US 20130035391A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0035391 A1 Katayama et al. (43) Pub. Date: Feb. 7, 2013

(54) FELBINAC-CONTAINING TRANSDERMALLY Publication Classi?cation ABSORBABLE PREPARATION (51) Int. Cl. (75) Inventors: Akiko Katayama, HigashikagaWa-shi A61K31/192 (200601) (JP); Katsuyuki [1100’ (52) US. Cl...... 514/570 HigashikagaWa-shi (JP) (57) ABSTRACT (73) Assignee: TEIKOKU SEIYAKU CO., LTD., An adhesive patch is a felbinac-containing transdermally KanagaWa (JP) absorbable preparation substantially free of a solubiliZer for felbinac in a ?nal preparation but still having high releasing of (21) Appl. NO.I 13/516,008 felbinac. The adhesive patch in Which lidocaine and felbinac are formulated has the releasing of felbinac Without losing the (22) PCT Filed: Dec- 14: 2010 releasing of lidocaine. The felbinac-containing transderrnally absorbable adhesive patch contains felbinac as an active com (86) PCT N05 PCT/JP2010/072453 ponent and lidocaine or a pharmaceutically acceptable salt § 371 (OX1), thereof as an absorption promoter. In particular, the content of (2)’ (4) Date; Aug 16, 2012 felbinac is from 0.1% to 10% by Weight to the total Weight of the drug-containing plaster and the content of lidocaine or the (30) Foreign Application Priority Data pharmaceutically acceptable salt thereof is from 0.01% to 20% by Weight to the total Weight of the drug-containing Dec. 15, 2009 (JP) ...... 2009-284325 plaster. Patent Application Publication Feb. 7, 2013 Sheet 1 0f 3 US 2013/0035391 A1

[FIG. 1]

FELB l NAG PERMEAB | L l TY 41. 000

8 12 086%%0 TIME (hr) —x— COMPARATIVE EXAMPLE 1 EXAMPLE 1

L | DOOAI NE PERMEABI LITY

m0 33 0 m 2 5 O 2. U D 235E555M222855%15 11 50500 “U0

TIME-‘(1.10 I ‘*"FGOMPARATIVE EXAMPLE 2! + EXAMPLE 1 Patent Application Publication Feb. 7, 2013 Sheet 2 0f 3 US 2013/0035391 A1

LFIIIG. ‘ s1

KETOPROFEN PERMEABILITY ' 100

600. D .U

TIME (hr) ‘

l —-‘+— COMPARATIVE EXAMPLE 3] +GQMPARAT|VE EXAMPLE 4 I

[FIG. 4],

LIDQCALNE PERMEABILITY" '

TIME (hrY -' K- COMPARATIVE EXAMPLE 2% —-—.i:—-COMPARATIVE EXAMPLE 4_‘ Patent Application Publication Feb. 7, 2013 Sheet 3 0f 3 US 2013/0035391 A1

[FIG. 5],

INDOMETHACIN PERMEABI LlTY L

5U @65353%‘@?EmEM5525

TIME (hr) ~2M-0OMPARATIME EXAMPLE 5 COMPARATIVE EXAMPLE 6

[FIG. 6]‘ LIDOCAINE PERMEAB] LITY

\nn

a.“ ___L LIMA A_ TM

w.@m%5 4W U8O \wi.

TIME Khl’)‘ -><- COMPARATIVE EXAMPLE 21+,c0MPARAnvE EXAMPLE 6! US 2013/0035391A1 Feb. 7, 2013

FELBINAC-CONTAINING TRANSDERMALLY patch, these formed salts and inhibited the drug releasing of ABSORBABLE PREPARATION each other, thereby failing to obtain a desired medicinal effect. TECHNICAL FIELD PRIOR ART DOCUMENTS [0001] The present invention relates to a transdermally absorbable preparation, and more particularly, to an adhesive Patent Documents patch containing felbinac, a non-steroidal anti-in?ammatory , as a medicinal component and lidocaine or a phar [0009] Patent Document 1: Japanese Patent Application maceutically acceptable salt thereof being a local anesthetic Laid-Open No. Hei. 4-321624 and as an absorption promoter to felbinac. [0010] Patent Document 2: Japanese Patent Application Laid-Open No. 2001-342130 BACKGROUND ART [0011] Patent Document 3: Japanese Patent Application [0002] Felbinac, Which is a non-steroidal anti-in?amma Laid-Open No. 2003-286162 tory analgesic, is an active metabolite of and a drug [0012] Patent Document 4: Japanese Patent Application having high anti-in?ammatory and analgesic activity. Felbi Laid-Open No. 2002-128699 nac has been transdermally administered to avoid systemic [0013] Patent Document 5: International Publication No. side effects and available as external preparations such as a WO 01/047559 gel, a liquid, a cataplasm, and a plaster. [0014] Patent Document 6: Japanese Patent Application [0003] Felbinac itself has very loW solubility in various Laid-Open No. 2005-145931 solvents. Thus, a variety of solubiliZers have been conven [0015] Patent Document 7: Japanese Patent Application tionally used in such external preparations to enhance the Laid-Open No. 2005-145932 transdermal absorption of felbinac. [0016] Thus, as for the adhesive patch in Which a non [0004] For example, Patent Document 1 has proposed a steroidal anti-in?ammatory analgesic and a local anesthetic felbinac -containing plaster Which contains crotamiton having as a transdermal absorption promoter are formulated, it has high solubiliZing ability for felbinac as an essential compo been desired to develop the transdermally absorbable prepa nent. Also, Patent Document 2 has proposed a plaster in ration Which achieves high anti-in?ammatory and analgesic Which N-methyl-2-pyrrolidone and polyethylene glycol are effects Without inhibiting drug releasing of each other. formulated as the solubiliZers. Many of such solubiliZers, hoWever, have caused irritation to the skin. Moreover, When [0017] Under such circumstances, as for felbinac among such liquid components are formulated in an adhesive patch, non-steroidal anti-in?ammatory , the present a change of the physical properties of the adhesive patch may inventors have intensively studied development of the trans be caused over time by the bleed-out to the surface (the dermally absorbable preparation, Which achieves high anti exudation to the surface) of the adhesive patch. in?ammatory and analgesic effects Without inhibiting the drug releasing of each other, by formulating felbinac With a [0005] In addition, Patent Document 3 has proposed a plas local anesthetic as a transdermal absorption promoter. ter free of crotamiton and containing a styrene-isoprene-sty rene block copolymer, a rosin resin, a plasticiZer, l-menthol, [0018] As a result, When lidocaine Was selected as the and felbinac. This plaster is an adhesive patch in Which fel absorption promoter and formulated together With the non binac is uniformly dispersed in a semi-molten state in the steroidal anti-in?ammatory analgesic felbinac in an adhesive adhesive layer, i.e., in a state Wherein felbinac is present in a patch base, it Was found that a uniform drug-containing plas molten state and in a ?ne crystalline state simultaneously. The ter Was obtained even substantially free of the solubiliZer for drug permeability hoWever Was not suf?cient because part of felbinac to provide a felbinac-containing transdermally felbinac Was present in a crystalline state. absorbable preparation having high releasing of main drugs While the transdermally absorbable preparation had excellent [0006] Further, a combination preparation in Which a non analgesic and anti-in?ammatory activity Without losing the steroidal anti-in?ammatory analgesic and a local anesthetic transdermal absorption of lidocaine as the local anesthetic, are formulated has been studied Wherein the preparation has thereby completing the present invention. both an anti-in?ammatory activity of the non-steroidal anti in?ammatory analgesic and an analgesic activity of the local SUMMARY OF THE INVENTION anesthetic. [0007] For example, Patent Document 4 and Patent Docu Problems to be Solved by the Invention ment 5 have proposed a cataplasm in Which a non-steroidal anti-in?ammatory analgesic such as indomethacin, felbinac, [0019] Thus, it is a ?rst object of the present invention to sodium and sodium and a local anes provide a felbinac-containing transdermally absorbable thetic such as lidocaine, benZocaine and dibucaine are formu preparation substantially free of a solubiliZer for felbinac in a lated. Also, Patent Document 6 and Patent Document 7 have ?nal preparation but still having high releasing of felbinac to proposed a tape in Which a non-steroidal anti-in?ammatory solve the above-mentioned conventional problems. analgesic and a local anesthetic are formulated respectively. [0020] Further, it is a second object of the present invention [0008] In general, hoWever, many local anesthetics are to provide an adhesive patch in Which a local anesthetic and basic drugs, While many non-steroidal anti-in?ammatory felbinac, Which is the non-steroidal anti-in?ammatory anal analgesics to be formulated together are acidic drugs includ gesic, are formulated, Wherein the adhesive patch has excel ing indomethacin and . Accordingly, When these lent releasing of the non-steroidal anti-in?ammatory analge both drugs Were simultaneously formulated in the adhesive sic Without losing the releasing of the local anesthetic. US 2013/0035391A1 Feb. 7, 2013

Means for Solving the Problem [0033] FIG. 6 is a graph shoWing the result of in vitro rat skin permeability test for lidocaine based on Comparative [0021] A basic aspect of the present invention to solve such Study (3) of Test Example 1. problems is a felbinac-containing transdermally absorbable adhesive patch, Which contains felbinac as an active compo EMBODIMENTS FOR CARRYING OUT THE nent and lidocaine or a pharmaceutically acceptable salt INVENTION thereof as an absorption promoter. [0022] Speci?cally, the present invention is the felbinac [0034] The basic aspect of the present invention, as containing transdermally ab sorbable adhesive patch Wherein described above, is the felbinac-containing transdermally the content of felbinac is from 0.1% to 10% by Weight to the absorbable adhesive patch, Which contains felbinac as an total Weight of the drug-containing plaster base material and anti-in?ammatory analgesic medicinal component and the content of lidocaine or the pharmaceutically acceptable lidocaine or a pharmaceutically acceptable salt thereof as an salt thereof is from 0.01% to 20% by Weight to the total absorption promoter. Weight of the drug-containing plaster base material. [0035] The formulated amount of the active component [0023] Especially, the present invention is the felbinac-con felbinac in the adhesive patch of the present invention is from taining transdermally absorbable adhesive patch Wherein an 0.1% to 10% by Weight and particularly preferably from 0.2% adhesive patch base is a rubber polymer and the rubber poly to 5% by Weight to the total Weight of the drug-containing mer is a styrene-isoprene-styrene block copolymer. base material. [0024] Also, the present invention is, from another point of [0036] When the formulated amount of felbinac is less than vieW, each felbinac-containing transdermally absorbable 0.1% by Weight, the medicinal effect of felbinac may not be preparation described above Which is substantially free of a suf?cient. More than 10% by Weight of felbinac formulated is solubiliZer for felbinac in the ?nal preparation. also not preferable because irritation to the skin may be caused or the physical properties of the plaster may be lost. Effects of the Invention [0037] On the other hand, in the present invention, lidocaine to be formulated With felbinac not only shoWs an [0025] The present invention provides the felbinac-con analgesic activity as the local anesthetic by itself but also acts taining transdermally absorbable adhesive patch, Which con as the absorption promoter for felbinac in the present inven tains felbinac as the anti-in?ammatory analgesic component tion. and lidocaine or the pharmaceutically acceptable salt thereof as the absorption promoter. [0038] In this case, the formulated amount of lidocaine is preferably from 0.01 % to 20% by Weight and more preferably [0026] Particularly, in the present invention, by combining from 0.1% to 10% by Weight to the total Weight of the drug With lidocaine or the pharmaceutically acceptable salt thereof containing base material. as the absorption promoter for felbinac in the adhesive patch base, felbinac can be uniformly contained in a plaster com [0039] The formulated amount of less than 0.01% by position Without substantially formulating a solubiliZer for Weight of lidocaine cannot enhance the skin permeability of felbinac. Accordingly, the present invention provides the felbinac suf?ciently. On the other hand, more than 20% by transdermally absorbable preparation having high releasing Weight of lidocaine is also not preferable because not only the of felbinac and excellent analgesic and anti-in?ammatory effect of lidocaine formulated cannot be expected but also effects at the same time Without the transdermal absorption of irritation to the skin may be caused or the physical properties lidocaine as the local anesthetic being decreased. of the plaster may be lost. [0027] As found in the results of Test Examples described [0040] In another feature of the present invention, by for beloW, the absorption promoting effect caused by formulating mulating lidocaine With felbinac in the adhesive patch base lidocaine is speci?c for felbinac among anti-in?ammatory material, the felbinac-containing transdermally absorbable analgesics. Thus, the present invention has a great medical adhesive patch substantially free of the solubiliZer for felbi effect in that the adhesive patch of the transdermally absorb nac in the ?nal preparation is provided. able preparation containing clinically extremely useful felbi [0041] In the present invention, “substantially free of the nac can be provided. solubiliZer” means that, although a small amount of used solvent is unavoidably remained in the preparation of interest BRIEF DESCRIPTION OF DRAWINGS due to the manufacturing process of the preparation, the solu biliZer is not contained as long as the amount of the solvent is [0028] FIG. 1 is a graph shoWing the result of in vitro rat suf?ciently small to have little effect on the transdermal skin permeability test for felbinac based on Comparative absorption of the ?nal preparation. Study (1) of Test Example 1. [0042] In other Words, the case in Which the amount of the [0029] FIG. 2 is a graph shoWing the result of in vitro rat residual solvent is suf?ciently small to have little effect on the skin permeability test for lidocaine based on Comparative drug releasing in the ?nal preparation can be regarded as Study (1) of Test Example 1. “substantially free of the solubiliZer”. [0030] FIG. 3 is a graph shoWing the result of in vitro rat [0043] The plaster composition used in the adhesive patch skin permeability test for ketoprofen of Comparative base material provided by the present invention can be pre Example based on Comparative Study (2) of Test Example 1. pared by mixing felbinac and lidocaine With the adhesive [0031] FIG. 4 is a graph shoWing the result of in vitro rat patch base component. skin permeability test for lidocaine based on Comparative [0044] Such an adhesive patch base component is not par Study (2) of Test Example 1. ticularly limited as long as it can become the base of an [0032] FIG. 5 is a graph shoWing the result of in vitro rat adhesive layer Which is the plaster composition, and hydro skin permeability test for indomethacin of Comparative phobic polymers such as a rubber polymer, an acrylic poly Example based on Comparative Study (3) of Test Example 1. mer and a silicon polymer are preferably used. US 2013/0035391A1 Feb. 7, 2013

[0045] Examples of the rubber polymer may include a sty Ltd.), a terpene resin (for example, Clearon P-125, Yasuhara rene-isoprene-styrene block copolymer (hereinafter, referred Chemical Co., Ltd.), a maleic acid resin and the like. to as SIS), polyisobutylene (hereinafter, referred to as PIB), a [0052] The formulated amount of such a tacki?er resin styrene-butadiene-styrene block copolymer (hereinafter, based on the total composition of the adhesive composition referred to as SBS), a styrene-butadiene rubber (hereinafter, can be from 5% to 70% by Weight, preferably from 5% to 60% referred to as SBR), an isoprene rubber and the like. Among by Weight and more preferably from 10% to 50% by Weight in them, SIS is particularly preferred. consideration of enough adhesion as the adhesive preparation [0046] Also, the acrylic polymer is not particularly limited and irritation to the skin upon being peeled. as long as one of (meth)acrylic acid derivatives represented [0053] Also, an antioxidant, a ?ller, a cross-linking agent, a by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, preservative and an ultraviolet absorber can be used if neces hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like sary. As the antioxidant, tocopherol and ester derivatives is contained and copolymeriZed. For example, the adhesives thereof, ascorbic acid, ascorbyl stearate, nordihydroguai listed in Japanese Pharmaceutical Excipients Directory 2007 aretic acid, dibutylhydroxy-toluene (hereinafter, referred to (edited by International Pharmaceutical Excipients Council as BHT), butylhydroxyanisole and the like are desirable. Japan) such as the adhesive of an acrylic polymer Which [0054] As the ?ller, calcium carbonate, magnesium carbon contains an acrylic acid/octyl acrylate copolymer, a 2-ethyl ate, silicate (for example, aluminum silicate, magnesium sili hexyl acrylate/vinylpyrrolidone copolymer solution, an acry cate and the like), silicic acid, barium sulfate, calcium sulfate, late-vinyl acetate copolymer, a 2-ethylhexyl acrylate-2-eth calcium Zincate, Zinc oxide, titanium oxide and the like are ylhexyl methacrylate/dodecyl methacrylate copolymer, a desirable. methyl acrylate-2-ethylhexyl acrylate copolymer resin emul [0055] As the cross-linking agent, a thermosetting resin sion, an acrylic resin alkanol amine solution and the like, such as an amino resin, a phenolic resin, an epoxy resin, an DURO-TAK acrylic adhesive series (produced by National alkyd resin and unsaturated polyester; an isocyanate com Starch and Chemical Company) and Eudragit series (HIGU pound; a blocked isocyanate compound; an organic cross CHI Inc.) can be used. linking agent; and an inorganic cross-linking agent such as a [0047] Moreover, speci?c examples of the silicon polymer metal and a metal compound are desirable. may include a silicone rubber such as polyorganosiloxane. [0056] As the preservative, paraben such as ethyl parahy [0048] Such hydrophobic polymers may be used in mixture droxybenZoate, propyl parahydroxybenZoate and butyl of tWo or more. The formulated amount of such polymers parahydroxybenZoate is desirable. based on the mass of the total composition is from 5% to 80% [0057] As the ultraviolet absorber, p-aminobenZoic acid by Weight, preferably from 10% to 70% by Weight and more derivatives, anthranilic acid derivatives, deriva preferably from 10% to 50% by Weight in consideration of the tives, amino acid compounds, dioxane derivatives, coumar‘in formation of the adhesive layer and su?icient drug perme derivatives, imidaZoline derivatives, pyrimidine derivatives ability. and the like are desirable. [0049] The adhesive composition in the adhesive patch [0058] Such an antioxidant, a ?ller, a cross-linking agent, a Which is the transdermally absorbable preparation provided preservative and an ultraviolet absorber can be formulated in by the present invention may contain a plasticiZer. Examples 10% by Weight or less, preferably 5% by Weight or less and of the plasticiZer to be used may include a petroleum-based more preferably 2% by Weight or less based on the mass of the oil (for example, a paraf?n-based process oil such as a liquid total composition of the adhesive layer of the preparation. paraf?n, a naphthene-based process oil, an aromatic process [0059] The adhesive patch, Which is the transdermally oil and the like), squalane, squalene, a vegetable oil (for absorbable preparation of the present invention having the example, an olive oil, a camellia oil, a tall oil, a peanut oil, a composition described above, can be produced by any meth castor oil and the like), a silicone oil, dibasic acid ester (for ods. example, dibutyl phthalate, dioctyl phthalate and the like), a [0060] Examples of the methods include generally called a liquid rubber (for example, polybutene, a liquid isoprene hot melt method and a solvent method. In the hot melt rubber and the like), liquid fatty acid esters (for example, method, the adhesive patch can be obtained by thermally isopropyl myr‘istate, hexyl laurate, diethyl sebacate, diisopro melting the drug-containing base component, coating it on a pyl sebacate and the like). A liquid paraf?n is particularly release ?lm or a support, and laminating the base component preferred. to a support or a release ?lm. In the solvent method, the [0050] Such components may be used in mixture of tWo or adhesive patch can be obtained by dissolving the drug-con more. The formulated amount of such plasticiZers based on taining base component in an organic solvent such as toluene, the total composition of the adhesive layer is from 1% to 70% hexane, ethyl acetate or N-methyl-2-pyrrolidone, spreading by Weight, preferably from 10% to 60% by Weight and more and coating it on a release ?lm or a support, removing the preferably from 10% to 50% by Weight in total in consider solvent by drying, and laminating the base component to a ation of the maintaining of enough cohesion as the adhesive support or a release ?lm. patch. [0061] In the adhesive patch, Which is the external trans [0051] In the adhesive layer of the present invention, it is dermal preparation provided by the present invention, the desirable to formulate a tacki?er resin to adjust the adhesion thickness of the adhesive layer is not particularly limited, but of the preparation. Examples of the tacki?er resin Which can generally 500 um or less and preferably from 20 pm to 300 be used may include rosin derivatives (for example, rosin, pm. rosin glycerin ester, hydrogenated rosin, hydrogenated rosin [0062] As the support of the adhesive patch, Which is the glycerin ester, rosin pentaerythritol ester and the like), an transdermally absorbable preparation of the present inven alicyclic saturated hydrocarbon resin (for example, Alcon tion, an elastic or a non-elastic support can be used. For P100, ArakaWa Chemical Industries Ltd.), an aliphatic hydro example, it is selected from fabrics, nonWoven fabrics, poly carbon resin (for example, Quinton B170, Nippon Zeon Co., urethane, polyester, polyvinyl acetate, polyvinylidene chlo US 2013/0035391A1 Feb. 7, 2013

ride, polyethylene, polyethylene terephthalate (hereinafter, (Components) referred to as PET), an aluminum sheet and the like, or the composite material thereof. [0070] [0063] The release ?lm is not particularly limited as long as it protects the adhesive layer Without the main drug compo nents being decomposed until the adhesive patch, Which is the SIS 16% transdermally absorbable preparation, is applied to the skin Liquid paraf?n 38% and it is silicon coated to be easily peeled. Speci?c examples BHT 1% Hydrogenated rosin glycerin ester 40% of the release ?lm include a silicon coated polyethylene ?lm, Felbinac 5% PET ?lm and polypropylene ?lm. Total 100% EXAMPLE

[0064] Hereinafter, the present invention Will be described more speci?cally by illustrating Examples, Preparation (Process) Examples and Test Examples of the present invention, but the [0071] Felbinac Was dissolved in advance in N-methyl-2 present invention is not limited to these Examples and Prepa pyrrolidone, and the solution Was mixed With other base ration Examples and various modi?cations thereof can be components Which Were already dissolved in toluene. The made Without departing from the technical idea of the present mixture Was coated on the release ?lm, and subsequently invention. toluene and N-methyl-2-pyrrolidone Were removed by dry [0065] Here, in the folloWing description, all of “%” mean ing. The obtained product Was laminated With the PET ?lm “% by Weight” unless otherWise speci?ed. support to provide a desirable transdermally absorbable preparation (the thickness of the adhesive layer Was 100 um). Example 1 Comparative Example 2 Felbinac/Lidocaine Formulated Preparation Lidocaine Formulated Preparation [0066] The external adhesive patch in Which both felbinac and lidocaine Were formulated Was prepared. [0072] The external adhesive patch in Which only lidocaine Was formulated Was prepared as Comparative Example 2. (Components) [0067] (Components) [0073]

SIS 16% Liquid parai?n 28% BHT 1% SIS 16% Hydrogenated rosin glycerin ester 40% Liquid paraf?n 33% Lidocaine 10% BHT 1% Felbinac 5% Hydrogenated rosin glycerin ester 40% Lidocaine 10% Total 100% Total 100%

(Process) (Process) [0068] Felbinac Was dissolved in advance in N-methyl-2 pyrrolidone and lidocaine Was dissolved in toluene. They [0074] Lidocaine Was dissolved in advance in toluene, and Were mixed With other base components, Which Were already the solution Was mixed With other base components Which dissolved in toluene. The mixture Was coated on the release Were already dissolved in toluene. The mixture Was coated on ?lm, and subsequently toluene and N-methyl-2-pyrrolidone the release ?lm, and subsequently toluene Was removed by Were removed by drying. The obtained product Was laminated drying. The obtained product Was laminated With the PET With the PET ?lm support to provide a desirable transder ?lm support to provide a desirable transdermally absorbable mally absorbable preparation (the thickness of the adhesive preparation (the thickness of the adhesive layer Was 100 um). layer Was 100 um). Comparative Example 3 Comparative Example 1 Ketoprofen Formulated Preparation Felbinac Formulated Preparation [0075] The external adhesive patch in Which only ketopro [0069] The external adhesive patch in Which only felbinac fen, Which is another anti-in?ammatory analgesic Was formu Was formulated Was prepared as Comparative Example 1. lated Was prepared as Comparative Example 3. US 2013/0035391A1 Feb. 7, 2013

(Components) (Components) [0076] [0082]

SIS 16% SIS 16% Liquid paral?n 38% Liquid paraf?n 38% BHT 1% BHT 1% Hydrogenated rosin glycerin ester 40% Hydrogenated rosin glycerin ester 40% Ketoprofen 5% Indomethacin 5%

Total 100% Total 100%

(Process) (Process) [0077] Ketoprofen Was dissolved in advance in N-methyl- [0083] Indomethacin Was dissolved in advance in N-me 2-pyrrolidone, and the solution Was mixed With other base thyl-2-pyrrolidone, and the solution Was mixed With other components Which Were already dissolved in toluene. The base components Which Were already dissolved in toluene. mixture Was coated on the release ?lm, and subsequently The mixture Was coated on the release ?lm, and subsequently toluene and N-methyl-Z-pyrrolidone Were removed by dry toluene and N-methyl-Z-pyrrolidone Were removed by dry ing. The obtained product Was laminated With the PET ?lm ing. The obtained product Was laminated With the PET ?lm support to provide a desirable transdermally absorbable support to provide a desirable transdermally absorbable preparation (the thickness of the adhesive layer Was 100 um). preparation (the thickness of the adhesive layer Was 100 um). Comparative Example 4 Comparative Example 6 Ketoprofen/Lidocaine Formulated Preparation Indomethacin/Lidocaine Formulated Preparation [0078] The external adhesive patch in Which ketoprofen [0084] The external adhesive patch in Which indomethacin Which is another anti-in?ammatory analgesic Was used in Which is another anti-in?ammatory analgesic Was used in combination With lidocaine Was prepared as Comparative combination With lidocaine Was prepared as Comparative Example 4. Example 5. (Components) (Components) [0079] [0085]

SIS 16% SIS 16% Liquid paral?n 28% Liquid paraf?n 28% BHT 1% BHT 1% Hydrogenated rosin glycerin ester 40% Hydrogenated rosin glycerin ester 40% Lidocaine 10% Lidocaine 10% Ketoprofen 5% Indomethacin 5%

Total 100% Total 100%

(Process) (Process) [0080] Ketoprofen Was dissolved in advance in N-methyl- [0086] Indomethacin Was dissolved in advance in N-me 2-pyrrolidone and lidocaine Was dissolved in toluene. They thyl-2-pyrrolidone and lidocaine Was dissolved in toluene. Were mixed With other base components, Which Were already They Were mixed With other base components, Which Were dissolved in toluene. The mixture Was coated on the release already dissolved in toluene. The mixture Was coated on the ?lm, and subsequently toluene and N-methyl-2-pyrrolidone release ?lm, and subsequently toluene and N-methyl-2-pyr Were removed by drying. The obtained product Was laminated rolidone Were removed by drying. The obtained product Was with the PET ?lm support to provide a desirable transder laminated with the PET ?lm support to provide a desirable mally absorbable preparation (the thickness of the adhesive transdermally absorbable preparation (the thickness of the layer Was 100 um). adhesive layer Was 100 um).

Comparative Example 3 Test Example 1

Indomethacin Formulated Preparation Rat Skin Permeability Test [0081] The external adhesive patch in Which only [0087] In vitro skin permeability test Was carried out With indomethacin, Which is another anti-in?ammatory analgesic the skin excised from the male rat (Wister strain, 8 Week old) Was formulated, Was prepared as Comparative Example 5. for each external preparation prepared in the above Example US 2013/0035391A1 Feb. 7, 2013

1 and Comparative Examples 1 to 6 to study the speci?city of enhances the releasing of felbinac in the external adhesive the releasing of felbinac and lidocaine in the external adhe patch of the present invention in Which both felbinac and sive patch of the present invention in Which both felbinac and lidocaine are formulated. lidocaine Were formulated in accordance With Comparative Studies (1) to (3) described beloW. Consideration to Comparative Study (2) [Method] [0096] On the other hand, When ketoprofen, Which is another anti-in?ammatory analgesic, Was subjected to the [0088] The rat abdominal skin Was exfoliated, the dermis same test to study the releasing of both formulations With or side of the skin Was directed to a side of a receptor layer, and Without formulating lidocaine, it Was found that lidocaine its inside Was ?lled With phosphate buffered saline. Water shoWed almost the same drug releasing (FIG. 4), but the kept at 370 C. Was circulated in a Water jacket. Each test releasing of ketoprofen Was inhibited signi?cantly by formu preparation prepared in Example 1 and Comparative lating lidocaine (FIG. 3). Examples 1 to 6 Was stamped out in a circle (1.77 cm2) and attached to the excised skin. The receptor solution Was Consideration to Comparative Study (3) sampled over time to measure the permeated amount of each drug (lidocaine, felbinac, ketoprofen, and indomethacin) by [0097] For indomethacin Which is another anti-in?amma high performance liquid chromatography. tory analgesic, the external adhesive patch of Comparative Example 6 in Which both indomethacin and lidocaine are [Comparative Study] formulated had the releasing of both indomethacin and lidocaine inhibited. [0089] (1) Comparison of the releasing of felbinac and/or lidocaine by comparing the preparation of Example 1 in [0098] According to the results of these Comparative Stud Which both felbinac and lidocaine are formulated in the ies (1) to (3), as for the adhesive patch of the present invention external adhesive patch of the present invention, the prepa in Which lidocaine is formulated as the local anesthetic ration of Comparative Example 1 in Which only felbinac is together With felbinac Which is a non-steroidal anti-in?am formulated, and the preparation of Comparative Example 2 matory analgesic, it Was found that it is the transdermally in Which only lidocaine is formulated. absorbable preparation in Which the releasing of lidocaine is not inhibited signi?cantly and is accompanied by excellent [0090] (2) For ketoprofen Which is another anti-in?amma tory analgesic, comparison of the releasing of ketoprofen felbinac releasing although it is the preparation in Which the and/or lidocaine by comparing the preparation of Com basic drug of the local anesthetic and the acidic drug of the parative Example 3 in Which only ketoprofen is formu non-steroidal anti-in?ammatory analgesic are formulated. lated, the preparation of Comparative Example 4 in Which [0099] Moreover, the releasing effect of the anti-in?amma both ketoprofen and lidocaine are formulated, and further tory analgesic, an active component, obtained by formulating more Comparative Example 2 in Which only lidocaine is lidocaine is not observed for ketoprofen and indomethacin formulated. and is speci?c only for felbinac among non-steroidal anti [0091] (3) For indomethacin Which is another anti-in?am in?ammatory analgesics. Therefore, it should be understood matory analgesic, comparison of the releasing of that the present invention has extremely excellent speci?city. indomethacin and/or lidocaine by comparing the prepara tion of Comparative Example 5 in Which only indometha PREPARATION EXAMPLE cin is formulated, the preparation of Comparative Example [0100] Hereinafter, speci?c Preparation Examples other 6 in Which both indomethacin and lidocaine are formu than the external adhesive patch of the present invention lated, and furthermore Comparative Example 2 in Which described above in Example 1 are shoWn beloW in Table 1. only lidocaine is formulated. Here, the present invention is not limited thereto.

[Result] TABLE 1 [0092] The results are shoWn in FIGS. 1 to 6. Preparation Fxamnle (unit: % by Weight)

[Consideration] Components 1 2 3 4 5 6

SIS 16 16 15 19 16 1 6 Consideration to Comparative Study (1) BHT 1 1 1 1 1 1 Hydrogenated Rosin 40 40 [0093] As is apparent in comparison of the results shoWn in Glycerin Ester FIGS. 1 and 2, the releasing of felbinac in the external adhe Terpene Resin 40 sive patch of Example 1 in Which both felbinac and lidocaine Alicyclic Saturated 40 4O 3 8 Were formulated Was dramatically high compared to the Hydrocarbon Resin Liquid Paraf?n 31 21 33 19.5 33 33 external adhesive patch of Comparative Example 1 in Which Lidocaine 10 15 10 20 5 8 only felbinac Was formulated (FIG. 1). Felbinac 2 7 1 0.5 5 4 [0094] Also, the releasing of lidocaine in the external adhe sive patch of Example 1 in Which both felbinac and lidocaine The thickness ofthe adhesive layer: 100 um Were formulated Was almost the same as that of the external adhesive patch of Comparative Example 2 in Which only INDUSTRIAL APPLICABILITY lidocaine Was formulated (FIG. 2). [0095] Considering these both results, it is understood that [01 01] As described above, the transdermally absorbable good releasing of lidocaine as the absorption promoter preparation according to the present invention can provide the US 2013/0035391A1 Feb. 7, 2013

preparation Which shows excellent analgesic effect caused by 5. The felbinac-containing transdermally absorbable adhe lidocaine and excellent anti-in?ammatory and analgesic sive patch according to claim 4, Wherein the rubber polymer effects caused by felbinac. is a styrene-isoprene-styrene block copolymer. [0102] Particularly, in the present invention, by combining 6. The felbinac-containing transdermally absorbable adhe felbinac With lidocaine as the absorption promoter for felbi sive patch according to claim 1, Wherein the adhesive patch is nac in the adhesive patch base, felbinac can be uniformly substantially free of a solubiliZer for felbinac in the ?nal contained in the plaster composition Without substantially preparation. formulating a solubiliZer for felbinac, and further high releas 7. The felbinac-containing transdermally absorbable adhe ing of felbinac is kept Without losing the releasing of sive patch according to claim 2, Wherein an adhesive patch base is a rubber polymer. lidocaine. As a result, the present invention can provide the transdermally absorbable preparation Which achieves excel 8. The felbinac-containing transdermally absorbable adhe lent analgesic and anti-in?ammatory effects, thereby having a sive patch according to claim 3, Wherein an adhesive patch great medical effect. base is a rubber polymer. 9. The felbinac-containing transdermally absorbable adhe 1. A felbinac-containing transdermally absorbable adhe sive patch according to claim 2, Wherein the adhesive patch is sive patch, comprising felbinac as an active component and substantially free of a solubiliZer for felbinac in the ?nal lidocaine or a pharmaceutically acceptable salt thereof as an preparation. absorption promoter. 10. The felbinac-containing transdermally absorbable 2. The felbinac-containing transdermally absorbable adhe adhesive patch according to claim 3, Wherein the adhesive sive patch according to claim 1, Wherein a content of felbinac patch is substantially free of a solubiliZer for felbinac in the is from 0.1% to 10% by Weight to a total Weight of a drug ?nal preparation. containing plaster. 11. The felbinac-containing transdermally absorbable 3. The felbinac-containing transdermally absorbable adhe adhesive patch according to claim 4, Wherein the adhesive sive patch according to claim 1, Wherein a content of patch is substantially free of a solubiliZer for felbinac in the lidocaine or the pharmaceutically acceptable salt thereof is ?nal preparation. from 0.01% to 20% by Weight to a total Weight of a drug 12. The felbinac-containing transdermally absorbable containing plaster. adhesive patch according to claim 5, Wherein the adhesive patch is substantially free of a solubiliZer for felbinac in the 4. The felbinac-containing transdermally absorbable adhe ?nal preparation. sive patch according to claim 1, Wherein an adhesive patch base is a rubber polymer.