KR20100117387A - A new transdermal combination composition of dexibuprofen and tulobuterol - Google Patents

Abstract

A first component comprising dexibuprofen or a pharmaceutically acceptable salt thereof; And two components of a second component comprising tulobuterol or a pharmaceutically acceptable salt thereof, wherein the two components combine to form a final composition for a single dosage form FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition for treating colds, antipyretics, and more specifically, a single dosage form containing dexibuprofen and tulobuterol.

Description

A new transdermal combination composition of dexibuprofen and tulobuterol}

The present invention relates to a transdermal agent of a pharmaceutical composition comprising two components, an analgesic antipyretic agent dexibuprofen or a pharmaceutically acceptable salt thereof and a tulobbuterol or a pharmaceutically acceptable salt thereof for treating cold asthma. Preferably, the present invention relates to a combined patch for the treatment of colds, antipyretics, containing a single dosage form of dexibuprofen and tulobuterol.

Dexibuprofen (formula 1) is a nonsteroidal antipyretic analgesic S-type isomer of ibuprofen. Dexibuprofen is known to have the same antipyretic and analgesic effect at half the dose of ibuprofen and to reduce side effects such as gastrointestinal disorders compared to ibuprofen. At present, oral preparations such as tablets and syrups containing dexibuprofen as active ingredients are commercially available.

Tolubuterol, on the other hand, is a drug that selectively acts on the β2 receptor of the sympathetic nerve to relax bronchial smooth muscle, thereby treating dyspnea in asthma and respiratory disorders. Representative bronchodilators include albuterol, clenbuterol, fenoterol, formoterol, salmeterol, tulobuterol and procaterol Can be mentioned.

Among them, Toulobuterol (formula 2) is currently marketed in the form of a trademark Hokunalin patch and its indication is for treating colds and asthma including infants.

These two pharmaceuticals can be administered to patients who need cold antipyretic therapy.

Is desired. Moreover, it may be desirable to have a way to administer these two agents in a single dosage form.

The present invention provides a complex transdermal absorbent composition comprising dexibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt oil thereof.

Accordingly, an object of the present invention is dexibuprofen or a pharmaceutically acceptable salt thereof and tolubuterol or a pharmaceutically acceptable salt thereof having an excellent transdermal permeability and less side effects to patients in need of cold antipyretic therapy including infants. It is to provide a transdermal agent of a single dosage form of the salt.

The present inventors can be formulated into a single dosage complex transdermal patch in which dexibuprofen or a pharmaceutically acceptable salt thereof and tolobuterol or a pharmaceutically acceptable salt thereof are stable, and wherein the complex patch is The present invention was completed by the discovery that the drug penetrates through the percutaneous body as when the drug is administered in a separate dosage form.

The present inventors have already developed a new transdermal agent of dexibuprofen from the Korean patent application (Application No. 10-2009-0018938) and applied for a patent and is currently pending.

In addition, Japanese Patent No. 3930984, Japanese Patent Publication No. 5-194202, Japanese Patent Publication No. 5-238953, Japanese Patent Publication No. 7-285854, and Japanese Patent Publication No. 7-25669 describe the contents of Tolubuterol transdermal drug. It is.

Dexibuprofen has a low melting point around 51 ° C and shows high solubility in organic solvents such as ethyl acetate, hexane, toluene, ethanol and isopropanol. In addition, tulobuterol also has a low melting point around 90 ° C. and similarly to dexibuprofen, it exhibits high solubility in organic solvents. Most acrylate adhesives used in transdermal preparations contain 20-70% of organic solvents such as ethyl acetate, which is suitable for storing dexibuprofen and tulobuterol in adhesives and storing them in the drug storage layer of transdermal preparations. This has the advantage of increasing the workability. In addition, when using a rubber-based pressure-sensitive adhesive that does not contain an organic solvent, dexibuprofen and tulobuterol having a low melting point can be melted at a suitable temperature and mixed with the rubber-based pressure-sensitive adhesive or melted together and stored in the drug storage layer.

In the present invention, dexibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt thereof can be appropriately stored in the drug storage layer, so that each drug may be constantly fixed through the percutaneous drug. The present invention provides a single dosage form of the new dexibuprofen and tulobuterol complex transdermal absorption preparation that can reduce side effects while being effective in treating colds and antipyretics.

Accordingly, the present invention provides a single dose of dexibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt thereof for the treatment of colds and antipyretics, and thus the drug is constantly released through the percutaneous drug. It is to provide a novel transdermal absorption preparation of dexibuprofen and tulobuterol that can reduce the number and effectively treat colds and antipyretics.

Accordingly, the present inventors use a new type of dexibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable agent thereof, through which the drug is constantly released through the percutaneous body using various types of polymer adhesives and drug release control agents. The present invention was completed by developing a complex absorbent preparation of salts.

The present invention is a new dosage form of dexibuprofen or a pharmaceutically acceptable salt thereof, which can reduce the side effects and release the drug constantly through the percutaneous in a single dosage form of dexibuprofen and tulobuterol for the treatment of colds and fever. And a combination transdermal absorption preparation of tulobuterol or a pharmaceutically acceptable salt thereof can be expected to have an elevated therapeutic effect.

The present invention relates to a novel multimodal transdermal absorbent with a single dosage form comprising dexibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a complex patch containing sibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, pharmaceutically acceptable salts of dexypropene include alkali metal or alkaline earth metal salts such as lithium salt, sodium salt, potassium salt or calcium salt, trimethylamine salt, triethylamine salt, diisopropylamine salt, Salts with organic bases such as triethanolamine salts can be used. Pharmaceutically acceptable salts of tolobuterol in the present invention include organic acid salts such as hydrochloric acid addition salts, hydrobromic acid addition salts, sulfuric acid addition salts, acid addition salts and formic acid addition salts of inorganic acids such as acetic acid addition salts and lactic acid addition salts. Salts selected from addition salts, benzoic acid addition salts, aromatic acid addition salts such as benzenesulfonate salts, sulfonate salts such as methanesulfonic acid salts and ethanesulfonic acid salts can be used.

Hereinafter, the present invention will be described in detail.

The composition of the complex transdermal agent of the present invention,

a) a support layer;

b) a polymer drug storage layer composed of two layers each containing an active ingredient dexibuprofen or a pharmaceutically acceptable salt thereof, or a tulobuterol or a pharmaceutically acceptable salt thereof; And,

c) or a drug storage layer consisting of one layer containing dexibuprofen or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt thereof.

The complex transdermal agent of the present invention is composed of one or two drug storage layers depending on the skin permeation control of the drug. Two drugs may be stored together in one drug storage layer or two active ingredients may be stored separately in two drug layers.

In the present invention, in the case of the transdermal drug consisting of two drug storage layers, a) drug storage layer 1: drug storage layer consisting of an acrylic pressure-sensitive adhesive containing tolubuterol or a pharmaceutically acceptable salt thereof, b) drug storage layer 2: It consists of a drug storage layer made of dexibuprofen or a rubber-based pressure-sensitive adhesive containing a pharmaceutically acceptable salt thereof, or a) drug storage layer 1: containing tulobuterol or a pharmaceutically acceptable salt thereof Drug storage layer made of a rubber-based adhesive, b) Drug storage layer 2: It consists of a drug storage layer consisting of an acrylic pressure-sensitive adhesive containing dexibuprofen or a pharmaceutically acceptable salt thereof. In the present invention, the same series of pressure-sensitive adhesives may be applied to the transdermal drug consisting of two drug storage layers. For example, a) drug storage layer 1: a drug storage layer consisting of an acrylic adhesive containing tolubuterol or a pharmaceutically acceptable salt thereof, b) drug storage layer 2: dexibuprofen or pharmaceutically acceptable It may be composed of a drug storage layer made of an acrylic pressure-sensitive adhesive containing a salt, and also, a) Drug storage layer 1: drug storage layer made of a rubber-based pressure-sensitive adhesive containing tolubuterol or a pharmaceutically acceptable salt thereof, b ) Drug storage layer 2: It may be composed of a drug storage layer consisting of a rubber-based pressure-sensitive adhesive containing dexibuprofen or pharmaceutically acceptable salts thereof.

In addition, when composed of one layer of drug storage layer, 1) a drug layer composed of an acrylic pressure-sensitive adhesive containing both tulobuterol or a pharmaceutically acceptable salt thereof and dexibuprofen or a pharmaceutically acceptable salt thereof. Or

2) It consists of a drug layer which consists of a rubber-based adhesive agent containing both tulobuterol or its pharmaceutically acceptable salt and dexibuprofen or its pharmaceutically acceptable salt.

In the composite material transdermal absorbent containing the dexibuprofen of the present invention or a pharmaceutically acceptable salt thereof and tulobuterol or a pharmaceutically acceptable salt thereof, the support includes polyester, polyurethane, polyethylene, and polypropylene. , A single layer film such as polyolefin, polyethylene terephthalate, aluminum-treated polyester, or the above-mentioned single layer film laminated with a non-woven fabric, cotton cloth, fabric, etc. having moisture absorption capability in order to prevent the patch from being released by moisture emitted from the human body. A multilayer laminate film or the like can be used, and any of drug-protective films used in conventional patching agents may be used.

Dexibuprofen or a pharmaceutically acceptable salt thereof, which is one of the active ingredients in the present invention, contains dexibuprofen or a pharmaceutically acceptable salt thereof per 0.3 cm 2 of a transdermal absorbent, from 0.3% by weight to the weight of the drug storage layer. It may contain 55% by weight, preferably from 0.5% to 25% by weight of the weight of the drug storage layer.

Another active ingredient, tulobuterol or a pharmaceutically acceptable salt thereof, contains 0.1% to 30% by weight of tulobuterol or a pharmaceutically acceptable salt thereof per 1 cm 2 of a transdermal absorbent. And preferably 0.5% to 12.0% by weight of the weight of the drug storage layer.

In the present invention, an acrylate-based, rubber-based polymer is used as an adhesive layer containing dexibuprofen or a pharmaceutically acceptable salt thereof or tulobuterol or a pharmaceutically acceptable salt thereof. The acrylate type is an acrylate polymer with a hydroxyl group, an acrylate polymer with a carboxyl group, an acrylate polymer without a functional group, an acrylate-vinylacetate polymer with a hydroxyl group, an acrylate-vinyl with a carboxyl group Acetate-based polymers or acrylate-vinylacetate-based polymers without functional groups may be used. For acrylates, National Starch's Duro-tak 87-2516 and 87-2052 are preferred and contain 25.0 wt% to 90.0 wt% of the total drug reservoir layer. Preferably from 65.0% to 85.0% by weight of the total weight of the drug storage layer.

In addition, a polyisobutylene (PIB), styrene-diene-styrene copolymer (styrene-) is an adhesive layer containing dexibuprofen or a pharmaceutically acceptable salt thereof or tulobuterol or a pharmaceutically acceptable salt thereof. Isoprene-styrene copolymer, SIS) -based rubber adhesive can be used to play a role in controlling the adhesive force and the release rate of the drug is mainly composed of a rubber-based adhesive and a tackifier mixed. Rubber-based adhesives are polyisobutylene, polyisoprene, polybutene, polyisobutylene-polybutene copolymer, isoprene-isobutylene copolymer, styrene-diene-styrene copolymer (e.g., styrene-butadiene-styrene copolymer) , Styrene-isoprene-styrene copolymer), isoprene-butadiene copolymer, styrene-butadiene copolymer, etc. can be used one or two or more selected, tackifiers rosin glycerin ester, hydrogenated rosin glycerin ester, rosin One or two or more kinds of rosin derivatives such as pentaerythritol esters, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins and terpene resins can be used. In the present invention, the PIB, SIS-based rubber-based adhesive is 32.5% by weight to 95.0% by weight of polyisobutylene (molecular weight: 200,000 to 20,000,000) or styrene-isoprene-styrene copolymer (styrene content: 10 to 20%) or 2 types, 3.0% to 15.0% by weight of polyisobutene (molecular weight: 10,000 to 60,000) and 12.5% to 40.0% by weight of tackifier, 0.1% to 15.0% by weight of polybutene (molecular weight: 1,000 to 6,000 ) Is preferably used in combination. The rubber-based adhesive prepared as described above contains 50.0 wt% to 90.0 wt% of the weight of the entire drug storage layer, but preferably 70.0 wt% to 85.0 wt% of the weight of the entire drug storage layer.

In the present invention, the drug release control agent is selected from the group consisting of fatty acid ethers, nonionic surfactants (twins), isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters and plasticizers. The selected species can be used. Drug release control agent of the present invention is adjusted to 0.1 to 30% by weight relative to the total drug storage layer weight, but more preferably 1 to 20% by weight.

Hereinafter, the present invention will be described in detail in the Examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example 1

Drug layer 1 is 8.3% by weight of dexibuprofen, 5.0% by weight of isopropylmyrilate (IPM), 85.6% by weight of polyacrylate (Duro-Tak 87-2516, National-Starch, USA), liquid crosslinker (TYZOR AA- 75, Dupont) 1.1 weight% was added and stirred to leave the dissolved drug layer at room temperature for 30 minutes to remove bubbles, and then dried using a lab coater (Labis, Switzerland, Mathis) to make the thickness of 150 ~ 170㎛. 30 cm <2> was apply | coated to this deposited polyester support body.

The drug layer 2 is 88.2% by weight of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0% by weight of polyisobutylene, 10.0% by weight of polybutene and 25.0% by weight of hydrogenated rosin glycerin ester. Stirring at a rate of 11.8% by weight of terrol was applied to 30 cm 2 on the peeling film to be 17 ~ 18㎛. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 2

Drug layer 1 is 8.0% by weight of dexibuprofen to 4.4% by weight of diisopropanolamine, 4.8% by weight of Tween 80, 81.7% by weight of polyacrylate (Duro-Tak 87-2516, National-Starch, USA), liquid crosslinker (TYZOR AA-75, Dupont Co., Ltd.) 1.1% by weight of the polyester layer was added by stirring to leave the dissolved drug layer at room temperature for 30 minutes to remove bubbles, and then dried using a lab coater to deposit a thickness of 150 ~ 170㎛ aluminum support polyester support 30 cm 2 was applied.

Drug layer 2 is 11.8% by weight of tulobuterol, 6.7% by weight of castor oil (HCO-40), 33.7% by weight of hydrocarbon resin (trade name: R-1100, Eastman), and butylated hydroxytoluene, an antioxidant, 0.7. After adding weight%, 26.9 weight% of styrene-isoprene-styrene copolymer, 6.7 weight% of polyisobutylene, and 13.5 weight% of polybutene, the drug layer melted by heating at 150 ° C. was dried using a lab coater. It applied on the peeling film so that it might be set to 17-19 micrometers. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 3

Drug layer 1 is 87.3 weight% of an acrylic adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate, and 1.2 weight of an acrylic adhesive having a carboxyl group which is a copolymer of vinyl acetate and butyl acrylate. 17 ~ 18㎛ thickness after mixing with a lab coater the drug layer completely dissolved in the solution of the tulobuterol in the mixed solution so that the ratio of the functional group hydroxy group and carboxyl group is 75 to 1 in the ratio of% by using a lab coater (Tulbuterol content: 11.5 Weight percent)) to a polyester support on which aluminum was deposited.

Drug layer 2 is 68.8% by weight of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0% by weight of polyisobutylene, 10.0% by weight of polybutene and 25.0% by weight of hydrogenated rosinglycerin ester. It stirred at the ratio of 20.8 weight% of propene, and 10.4 weight% of isopropylmyrirates, and apply | coated in 30 cm <2> on the peeling film so that it might become 120-140 micrometers. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 4

Drug layer 1 is 87.3 weight% of an acrylic adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate, and 1.2 weight of an acrylic adhesive having a carboxyl group which is a copolymer of vinyl acetate and butyl acrylate. 17 ~ 18㎛ thickness after drying with a lab coat the drug layer completely dissolved in the solution of the tulobuterol in the mixed solution so that the ratio of the functional group hydroxy group and carboxyl group is 75 to 1 by mixing in a ratio of% (Tulbuterol content: 11.5 Weight percent)) to a polyester support on which aluminum was deposited.

Drug layer 2 is 18.6% by weight of dexibuprofen, 6.2% by weight of castor oil (trade name: HCO-40), 31.1% by weight of hydrocarbon resin (trade name: R-1100, Eastman), butylated hydroxide as an antioxidant 0.6 wt% of oxytoluene, 24.8 wt% of styrene-isoprene-styrene copolymer as an adhesive, 6.2 wt% of polyisobutylene, 12.4 wt% of polybutene, and 11.0 wt% of transcutol, and then heated to 150 ° C. to melt the drug layer. Using a wrap coater, it was applied on the peeling film so that the thickness after drying was 80 to 120 µm. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 5

Drug layer 1 is 63.8 wt% of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0 wt% of polyisobutylene, 10.0 wt% of polybutene and 25.0 wt% of hydrogenated rosinglycerin ester. Agitated at a ratio of 21.3 wt% propene and 14.9 wt% polyoxyethylene lauryl ether (BL 2), and was applied (30 cm 2) onto a polyester support on which aluminum was deposited so as to be 120 to 140 μm.

Drug layer 2 is 11.8% by weight of tulobuterol, 6.7% by weight of castor oil (trade name: HCO-40), 33.7% by weight of hydrocarbon resin (trade name: R-1100, Eastman), and butylated hydroxytoluene as an antioxidant. 0.7 weight%, 26.9 weight% of styrene-isoprene-styrene copolymer as an adhesive, 6.7 weight% of polyisobutylene, and 13.5 weight% of polybutene were added, and the drug layer melt | dissolved by heating at 150 degreeC and dried using the wrap coater It applied on the peeling film so that it might be set to 17-19 micrometers. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 6

The drug layer 1 is 88.2% by weight of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0% by weight of polyisobutylene, 10.0% by weight of polybutene and 25.0% by weight of hydrogenated rosinglycerin ester. Stirring at a rate of 11.8% by weight of terrol was applied to 30 cm 2 to the polyester support on which aluminum was deposited so as to be 17 to 18㎛.

Drug layer 2 is 15.7% by weight of dexibuprofen to 15.7% by weight of propylene glycol monolauryllate, 5.2% by weight of castor oil (trade name: HCO-40), and hydrocarbon resin (trade name: R-1100, Eastman). % By weight, 0.5% by weight of butylated hydroxytoluene as an antioxidant, 20.9% by weight of styrene-isoprene-styrene copolymer as an adhesive, 5.2% by weight of polyisobutylene, and 10.5% by weight of polybutene, and then heated to 150 ° C. The melted drug layer was applied onto the peeling film so that the thickness after drying was 80 to 120 µm using a lab coater. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 7

The drug layer is 26.4 weight% of an acrylic adhesive having a hydroxy group which is a copolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate, and 0.3 weight of an acrylic adhesive having a carboxyl group which is a copolymer of vinyl acetate and butyl acrylate. The drug layer was completely dissolved in a solution of 3.5% by weight of tulobuterol, 52.3% by weight of dexibuprofen, and 17.4% by weight of Tween 80 in a solution mixed with the ratio of functional hydroxyl group and carboxyl group at 75 to 1 ratio. After drying by using a coating on the peeling film to be 60 ~ 80㎛ thickness, and then laminated with a polyester support on which aluminum is deposited to complete a 30cm patch, a thermo-hygrostat (40 ± 2 ℃, 75 ± 5%) Aged for 1 week at.

Example 8

The drug layer is 66.0 wt% of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0 wt% of polyisobutylene, 10.0 wt% of polybutene, and 25.0 wt% of hydrogenated rosinglycerin ester. Agitated at a ratio of 21.3 wt% pen, 1.5 wt% tulobuterol and 11.3 wt% Tween 80, and applied onto the peeling film so as to be 130 to 160 μm, and then laminated with a polyester support on which aluminum was deposited to apply a 30 cm 2 patch. After completion, it was aged for 1 week in a thermo-hygrostat (40 ± 2 ℃, 75 ± 5%).

Example 9

The drug layer is 15.5% by weight of dexibuprofen and 1.0% by weight of tulobuterol, 15.5% by weight of Tween 80, 5.2% by weight of castor oil (HCO-40), and hydrocarbon resin (trade name: R-1100, Eastman Corporation). 25.9% by weight, 0.5% by weight of butylated hydroxytoluene as antioxidant, 20.7% by weight of styrene-isoprene-styrene copolymer as adhesive, 5.2% by weight of polyisobutylene, 10.4% by weight of polybutene, and then heated to 150 ° C The melted drug layer was applied on the peeling film so that the thickness after drying was 80 to 120 µm using a lab coater, and then laminated with a polyester support on which aluminum was deposited to complete a 30 cm 2 patch, followed by a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%) for 1 week.

Example 10

Drug layer 1 is 63.8 wt% of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0 wt% of polyisobutylene, 10.0 wt% of polybutene and 25.0 wt% of hydrogenated rosinglycerin ester. It was applied at 30 cm 2 to a polyester support on which aluminum was deposited so as to stir at a ratio of 21.3 wt% propene and 14.9 wt% alpha monoisoisoaryl glyceryl ether. Drug layer 2 is 88.2% by weight of the pressure-sensitive adhesive using a polyisobutylene pressure-sensitive adhesive made by uniformly mixing 65.0% by weight of polyisobutylene, 10.0% by weight of polybutene and 25.0% by weight of hydrogenated rosinglycerin ester. Stirring at a rate of 11.8% by weight of terrol was applied to the peeling film to 30 ~ 17cm to 17 ~ 18㎛ finish the patch and then laminated on the drug layer (drug layer 1) applied to the previously prepared support, constant temperature and humidity (40 ± 2 ° C., 75 ± 5%) for 1 week.

Example 11

Drug layer 1 is 15.7% by weight of dexibuprofen, 15.7% by weight of alpha monoisostearylglyceryl ether, 5.2% by weight of castor oil (HCO-40), and hydrocarbon resin (trade name: R-1100, Eastman Co., Ltd.) 26.2 % By weight, 0.5% by weight of butylated hydroxytoluene as an antioxidant, 20.9% by weight of styrene-isoprene-styrene copolymer as a pressure-sensitive adhesive, 5.2% by weight of polyisobutylene, and 10.6% by weight of polybutene, and then heated to 150 ° C. The dissolved drug layer was applied to the polyester support on which aluminum was deposited at 30 cm 2 so that the thickness after drying was 80 to 120 µm using a lab coater.

Drug layer 2 is 11.8% by weight of tulobuterol, 6.7% by weight of castor oil (trade name: HCO-40), 33.7% by weight of hydrocarbon resin (trade name: R-1100, Eastman), and butylated hydroxy as an antioxidant. After adding 0.7% by weight of toluene, 26.9% by weight of the styrene-isoprene-styrene copolymer as an adhesive, 6.7% by weight of polyisobutylene, and 13.5% by weight of polybutene, and heated to 150 ° C, the drug layer was dried by using a lab coater. It applied on the peeling film so that thickness might be 17-19 micrometers. The drug layer 2 applied to the peeling film was laminated on the drug layer (drug layer 1) applied to the previously prepared support, and then aged for one week in a thermo-hygrostat (40 ± 2 ° C., 75 ± 5%).

Example 12

In Example 1, a patch was prepared in the same manner as in Example 1 except that dexpropene sodium salt was used instead of dexpropene.

Example 13

In Example 1, a patch was prepared in the same manner as in Example 1 except that dexpropene sodium salt was used instead of dexpropene and tolobuterol hydrochloride addition salt was used instead of tolobuterol.

Example 14

EXAMPLES In Example 4, a patch was prepared in the same manner as in Example 4 except that dexpropene potassium salt was used instead of dexpropene and tolobuterol hydrobromide addition salt was used instead of tolobuterol. .

Example 15

In Example 7, a patch was prepared in the same manner as in Example 7, except that dexifene sodium salt was used instead of dexifene and tolobuterol hydrochloride salt was used instead of tolobuterol.

Test Example 1: Transdermal Permeation Test

The drug release of the complex transdermal absorption preparations prepared in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 was extracted from hairless mice (6 weeks old). 3 × 3 cm 2) for evaluation. The skin permeability test was performed using a Franz type diffusion cell having a diffusion region of 1.77 cm 2. The volume of the chamber solution was 12.5 mL. Patches prepared in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 were pressed against the skin of the extracted white rats, and the skin / patch laminates were placed in the chamber solution. On the surface of the skin, a clamp was fixed between the supply chamber and the receiving chamber of the Franz Cell. Phosphate buffer solution (pH 7.4) was added to the chamber of Franz Cell, and the temperature of the diffusion apparatus was maintained at 32 ° C. The buffer solution of the receptor was stirred at a constant speed of 600 rpm, 0.2 mL of sample was taken from the receptor at each time point, and the same volume of fresh phosphate buffered saline was added to maintain the sink condition. The transdermal doses of dexibuprofen and tulobuterol penetrated through the skin are shown in FIGS. 1 and 2.

Figure 1 shows the transdermal permeation amount of dexibuprofen for Examples 1 to 11 of the present invention,

Figure 2 shows the transdermal permeation dose of tulobuterol for Examples 1 to 11 of the present invention.

Claims (10)

(a) a first component comprising dexibuprofen or a pharmaceutically acceptable salt thereof; And (b) two components of a second component comprising tulobuterol or a pharmaceutically acceptable salt thereof, wherein the two components are combined between the support and the exfoliation film to form the final composition for a single dosage form. Percutaneous absorbents of complex pharmaceutical compositions for treating colds, asthma and antipyretics. The pharmaceutically acceptable salt of dexpropene according to claim 1 is an alkali metal or alkaline earth metal salt such as lithium salt, sodium salt, potassium salt or calcium salt, trimethylamine salt, triethylamine salt or diisopropyl. Percutaneous absorbent of a composite pharmaceutical composition which is a salt with an organic base such as an amine salt or triethanolamine salt. The pharmaceutically acceptable salts of tolobuterol according to claim 1 are acid addition salts of inorganic acids such as hydrochloric acid addition salts, hydrobromic acid addition salts, sulfuric acid addition salts, phosphates and formic acid addition salts, acetic acid addition salts, and lactic acid addition salts. Percutaneous absorbent of the composite pharmaceutical composition is a salt selected from organic acid addition salts, such as benzoic acid addition salts, aromatic acid addition salts such as benzene sulfonate salts, methane sulfonate salts, ethane sulfonate salts. The method according to claim 1, wherein dexibuprofen or a pharmaceutically acceptable salt thereof per 1 cm 2 of the transdermal absorbent is 0.3% to 55% by weight of the drug storage layer, tolobuterol or a pharmaceutically acceptable salt thereof 0.1 The transdermal absorbent of the composite pharmaceutical composition containing 30 weight%-30 weight% of an adhesive, 0.1 weight%-30 weight% of a drug release control agent. The method of claim 4, wherein the adhesive includes an acrylate polymer having a hydroxyl group, an acrylate polymer having a carboxyl group, an acrylate polymer having no functional group, an acrylate-vinylacetate polymer having a hydroxyl group, and a carboxyl group. Acrylate-vinylacetate polymer or acrylate-vinylacetate polymer without functional groups, polyisobutylene (PIB), styrene-diene-styrene copolymer (styrene-isoprene-styrene copolymer, SIS) rubber adhesive and adhesive Composite transdermal absorbent, characterized in that composed of at least one adhesive layer selected from the imparting agent. The drug release modifier of claim 4, wherein the drug release modifier is composed of fatty acid ether, nonionic surfactants (twin), isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters and plasticizers. A complex transdermal absorbent, characterized in that it contains at least one drug release modulator selected from the group. Dexibuprofen or a pharmaceutically acceptable salt thereof is dissolved together with a pressure-sensitive adhesive and drug release control agent and applied to a support (or release layer) film to prepare Drug Layer 1, tolubuterol or a pharmaceutically acceptable salt thereof. To a drug release layer (or support) by dissolving with a pressure-sensitive adhesive and drug release control agent to prepare a drug layer 2, the drug layer 1 and drug layer 2 is laminated and aged to contain a dexpropene and tolobuterol together A method of preparing a transdermal absorbent of a composite pharmaceutical composition. Dexibuprofen or a pharmaceutically acceptable salt thereof, tulobuterol or a pharmaceutically acceptable salt thereof is dissolved together with a pressure-sensitive adhesive and a drug release control agent and applied to a support, and the release layer is adhered to and aged to decipro A method for preparing a transdermal absorbent of a complex pharmaceutical composition containing pen and tolobuterol together. The acrylate-based polymer having a hydroxyl group, the acrylate-based polymer having a carboxyl group, the acrylate-based polymer having no functional group, and the acrylate-vinylacetate-based polymer having a hydroxyl group as an adhesive. , Acrylate-vinylacetate polymer with carboxyl group or acrylate-vinylacetate polymer without functional group, polyisobutylene (PIB), styrene-diene-styrene copolymer (styrene-isoprene-styrene copolymer, SIS) A method for preparing a transdermal absorbent of a composite pharmaceutical composition containing dexpropene and tolobuterol, comprising at least one pressure-sensitive adhesive layer selected from a rubber-based adhesive and a tackifier. The drug release modulator according to claim 7 or 8, wherein the drug release modifier is a fatty acid ether, nonionic surfactants (twin), isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters and plasticizers. A method for preparing a transdermal absorbent of a complex pharmaceutical composition containing dexpropene and tolobuterol, characterized in that it contains at least one drug release modifier selected from the group consisting of:

Images