WO2011074565A1 - ピロキシカム含有経皮吸収製剤 - Google Patents
ピロキシカム含有経皮吸収製剤 Download PDFInfo
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- WO2011074565A1 WO2011074565A1 PCT/JP2010/072452 JP2010072452W WO2011074565A1 WO 2011074565 A1 WO2011074565 A1 WO 2011074565A1 JP 2010072452 W JP2010072452 W JP 2010072452W WO 2011074565 A1 WO2011074565 A1 WO 2011074565A1
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- piroxicam
- oxybuprocaine
- patch
- present
- weight
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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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]
Definitions
- the present invention relates to a transdermally absorbable preparation, and in particular, piroxicam as a non-steroidal anti-inflammatory analgesic as a medicinal ingredient, and oxybuprocaine or a pharmaceutical thereof as a local anesthetic and as an absorption enhancer for piroxicam
- piroxicam as a non-steroidal anti-inflammatory analgesic as a medicinal ingredient
- oxybuprocaine or a pharmaceutical thereof as a local anesthetic and as an absorption enhancer for piroxicam
- the present invention relates to a patch containing an acceptable salt.
- Patent Documents 1 to 9 various developments and examinations of patches that are percutaneous absorption preparations containing various local anesthetics have been made as percutaneous absorption enhancers for non-steroidal anti-inflammatory analgesics. This is because the release of non-steroidal anti-inflammatory analgesics is promoted along with the release of the absorption enhancer compounded in the patch preparation, and as a result, excellent transdermal absorbability and effective transdermal absorption patch Is based on the idea.
- transdermal absorption preparation that exhibits high anti-inflammatory analgesic effects in a patch containing a non-steroidal anti-inflammatory analgesic and a local anesthetic as a transdermal absorption enhancer without inhibiting each other's drug release properties was requested.
- oxicam-based anti-inflammatory analgesics such as piroxicam exert excellent effects on chronic rheumatism, osteoarthritis, low back pain, postoperative anti-inflammatory analgesia, etc. It is an anti-inflammatory analgesic that is commonly used. So far, piroxicam ointment has been known as an external preparation for oxicam anti-inflammatory analgesics, but no external patch containing piroxicam has appeared.
- the present inventors have studied the development of an external patch excellent in transdermal absorbability for piroxicam, which is an oxicam anti-inflammatory analgesic.
- the present inventors in particular, in a patch containing a local anesthetic as a non-steroidal anti-inflammatory analgesic and a transdermal absorption enhancer, have high anti-inflammatory analgesia without greatly suppressing each other's drug release properties.
- the present invention provides a local anesthetic and a non-steroidal anti-inflammatory agent that exhibits a high anti-inflammatory analgesic effect in a patch containing a local anesthetic and a non-steroidal anti-inflammatory analgesic without suppressing each other's drug release properties. It is an object of the present invention to provide a patch containing an analgesic.
- piroxicam-containing transdermal characterized in that it contains piroxicam as a medicinal ingredient and oxybuprocaine or a pharmaceutically acceptable salt thereof as an absorption enhancer.
- Absorption patch characterized in that it contains piroxicam as a medicinal ingredient and oxybuprocaine or a pharmaceutically acceptable salt thereof as an absorption enhancer.
- the content of piroxicam is 0.1 to 5% by weight relative to the total weight of the drug-containing plaster, and the content of oxybuprocaine or a pharmaceutically acceptable salt thereof is It is a piroxicam-containing transdermal absorption patch that is 1 to 30% by weight based on the total weight of the drug-containing plaster.
- the present invention is a piroxicam-containing transdermal absorption patch in which the mixing ratio of piroxicam and oxybuprocaine or a pharmaceutically acceptable salt thereof is piroxicam: oxybuprocaine ⁇ 1: 2.
- the patch base is a rubber polymer
- the rubber polymer is a piroxicam-containing transdermal absorption patch, which is a styrene-isoprene-styrene block copolymer.
- a piroxicam-containing percutaneous absorption patch comprising piroxicam as a medicinal ingredient and oxybuprocaine or a pharmaceutically acceptable salt thereof as an absorption accelerator.
- a specific amount of oxybuprocaine as an absorption enhancer for piroxicam is incorporated into the patch base in combination with piroxicam, so that the release of oxybuprocaine is not greatly impaired and high release of piroxicam is achieved. Therefore, it is possible to provide a transdermally absorbable preparation that exhibits excellent anti-inflammatory analgesic effect.
- the absorption promoting effect by the addition of oxybuprocaine is specific only to piroxicam among oxicam anti-inflammatory analgesics. Therefore, the medical effect of the present invention is great in that a patch which is a transdermally absorbable preparation containing piroxicam which is extremely useful clinically can be provided.
- FIG. 6 is a graph showing the results of an in vitro rat skin permeability test for piroxicam based on contrast study (1) -5. 6 is a graph showing the results of an in vitro rat skin permeability test for oxybuprocaine based on contrast study (1) -5.
- FIG. 7 is a graph showing the results of an in vitro rat skin permeability test for piroxicam based on contrast study (1) -6.
- 6 is a graph showing the results of an in vitro rat skin permeability test for oxybuprocaine based on Comparative Study (1) -6. It is a graph which shows the result of the in-vitro rat skin permeability test regarding meloxicam based on contrast examination (2). It is a graph which shows the result of the in-vitro rat skin permeability test regarding oxybuprocaine based on contrast study (2).
- the present invention is a piroxicam-containing percutaneous absorption patch comprising piroxicam as a medicinal ingredient and oxybuprocaine or a pharmaceutically acceptable salt thereof as an absorption enhancer.
- the compounding amount of piroxicam which is an active ingredient in the patch of the present invention, is 0.1 to 5% by weight, preferably 0.1 to 3% by weight, particularly preferably 0.1% by weight based on the total weight of the drug-containing plaster. 1 to 2% by weight. If the amount of piroxicam is less than 0.1% by weight, the effect of piroxicam may not be sufficiently obtained, and even if it exceeds 5% by weight, the effect of promoting absorption by oxybuprocaine is reduced. Therefore, it is not preferable.
- oxybuprocaine blended with piroxicam itself exhibits analgesic action as a local anesthetic, and acts as an absorption accelerator for piroxicam in the present invention.
- the amount of oxybuprocaine is preferably 1 to 30% by weight, more preferably 1 to 20% by weight, based on the total weight of the drug-containing plaster. If the blending amount is less than 1% by weight, the skin permeability of piroxicam cannot be sufficiently increased, and conversely, even if blending more than 30% by weight, the blending effect of oxybuprocaine cannot be expected. On the other hand, it may cause skin irritation or may impair the physical properties of the plaster, which is not preferable.
- the mixing ratio of piroxicam and oxybuprocaine is preferably set to piroxicam: oxybuprocaine ⁇ 1: 2. More preferably, piroxicam: oxybuprocaine ⁇ 1:10, and particularly preferably piroxicam: oxybuprocaine ⁇ 1:15.
- the plaster composition used in the patch provided by the present invention can be prepared by mixing piroxicam and oxybuprocaine with a patch base component.
- a patch base component is not particularly limited as long as it becomes a base of the adhesive layer that is a plaster composition, but is hydrophobic such as rubber polymer, acrylic polymer, and silicon polymer. Polymers are preferably used.
- Examples of rubber polymers include styrene-isoprene-styrene block copolymer (hereinafter referred to as SIS), polyisobutylene (hereinafter referred to as PIB), and styrene-butadiene-styrene block copolymer (hereinafter referred to as SBS). ), Styrene-butadiene rubber (hereinafter referred to as SBR), isoprene rubber and the like, among which SIS is particularly preferable.
- SIS styrene-isoprene-styrene block copolymer
- PIB polyisobutylene
- SBS styrene-butadiene-styrene block copolymer
- SBR Styrene-butadiene rubber
- isoprene rubber and the like among which SIS is particularly preferable.
- the acrylic polymer is a copolymer obtained by containing at least one (meth) acrylic acid derivative represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate, etc.
- the acrylic acid / octyl acrylate ester copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone acrylate which are listed as adhesives in the Pharmaceutical Additives Dictionary 2007 (edited by Japan Pharmaceutical Additives Association).
- Copolymer solution acrylic ester-vinyl acetate copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, methyl acrylate-2-ethylhexyl acrylate copolymer resin
- Emma John acrylic polymer alkanolamine liquid-containing pressure sensitive adhesive, DURO-TAK acrylic pressure sensitive adhesive series (National Starch and Chemical Co., Ltd.), Eudragit series (Higuchi Shokai), etc. can be used. .
- a silicone rubber such as polyorganosiloxane can be given as a specific example of the silicon polymer.
- Two or more of these hydrophobic polymers may be used as a mixture, and the blending amount based on the total mass of these polymers is determined in consideration of the formation of the adhesive layer and sufficient drug permeability. 5 to 80% by weight, preferably 10 to 70% by weight, more preferably 10 to 50% by weight.
- the adhesive composition in the patch that is a transdermally absorbable preparation provided by the present invention may contain a plasticizer.
- Plasticizers that can be used include petroleum oils (eg, paraffinic process oils such as liquid paraffin, naphthenic process oils, aromatic process oils), squalane, squalene, vegetable oils (eg, olive oil, camellia oil) , Tall oil, peanut oil, castor oil, etc.), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), liquid fatty acid esters (eg, myristin) Isopropyl acid, hexyl laurate, diethyl sebacate, diisopropyl sebacate, etc.). Liquid paraffin is particularly preferable.
- the blending amount based on the entire composition of the adhesive layer of such a plasticizer is a total in consideration of maintaining sufficient cohesive strength as a patch. It is 1 to 70% by weight, preferably 10 to 60% by weight, and more preferably 10 to 50% by weight.
- tackifier resins that can be used include rosin derivatives (eg, rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester, rosin pentaerythrester, etc.), alicyclic saturated hydrocarbon resins (eg, alkone). P100, Arakawa Chemical Industries), aliphatic hydrocarbon resins (for example, Quinton B170, Nippon Zeon), terpene resins (for example, Clearon P-125, Yasuhara Chemical), maleic resin, and the like.
- the blending amount of such a tackifying resin based on the entire composition of the pressure-sensitive adhesive composition is 5 to 70% by weight, preferably in consideration of sufficient adhesive strength as a patch preparation and irritation to the skin upon peeling. It can be 5 to 60% by weight, more preferably 10 to 50% by weight.
- an antioxidant if necessary, an antioxidant, a filler, a crosslinking agent, an antiseptic, and an ultraviolet absorber can be used.
- an antioxidant tocopherol and an ester derivative thereof, ascorbic acid, ascorbic acid stearate ester , Nordi-human log ayaretinic acid, dibutylhydroxytoluene (hereinafter referred to as BHT), butylhydroxyanisole and the like are desirable.
- filler calcium carbonate, magnesium carbonate, silicate (eg, aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like are desirable.
- silicate eg, aluminum silicate, magnesium silicate, etc.
- silicic acid barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like are desirable.
- crosslinking agent examples include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. desirable.
- parabens such as ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate are desirable.
- UV absorber p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, amino acid compounds, dioxane derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, and the like are desirable.
- Such antioxidants, fillers, crosslinking agents, preservatives, UV absorbers are 10 wt% or less, preferably 5 wt% or less, more preferably based on the total mass of the adhesive layer of the preparation. It can mix
- the patch which is the transdermally absorbable preparation of the present invention having the composition as described above can be produced by any method.
- a method generally referred to as a hot melt method in which a base component containing a drug is melted by heat, applied to a release film or a support, and then bonded to the support or the release film to obtain this agent, or generally a solvent method
- the base component containing the drug is dissolved in an organic solvent such as toluene, hexane, ethyl acetate, and N-methyl-2-pyrrolidone, stretched onto a release film or support, applied, and the solvent is dried.
- the thickness of the pressure-sensitive adhesive layer in the patch that is a transdermal preparation for external use provided by the present invention is not particularly limited, but is usually 500 ⁇ m or less, preferably 20 to 300 ⁇ m.
- a stretchable or non-stretchable support can be used.
- it is selected from cloth, non-woven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate (hereinafter abbreviated as PET), aluminum sheet, or a composite material thereof.
- the release film protects the adhesive layer until the patch, which is a transdermally absorbable preparation, is applied to the skin, does not alter the main ingredient, and is coated with silicon so that it can be easily peeled off.
- specific examples thereof include a silicon film coated polyethylene film, PET film or polypropylene film.
- Example 1 0.5% piroxicam / 20% oxybuprocaine combination preparation An external patch containing both piroxicam and oxybuprocaine was prepared. (Prescription) SIS 25% Liquid paraffin 11.5% BHT 1% Hydrogenated rosin glycerin ester 42% Oxybuprocaine 20% Piroxicam 0.5% Total amount 100%
- Piroxicam was previously dissolved in N-methyl-2-pyrrolidone, and oxybuprocaine was dissolved in toluene and mixed with the remaining base components previously dissolved in toluene. After the mixture was applied onto a release film, toluene and N-methyl-2-pyrrolidone were removed by drying and bonded to a PET film support to obtain a desired transdermally absorbable preparation (adhesive layer thickness 100 ⁇ m). .
- Example 2 to Example 6 According to the formulation shown in Table 1 below, the percutaneously absorbable preparations of Examples 2 to 6 of the present invention were obtained according to the method described in Example 1 above. In the table, the formulation of Example 1 is also shown.
- Comparative Examples 1 to 12 According to the formulation shown in Table 2 below, percutaneous absorption preparations of Comparative Examples 1 to 12 were obtained according to the method described in Example 1 above.
- Test Example 1 Rat skin permeability test Comparison study in Table 3 (1) -1, Comparison study (1) -5 and Comparison study (1) -6, and each preparation used for the comparison study (2) An in vitro skin permeability test was conducted using rat (Wistar, 8-week-old) isolated skin, and the release properties of piroxicam and oxybuprocaine in the external patch containing both piroxicam and oxybuprocaine of the present invention Specificity was examined.
- Test Example 2 Rat skin permeability test Male hairless rats (HWY strain) for each preparation used in the comparison study (1) -2, comparison study (1) -3, and comparison study (1) -4 in Table 3 above , 7 weeks old) In vitro skin permeability test using excised skin to examine the specificity of piroxicam and oxybuprocaine release in external patches containing both piroxicam and oxybuprocaine of the present invention did.
- the rat abdominal skin was peeled, the dermis side was the receptor layer side, the inside was filled with phosphate buffered saline, and warm water at 37 ° C. was refluxed to the water jacket.
- Each test preparation was punched into a circular shape (1.77 cm 2 ), the excised skin was affixed, the receptor fluid was sampled over time, and each drug (oxybuprocaine, piroxicam) was sampled by high performance liquid chromatography. The amount of permeation was measured.
- the external patches of Examples 1 to 3 in which the mixing ratio of piroxicam and oxybuprocaine is piroxicam: oxybuprocaine ⁇ 1:15 are almost the same as the comparative examples in which only the corresponding oxybuprocaine is blended. It showed the release of oxybuprocaine. Taking these results into account, the patch for external use containing both piroxicam and oxybuprocaine of the present invention has improved release of piroxicam due to good release of oxybuprocaine as an absorption enhancer. Is understood.
- the release effect of the anti-inflammatory analgesic agent which is an active ingredient obtained by blending this oxybuprocaine, is specific only to piroxicam among oxicam anti-inflammatory analgesics, and is extremely excellent in the present invention. Specificity is understood.
- Adhesive layer thickness 100 ⁇ m
- the percutaneous absorption preparation provided by the present invention can provide a preparation exhibiting an excellent analgesic effect by oxybuprocaine and an excellent anti-inflammatory effect by piroxicam.
- a specific amount of oxybuprocaine and piroxicam as an absorption enhancer for piroxicam is combined in a patch base, so that the release of oxybuprocaine is not greatly impaired and high release of piroxicam is achieved.
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Abstract
Description
これは、貼付剤製剤に配合される吸収促進剤の放出に伴い、非ステロイド系消炎鎮痛剤の放出が促進され、その結果優れた経皮吸収性を示し、効果的な経皮吸収貼付剤となる考え方に基づいている。
これまでに、オキシカム系消炎鎮痛剤についての外用剤としては、ピロキシカムの軟膏剤が知られているが、ピロキシカムを含有する外用貼付剤は登場していない。
その結果、ピロキシカムを含有する外用貼付剤において、ピロキシカムに対する経皮吸収促進剤として局所麻酔剤であるオキシブプロカインを特定量配合した場合には、オキシブプロカインの吸収促進効果により、ピロキシカムの極めて良好な経皮吸収性が得られること、更には、かかる効果は、オキシブプロカインとピロキシカムとの組合せによる特異的な効果であることを新規に見出し、本発明を完成させるに至った。
そのなかでも、特に、非ステロイド性消炎鎮痛剤としてピロキシカムを配合した貼付剤において、ピロキシカムに対する吸収促進剤としてオキシブプロカインを配合させ、互いの薬物放出性を大きく抑制することなく、高い消炎鎮痛効果を発揮するピロキシカム含有経皮吸収貼付剤を提供することを課題とする。
特に本発明は、貼付剤基剤中に、ピロキシカムに対する吸収促進剤としてのオキシブプロカインをピロキシカムと組み合わせて特定量配合するにより、オキシブプロカインの放出性を大きく損なうことなく、かつピロキシカムの高い放出性が維持され、その結果、優れた消炎鎮痛効果を発揮する経皮吸収製剤を提供できるものである。
したがって、臨床的に極めて有用なピロキシカムを含有する経皮吸収製剤である貼付剤を提供できる点で、本発明の医療上の効果は多大なものである。
本発明の貼付剤における有効成分であるピロキシカムの配合量は、薬物含有膏体全重量に対して0.1~5重量%であり、好ましくは0.1~3重量%、特に好ましくは0.1~2重量%である。
ピロキシカムの配合量が、0.1重量%未満であるとピロキシカムの薬効が十分に得られない場合があり、また、5重量%を超えて配合しても、オキシブプロカインによる吸収促進効果が低下するため好ましいものでない。
その場合のオキシブプロカインの配合量は、薬物含有膏体全重量に対して1~30重量%配合するのが好ましく、より好ましくは1~20重量%である。
配合量が1重量%未満であると、ピロキシカムの皮膚透過性を十分に高めることができず、逆に30重量%を超えて配合しても、オキシブプロカインの配合効果は期待できないばかりか、かえって皮膚刺激を生じたり、膏体の物性を損なったりする場合があるため、好ましいものではない。
本発明者らの検討の結果、ピロキシカムとオキシブプロカインの配合量における配合比を、ピロキシカム:オキシブプロカイン<1:2とするのが好ましいことが判明した。より好ましくはピロキシカム:オキシブプロカイン<1:10であり、特に好ましくは、ピロキシカム:オキシブプロカイン<1:15とするのがよい。
ピロキシカムとオキシブプロカインの配合比率を1:2より高くしても(すなわち、ピロキシカムの配合比率をそれより高くしても)、ピロキシカムの放出性は頭打ち傾向となり、逆にオキシブプロカインの放出が抑制されてくる。
かかる貼付剤基剤成分は、膏体組成物である粘着剤層の基剤となるものであれば特に限定されないが、ゴム系高分子、アクリル系高分子、およびシリコン系高分子等の疎水性高分子が好ましく使用される。
例えば、一般にホットメルト法と呼ばれる、薬物を含む基剤成分を熱融解させ、剥離フィルム又は支持体に塗工後、支持体又は剥離フィルムと貼り合わせて本剤を得る方法と、もしくは一般に溶媒法と呼ばれる、薬物を含む基剤成分をトルエン、ヘキサン、酢酸エチル、およびN-メチル-2-ピロリドン等の有機溶媒に溶解させ、剥離フィルム又は支持体上に伸展して塗工し、溶剤を乾燥除去後、支持体又は剥離フィルムと貼り合わせ本剤を得る方法である。
なお、以下の記載において、%は、特に示さない限り全て重量%を意味する。
ピロキシカムとオキシブプロカインの両者を配合した外用貼付剤を調製した。
(処方)
SIS 25%
流動パラフィン 11.5%
BHT 1%
水添ロジングリセリンエステル 42%
オキシブプロカイン 20%
ピロキシカム 0.5%
全 量 100%
予め、ピロキシカムをN-メチル-2-ピロリドンに溶解させ、およびオキシブプロカインをトルエンに溶解させ、それらを予めトルエンに溶解させた残りの基剤成分と混合した。混合物を剥離フィルム上に塗工後、トルエン、およびN-メチル-2-ピロリドンを乾燥除去し、PETフィルム支持体と貼り合わせて、所望の経皮吸収製剤(粘着層の厚み100μm)を得た。
下記表1に示す配合により、上記実施例1に記載の方法に準じ、本発明の実施例2~実施例6の経皮吸収製剤を得た。なお、表中には合わせて実施例1の配合も記載した。
下記表2に示す配合により、上記実施例1に記載の方法に準じ、比較例1~比較例12の経皮吸収製剤を得た。
[対比検討]
(1)本発明のピロキシカム及びオキシブプロカインの両者を配合した外用貼付剤である実施例1~6の製剤と、ピロキシカムのみを配合した比較例1~5の製剤、及びオキシブプロカインのみを配合した比較例6~10の製剤について、各実施例と、それに対応する各比較例との対比による、ピロキシカム及び/又はオキシブプロカインの放出性の検討。(それぞれの実施例とそれに対応する比較例の組み合わせは表3に示す。)
表3における対比検討(1)-1、対比検討(1)-5および対比検討(1)-6、ならびに対比検討(2)に使用する各製剤について、雄性ラット(ウィスター系、8週齢)の摘出皮膚を使用したin vitro皮膚透過性試験を行い、本発明のピロキシカム及びオキシブプロカインの両者を配合した外用貼付剤におけるピロキシカム及びオキシブプロカインの放出性の特異性を検討した。
ラットの腹部皮膚を剥離し、真皮側をレセプター層側にし、その内側にはリン酸緩衝生理食塩水を満たし、ウォータージャケットには37℃の温水を還流させた。供試の各製剤を、円状(1.77cm2)に打ち抜き、摘出皮膚に貼付し、経時的にレセプター液をサンプリングし、高速液体クロマトグラフ法により、各薬物(オキシブプロカイン、ピロキシカム、メロキシカム)の透過量を測定した。
上記表3における対比検討(1)-2、対比検討(1)-3、および対比検討(1)-4に使用する各製剤について、雄性ヘアレスラット(HWY系、7週齢)の摘出皮膚を使用したin vitro皮膚透過性試験を行い、本発明のピロキシカム及びオキシブプロカインの両者を配合した外用貼付剤におけるピロキシカム及びオキシブプロカインの放出性の特異性を検討した。
ラットの腹部皮膚を剥離し、真皮側をレセプター層側にし、その内側にはリン酸緩衝生理食塩水を満たし、ウォータージャケットには37℃の温水を還流させた。供試の各製剤を、円状(1.77cm2)に打ち抜き、摘出皮膚を貼付し、経時的にレセプター液をサンプリングし、高速液体クロマトグラフ法により、各薬物(オキシブプロカイン、ピロキシカム)の透過量を測定した。
その結果を図1~図14に示した。なお表4に各図の対応関係を示す。
対比検討(1)に対する考察
表4に示した対応関係にある図の対比より明らかなように、ピロキシカムとオキシブプロカインの両者を配合した本発明の外用貼付剤は、ピロキシカムのみを配合した各比較例の外用貼付剤と比較して、ピロキシカムの放出性は、飛躍的に高いものであった(図1、図3、図5、図7、図9及び図11)。
また、本発明の外用貼付剤は、オキシブプロカインのみを配合した各比較例の外用貼付剤と比較して、オキシブプロカインの放出性が大きく抑制されることはなかった。特にピロキシカムとオキシブプロカインの配合比率がピロキシカム:オキシブプロカイン<1:15である実施例1~実施例3の外用貼付剤は、それぞれ対応するオキシブプロカインのみ配合する比較例と、ほぼ同等なオキシブプロカインの放出性を示していた。
この両者の結果を加味すると、本発明のピロキシカムとオキシブプロカインの両者を配合した外用貼付剤は、吸収促進剤としてのオキシブプロカインの良好な放出性により、ピロキシカムの放出性も高まっていることが理解される。
一方、同様な試験を、別のオキシカム系消炎鎮痛剤であるメロキシカムについて検討した場合には、オキシブプロカインについては、メロキシカムの配合の有無に関わらず、ほぼ同等の薬物放出性を示した(図13)ものの、メロキシカムの放出性については、オキシブプロカインの配合により、大きく抑制されていることが判明した(図14)。
以下に、上記の実施例1に示した本発明の外用貼付剤以外の具体的製剤例を、下記表5に示した。但し、本発明はこれらに限定されるものではない。
特に本発明は、貼付剤基剤中に、ピロキシカムに対する吸収促進剤としてのオキシブプロカインとピロキシカムを組み合わせて特定量配合するにより、オキシブプロカインの放出性を大きく損なうことなく、かつピロキシカムの高い放出性が維持され、その結果、優れた消炎鎮痛効果を発揮する経皮吸収製剤を提供できるものであり、その医療上の効果は多大なものである。
Claims (7)
- 薬効成分としてピロキシカム、及び吸収促進剤としてオキシブプロカイン又はその薬学的に許容される塩を含有してなることを特徴とするピロキシカム含有経皮吸収貼付剤。
- ピロキシカムの含有量が、薬物含有膏体全重量に対して0.1~5重量%である請求項1に記載のピロキシカム含有経皮吸収貼付剤。
- オキシブプロカイン又はその薬学的に許容される塩の含有量が、薬物含有膏体全重量に対して1~30重量%である請求項1に記載のピロキシカム含有経皮吸収貼付剤。
- ピロキシカムとオキシブプロカイン又はその薬学的に許容される塩の配合比が、ピロキシカム:オキシブプロカイン<1:2である請求項1、2又は3に記載のピロキシカム含有経皮吸収貼付剤。
- ピロキシカムとオキシブプロカイン又はその薬学的に許容される塩の配合比が、ピロキシカム:オキシブプロカイン<1:10である請求項1、2又は3に記載のピロキシカム含有経皮吸収貼付剤。
- 貼付剤基剤が、ゴム系高分子である請求項1ないし5のいずれかに記載のピロキシカム含有経皮吸収貼付剤。
- ゴム系高分子が、スチレン-イソプレン-スチレンブロック共重合体である請求項6に記載のピロキシカム含有経皮吸収貼付剤。
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JP2011546127A JP5748346B2 (ja) | 2009-12-15 | 2010-12-14 | ピロキシカム含有経皮吸収製剤 |
US13/516,014 US9119861B2 (en) | 2009-12-15 | 2010-12-14 | Piroxicam-containing transdermally absorbable preparation |
CN201080063932.0A CN102753178B (zh) | 2009-12-15 | 2010-12-14 | 含吡罗昔康的经皮吸收制剂 |
AU2010331355A AU2010331355B2 (en) | 2009-12-15 | 2010-12-14 | Piroxicam-containing endermic preparation |
CA2783964A CA2783964C (en) | 2009-12-15 | 2010-12-14 | Piroxicam-containing transdermally absorbable preparation |
ES10837591.6T ES2626597T3 (es) | 2009-12-15 | 2010-12-14 | Preparación endérmica que contiene piroxicam |
EP10837591.6A EP2514424B1 (en) | 2009-12-15 | 2010-12-14 | Piroxicam-containing endermic preparation |
HK13100182.3A HK1172846A1 (zh) | 2009-12-15 | 2013-01-07 | 含吡羅昔康的經皮吸收製劑 |
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CN104173322B (zh) * | 2014-09-16 | 2017-06-06 | 徐淑峰 | 一种含吡罗昔康的经皮吸收制剂及其制备方法 |
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TWI498399B (zh) | 2015-09-01 |
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CN102753178A (zh) | 2012-10-24 |
EP2514424A1 (en) | 2012-10-24 |
US20120309749A1 (en) | 2012-12-06 |
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CA2783964C (en) | 2017-09-12 |
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AU2010331355B2 (en) | 2014-04-24 |
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US9119861B2 (en) | 2015-09-01 |
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