto a polyethylene terephthalate liner and dried at 80 ° C. for 15 minutes to obtain a drug-containing layer.
- the weight of the drug-containing layer after drying was adjusted to 100 g / m 2 .
- a support layer (Scotchpak TM 9732, manufactured by 3M) was laminated on one side of the drug-containing layer opposite to the liner. Thereafter, the liner was peeled from the drug-containing layer, and the drug-containing layer and the microporous polypropylene film were laminated to obtain a laminate.
- a fixing means was prepared and placed on the laminate to obtain a transdermal absorption preparation.
- Example 4 Preparation of percutaneously absorbable preparation (with inner layer)
- an inner layer (Scotchpak (trademark) 9732; 50 mm x 50 mm, hole; 40 mm x 40 mm) having a square hole was prepared.
- an adhesive layer of fixing means (65 mm ⁇ 65 mm) prepared in the same manner as above.
- the laminate layer (45 mm ⁇ 45 mm) prepared in the same manner as in Example 1 was bonded to the inner layer to obtain a percutaneous absorption preparation.
- the inner layer is disposed so as to extend outward from the peripheral edge of the support layer, and the support layer is directly connected to the adhesive layer of the fixing means through the hole of the inner layer. To come into contact.
- Example 5 Preparation of transdermal absorption preparation (with inner layer) First, an inner layer having a square hole (Scotchpak (trademark) 9732; 50 mm x 50 mm, hole; 40 mm x 40 mm) was prepared, and foam tape was used as a fixing means (65 mm ⁇ 65 mm) was prepared. Next, the inner layer and the adhesive layer of the foam tape were bonded together. Next, the laminate layer (45 mm ⁇ 45 mm) prepared in the same manner as in Example 1 was bonded to the inner layer to obtain a percutaneous absorption preparation. In this transdermally absorbable preparation, the inner layer is disposed so as to extend outward from the peripheral edge of the support layer, and the support layer is directly connected to the adhesive layer of the foam tape through the hole of the inner layer. To come into contact.
- Scotchpak trademark
- Duro-Tak (trademark) 387-2516, isopropyl myristate and oleyl alcohol were mixed in the proportions described in Formula 4 to obtain a plaster solution.
- the plaster solution was coated on a polyethylene terephthalate liner so that the weight after drying was 50 g / m 2 and dried at 70 ° C. for 10 minutes to obtain an adhesive layer.
- This adhesive layer was bonded to the outer membrane of the laminate obtained during the production process of Example 1 to obtain a reservoir-type transdermal absorption preparation.
- Phosphate buffered saline pH 7.4
- the skin permeation rate and drug utilization rate of the laminates of Examples 1 to 3 were as shown in Table 1.
- the skin permeation rate and drug utilization rate of the laminates of Examples 1 to 3 were higher than those of Reference Example 1 which is a reservoir-type transdermal absorption preparation.
- Test example 2 In vitro human skin permeation test The laminate of Example 2 (application area 4.5 cm 2 ) is placed on the stratum corneum of human skin and set in a flow-through cell in which warm water is circulated so that the skin surface is about 32 ° C. did. Phosphate buffered physiological saline (pH 7.4) was used as the receiver solution, and the receiver solution was collected every 5 hours at 5 mL / hr up to 168 hours. The flow rate of the collected solution was measured, and the drug amount was measured by HPLC. From the obtained results, the skin permeation rate per hour and the drug utilization rate in the preparation (total for one week) were calculated.
- Phosphate buffered physiological saline pH 7.4
- the skin permeation rate per hour and the drug utilization rate in the preparation were as shown in Table 2. Further, the cumulative drug permeation amount was as shown in FIG.
- the laminate of Example 2 was confirmed to release the drug to the skin at a substantially constant skin permeation rate for 1 week (168 hours).
- Test Example 3 Confirmation of stability of percutaneously absorbable preparation on skin Preparation of placebo preparation (with inner layer) A placebo preparation was prepared in the same manner as in Example 4 except that bisoprolol fumarate was excluded from the formulation of the drug-containing layer. did.
- the result was as shown in FIG.
- the placebo formulation having an inner layer maintained an adhesion rate of 90% or more for one week.
- Test Example 4 Drug Storage Stability of Transdermal Absorption Formulation 4-1: Storage Stability Test As a test target, the percutaneous absorption preparation of Example 5 having an inner layer is selected, and the transdermal absorption preparation is enclosed in an aluminum packaging bag. And stored at 40 ° C. for 1 month. Then, the drug release rate of the transdermally absorbable preparation before and after storage was measured by the method described below. First, degassed purified water (900 mL) was prepared as a test solution, poured into an eluent container, and the liquid temperature was kept at 32 ⁇ 0.5 ° C. Next, a percutaneous absorption preparation before or after storage is prepared.
- degassed purified water 900 mL
- Example 5 having an inner layer
- the release rate of bisoprolol fumarate after storage at 40 ° C. for 1 month was significant compared to the initial value (40 ° C., before storage for 1 month). No decrease was observed, and the storage stability of the transdermal absorption preparation was confirmed.
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Abstract
Description
したがって、本発明は、長期間効率的かつ安定に薬物を生体に投与しうる新規な経皮吸収製剤の提供をその目的とする。
該積層体を皮膚上に固定しうる固定手段と
を含んでなる、経皮吸収製剤であって、
外膜が、薬物の皮膚への放出を制御しうる、薬物透過性高分子膜であり、積層体の皮膚接触面に配置されていることを特徴とする。
本発明による経皮吸収製剤は、上述の通り、その皮膚接触面薬物に薬物透過性高分子膜が配置されていることを一つの特徴とするものである。かかる本発明による経皮吸収製剤は、薬物の保持安定性、皮膚上での付着安定性に優れ、薬物放出速度をコントロールすることが容易であり、長期間効率的かつ安定に薬物を生体へ投与する上で有利に利用できる。
図1は、本発明による経皮吸収製剤の一実施形態を示す断面図である。
図1に示される通り、経皮吸収製剤1は、皮膚2側から順に、外膜3、薬物含有層4、および支持体層5を含む積層体6と、積層体6を皮膚2上に固定しうる固定手段7とを備えている。そして、外膜3は、薬物の皮膚2への放出を制御しうる薬物透過性高分子膜により構成されており、積層体6の皮膚接触面8に配置されている。このように、粘着層を介することなく、薬物透過性高分子膜と、皮膚とが直接的に接触するのみで、薬物が皮膚を効率的に透過することは意外な事実である。
図2AおよびBに示される通り、経皮吸収製剤における背面(皮膚接触面)は、外膜3と、外膜3の周縁部・端部に配置された粘着層10とから構成され、外膜3は皮膚2と直接に接触しうるように配置されている。このように、本発明による経皮吸収製剤の皮膚接触面において、粘着層は、その全面ではなく、外膜の周縁部・端部に配置されており、経皮吸収製剤の剥離時の皮膚刺激を低減する上で有利である。
なお、経皮吸収製剤の皮膚接触面には、適宜公知のライナーを配置してもよく、製剤使用時にはライナーは剥離される。
図3Aは、本発明による経皮吸収製剤の製造工程において、各層が積層された状態を示し、経皮吸収製剤1は積層体6と、固定手段7との間に、内層12をさらに含んでいることを一つの特徴とする。そして、内層12は、固定手段7上で、支持体層5の周縁部から外側に向けて延在している。また、内層12は、リング状に構成され、内側の穴13を有している。
また、図3Bは、内層12を有する上記経皮吸収製剤1の背面(皮膚接触面)図である。経皮吸収製剤1の皮膚接触面では、外側から順に、粘着層10、内層12、および外膜3が配置されている。
さらに、図3Cは、内層12を有する経皮吸収製剤1の皮膚上における断面図である。皮膚2上の経皮吸収製剤1において、内層12は、薬物含有層4と、粘着層10とを離隔している。このように、内層12を配置することは、薬物の粘着層への移行を抑制し、経皮吸収製剤1の付着安定性、さらには薬物の保持安定性を向上する上で有利である。
また、粘着層10は、内層12の内側の穴13を介して、内層12に囲繞された支持体層5と直接的に接触し、積層体6を内側から固定している。このような構成は、貼付期間中、積層体を安定に皮膚上に固定する上で有利である。
また、薬物は、遊離体であっても塩であってもよい。
薬物の具体例としては、局所麻酔剤(塩酸ブピバカイン、塩酸メピバカイン等)、抗てんかん薬(バルプロ酸ナトリウム等)、鎮痛剤(塩酸モルヒネ、クエン酸フェンタニル、塩酸ブプレノルフィン等)、解熱鎮痛剤(スルピリン、アンチピリン、アセトアミノフェン)、抗精神病薬(塩酸クロルプロマジン、塩酸レボメプロマジン、塩酸クロカプラミン等)、うつ病治療薬(塩酸イミプラミン、塩酸トラゾドン、マレイン酸フルボキサミン等)、抗不安薬(ジアゼパム、アルプラゾラム、クエン酸タンドスピロン等)、精神安定剤(塩酸ヒドロキシジン等)、脳機能賦活薬(塩酸チアプリド、酒石酸プロチレリン等)、脳循環改善薬(イソソルビド、ペントキシフィリン、塩酸ファスジル等)、パーキンソン治療剤(塩酸ベンセラジド、塩酸アマンタジン、塩酸タリペキソール等)、筋弛緩剤(塩酸エピリゾン、塩酸チザニジン、塩酸トルペリゾン等)、消化性潰瘍治療薬(臭化ブチルスコポラミン、塩酸ピレンゼピン、臭化チメピジウム等)、抗ヒスタミン薬(マレイン酸クロルフェニラミン、塩酸プロメタジン、塩酸セチリジン等)、化学伝達物質遊離抑制薬(フマル酸エメダスチン、トシル酸スプラタスト、塩酸エピナスチン等)、心疾患治療薬(アミノフィリン、塩酸ジルチアゼム、ニコランジル、塩酸プロプラノロール、塩酸イソプレナリン、リン酸ジソピラミド、塩酸プロカインアミド等)、高血圧治療薬(カプトプリル、マレイン酸エナラプリル、塩酸アモスラロール、塩酸プラゾシン、ウラピジル、塩酸クロニジン等)、血管拡張薬(塩酸トラゾリン等)、血管収縮薬(メチル硫酸アメジニウム、塩酸エチレフリン、塩酸フェニレフリン、塩酸ミドドリン等)、高脂血症治療薬(プラバスタチンナトリウム、フルバスタチンナトリウム、セリバスタチンナトリウム等)、鎮咳・去痰薬(臭化水素酸デキストロメトルファン、塩酸ホミノベン、アセチルシステイン等)、喘息治療薬(塩酸クレンブテロール、臭化水素酸フェノテロール、塩酸プロカテロール等)、H2遮断薬(塩酸ラニチジン、塩酸ロキサチジンアセテート等)、プロトンポンプ阻害薬(オメプラゾール、ランソプラゾール、ラベプラゾール等)、制吐剤(塩酸グラニセトロン、塩酸アザセトロン、塩酸オンダンセトロン、塩酸ラモセトロン等)、非ステロイド性抗炎症剤(ロキソプロフェンナトリウム、フルルビプロフェン、ジクロフェナクナトリウム、塩酸チアラミド等)、抗リウマチ剤(ブシラミン、ペニシラミン等)、泌尿器疾患用薬(塩酸オキシブチニン、塩酸タムスロシン、塩酸プロピベリン等)、)、β遮断薬(フマル酸ビソプロロール、塩酸ベタキソロール等)が挙げられるが、これらに限定されない。
薬物含有層における基剤は、薬物の性質・含有量等に応じて適宜決定できるが、好ましくは(メタ)アクリル酸ジアルキルアミノアルキル・(メタ)アクリル酸アルキル・(メタ)アクリル酸ヒドロキシアルキル・コポリマー、(メタ)アクリル酸エステル・ビニルエステル・コポリマー、ポリアクリレート、ポリジメチルシロキサン、ポリイソブチレン、スチレン・イソプレン・スチレン・ブロックコポリマー、ポリイソプレンまたはそれらの組み合わせ等であり、より好ましくは(メタ)アクリル酸ジアルキルアミノアルキル・(メタ)アクリル酸アルキル・(メタ)アクリル酸ヒドロキシアルキル・コポリマー、(メタ)アクリル酸エステル・ビニルエステル・コポリマーまたはそれらの組み合わせであり、さらに好ましくは(メタ)アクリル酸ジC1~12アルキルアミノC1~10アルキル・(メタ)アクリル酸C1~10アルキル・コポリマー、(メタ)アクリル酸C1~10アルキル・(メタ)アクリル酸ヒドロキシC1~10アルキル・(メタ)アクリル酸グリシジル・酢酸ビニル・コポリマーまたはそれらの組み合わせであり、さらに好ましくは(メタ)アクリル酸ジC1~6アルキルアミノC1~6アルキル・(メタ)アクリル酸C1~8アルキル・コポリマー、(メタ)アクリル酸C1~12アルキル・(メタ)アクリル酸ヒドロキシC1~8アルキル・(メタ)アクリル酸グリシジル・酢酸ビニル・コポリマーまたはそれらの組み合わせであり、さらに好ましくは、(メタ)アクリル酸メチル・(メタ)アクリル酸ブチル・(メタ)アクリル酸ジメチルアミノエチル・コポリマー、アクリル酸2-エチルヘキシル・アクリル酸ヒドロキシエチル・(メタ)アクリル酸グリシジル・酢酸ビニル・コポリマーまたはそれらの組み合わせ等である。
薬物透過性高分子膜は、薬物の皮膚への放出をコントロールしうる限り特に限定されないが、好ましくは薬物を透過しうる細孔を有する微孔質膜である。微孔質膜における孔径および孔密度は、所望の薬物皮膚透過速度等を勘案して適宜決定することができるが、例えば、細孔の平均孔径としては、0.03~0.25μmである。また、薬物透過性膜の皮膚側片面の面積についても所望の薬物放出速度、貼付部位等を勘案して適宜決定することができる。
このような内層の材料としては、好ましくは薬物不透過性材料であり、具体的には、ポリエチレンテレフラレート、ポリエステル、ポリエチレン、ポリウレタン、ポリアミド、ポリプロピレン、およびエチレン-酢酸ビニル共重合体等が挙げられる。
また、支持体層は、内層と同様の材料を用いて構成することができる。
本発明による経皮吸収製剤の好ましい製造方法としては、以下の通りである。
まず、薬物含有層を構成する材料を混合して得られる膏体溶液を、ライナー上に塗布する。次に、膏体溶液を60~120℃程度で乾燥させて薬物含有層を得、その上に支持体層をラミネートする。次に、薬物含有層からライナーを剥離し、ライナーが配置されていた薬物含有層の片面に外膜をラミネートし、積層体を得る。次に、片面に粘着層が配置されたカバー層を用意する。この際、粘着層上には、所望により、内部の穴を有する内層をさらに配置してよい。次に、カバー層によって積層体の皮膚接触面以外を被覆し、経皮吸収製剤を得る。この際、粘着層は、外膜の皮膚接触面の周縁部または端部に配置されるように、固定手段の位置・サイズを予め設定する。また、内層を設ける場合には、内層は、支持体層と粘着層との間で、支持体層の周縁部から外側に向けて延在し、貼付時には、粘着層と、薬物含有層とを離隔するように、予め設定する。
本発明による経皮吸収製剤は、薬物を安定かつ効率的に生体に投与しうることから、長期間の薬物投与を必要とする疾患に好ましく用いられる。
また、経皮吸収製剤の貼付期間は、単回投与であっても長期間に設定をすることができ、好ましくは3~7日間、より好ましくは1週間程度である。具体的な投与計画は、薬物の種類、患者の症状、投与期間、製剤のサイズ等に応じ、当業者によって適宜決定される。
次に、薬物含有層のライナーと反対側の片面に支持体層(Scotchpak(商標)9732、3M製)をラミネートした。その後、薬物含有層からライナーを剥離し、薬物含有層と、微孔性ポリプロピレン膜(外膜)とを貼り合わせ、積層体を得た。
Duro-Tak(商標) 87-2287(National Starch & Chemical製)をポリエチレンテレフタレート製ライナー上に塗工し、80℃15分間乾燥させ、粘着層を得た。乾燥後の粘着層の重量は、100g/m2とした。次に、ライナーと反対側の粘着層の片面にカバー層(ポリエステル製織布)をラミネートし、固定手段を得た。
次に、固定手段の粘着層上のライナーを剥離し、予め45×45mmに裁断しておいた積層体の支持体層と、固定手段の粘着層とを貼り合わせた。次に、粘着層および微孔質ポリプロピレン膜により形成される面に、ポリエチレンテレフタレート製ライナーを貼り合わせ、皮膚接触面を整え、裁断を行い、経皮吸収製剤(形状:正方形、65×65mm)を得た。
この膏体溶液を、ポリエチレンテレフタレート製ライナー上に塗工し、70℃15分間乾燥させ、薬物含有層を得た。乾燥後の薬物含有層の重量は100g/m2となるように調整した。
次に、薬物含有層のライナーと反対側の片面に支持体層(Scotchpak(商標)9732、3M製)をラミネートした。その後、薬物含有層からライナーを剥離し、薬物含有層と微孔性ポリプロピレン膜とをラミネートし積層体を得た。
次に、実施例1と同様に、固定手段を用意して上記積層体に設置し、経皮吸収製剤を得た。
まず、正方形状の穴を有する内層(Scotchpak(商標)9732;50mm×50mm、穴;40mm×40mm)を用意し、内層と、実施例1と同様にして調製した固定手段(65mm×65mm)の粘着層とを張り合わせた。次に、実施例1と同様にして調製した積層体(45mm×45mm)の支持体層と、内層とを張り合わせ、経皮吸収製剤を得た。なお、この経皮吸収製剤において、内層は支持体層の周縁部から外側に向けて延在するように配置し、支持体層は、内層の有する穴を介して、固定手段の粘着層と直接に接触するようにした。
まず、正方形状の穴を有する内層(Scotchpak(商標)9732;50mm×50mm、穴;40mm×40mm)を用意し、固定手段として、フォームテープ(65mm×65mm)を用意した。次に、内層と、フォームテープの粘着層とを張り合わせた。次に、実施例1と同様にして調製した積層体(45mm×45mm)の支持体層と、内層とを張り合わせ、経皮吸収製剤を得た。なお、この経皮吸収製剤において、内層は支持体層の周縁部から外側に向けて延在するように配置し、支持体層は、内層の有する穴を介して、フォームテープの粘着層と直接に接触するようにした。
上記膏体溶液をポリエチレンテレフタレート製ライナー上に、乾燥後の重量が50g/m2となるように塗工し、70℃で10分間乾燥させ、粘着層を得た。
この粘着層を実施例1の製造工程中に得られた積層体の外膜に貼りあわせ、リザーバー型経皮吸収製剤を得た。
in vitro ヘアレスマウス皮膚透過試験
ヘアレスマウス(7週齢、メス、n=3)の皮膚の角質層上に、実施例1~3の製造工程中に得られた積層体または参考例1のリザーバー型経皮吸収製剤(いずれも適用面積4.5cm2)を配置し、これを皮膚表面が約32℃となるように温水を循環させたフロースルーセルにセットした。レシーバー液としてりん酸緩衝生理食塩液(pH 7.4)を使用し、5mL/hrで2時間毎に24時間までレシーバー液を回収した。回収した溶液について流量を測定し、HPLCにより薬物量を測定した。得られた結果から、1時間当たりの皮膚透過速度および薬物含有層中の薬物利用率(24時間総計)を算出した。
in vitro ヒト皮膚透過試験
ヒト皮膚の角質層上に実施例2の積層体(適用面積4.5cm2)を配置し、皮膚表面が約32℃となるように温水を循環させたフロースルーセルにセットした。レシーバー液としてりん酸緩衝生理食塩液(pH 7.4)を使用し、5mL/hrで2時間毎に168時間までレシーバー液を回収した。回収した溶液について流量を測定し、HPLCにより薬物量を測定した。得られた結果から、1時間当たりの皮膚透過速度および製剤中の薬物利用率(1週間総計)を算出した。
また、累積の薬物透過量は図4に示される通りであった。実施例2の積層体は1週間(168時間)、ほぼ一定の皮膚透過速度にて薬物を皮膚へ放出することが確認された。
プラセボ製剤(内層あり)の調製
薬物含有層の処方からフマル酸ビソプロロールを除いた以外、実施例4と同様にして、プラセボ製剤を調製した。
プラセボ製剤をそれぞれ、成人男性(4名)の胸部左または右に1週間貼付した。試験期間中、被験者は24時間毎にシャワーを浴びた。
貼付開始後、24時間おきに(シャワー前に)、プラセボ製剤の貼付面積に対する、実際に皮膚に付着していた面積の割合(付着率)を、以下の式に従い、測定した。
[式1]
(付着率)=(実際に皮膚に付着していた面積)/(プラセボ製剤の貼付面積)×100
内層を有する上記プラセボ製剤は、1週間90%以上の付着率を維持していた。
4-1:保存安定性試験
試験対象として、内層を有する実施例5の経皮吸収製剤を選択し、経皮吸収製剤をアルミニウム包装袋に封入し、40℃で1ヶ月間保存した。そして、保存前後における経皮吸収製剤の薬物放出率を、以下に記載の手法により測定した。
まず、試験液として脱気した精製水(900mL)を用意し、溶出液用容器に注ぎ、液温を32±0.5℃に保った。次に、保存前または保存後の経皮吸収製剤を用意し、経皮吸収製剤の支持体層側の片面と、溶出試験機(機器名VK7010、Vankel社製)における回転シリンダーの下端の面とを両面テープ(ナイスタック(商標)、ニチバン株式会社)により張り合わせ、経皮吸収製剤のライナーを剥離した。次に、回転シリンダーの下端と、溶出液用容器の内側の底との距離を25±2mmとなるように固定し、回転シリンダーの回転数を毎分50回転に設定し、第14改正日本薬局方に準じて、溶出試験を行った。
試験開始後、1、3、6、12、24時間において、試験液5mLを採取し、採取後、試験液を直ちに試験溶液に補充した。
HPLCにより各サンプリング時間におけるフマル酸ビソプロロールの放出量を算出し、さらに、経皮吸収製剤中の薬物量を基準として、フマル酸ビソプロロールの放出率を算出した。
内層を有する実施例5の経皮吸収製剤を用いた場合、40℃、1ヶ月保存後のフマル酸ビソプロロールの放出率は、初期値(40℃、1ヶ月保存前)と比較して、有意な低下は見られず、上記経皮吸収製剤の保存安定性が確認された。
Claims (10)
- 皮膚側から順に、外膜、薬物含有層、および支持体層を含んでなる積層体と、
該積層体を皮膚上に固定しうる固定手段と
を含んでなる、経皮吸収製剤であって、
前記外膜が、薬物の皮膚への放出を制御しうる、薬物透過性高分子膜であり、前記積層体の皮膚接触面に配置されている、経皮吸収製剤。 - 前記固定手段が、皮膚側から順に、粘着層およびカバー層を含んでなり、前記積層体を被覆する、請求項1に記載の経皮吸収製剤。
- 前記支持体層と、前記粘着層との間に配置され、前記支持体層の周縁部から外側に向けて延在する内層をさらに含んでなり、
該内層が、前記経皮吸収製剤の貼付時に、前記粘着層と、前記薬物含有層とを離隔しうる、請求項2に記載の経皮吸収製剤。 - 前記内層に囲繞された支持体層の片面に、前記粘着層が直接的に接触して前記積層体を固定する、請求項3に記載の経皮吸収製剤。
- 前記内層および支持体層が薬物不透過性である、請求項4に記載の経皮吸収製剤。
- 前記内層および支持体層が、ポリエチレンテレフラレート、ポリエステル、ポリエチレン、ポリウレタン、ポリアミド、ポリプロピレン、およびエチレン-酢酸ビニル共重合体からなる群から選択される少なくとも一つの材料からなる、請求項5に記載の経皮吸収製剤。
- 前記薬物透過性高分子膜が、薬物を透過しうる細孔を有する微孔質膜である、請求項1に記載の経皮吸収製剤。
- 前記薬物透過性高分子膜が、エチレン-酢酸ビニル共重合体、ポリエチレン、ポリプロピレン、ポリアクリロニトリル、ポリメチルメタクリレートおよびそれらの架橋体からなる群から選択される少なくとも一つの材料からなる、請求項1に記載の経皮吸収製剤。
- 前記薬物含有層が、該薬物含有層の15質量%以上の薬物を含んでなる、請求項1に記載の経皮吸収製剤。
- 前記粘着層が感圧性接着剤を含んでなる、請求項1に記載の経皮吸収製剤。
Priority Applications (7)
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JP2010505734A JP5591685B2 (ja) | 2008-03-25 | 2009-03-25 | 経皮吸収製剤 |
CN200980114560.7A CN102026629B (zh) | 2008-03-25 | 2009-03-25 | 透皮吸收制剂 |
EP09726157.2A EP2269593B1 (en) | 2008-03-25 | 2009-03-25 | Transdermally absorbable preparation |
CA2719605A CA2719605C (en) | 2008-03-25 | 2009-03-25 | Transdermally absorbable preparation |
US12/934,425 US8974817B2 (en) | 2008-03-25 | 2009-03-25 | Transdermally absorbable preparation |
ES09726157.2T ES2672025T3 (es) | 2008-03-25 | 2009-03-25 | Preparación transdérmicamente absorbible |
AU2009229994A AU2009229994B2 (en) | 2008-03-25 | 2009-03-25 | Transdermally absorbable preparation |
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JP2008077903 | 2008-03-25 | ||
JP2008-077903 | 2008-03-25 |
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Family
ID=41113863
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PCT/JP2009/055965 WO2009119673A1 (ja) | 2008-03-25 | 2009-03-25 | 経皮吸収製剤 |
PCT/JP2009/055964 WO2009119672A1 (ja) | 2008-03-25 | 2009-03-25 | β遮断剤の安定化組成物およびそれを用いた経皮吸収製剤 |
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US (2) | US20110104247A1 (ja) |
EP (2) | EP2269593B1 (ja) |
JP (2) | JP5591685B2 (ja) |
KR (2) | KR20100134058A (ja) |
CN (2) | CN102026629B (ja) |
AU (2) | AU2009229994B2 (ja) |
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US20120323191A1 (en) * | 2010-02-26 | 2012-12-20 | Nitto Denko Corporation | Adhesive skin patch |
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JP2020525112A (ja) * | 2017-06-23 | 2020-08-27 | ニチバン株式会社 | サポートライナー付き貼付剤並びにその製造方法 |
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Also Published As
Publication number | Publication date |
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CA2719605C (en) | 2016-07-12 |
CN102026664A (zh) | 2011-04-20 |
KR20100126830A (ko) | 2010-12-02 |
AU2009229993A1 (en) | 2009-10-01 |
EP2269593A1 (en) | 2011-01-05 |
JPWO2009119672A1 (ja) | 2011-07-28 |
CA2719601A1 (en) | 2009-10-01 |
WO2009119672A1 (ja) | 2009-10-01 |
EP2269653A1 (en) | 2011-01-05 |
EP2269593B1 (en) | 2018-05-02 |
AU2009229994B2 (en) | 2015-04-16 |
CN102026664B (zh) | 2013-05-29 |
KR20100134058A (ko) | 2010-12-22 |
AU2009229994A1 (en) | 2009-10-01 |
EP2269653A4 (en) | 2013-10-23 |
US20110104247A1 (en) | 2011-05-05 |
US8974817B2 (en) | 2015-03-10 |
JP5591685B2 (ja) | 2014-09-17 |
CN102026629B (zh) | 2015-01-14 |
CN102026629A (zh) | 2011-04-20 |
JPWO2009119673A1 (ja) | 2011-07-28 |
EP2269593A4 (en) | 2013-10-23 |
CA2719605A1 (en) | 2009-10-01 |
KR101601335B1 (ko) | 2016-03-08 |
US20110104215A1 (en) | 2011-05-05 |
ES2672025T3 (es) | 2018-06-12 |
JP5615697B2 (ja) | 2014-10-29 |
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