WO2012060376A1 - フェルビナク含有外用貼付剤 - Google Patents
フェルビナク含有外用貼付剤 Download PDFInfo
- Publication number
- WO2012060376A1 WO2012060376A1 PCT/JP2011/075182 JP2011075182W WO2012060376A1 WO 2012060376 A1 WO2012060376 A1 WO 2012060376A1 JP 2011075182 W JP2011075182 W JP 2011075182W WO 2012060376 A1 WO2012060376 A1 WO 2012060376A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- felbinac
- weight
- styrene
- patch
- drug
- Prior art date
Links
Classifications
-
- 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
-
- 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
- A61K9/7007—Drug-containing films, membranes or sheets
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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 percutaneously absorbable external anti-inflammatory analgesic preparation, and more particularly to a felbinac-containing anti-inflammatory analgesic external patch having good drug release, low skin irritation and high drug stability.
- Felbinac (Felbinac: 4-biphenylacetic acid) is an active metabolite of the non-steroidal anti-inflammatory analgesic agent fenbufen, and is a drug exhibiting a strong anti-inflammatory analgesic action. Since felbinac has the problem of causing side effects in the digestive system and causing gastrointestinal disorders when administered orally, it has been studied as a percutaneous absorption preparation. To date, gels, liquids, etc. External preparations are commercially available.
- aqueous patches (patches) and oil-based patches (plasters) containing various anti-inflammatory analgesics such as felbinac have been developed.
- oil-based patches (plasters) have become mainstream as non-steroidal anti-inflammatory analgesic patches for reasons such as no cooling sensation when applied, and combined a rubber base and a tackifying resin. Prescriptions are widely used.
- L-menthol is useful as a solubilizing agent for felbinac and is an additive blended in many commercially available felbinac-containing patches.
- fervinac reacts with L-menthol to produce an L-menthol ester which is a decomposition product, and the formulation of L-menthol stabilizes ferbinac in the patch. It is one of the causes of sexual deterioration.
- many people feel uncomfortable with the irritating odor associated with sublimation of L-menthol and it is also true that there is a high demand for patch preparations that do not contain L-menthol or suppress L-menthol odor in the market. .
- Patent Document 1 proposes a felbinac-containing patch having a pressure-sensitive adhesive layer containing crotamiton, which is excellent in dissolving ability for felbinac, as an essential component.
- crotamiton has a problem that it tends to bleed out on the surface of the pressure-sensitive adhesive layer, and the adhesive force decreases with time.
- Patent Document 2 discloses an anti-inflammatory analgesic tape agent containing felbinac, in which styrene-isoprene-styrene block copolymer is used as an adhesive and L-menthol and various absorption accelerators are combined.
- L-menthol blended with this tape may react with ferbinac to produce a decomposition product, and in addition, by combining L-menthol and an absorption accelerator.
- L-menthol blended with this tape may react with ferbinac to produce a decomposition product, and in addition, by combining L-menthol and an absorption accelerator.
- Patent Document 3 discloses a felbinac-containing patch containing terpene, sebacic acid ester, and alkyl glyceryl ether. Similar to Patent Document 2, the stability of the drug, the physical properties of the base, and skin irritation are disclosed. There is room for improvement in gender.
- a patch containing various percutaneous absorption accelerators such as felbinac patch containing a combination of N-methyl-2-pyrrolidone and polyethylene glycol (Patent Document 4) and one containing hardened oil (Patent Document 5). Although agents have been studied, no percutaneously absorbable preparations having both high percutaneous absorption and safety of drugs and excellent drug stability have been found.
- Patent Document 6 discloses a water-containing plaster agent in which lanolin is blended in an adhesive base based on a styrene-isoprene-styrene block copolymer so that the lanolin retains moisture. This is an attempt to increase the solubility of felbinac by the moisture contained in the preparation and, as a result, improve the transdermal absorbability.
- the inclusion of moisture in the oily patch makes the manufacturing process complicated.
- the possibility of deterioration of physical properties of the preparation during storage cannot be denied.
- percutaneous absorption there is a problem that it is slightly inferior to a plaster using a transdermal absorption enhancer.
- Patent Document 7 proposes a patch in which felbinac is uniformly dispersed in an adhesive base containing rosin-based resin and the like based on styrene-isoprene-styrene block copolymer without using crotamiton.
- the rosin resin blended in the patch acts as a skin sensation preparation, and the blending is undesirable.
- Skin sensitization is a type of delayed hypersensitivity reaction, which is a phenomenon in which an excessive immune reaction is caused by a chemical substance, causing skin irritation and the like.
- the present invention solves the above-mentioned problems, and exhibits high drug release without blending L-menthol, which is an excellent solubilizing agent for felbinac, and has low skin irritation and high drug stability. It is an object of the present invention to provide a felbinac-containing external patch that can be exerted.
- the inventor contains a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, a softener, and diethyl sebacate, -Disperse and blend felbinac with an average particle size of 5 ⁇ m or more and less than 100 ⁇ m in an adhesive base that does not contain menthol, resulting in low skin irritation and excellent drug release and drug stability of felbinac.
- the present invention has been completed by finding out that it is a patch for external use which is also combined.
- an adhesive base containing no styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, a softener, and diethyl sebacate does not contain L-menthol.
- This is a felbinac-containing external patch characterized by having dispersed and blended felbinac having a particle size of 5 ⁇ m or more and less than 100 ⁇ m.
- the present invention does not contain L-menthol, styrene-isoprene-styrene block copolymer 10 to 30% by weight, alicyclic saturated hydrocarbon resin 10 to 50% by weight, softener 10 to 75% by weight And felbinac having an average particle size of 5 ⁇ m or more and less than 100 ⁇ m and 0.1 to 10% by weight of felbinac dispersed in 0.1% to 10% by weight of diethyl sebacate It is a patch for external use.
- the present invention it is possible to provide a felbinac-containing external patch that exhibits excellent drug release, low skin irritation, and high drug stability in a percutaneous absorption preparation containing felbinac. .
- the external patch containing felbinac provided by the present invention is effective for the anti-inflammatory analgesic effect of felbinac. It is useful for the prevention and treatment of flame (tennis elbow etc.), muscle pain, swelling and pain after trauma.
- the basic aspect of the present invention does not contain L-menthol and comprises a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, a softening agent, and diethyl sebacate.
- a felbinac-containing external patch characterized in that a felbinac having an average particle diameter of 5 ⁇ m or more and less than 100 ⁇ m is dispersed and blended into an adhesive base.
- the present invention is characterized in that felbinac as an active ingredient is dispersed in the adhesive base layer using a felbinac having an average particle diameter of 5 ⁇ m or more and less than 100 ⁇ m.
- the blending amount of the active ingredient felbinac in the preparation is not particularly limited as long as it can be formulated, but is preferably 0.1 to 10% by weight, more preferably 0. It is preferable to blend in the range of 5 to 6% by weight. If the amount of felbinac in the pressure-sensitive adhesive is less than 0.1% by weight, the transdermal absorbability is insufficient, and no effect is observed. An effect is not recognized and it is economically disadvantageous and is not preferable.
- the average particle size is 5 ⁇ m or more and less than 100 ⁇ m, more preferably 10 ⁇ m, considering the dispersibility in the adhesive or the workability of the production process. It is preferable to use one having a thickness of less than 70 ⁇ m, particularly preferably 15 ⁇ m or more and less than 40 ⁇ m. If the average particle size is less than 5 ⁇ m, the ferbinac drug substance may undergo secondary aggregation in the production process and may not be uniformly dispersed, resulting in a decrease in the transdermal absorbability of the drug. Conversely, if the average particle size is 100 ⁇ m or more, the drug may not be uniformly dispersed in the adhesive.
- the particle size is large, not only the percutaneous absorbability of the drug is lowered, but also unfavorable effects are observed in the production process, particularly in the process of applying the adhesive to the release film. That is, the Felbinac drug substance aggregates during production, and unevenness of the pressure-sensitive adhesive surface due to the aggregation may be observed.
- a styrene-isoprene-styrene block copolymer (hereinafter sometimes abbreviated as SIS) blended in the present invention is a synthetic rubber which is a basic skeleton of an adhesive, and its blending amount is 10 to 30% by weight. , Preferably in the range of 10 to 20% by weight.
- SIS styrene-isoprene-styrene block copolymer blended in the present invention
- SIS styrene-isoprene-styrene block copolymer blended in the present invention
- SIS styrene-isoprene-styrene block copolymer blended in the present invention
- SIS styrene-isoprene-styrene block copolymer
- an alicyclic saturated hydrocarbon resin is preferably used as the tackifier resin in consideration of safety to the skin.
- alicyclic saturated hydrocarbon resins include Alcon P90, P100, and P115 (Arakawa Chemical Industries, Ltd.).
- the blending amount is not particularly limited as long as it can be formulated, but it is preferably blended within a range of 10 to 50% by weight with respect to the weight of the pressure-sensitive adhesive.
- the content of the alicyclic saturated hydrocarbon resin in the pressure-sensitive adhesive is less than 10% by weight, the adhesive strength is weak, and when the content exceeds 50% by weight, the adhesive strength of the preparation becomes strong and painful at the time of peeling. There is.
- Diethyl sebacate used in the present invention functions as a skin absorption enhancer for felbinac.
- the amount of diethyl sebacate is not particularly limited as long as it can be formulated, but is preferably within a range of 0.1 to 10% by weight, more preferably 1 to 7% by weight with respect to the weight of the adhesive. It is good to mix. If the blending amount of diethyl sebacate in the adhesive is less than 0.1% by weight, the skin permeability of felbinac is insufficient, and if it exceeds 10% by weight, problems such as skin irritation occur, which is preferable. is not.
- the blending ratio is less than 1: 0.1, the effect of promoting absorption by diethyl sebacate cannot be obtained, and sufficient drug absorbability cannot be obtained.
- felbinac dissolves in excess diethyl sebacate, resulting in a preparation with low drug stability.
- the softener blended in the present invention gives flexibility to the adhesive, and liquid rubber such as liquid polybutene, liquid polyisoprene, and liquid polyisobutylene; paraffin oil such as liquid paraffin; isopropyl myristate, diisopropyl adipate Fatty acid esters such as: higher alcohols such as octyldodecanol; silicone oil; lanolin; squalane; squalene; castor oil, and the like, preferably liquid polybutene and liquid paraffin.
- the blending amount of the softening agent is 10 to 75% by weight, preferably 15 to 60% by weight, more preferably 20 to 50% by weight based on the weight of the pressure-sensitive adhesive.
- the base component is not particularly limited, but for example, a hydrophobic elastomer such as a styrene-butadiene-styrene block copolymer, a rubber elastomer such as a styrene-butadiene rubber, a natural rubber, or an isoprene rubber, a polyacrylic acid polymer, or a silicone rubber.
- a hydrophobic elastomer such as a styrene-butadiene-styrene block copolymer
- a rubber elastomer such as a styrene-butadiene rubber, a natural rubber, or an isoprene rubber
- a polyacrylic acid polymer or a silicone rubber.
- Polymer Dibutylhydroxytoluene, pentaerythrityl-tetrakis- [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate], antioxidant such as tocopherol acetate, aluminum hydroxide, hydrous silicic acid Examples include inorganic fillers such as aluminum, titanium oxide, zinc oxide, anhydrous silicic acid, and magnesium silicate. Furthermore, absorption promoters, preservatives, refreshing agents, bactericides, flavoring agents, coloring agents and the like can be added as necessary.
- the support of the patch of the present invention various supports used in ordinary external preparations can be used as long as they do not affect others.
- the support is not particularly limited, and for example, a porous body such as polyethylene, polypropylene, polyvinyl chloride, polyester, nylon, polyurethane and rayon, a foam, a woven fabric, a laminate with a nonwoven fabric, and the like are used.
- release liner used in the patch of the present invention various types of liners used in ordinary external preparations can be used as long as they do not affect others. Although it does not specifically limit as this release liner, For example, a polyethylene terephthalate film, a polypropylene film, paper etc. can be used, and a polyethylene terephthalate film is especially preferable.
- the release liner may be subjected to silicone treatment as necessary in order to optimize the peeling force from the pressure-sensitive adhesive layer.
- the external patch provided by the present invention can be produced, for example, as follows. That is, the SIS, the softener, the alicyclic saturated hydrocarbon resin, and the antioxidant constituting the pressure-sensitive adhesive layer are heated and dissolved. Next, the active ingredients felbinac and diethyl sebacate are added to the adhesive base and stirred and mixed to prepare an adhesive in the patch. Next, the prepared pressure-sensitive adhesive (plaster) is applied onto a silicone-treated polyethylene terephthalate film to form a pressure-sensitive adhesive layer having a thickness of 50 to 300 ⁇ m. After laminating a polyester woven fabric or non-woven fabric as a support to the obtained pressure-sensitive adhesive layer, it can be cut into an appropriate size and shape to obtain the external patch of the present invention.
- Example 1 After kneading and melting SIS, polybutene, liquid paraffin, and dibutylhydroxytoluene at 170 ° C. under heating conditions, an alicyclic saturated hydrocarbon resin is further added, and kneading under 130 ° C. under heating conditions. Admixed to prepare an adhesive base. Separately, felbinac having an average particle size of 5 ⁇ m or more and less than 100 ⁇ m was uniformly dispersed with stirring in a liquid in which diethyl sebacate and an appropriate amount of liquid paraffin were mixed to prepare a felbinac dispersion.
- This felbinac dispersion was added to the above-mentioned adhesive base and kneaded until it was uniformly dispersed to prepare an adhesive.
- the pressure-sensitive adhesive was applied to a silicone-treated polyethylene terephthalate film with a thickness of 100 ⁇ m and then laminated with a polyester woven fabric to obtain a test preparation.
- Examples 2 to 16 The target patch of the present invention was prepared according to the composition shown in Tables 1 to 3 in the same procedure as in Example 1.
- Comparative Examples 1 to 7 The patch for external use of each comparative example was produced in the same procedure as Example 1 except changing to the component composition shown in Table 4 below. In the preparation of Comparative Example 7, the ferbinac drug substance aggregated during production (at the time of preparation of the adhesive), which caused irregularities on the surface of the preparation, and the following preparation evaluation test could not be performed.
- Test Example 1 Human skin primary irritation test (human patch test) The preparations of Examples 1 and 2 and Comparative Examples 1 and 2 were each punched out to 25 mm in diameter and applied to the inside of the upper arm of 15 healthy men for 24 hours, and skin irritation at 1 hour and 24 hours after peeling was determined. The results are shown in Table 5 below.
- Test Example 2 Residual human sticking test The preparations of Example 1 and Comparative Examples 3 to 4 were each punched out to 5 cm ⁇ 7 cm, applied to the back of 6 healthy boys for 12 hours, and the drug remaining in the collected preparation was extracted. The drug amount was measured by HPLC. The amount of drug disappearance was calculated by subtracting the amount of drug remaining from the amount of drug applied for 0 hours. The results are shown in Table 6 below.
- Example 1 which is a patch of the present invention is a preparation having a high drug disappearance amount and a high transdermal absorbability compared with Comparative Examples 3 to 4. .
- Test Example 3 Stability Test Samples (7 cm ⁇ 10 cm) of Example 1, Comparative Example 2 and Comparative Example 5 were stored at 40 ° C. for 3 months, and then the drug in the test preparation was extracted and the content of felbinac was measured. Comparison was made with the felbinac content (initial value) of each sample before the test and calculated as the initial value (%). The results are shown in Table 7.
- Example 1 which is an external patch of the present invention, is superior in drug stability to Comparative Example 2 or Comparative Example 5.
- Test Example 4 Release of main drug
- Each formulation of Example 1, Example 16 and Comparative Example 6 was punched out to a diameter of 20 mm, and the adhesive side was the inner side of the beaker using a double-sided tape on the inner side of a 100 mL beaker. It stuck so that it might face.
- the application position of the preparation was adjusted so that the lowermost part of the preparation was about 30 mm from the bottom of the beaker.
- 100 mL of the release solution PBS buffer solution
- the release solution was stirred with a magnetic stirrer.
- the content of felbinac in the release solution 90 minutes after the start of the test was measured by high performance liquid chromatography, and the release rate of the active ingredient was calculated.
- the results are shown in Table 8.
- Example 1 and Example 16 which are external patches of the present invention, have significantly better release of the active ingredient than the preparation of Comparative Example 6.
- a felbinac-containing anti-inflammatory analgesic external patch that exhibits good drug release, low skin irritation, and high drug stability.
- the external patch of the present invention include osteoarthritis, rheumatoid arthritis, lumbago, shoulder periarthritis, tendonitis, tendonitis, humerus condyle (such as tennis elbow), myalgia, swelling after trauma -It is useful for the prevention and treatment of pain and the like, and its utility is enormous.
Abstract
Description
このようなゲル剤、液剤の問題点を改善するために、フェルビナクを初め、様々な消炎鎮痛薬を含有する水性貼付剤(パップ剤)や油性貼付剤(プラスター剤)が開発されている。とりわけ、油性貼付剤(プラスター剤)は、貼付時の冷感がない等の理由から、非ステロイド系消炎鎮痛貼付剤として主流となってきており、ゴム系基剤と粘着付与樹脂とを組み合わせた処方のものが汎用されている。
また、L-メントールの昇華に伴う刺激臭を不快と感じる人も多く、市場においてもL-メントールを配合しない、或いはL-メントール臭を抑えた貼付製剤の需要が高いことも、また事実である。
例えば特許文献1には、フェルビナクに対する溶解能力に優れているクロタミトンを必須成分として含有させた粘着剤層を有するフェルビナク含有貼付剤が提案されている。しかしながら、クロタミトンは、粘着剤層の表面にブリードアウトしやすく、経時的に粘着力が低下する、という問題を有している。
その他、N-メチル-2-ピロリドンとポリエチレングリコールを組み合わせて配合したフェルビナク貼付剤(特許文献4)、硬化油を配合するもの(特許文献5)等、様々な経皮吸収促進剤を配合した貼付剤が検討されてきているが、高い薬物の経皮吸収性と安全性、および優れた薬物の安定性を兼ね備えた経皮吸収製剤は見当たらない。
例えば、特許文献6は、スチレン-イソプレン-スチレンブロック共重合体をベースとした粘着剤基剤中にラノリンを配合し、ラノリンに水分を保持させる含水型のプラスター剤が開示されている。
これは製剤中に含有される水分によってフェルビナクの溶解性を高め、その結果、経皮吸収性を向上させようという試みであるが、油性貼付剤中に水分を含有させることは製造工程を複雑なものとし、また保存中の製剤の物性低下の可能性を否定しきれないものである。
加えて経皮吸収性の面では、経皮吸収促進剤を使用したプラスター剤と比較するとやや劣るという問題がある。
しかしながら、本貼付剤に配合されるロジン系樹脂は、皮膚感作成分として作用し、その配合は望ましくないことが知られている。皮膚感作とは、遅延性過敏反応の一種で、化学物質により過剰な免疫反応が起こり、皮膚にかぶれ等が起こる現象のことである。
本発明が提供するフェルビナク含有外用貼付剤は、フェルビナクの優れた消炎鎮痛効果により、例えば、変形性関節症、慢性関節リウマチ、腰痛症、肩関節周囲炎、腱鞘炎、腱周囲炎、上腕骨上顆炎(テニス肘等)、筋肉痛、外傷後の腫脹・疼痛などの予防、治療に有用である。
すなわち、本発明にあっては、有効成分としてのフェルビナクについて、特に、平均粒子径が5μm以上であり、かつ100μm未満のフェルビナクを用い、粘着基剤層に分散させることを特徴とする。
粘着剤中のフェルビナク配合量が0.1重量%未満であると、経皮吸収性が不十分であり、効果が認められず、また、10重量%を超えて配合しても、それ以上の効果が認められず、経済的に不利であり好ましくない。
その平均粒子径が5μm未満であると製造工程においてフェルビナク原薬が二次凝集を起こし、均一に分散しない虞があり、薬物の経皮吸収性の低下を招く。反対に平均粒子径が100μm以上であると、粘着剤中で薬物が均一に分散しない可能性がある。特に粒子径が大きい場合は、薬物の経皮吸収性の低下はもとより、製造工程、特に粘着剤の剥離フィルムへの塗工工程において好ましくない影響がみられる。すなわちフェルビナク原薬が製造中に凝集し、それが原因による、粘着剤表面の凹凸が見られる場合がある。
その配合量は、製剤化が可能である限り特に限定はないが、好ましくは粘着剤重量に対して、10~50重量%の範囲内で配合するのがよい。
粘着剤中の脂環族飽和炭化水素樹脂の含量が10重量%未満であると粘着力が弱く、50重量%を超えて配合すると、製剤の粘着力が強くなり、剥離時に痛みを伴うといった問題がある。
粘着剤中のセバシン酸ジエチルの配合量が0.1重量%未満であるとフェルビナクの皮膚透過性が不十分であり、10重量%を超えて配合すると、皮膚刺激等の問題が生じ、好ましいものではない。
配合比率が1:0.1未満であるとセバシン酸ジエチルによる吸収促進効果が得られず、十分な薬物吸収性が得られない。また、配合比率が1:15を超える場合には、フェルビナクが過剰なセバシン酸ジエチルに溶解し、薬物安定性が低い製剤となる。
軟化剤の配合量は、粘着剤重量に対して10~75重量%、好ましくは15~60重量%、より好ましくは20~50重量%の範囲内で配合するのがよい。
すなわち、粘着剤層を構成するSIS、軟化剤、および脂環族飽和炭化水素樹脂、酸化防止剤を加熱溶解する。次いで、有効成分であるフェルビナクとセバシン酸ジエチルを前記粘着基剤に加え、撹拌・混合し、貼付剤における粘着剤を調製する。
次いで、調製された粘着剤(膏体)を、シリコーン処理されたポリエチレンテレフタレートフィルム上に塗工し、厚み50~300μmの粘着剤層を形成する。得られた粘着剤層に支持体のポリエステル製織布または不織布をラミネートした後、適当な大きさと形状に切断して、本発明の外用貼付剤を得ることができる。
なお、実施例及び比較例における各表中の配合成分の配合量は、特に断らない限り重量%で表示している。
SIS、ポリブテン、流動パラフィン、ジブチルヒドロキシトルエンを170℃加温条件下にて練合、溶融させた後、さらに脂環族飽和炭化水素樹脂を添加し、130℃加温条件下にて練合、混和し粘着基剤を作製した。
別にセバシン酸ジエチルと適量の流動パラフィンを混和した液中に平均粒子径が5μm以上であり、かつ100μm未満のフェルビナクを攪拌しながら均一に分散し、フェルビナク分散液を調製した。このフェルビナク分散液を上述の粘着基剤に添加し、均一に分散するまで練合し、粘着剤を調製した。粘着剤をシリコーン処理されたポリエチレンテレフタレートフィルム上に100μm厚で塗工後、ポリエステル織布とラミネートし、試験製剤を得た。
実施例1と同様の手順で、表1~表3に示す成分組成により、目的とする本発明の貼付剤を作製した。
下記表4に示す成分組成に変更する他は、実施例1と同様の手順で各比較例の外用貼付剤を作製した。
なお比較例7の製剤は、製造時(粘着剤調製時)にフェルビナク原薬が凝集し、それが原因で製剤表面の凹凸が見られ、以下の製剤評価試験を行うことができなかった。
実施例1~2と比較例1~2の製剤を、各々φ25mmに打ち抜き、健常男子15名の上腕内側に24時間貼付し、剥離後1時間、及び24時間目の皮膚刺激性を判定した。
その結果を、下記表5に示した。
実施例1と比較例3~4の製剤を各々5cm×7cmに打ち抜き、健常男子6名の背部に12時間貼付し、回収した製剤中に残存する薬物を抽出し、薬物量をHPLCで測定した。
0時間貼付の薬物量から残存薬物量を差し引いて、薬物消失量を計算した。その結果を下記表6に示した。
実施例1、比較例2及び比較例5のサンプル(7cm×10cm)を40℃で3ヶ月間保存した後、試験製剤中の薬物を抽出しフェルビナク含量を測定した。
試験前の各サンプルのフェルビナク含量(初期値)と比較し、対初期値(%)として算出した。その結果を表7に示した。
実施例1、実施例16及び比較例6の各製剤を、各々φ20mmに打ち抜き、100mL容ビーカーの内側側面に、両面テープを使用して粘着剤面がビーカーの内側に面するように貼付した。
製剤の貼付位置は製剤の最も下端の部分がビーカーの底から約30mmの位置となるように調整した。その後、ビーカーの内側に100mLの放出溶液(PBS緩衝溶液)を注ぎ入れ、マグネチックスターラーで放出溶液を攪拌した。そして試験開始90分後の放出溶液中のフェルビナク含量を高速液体クロマトグラフ法により測定し、主薬の放出率を算出した。その結果を表8に示した。
本発明の外用貼付剤は例えば、変形性関節症、慢性関節リウマチ、腰痛症、肩関節周囲炎、腱鞘炎、腱周囲炎、上腕骨上顆炎(テニス肘等)、筋肉痛、外傷後の腫脹・疼痛などの予防、治療に有用であり、その利用性は多大なものである。
Claims (2)
- L-メントールを含有せず、スチレン-イソプレン-スチレンブロック共重合体、脂環族飽和炭化水素樹脂、軟化剤、およびセバシン酸ジエチルからなる粘着基剤に、平均粒子径が5μm以上であり、かつ100μm未満のフェルビナクを分散配合したことを特徴とするフェルビナク含有外用貼付剤。
- L-メントールを含有せず、スチレン-イソプレン-スチレンブロック共重合体10~30重量%、脂環族飽和炭化水素樹脂10~50重量%、軟化剤10~75重量%、セバシン酸ジエチル0.1~10重量%からなる粘着基剤に、平均粒子径が5μm以上であり、かつ100μm未満のフェルビナク0.1~10重量%を分散配合したことを特徴とするフェルビナク含有外用貼付剤。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11838026.0A EP2636405B1 (en) | 2010-11-02 | 2011-11-01 | Felbinac-containing external patch |
KR1020137013618A KR101900519B1 (ko) | 2010-11-02 | 2011-11-01 | 펠비낙 함유 외용 첩부제 |
AU2011324394A AU2011324394B2 (en) | 2010-11-02 | 2011-11-01 | Felbinac-containing external patch |
CA2815792A CA2815792C (en) | 2010-11-02 | 2011-11-01 | Felbinac-containing external patch |
US13/882,747 US9833417B2 (en) | 2010-11-02 | 2011-11-01 | Felbinac-containing external patch |
JP2012541875A JP5856975B2 (ja) | 2010-11-02 | 2011-11-01 | フェルビナク含有外用貼付剤 |
ES11838026.0T ES2669306T3 (es) | 2010-11-02 | 2011-11-01 | Parche externo que contiene felbinaco |
CN201180063899.6A CN103269696B (zh) | 2010-11-02 | 2011-11-01 | 含有联苯乙酸的外用贴剂 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010246666 | 2010-11-02 | ||
JP2010-246666 | 2010-11-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012060376A1 true WO2012060376A1 (ja) | 2012-05-10 |
Family
ID=46024490
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2011/075182 WO2012060376A1 (ja) | 2010-11-02 | 2011-11-01 | フェルビナク含有外用貼付剤 |
Country Status (10)
Country | Link |
---|---|
US (1) | US9833417B2 (ja) |
EP (1) | EP2636405B1 (ja) |
JP (1) | JP5856975B2 (ja) |
KR (1) | KR101900519B1 (ja) |
CN (1) | CN103269696B (ja) |
AU (1) | AU2011324394B2 (ja) |
CA (1) | CA2815792C (ja) |
ES (1) | ES2669306T3 (ja) |
TW (1) | TWI519323B (ja) |
WO (1) | WO2012060376A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7374045B2 (ja) | 2020-06-02 | 2023-11-06 | 三菱電機株式会社 | 負担調整回路 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04321624A (ja) * | 1991-04-19 | 1992-11-11 | Hisamitsu Pharmaceut Co Inc | 消炎鎮痛貼付剤 |
JPH07233050A (ja) * | 1994-02-23 | 1995-09-05 | Sekisui Chem Co Ltd | 外用貼付剤 |
WO2001078690A1 (fr) * | 2000-04-18 | 2001-10-25 | Hisamitsu Pharmaceutical Co., Inc. | Piece contenant un agent anti-inflammatoire |
JP2001342130A (ja) * | 2000-06-01 | 2001-12-11 | Teikoku Seiyaku Co Ltd | 4−ビフェニル酢酸含有貼付剤 |
JP2007007189A (ja) * | 2005-06-30 | 2007-01-18 | Lion Corp | 外用剤組成物及び貼付剤、並びに薬物の経皮吸収組成物 |
JP2007296120A (ja) * | 2006-04-28 | 2007-11-15 | Lion Corp | 貼付剤 |
JP2008069127A (ja) * | 2006-09-15 | 2008-03-27 | Toko Yakuhin Kogyo Kk | 消炎鎮痛クリーム製剤及びその製造方法 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996011002A1 (fr) * | 1994-10-05 | 1996-04-18 | Hisamitsu Pharmaceutical Co., Inc. | Agent anti-inflammatoire a usage externe |
JP3782834B2 (ja) * | 1994-10-26 | 2006-06-07 | 株式会社トクホン | 鎮痛抗炎症貼付剤 |
EP0968712B1 (en) * | 1996-12-06 | 2008-07-09 | Hisamitsu Pharmaceutical Co., Inc. | Felbinac-containing patch |
JP3495733B2 (ja) * | 1996-12-06 | 2004-02-09 | 久光製薬株式会社 | フェルビナク含有貼付剤 |
US6620430B2 (en) | 1996-12-06 | 2003-09-16 | Hisamitsu Pharmaceutical Co., Inc. | Plaster containing felbinac |
JPH10218793A (ja) | 1997-02-03 | 1998-08-18 | Nichiban Co Ltd | 経皮吸収型消炎鎮痛用テープ剤及びその製造方法 |
JP4676042B2 (ja) | 1999-10-01 | 2011-04-27 | 帝國製薬株式会社 | フェルビナク含有鎮痛・消炎外用貼付剤 |
KR100803010B1 (ko) * | 2000-11-29 | 2008-02-14 | 데이고꾸세이약꾸가부시끼가이샤 | 외용 첨부제 |
PT1400240E (pt) * | 2001-05-31 | 2010-06-18 | Hisamitsu Pharmaceutical Co | Pensos de absorção percutânea |
TWI341736B (en) * | 2003-12-26 | 2011-05-11 | Hisamitsu Pharmaceutical Co | Anti-infammatory adhesive preparations |
TWI414320B (zh) | 2004-05-13 | 2013-11-11 | Hisamitsu Pharmaceutical Co | 含有非類固醇系消炎鎮痛劑之外用經皮製劑 |
US8747885B2 (en) * | 2004-12-15 | 2014-06-10 | Teikoku Seiyaku Co., Ltd. | External patches containing etofenamate |
KR20080000647A (ko) * | 2005-04-28 | 2008-01-02 | 오노 야꾸힝 고교 가부시키가이샤 | 경피 흡수 제제 |
JP4939113B2 (ja) | 2005-06-01 | 2012-05-23 | ニプロパッチ株式会社 | 貼付剤 |
JP5085062B2 (ja) | 2006-07-06 | 2012-11-28 | リンテック株式会社 | 経皮吸収貼付剤 |
JP4590418B2 (ja) * | 2007-01-25 | 2010-12-01 | ニチバン株式会社 | 消炎鎮痛貼付剤 |
WO2010032434A1 (ja) * | 2008-09-19 | 2010-03-25 | 株式会社アクティバスファーマ | 医療用複合有機化合物粉体、その製造方法ならびに懸濁液 |
-
2011
- 2011-11-01 EP EP11838026.0A patent/EP2636405B1/en active Active
- 2011-11-01 KR KR1020137013618A patent/KR101900519B1/ko active IP Right Grant
- 2011-11-01 WO PCT/JP2011/075182 patent/WO2012060376A1/ja active Application Filing
- 2011-11-01 JP JP2012541875A patent/JP5856975B2/ja active Active
- 2011-11-01 TW TW100139701A patent/TWI519323B/zh active
- 2011-11-01 AU AU2011324394A patent/AU2011324394B2/en active Active
- 2011-11-01 ES ES11838026.0T patent/ES2669306T3/es active Active
- 2011-11-01 CA CA2815792A patent/CA2815792C/en active Active
- 2011-11-01 CN CN201180063899.6A patent/CN103269696B/zh active Active
- 2011-11-01 US US13/882,747 patent/US9833417B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04321624A (ja) * | 1991-04-19 | 1992-11-11 | Hisamitsu Pharmaceut Co Inc | 消炎鎮痛貼付剤 |
JPH07233050A (ja) * | 1994-02-23 | 1995-09-05 | Sekisui Chem Co Ltd | 外用貼付剤 |
WO2001078690A1 (fr) * | 2000-04-18 | 2001-10-25 | Hisamitsu Pharmaceutical Co., Inc. | Piece contenant un agent anti-inflammatoire |
JP2001342130A (ja) * | 2000-06-01 | 2001-12-11 | Teikoku Seiyaku Co Ltd | 4−ビフェニル酢酸含有貼付剤 |
JP2007007189A (ja) * | 2005-06-30 | 2007-01-18 | Lion Corp | 外用剤組成物及び貼付剤、並びに薬物の経皮吸収組成物 |
JP2007296120A (ja) * | 2006-04-28 | 2007-11-15 | Lion Corp | 貼付剤 |
JP2008069127A (ja) * | 2006-09-15 | 2008-03-27 | Toko Yakuhin Kogyo Kk | 消炎鎮痛クリーム製剤及びその製造方法 |
Also Published As
Publication number | Publication date |
---|---|
KR20140005887A (ko) | 2014-01-15 |
AU2011324394A1 (en) | 2013-05-23 |
US20130236516A1 (en) | 2013-09-12 |
TW201304824A (zh) | 2013-02-01 |
EP2636405B1 (en) | 2018-03-14 |
JP5856975B2 (ja) | 2016-02-10 |
CN103269696A (zh) | 2013-08-28 |
CN103269696B (zh) | 2015-04-01 |
EP2636405A4 (en) | 2014-04-23 |
JPWO2012060376A1 (ja) | 2014-05-12 |
CA2815792C (en) | 2019-01-08 |
KR101900519B1 (ko) | 2018-09-19 |
ES2669306T3 (es) | 2018-05-24 |
EP2636405A1 (en) | 2013-09-11 |
TWI519323B (zh) | 2016-02-01 |
AU2011324394B2 (en) | 2016-02-25 |
US9833417B2 (en) | 2017-12-05 |
CA2815792A1 (en) | 2012-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9918945B2 (en) | Ropinirole-containing patch and package thereof | |
JP5856153B2 (ja) | 非水性貼付剤 | |
TW201004617A (en) | Anti-inflammatory analgesic agent for external use | |
JP5581080B2 (ja) | 外用貼付剤 | |
WO2006093139A1 (ja) | 経皮吸収製剤 | |
JP5365964B2 (ja) | 経皮吸収型鎮痛消炎貼付剤 | |
WO2013046335A1 (ja) | 非水性貼付剤 | |
JP5285279B2 (ja) | 経皮吸収型製剤 | |
JP2005002040A (ja) | 消炎鎮痛貼付剤 | |
TW201223562A (en) | Transdermal absorption preparation | |
JP2010280634A (ja) | 消炎鎮痛貼付剤 | |
JP2008179564A (ja) | 消炎鎮痛貼付剤 | |
JP4764337B2 (ja) | 消炎鎮痛貼付剤 | |
JP5684441B2 (ja) | インドメタシン含有貼付剤 | |
JP5856975B2 (ja) | フェルビナク含有外用貼付剤 | |
JP5888706B2 (ja) | ロキソプロフェンナトリウム含有外用貼付剤 | |
CN105327351A (zh) | 一种消炎镇痛外用剂 | |
JP6963663B2 (ja) | 貼付剤の製造方法 | |
TW201002313A (en) | Antipruritic and analgesic medicine containing oxybuprocaine for external use | |
JP2016094446A (ja) | 非水性貼付剤 | |
WO2022186351A1 (ja) | ロキソプロフェン含有貼付剤およびその製造方法 | |
CN104208698A (zh) | 一种经皮吸收镇痛消炎药物组合物及其应用 | |
JPH07267860A (ja) | エペリゾンまたはトルペリゾン経皮吸収製剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11838026 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2815792 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2012541875 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011838026 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2011324394 Country of ref document: AU Date of ref document: 20111101 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20137013618 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13882747 Country of ref document: US |