WO2013008909A1 - ロキソプロフェンナトリウム含有外用貼付剤 - Google Patents

ロキソプロフェンナトリウム含有外用貼付剤 Download PDF

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Publication number
WO2013008909A1
WO2013008909A1 PCT/JP2012/067915 JP2012067915W WO2013008909A1 WO 2013008909 A1 WO2013008909 A1 WO 2013008909A1 JP 2012067915 W JP2012067915 W JP 2012067915W WO 2013008909 A1 WO2013008909 A1 WO 2013008909A1
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WIPO (PCT)
Prior art keywords
acid
weight
higher fatty
loxoprofen sodium
patch
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Application number
PCT/JP2012/067915
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English (en)
French (fr)
Japanese (ja)
Inventor
和葉 谷
勝幸 猪尾
Original Assignee
帝國製薬株式会社
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Priority to JP2013523997A priority Critical patent/JP5888706B2/ja
Publication of WO2013008909A1 publication Critical patent/WO2013008909A1/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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]

Definitions

  • solubilizing agents such as crotamiton, pyrrolidones, higher fatty acids and fatty acid esters, or cooling agents such as L-menthol, mint oil, and DL-camphor Attempts have been made to improve transdermal absorbability by adding.
  • solubilizing agents such as crotamiton, pyrrolidones, higher fatty acids and fatty acid esters, or cooling agents such as L-menthol, mint oil, and DL-camphor
  • Patent Document 1 discloses a plaster agent in which a rosin ester derivative is used as a solubilizing agent for a non-steroidal anti-inflammatory analgesic such as loxoprofen and is blended in a patch together with L-menthol.
  • Patent Document 2 discloses a loxoprofen-containing patch containing styrene-isoprene-styrene block copolymer as a base base and blended with crotamiton.
  • Patent Document 3 describes a loxoprofen-containing patch containing a pyrrolidone compound, but the pyrrolidone compound, like crotamiton, easily deteriorates the physical properties of the preparation, and the pyrrolidone compound has a highly volatile component. In addition, when blended into a patch, it volatilizes during storage and the transdermal absorbability may be reduced. Furthermore, Patent Document 4 describes a loxoprofen-containing patch containing a terpene resin or a rosin resin, and the rosin resin in this patch is a skin sensation preparation as described above, which is preferable for the skin. There is no influence.
  • the present invention solves the above-mentioned problem, and in a loxoprofen sodium-containing external patch, it exhibits a high percutaneous absorption of the active ingredient and is stable enough to suppress the formation of degradation products for a preparation during storage. It is an object to provide an external patch having high properties.
  • the present inventors have found that in an external patch in which a pressure-sensitive adhesive layer containing loxoprofen sodium is provided on a support, the pressure-sensitive adhesive layer is a main base.
  • Styrene-isoprene-styrene block copolymer as an adhesive, an alicyclic saturated hydrocarbon resin that is a highly safe tackifier for the skin, and lactic acid and higher fatty acids as specific agents for topical use
  • loxoprofen sodium was stably dissolved in the adhesive base, and the percutaneous absorbability was improved while maintaining high stability of loxoprofen sodium, and the present invention was completed. It was.
  • the higher fatty acid is one or two selected from isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, and caproic acid. This is an external patch as described above.
  • the external patch provided by the present invention is an external patch in which an adhesive layer containing loxoprofen sodium is provided on one side of a support, and the adhesive layer is a styrene-isoprene-styrene block copolymer as a main base.
  • loxoprofen sodium can be stably dissolved in the adhesive base, and has high transdermal absorbability and stability of the active ingredient, which could not be achieved with conventional patches. It has become possible to provide an external patch containing loxoprofen sodium.
  • lactic acid and higher fatty acid isostearic acid alone, a combination of isostearic acid and myristic acid, or a combination of isostearic acid, myristic acid and palmitic acid, such that lactic acid / higher fatty acid 1/50 to 1/5. Therefore, very good solubility and transdermal absorbability are exhibited.
  • the amount of loxoprofen sodium as the main drug in the external patch is not particularly limited as long as it can be formulated, but is preferably 0.1 to It can be blended in an amount of 10% by weight, more preferably 0.5 to 6% by weight.
  • the loxoprofen sodium content in the preparation is less than 0.1% by weight, the transdermal absorbability is insufficient, and when it exceeds 10% by weight, not only the physical properties of the patch are impaired, but also economically. Is also disadvantageous and not preferred.
  • the styrene-isoprene-styrene block copolymer (hereinafter referred to as “SIS”) as a base component imparts adhesiveness to the adhesive layer, and each component is contained in the adhesive. It has a role to hold.
  • the amount of SIS is blended in consideration of the blending amount of other components, but is usually 5 to 30% by weight, preferably 10 to 25% by weight. When the blending amount is less than 5% by weight, the cohesive strength and shape retention of the base are lowered. On the other hand, if the blending amount exceeds 30% by weight, it is not preferable because it causes a decrease in adhesive strength, unevenness of the plaster, and a decrease in workability in the manufacturing process.
  • the alicyclic saturated hydrocarbon resin blended in the base in the external patch of the present invention is used as a tackifier.
  • alicyclic saturated hydrocarbon resins In addition to high safety to the skin, alicyclic saturated hydrocarbon resins have low polarity, so they are less reactive with loxoprofen sodium and other ingredients, improving the stability of loxoprofen sodium in the formulation From this point of view, it is a preferable tackifier.
  • alicyclic saturated hydrocarbon resins include Alcon P100, Alcon P90, and Alcon P115 (all trade names: manufactured by Arakawa Chemical Industries).
  • the blending amount of the alicyclic saturated hydrocarbon resin in the external patch of the present invention is not particularly limited as long as it can be formulated, but it is preferably blended in the range of 10 to 50% by weight based on the total weight of the formulation. It is good to do. More preferably, it is 15 to 40% by weight. If the blending amount of the alicyclic saturated hydrocarbon resin in the preparation is less than 10% by weight, the adhesive strength is weak, causing problems such as peeling during sticking. On the contrary, the force becomes too strong and the skin irritation becomes high, which is not preferable.
  • lactic acid is a very excellent solubilizing agent for loxoprofen sodium, and by mixing it, loxoprofen sodium is stably dissolved in the adhesive base and exhibits an excellent transdermal absorption promoting effect. It is a component that can.
  • lactic acid is an additive with one aspect that it reacts with loxoprofen sodium to produce a decomposition product and reduce the stability of the preparation. Therefore, the blending amount of lactic acid in the external patch of the present invention is 0.1 to 1.0% by weight, preferably 0.1 to 0.8% by weight, more preferably 0.00%, based on the total weight of the preparation. It is preferable to blend in the range of 2 to 0.6% by weight.
  • the amount of lactic acid is less than 0.1% by weight, it is impossible to sufficiently dissolve loxoprofen sodium in the adhesive base, and the percutaneous absorbability of the preparation is reduced, or the crystal of the main ingredient in the preparation during storage Precipitation or the like occurs, and conversely, when the blending amount of lactic acid exceeds 1.0% by weight, the decomposition product derived from lactic acid increases and the stability of the preparation decreases.
  • a higher fatty acid is blended together with the above lactic acid to ensure the function as a solubilizer for loxoprofen sodium.
  • fatty acids examples include isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, caproic acid, and the like, or a combination of one or more of them
  • isostearic acid, myristic acid, and palmitic acid are particularly preferably used in the present invention.
  • a combination of a relatively small amount of lactic acid and a relatively large amount of a higher fatty acid is added to the preparation in order to achieve both the percutaneous absorption of the active ingredient and the stability of the active ingredient. It is characterized by that.
  • the blending amount of lactic acid or higher fatty acid is as described above, but in addition, it has been found preferable to adjust the blending ratio of lactic acid and higher fatty acid within a certain range.
  • a preferable combination of lactic acid and higher fatty acid is lactic acid and isostearic acid, or lactic acid, isostearic acid and myristic acid. More preferred is a combination of lactic acid and isostearic acid, myristic acid and palmitic acid.
  • the softener blended in the external patch of the present invention has good compatibility with other base components and gives flexibility to the base.
  • polyisobutylene, liquid polyisoprene, polybutene examples include lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin. Among them, polybutene and liquid paraffin are preferable.
  • These softeners can be used alone or in combination of two or more.
  • the blending amount of the softening agent is usually 10 to 75% by weight, preferably 15 to 50% by weight, although the blending amount of other liquid components blended in the preparation is also considered.
  • L-menthol is preferably blended as a cooling agent.
  • L-menthol itself may react with loxoprofen sodium, which is a nonsteroidal anti-inflammatory analgesic having a carboxylic acid group in the molecule, to produce a decomposition product (L-menthol ester). Therefore, when a large amount is added, the amount of decomposition products (L-menthol ester) tends to increase with the amount. If too much L-menthol is added, the skin feels too cold and may be uncomfortable for some people. Therefore, the amount of L-menthol in the external patch of the present invention is 0.1 to 10% by weight, preferably 0.5 to 5% by weight.
  • blend a polyvalent metal salt with the external patch of this invention in order to suppress the increase in this decomposition product.
  • the incorporation of aluminum glycinate is effective for degradation products derived from lactic acid.
  • the polyvalent metal salt is blended in the range of 0.001 to 5% by weight, and preferably 0.005 to 3% by weight.
  • solubilizers or absorption enhancers include fatty acid esters such as isopropyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, isopropyl palmitate, and polyvalent polyols such as propylene glycol, polyethylene glycol, butylene glycol, and glycerin.
  • Examples include pyrrolidone compounds such as alcohol, N-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, N-octyl-2-pyrrolidone, crotamiton, and other various surfactants.
  • pyrrolidone compounds such as alcohol, N-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, N-octyl-2-pyrrolidone, crotamiton, and other various surfactants.
  • the base component is not particularly limited, and examples thereof include rubber-based elastomers such as butyl rubber, polyisobutylene, natural rubber, and polyisoprene rubber; water-soluble polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, and polyacrylic acid; ethyl cellulose, hydroxy Cellulose derivatives such as propylcellulose and hydroxypropylmethylcellulose, silicon compounds such as silicic anhydride and light silicic anhydride, dibutylhydroxytoluene, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxy Phenyl) propionate], tocopherol acetate, ascorbic acid and the like; inorganic fillers such as zinc oxide, aluminum oxide, titanium dioxide, silicas, magnesium oxide, iron oxide and zinc stearate.
  • rubber-based elastomers such as butyl rubber, polyisobutylene, natural rubber, and poly
  • Examples of the support for external patches include films, nonwoven fabrics, knitted fabrics, and laminate composites of nonwoven fabrics and films.
  • materials for these supports include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.
  • release liner used for the external patch polyethylene terephthalate, polypropylene, paper, or the like can be used, and polyethylene terephthalate is particularly preferable.
  • the release liner may be subjected to silicon treatment as necessary in order to optimize the peeling force.
  • Example 1 SIS (Quintac 3570C; manufactured by Nippon Zeon), alicyclic saturated hydrocarbon resin (Alcon P-100; manufactured by Arakawa Chemical Industries), polybutene (HV-300F; manufactured by Nippon Petroleum), liquid paraffin (High Coal M-352; Kaneda) And BHT (butylhydroxytoluene) were dissolved by stirring under heating in a nitrogen atmosphere. Next, loxoprofen sodium, L-menthol, lactic acid, isostearic acid, palmitic acid, and myristic acid, which are the main agents, were added to the adhesive, and further stirred and mixed to prepare an adhesive.
  • SIS Quintac 3570C; manufactured by Nippon Zeon
  • alicyclic saturated hydrocarbon resin Alcon P-100; manufactured by Arakawa Chemical Industries
  • polybutene HV-300F; manufactured by Nippon Petroleum
  • liquid paraffin High Coal M-352; Kaneda
  • BHT butylhydroxytol
  • the prepared pressure-sensitive adhesive was coated on a silicon-treated polyethylene terephthalate film to form a pressure-sensitive adhesive layer of about 150 ⁇ m.
  • the obtained pressure-sensitive adhesive layer was laminated to a polyester woven fabric as a support to obtain an external patch of the present invention. Table 1 shows the amount of each component.
  • Comparative Examples 1 to 9 According to the production method of Example 1, the patches for external use of Comparative Examples 1 to 9 were obtained with the compositions shown in Tables 2 and 3 below. In addition, in the test example described later, as Comparative Example 10, a commercially available loxoprofen-containing plaster agent was used.
  • Example 10 the external patch of Example 1 of the present invention showed a transdermal absorbability equivalent to or higher than that of a commercially available loxoprofen-containing plaster (Comparative Example 10).
  • Test Example 3 Mouse Skin Permeability Test In vitro mouse skin permeability test using hairless mice was performed to examine the main drug release of the external patches of Examples 1 to 6 and Comparative Examples 2 to 10. .
  • the back skin of 8-10 week old hairless mice was peeled off, and attached to a Franz type cell (opening area: 1.77 cm 2 ) in which warm water at 37 ° C. was circulated around the outer periphery with the dermis side as the receptor layer side.
  • each patch is affixed to the stratum corneum side of the skin, and the receptor liquid is sampled for 90 minutes at a rate of 2.25 mL / hr using a PBS (pH 7.4) solution as the receptor liquid.
  • PBS pH 7.4
  • Flux ratio (flux value in steady state of each example and comparative example) / (flux value in steady state of comparative example 10)
  • Test Example 4 Stability test (quantitative test of decomposition products) For each of the preparations of Examples 1 to 4, Example 6, Comparative Example 4 and Comparative Example 5, degradation products in the storage samples were measured in a storage period of 1 month under storage conditions of 60 ° C. Further, for each of the preparations of Example 1 and Example 4, the amount of degradation products in the storage sample during the storage period of 3 months was also measured. The sample preparation method and HPLC measurement conditions are shown below. In this stability test, degradation products derived from lactic acid were particularly measured.
  • decomposition product 1 a decomposition product detected at a relative retention time of 1.55 to 1.60 when the retention time of loxoprofen sodium is 1
  • decomposition product 2 relative A decomposition product detected at a retention time of 1.65 to 1.70 is a main decomposition product derived from lactic acid.
  • Table 8 shows the quantification results of the degradation products in each preparation used for the test. Particularly, regarding the quantification results of Example 1 and Comparative Example 4, the quantification results of the degradation product 1 are shown in FIG. The quantitative results are shown in FIG.
  • an oily external patch containing loxoprofen sodium having excellent drug release properties and having high stability is provided.
  • the patch provided by the present invention is an anti-inflammatory analgesic external preparation containing loxoprofen sodium, for example, osteoarthritis, rheumatoid arthritis, low back pain, periarthritis, tendonitis, peritonitis, suprahumeral It is useful for the prevention and treatment of condyleitis (tennis elbow, etc.), muscle pain, swelling and pain after trauma.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
PCT/JP2012/067915 2011-07-13 2012-07-13 ロキソプロフェンナトリウム含有外用貼付剤 WO2013008909A1 (ja)

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JP2011154983 2011-07-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017226623A (ja) * 2016-06-23 2017-12-28 救急薬品工業株式会社 非水性貼付剤
WO2019160067A1 (ja) * 2018-02-16 2019-08-22 株式会社大石膏盛堂 非水系貼付剤
WO2022186351A1 (ja) 2021-03-04 2022-09-09 帝國製薬株式会社 ロキソプロフェン含有貼付剤およびその製造方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008214337A (ja) * 2007-02-05 2008-09-18 Yuutoku Yakuhin Kogyo Kk 外用貼付剤
EP2116234A1 (en) * 2006-12-06 2009-11-11 NIPRO Patch Co., Ltd. Pharmaceutical composition for external application and adhesive skin patch
JP2010280634A (ja) * 2009-06-05 2010-12-16 Kyoritsu Yakuhin Kogyo Kk 消炎鎮痛貼付剤
JP2011020997A (ja) * 2009-03-19 2011-02-03 Kyoritsu Yakuhin Kogyo Kk 外用貼付剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2116234A1 (en) * 2006-12-06 2009-11-11 NIPRO Patch Co., Ltd. Pharmaceutical composition for external application and adhesive skin patch
JP2008214337A (ja) * 2007-02-05 2008-09-18 Yuutoku Yakuhin Kogyo Kk 外用貼付剤
JP2011020997A (ja) * 2009-03-19 2011-02-03 Kyoritsu Yakuhin Kogyo Kk 外用貼付剤
JP2010280634A (ja) * 2009-06-05 2010-12-16 Kyoritsu Yakuhin Kogyo Kk 消炎鎮痛貼付剤

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017226623A (ja) * 2016-06-23 2017-12-28 救急薬品工業株式会社 非水性貼付剤
WO2019160067A1 (ja) * 2018-02-16 2019-08-22 株式会社大石膏盛堂 非水系貼付剤
WO2022186351A1 (ja) 2021-03-04 2022-09-09 帝國製薬株式会社 ロキソプロフェン含有貼付剤およびその製造方法

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JPWO2013008909A1 (ja) 2015-02-23
TW201306883A (zh) 2013-02-16
TWI526227B (zh) 2016-03-21
JP5888706B2 (ja) 2016-03-22

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