JP2008214337A - Patch for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a patch for external use improving lowering of solubility, a releasing property and a medicine content in the patch for external use containing an acidic medicine or its alkali salt in a paste layer. <P>SOLUTION: The patch for external use is composed of a support, a paste layer and a peeling liner and contains an acidic medicine or its alkali salt as an active ingredient in the paste layer. In the patch, a rubber-based elastomer and a terpene-based resin and/or a hydrogenated rosin ester are included as base ingredients of the paste layer. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an external patch containing an acidic drug or an alkali salt thereof in a paste layer containing a rubber-based elastomer as a main base component, and more specifically, the solubility of the drug in the paste layer and the paste layer The present invention relates to a patch for external use that is excellent in drug release from the skin and does not cause a decrease in the content of the drug in the plaster layer.

  An external patch is a very excellent dosage form in that it does not cause side effects of the drug that causes problems when taken as an oral preparation, does not decrease the bioavailability, and the drug can be administered continuously. One. For this reason, for example, an anti-inflammatory analgesic such as indomethacin, an angina / heart failure treatment such as nitroglycerine, a climacteric / osteoporosis treatment such as estradiol, a bronchodilator such as tulobuterol, etc. Has been developed and is commercially available.

  Among the above, a wide variety of techniques have been developed for patches containing anti-inflammatory analgesics such as indomethacin, and the techniques are used in commercially available patches and the like. For example, in order to dissolve an anti-inflammatory analgesic into a patch base, a patch containing a solubilizing agent such as an organic acid (Patent Document 1), crotamiton (Patent Document 2, Patent Document 3), or a rosin ester derivative A patch using l-menthol in combination (Patent Document 4) has been developed. In addition, a patch containing propylene carbonate (Patent Document 5) and various absorption promoters has been developed to improve the drug release from the patch layer when the patch is applied to the affected skin. Has been. In addition, fatty acid metal salts (Patent Document 6), metal oxides (Patent Document 7), metal hydroxides (Patent Document 8), and the like were included in order to suppress a decrease in drug content in the patch. A patch has been developed. Furthermore, in order to solve the above problem, a patch containing a specific polymer compound such as a non-polar adhesive polymer (Patent Document 9), a polymer polyisobutylene and a low-molecular polyisobutylene (Patent Document 10). Etc. are also being developed. However, since the physicochemical properties of anti-inflammatory analgesics vary greatly depending on the compound, it is necessary to select or newly develop a technique suitable for the compound.

  Among anti-inflammatory analgesics, propionic acid-type anti-inflammatory analgesics have characteristics such as strong analgesic / anti-inflammatory effects and stable physical properties, and their clinical usefulness has been confirmed. On the other hand, the propionic acid-based anti-inflammatory analgesic has poor solubility in commonly used bases and has problems such as the occurrence of crystal precipitation and a decrease in transdermal absorbability. It was difficult.

  Among the propionic acid-based anti-inflammatory analgesics, loxoprofen sodium has an excellent anti-inflammatory analgesic action, and an aqueous patch (pap) formulated in an aqueous patch base is commercially available. However, the release of loxoprofen sodium from the aqueous patch base was relatively low, and the bioavailability was not good. In contrast, when loxoprofen sodium is incorporated into a non-aqueous patch base such as a rubber elastomer, it is possible to obtain a patch for external use with good release of loxoprofen sodium and sufficient bioavailability. However, the solubility of loxoprofen sodium in a non-aqueous patch base is very poor, and when dissolved in a non-aqueous patch base using a general solubilizer, the content of loxoprofen sodium over time New problems, such as a decrease, were recognized.

JP-A-62-126119 JP-A-4-321624 JP-A-10-120560 WO93 / 04677 JP 2002-87954 A WO96 / 08245 JP 2002-226366 A JP 2005-314328 A JP-A-10-95729 WO01 / 78690 publication

  The present invention solves the above problems, and in an external patch containing an acidic drug or an alkali salt thereof in a plaster layer containing a rubber elastomer, the solubility, release and drug content of the drug are reduced. It is intended to provide an external patch capable of improving the above.

  As a result of intensive studies to solve the above problems, the present inventors have found that in an external patch comprising a support, a paste layer containing a rubber-based elastomer as a main base component, and a release liner, By incorporating an acidic drug or an alkali salt thereof as an active ingredient into an external patch and further containing a terpene resin and / or a hydrogenated rosin ester as a base component of the plaster layer, As a result, the present invention has been completed.

  That is, the present invention comprises a support, a paste layer and a release liner, and an external patch containing an acidic drug or an alkali salt thereof as an active ingredient in the paste layer, as a base component in the paste layer An external patch characterized by comprising a rubber elastomer and a terpene resin and / or hydrogenated rosin ester.

  The external patch of the present invention is excellent in solubility and release of an acidic drug or an alkali salt thereof as an active ingredient, and can improve a decrease in the content of the drug over time.

  The acidic drug or the alkali salt thereof, which is an active ingredient of the external patch of the present invention, is contained in the plaster layer. Here, examples of the alkali salt of the acidic drug include sodium salt, potassium salt, ammonium salt and the like. The acidic drug or alkali salt contained therein is not particularly limited, and examples thereof include propionic acid pharmaceutical components such as ketoprofen, flurbiprofen and loxoprofen sodium, and phenylacetic acid pharmaceutical components such as diclofenac sodium. . Among them, a propionic acid-type anti-inflammatory analgesic agent is preferable in view of strong analgesic / anti-inflammatory action and stability in physical properties, and loxoprofen sodium is particularly preferable.

  In addition, the plaster layer of the external patch of the present invention is made of a rubber-based elastomer as a base component in consideration of manufacturing cost, control of physical properties and quality, that is, formulation design is easy. Used. Examples of the rubber elastomer include styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-butadiene rubber, polyisobutylene, polybutene, butyl rubber, natural rubber, and isoprene rubber. Of these, styrene-isoprene-styrene block copolymers, polyisobutylene, polybutene, butyl rubber, and isoprene rubber are preferably used. These can be used alone or in combination of two or more.

  In the paste layer of the external patch of the present invention, a terpene resin and / or a hydrogenated rosin ester is used as another base component. The terpene resin and / or hydrogenated rosin ester is generally used as a tackifier, but is compatible with a rubber-based elastomer, and dissolves an acid drug or alkali salt and releases it from the base. It has the effect of improving the properties and improving the decrease in the content of acidic drugs or alkali salts over time. Other common tackifiers include alicyclic saturated hydrocarbon resins, but when such alicyclic saturated hydrocarbon resins are used, the content of acidic drugs or alkali salts decreases with time. Therefore, it is not preferable.

  The content of the rubber elastomer used in the paste layer of the external patch of the present invention and the terpene resin and / or hydrogenated rosin ester is not particularly limited, but is based on the total mass of the paste layer composition. The rubber-based elastomer is preferably contained in an amount of 15 to 50% by mass, and the terpene resin and / or the hydrogenated rosin ester is preferably contained in an amount of 10 to 40% by mass. Here, if the content of the rubber-based elastomer is less than 15% by mass, the plaster becomes soft, so that the cohesive force (the adhesive strength of the patch can withstand internal destruction) is insufficient, and stringing (adhesive adhesive of the patch) In the case where the content exceeds 50% by mass, the plaster becomes too hard and the adhesive strength is lowered, which is not preferable. On the other hand, when the content of the terpene resin and / or hydrogenated rosin ester is less than 10% by mass, an appropriate adhesive strength cannot be obtained. When the content exceeds 40% by mass, the adhesive strength of the plaster is strong. There is a problem that the cohesive force becomes weak and the adhesive remains, and none of them is preferable.

  In the external patch of the present invention, the content of the acidic drug or its alkali salt in the plaster layer is not particularly limited, but is 0.5 to 10% by mass with respect to the total composition of the plaster layer. It is preferable that it is 5-10 mass% especially. If the content of the acidic drug or alkali salt is less than 0.5% by mass, a sufficient pharmacological action cannot be obtained. Cannot be obtained, and the bioavailability of the drug is low.

  The plaster layer of the external patch of the present invention preferably further contains an organic acid for the purpose of improving the solubility and transdermal absorbability of acidic drugs or alkali salts. Although there is no restriction | limiting in particular in this organic acid, C2-C18 carboxylic acid is a point which is compatible with the other component used for a paste layer, and there is no content fall of an acidic drug or an alkali salt. Among the carboxylic acids having 2 to 18 carbon atoms, acetic acid, lactic acid, tartaric acid, citric acid, malic acid, isostearic acid, oleic acid, adipic acid, benzoic acid and salicylic acid are particularly preferable. These organic acids can be used alone or in combination of two or more.

  The content of the organic acid is preferably 0.1 to 10 times, more preferably 0.3 to 5 times the content of the acidic drug or the alkali salt thereof. If the content of the organic acid is less than 0.1 mass times the content of the acidic drug or its alkali salt, there is a problem that the effect of improving the solubility or transdermal absorbability of the acidic drug or alkali salt is low. If the content exceeds twice, there is a problem that skin irritation derived from organic acid occurs, which is not preferable.

  In a preferred embodiment of the present invention, the content of the terpene resin and / or hydrogenated rosin ester and the organic acid in the plaster layer of the external patch is based on the total mass of the paste layer composition and the terpene resin and / or Alternatively, the content of the hydrogenated rosin ester is 10 to 40% by mass, and the content of the organic acid is 1/40 to 1/2 times the content of the terpene resin and / or the hydrogenated rosin ester. It is. When the content of the terpene resin and / or hydrogenated rosin ester is less than 10% by mass, an appropriate adhesive strength cannot be obtained. When the content exceeds 40% by mass, the adhesive strength of the plaster becomes too strong. , There is a problem that the cohesive force becomes weak and glue remains, which is not preferable. On the other hand, if the content of the organic acid is less than 1/40 mass times the content of the terpene resin and / or hydrogenated rosin ester, the effect of improving the solubility and transdermal absorbability of the acidic drug or alkali salt is low. However, when the content exceeds 1/2 mass, there is a problem that skin irritation derived from an organic acid occurs, which is not preferable.

  The plaster layer of the external patch of the present invention may further contain a dissolving agent as necessary. There is no particular limitation on the solubilizer, but an acidic or neutral solubilizer is preferable, and among these acidic or neutral solubilizers, ethanol, octyldodecanol, isopropanol, propylene glycol, propylene glycol stearate, concentrated glycerin, Particular preference is given to esters or ethers such as butylene glycol, polyethylene glycol, isopropyl myristate, octyldodecyl myristate, myristyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, isopropyl palmitate. These solubilizers can be used alone or in combination of two or more. The inclusion of the solubilizer is preferable because it has the effects of improving the solubility of the acidic drug or its alkali salt in the plaster layer and the transdermal absorbability.

  In addition to the components described above, known optional components can be added to the plaster layer of the external patch of the present invention. Examples of such optional components include softening agents such as liquid paraffin, castor oil, lanolin, and l-menthol, pentaerythrityl-tetrakis- [3- (3,5-di-t-butyl-4-hydroxyphenyl). Propionate], and antioxidants such as dibutylhydroxytoluene.

  Further, as the support in the external patch of the present invention, a drug-impermeable, stretchable or non-stretchable support can be used. Examples of such a support include, for example, synthetic resin films or sheets of polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, etc., or laminates, porous bodies, foams thereof. Examples include body, paper, woven fabric and non-woven fabric.

  Furthermore, a drug-impermeable release liner can be used as the release liner in the external patch of the present invention. As such a release liner, for example, a film made of a polymer material such as polyethylene, polypropylene, or polyester, a film in which aluminum is vapor-deposited on a film, a film in which silicone oil or the like is coated on paper, etc. Although it is mentioned, a polyester film is preferable and polyethylene terephthalate film is particularly preferable from the viewpoints of lack of permeation of an acidic drug or an alkali salt thereof, processability and low cost. Further, the release liner may be a laminate film obtained by bonding a plurality of materials.

  Production of the external patch of the present invention is not particularly limited, and can be performed according to a known production method. As a preferable known production method of the external patch of the present invention, for example, an acidic drug or an alkali salt thereof and a component to be included in the paste layer such as a base component are dissolved in an organic solvent such as ethyl acetate, hexane, toluene and the like. (1) A method for obtaining an external patch by spreading the dissolved material on a release liner or a support, evaporating the solvent in the dissolved material to form a paste layer, and then bonding the support or the release liner ( Solvent method), acidic drugs or their alkali salts and base components, etc., components to be included in the paste layer were heated and melted, and this melt was spread on a release liner or support to form a paste layer. Thereafter, a method of obtaining an external patch by bonding a support or a release liner (hot melt method) can be used.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 18 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 15 parts of isoprene rubber
(Product name: IR-2200, Nippon Zeon)
(4) 28 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) 23 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) 3 parts of isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(7) 5 parts isopropyl myristate
(Product name: IPM-EX, Nikko Chemicals)
(8) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, isoprene rubber, liquid paraffin and terpene resin are dissolved in a solvent (toluene / hexane), l-menthol is added to a uniform state, and then loxoprofen sodium, isostearic acid and myristic acid A mixture of isopropyl was added to obtain a uniform lysate. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Product 1 of the present invention).

Example 2
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 24 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 38 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(4) 20 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(5) 5 parts of isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(6) 5 parts diisopropyl sebacate
(Product name: DIS, Nikko Chemicals)
(7) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, liquid paraffin and terpene resin are heated and melted, l-menthol is added to a uniform state, loxoprofen sodium, isostearic acid and diisopropyl sebacate are added, and the uniform melt is obtained. did. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Product 2 of the present invention).

Comparative Example 1
A comparative external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 20 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) Isoprene rubber 20 parts
(Product name: IR-2200, Nippon Zeon)
(4) 35 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Alicyclic saturated hydrocarbon resin 20 parts
(Product name: Alcon P-100, Arakawa Chemical)

(Manufacturing method)
Dissolve the styrene-isoprene-styrene block copolymer, isoprene rubber, liquid paraffin and alicyclic saturated hydrocarbon resin in a solvent (toluene / hexane) to make it uniform, and then add loxoprofen sodium to form a uniform solution It was. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Comparative product 1).

Comparative Example 2
A comparative external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 18 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 18 parts of isoprene rubber
(Product name: IR-2200, Nippon Zeon)
(4) 32 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Alicyclic saturated hydrocarbon resin 20 parts
(Product name: Alcon P-100, Arakawa Chemical)
(6) 4 parts of triethanolamine
(Product name: Triethanolamine, Nagase Sangyo)
(7) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
A styrene-isoprene-styrene block copolymer, isoprene rubber, liquid paraffin and alicyclic saturated hydrocarbon resin are dissolved in a solvent (toluene / hexane), and l-menthol is added to obtain a uniform state. Then, loxoprofen sodium and A mixture of triethanolamine was added to obtain a uniform lysate. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Comparative product 2).

Comparative Example 3
A comparative external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 20 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 20 parts of polyisobutylene
(Product name: Opanol B100, BASF)
(4) 28 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Alicyclic saturated hydrocarbon resin 19 parts
(Product name: Alcon P-100, Arakawa Chemical)
(6) 3 parts of isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(7) Crotamiton 5 parts
(Product name: Crotamiton, Kongo Chemical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, liquid paraffin and alicyclic saturated hydrocarbon resin are heated and melted to a uniform state, and then loxoprofen sodium, isostearic acid and crotamiton are added to obtain a uniform melt. did. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Comparative product 3).

Test example 1
Stability test:
The external patches of the present invention products 1-2 and comparative products 1-3 were stored at 60 ° C. for 2 weeks or 4 weeks, and loxoprofen sodium content after 2 weeks or 4 weeks was measured, respectively. The results are shown in Table 1.

  As apparent from Table 1, the contents of sodium loxoprofen after storage at 60 ° C. for 4 weeks of the products 1 and 2 of the present invention (both containing a terpene resin) when the content at the start of storage is 100% are as follows: The content of Comparative Products 1, 2 and 3 (all blended with alicyclic saturated hydrocarbon resin) under the same conditions was 87. 9% to 99.4%. It was 7 to 95.4%, and a decrease in the content was observed. From these results, it was confirmed that the external patch of the present invention was a patch excellent in drug stability without a decrease in the content of the drug in the plaster layer.

Example 3
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 25 parts
(Product name: Clayton KX-401, JSR Clayton
Elastomer)
(3) 40 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(4) Butyl rubber 3 parts
(Product name: Butyl 065, ExxonMobil)
(5) 5 parts polybutene
(Product name: HV-300, Nippon Oil)
(6) Terpene resin 10 parts
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(7) 2 parts of isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(8) 5 parts diisopropyl sebacate
(Product name: NIKKOL PMS-SE, Nikko Chemicals)
(9) 5 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, butyl rubber, polybutene, liquid paraffin and terpene resin were heated and melted to a uniform state, and then loxoprofen sodium, isostearic acid and diisopropyl sebacate were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric, which was cut into a desired size to obtain an external patch (Product 3 of the present invention).

Example 4
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 30 parts
(Product name: Clayton KX-401, JSR Clayton
Elastomer)
(3) 34 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(4) 10 parts of polybutene
(Product name: HV-300, Nippon Oil)
(5) 12 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) 5 parts of isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(7) 1 part diisopropyl sebacate
(Product name: NIKKOL PMS-SE, Nikko Chemicals)
(8) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, butyl rubber, polybutene, liquid paraffin and terpene resin were heated and melted to a uniform state, and then loxoprofen sodium, isostearic acid and diisopropyl sebacate were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric and cut into a desired size to obtain an external patch (Product 4 of the present invention).

Test example 2
Release test:
The external patches of the present invention products 1 to 4 and comparative products 1 to 2 are attached to a horizontal diffusion cell, and each topical application after 2, 4, 6 and 8 hours using an acetic acid / sodium acetate buffer as a receptor solution The amount of loxoprofen sodium released from the patch was measured under the following analysis conditions, and the cumulative release rate of loxoprofen sodium was confirmed. The results are shown in FIG.

Analysis conditions:
Liquid chromatograph: Shimadzu LC10 (manufactured by Shimadzu Corporation)
Detector: UV absorptiometer (measurement wavelength: 225 nm)
Mobile phase: methanol: water: acetic acid 600: 400: 1
Column: Mightysil RP-18GP (manufactured by Kanto Chemical)
Column temperature: 40 ° C
Flow rate: 0.8mL / min

As is clear from FIG. 1, the products 1 to 4 of the present invention (both containing a terpene resin) all showed good loxoprofen sodium release properties, whereas the comparative products 1 and 2 (both were alicyclic saturated) The release property of the hydrocarbon resin blend) was low, and the cumulative release rate of these comparative products was less than 20% even after 8 hours. From these results, it was confirmed that the external patch of the present invention was a patch excellent in drug release.
Example 5
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 17.5 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 17.5 parts of polyisobutylene
(Product name: Opanol B100, BASF)
(4) 32 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) 18 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) 5 parts of isostearic acid
(Product name: Isostearic acid EX, higher alcohol industry)
(7) 5 parts propylene glycol
(Product name: Propylene glycol, Asahi Glass)

(Manufacturing method)
Dissolve the styrene-isoprene-styrene block copolymer, polyisobutylene, liquid paraffin and terpene resin in a solvent (toluene / hexane) to a uniform state, and then add a mixture of loxoprofen sodium, isostearic acid and propylene glycol Lysate. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Product 5 of the present invention).

Example 6
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 1 part (2) Styrene-isoprene-styrene block copolymer 30 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 42 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(4) Hydrogenated rosin ester 23 parts
(Product name: KE311, Arakawa Chemical Industries)
(5) Lactic acid 2 parts
(Product name: Lactic acid, Showa Kako)
(6) Propylene glycol 2 parts
(Product name: Propylene glycol, Asahi Glass)

(Manufacturing method)
A styrene-isoprene-styrene block copolymer, liquid paraffin and hydrogenated rosin ester were heated and melted to obtain a uniform state, and then loxoprofen sodium, lactic acid and propylene glycol were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 6).

Example 7
An external patch was produced by the following composition and production method.

(Composition) Part by weight (1) Loxoprofen sodium 10 parts (2) Styrene-isoprene-styrene block copolymer 20 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 38 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(4) 25 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(5) Phosphoric acid 2 parts
(Product name: Phosphate, Pure Chemical)
(6) Propylene glycol stearate 2 parts
(Product name: NIKKOL PMS-SE, Nikko Chemicals)
(7) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
A styrene-isoprene-styrene block copolymer, liquid paraffin and terpene resin are dissolved in a solvent (toluene / hexane), and l-menthol is added to a uniform state. Then, sodium loxoprofen, phosphoric acid and propylene glycol stearate The mixture was added to obtain a uniform lysate. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 7).

Example 8
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 1 part (2) Natural rubber 30 parts (3) Liquid paraffin 13 parts
(Product name: High Call M-352, Kaneda)
(4) 55 parts of hydrogenated rosin ester
(Product name: KE311, Arakawa Chemical Industries)
(5) 1 part of polyethylene glycol
(Product name: Macrogoal 400, Sanyo Chemical Industries)

(Manufacturing method)
Natural rubber, liquid paraffin and hydrogenated rosin ester were dissolved in a solvent (toluene / hexane) to obtain a uniform state, and then a mixture of loxoprofen sodium and polyethylene glycol was added to obtain a uniform dissolved product. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm to form a paste layer. After the solvent was distilled off, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Product 8 of the present invention).

Example 9
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 5 parts (2) Polyisobutylene 20 parts
(Product name: Opanol B100, BASF)
(3) 10 parts butyl rubber
(Product name: Butyl 065, ExxonMobil)
(4) 20 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) 25 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) 17 parts of propylene glycol
(Product name: Propylene glycol, Asahi Glass)
(7) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Polyisobutylene, butyl rubber, liquid paraffin, and terpene resin were heated and melted, l-menthol was added to obtain a uniform state, and then loxoprofen sodium and propylene glycol were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. Then, it was cut into a desired size to obtain an external patch (Product 9 of the present invention).

Example 10
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 3 parts (2) Isoprene rubber 20 parts
(Product name: IR-2200, Nippon Zeon)
(3) 11 parts of polyisobutylene
(Product name: Opanol B100, BASF)
(4) 21 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Hydrogenated rosin ester 25 parts
(Product name: KE311, Arakawa Chemical Industries)
(6) 20 parts of malic acid
(Product name: DL-malic acid, Showa Kako)

(Manufacturing method)
Isoprene rubber, polyisobutylene, liquid paraffin and hydrogenated rosin ester were dissolved in a solvent (toluene / hexane) to obtain a uniform state, and then a mixture of loxoprofen sodium and malic acid was added to obtain a uniform solution. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 10).

Example 11
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 1 part (2) Styrene-isoprene-styrene block copolymer 20 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) 20 parts of polyisobutylene
(Product name: Opanol B100, BASF)
(4) 10 parts butyl rubber
(Product name: Butyl 065, ExxonMobil)
(5) Liquid paraffin 32 parts
(Product name: High Call M-352, Kaneda)
(6) Terpene resin 13 parts
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(7) Benzoic acid 1 part
(Product name: Benzoic acid, Mitsubishi Kasei)
(8) Butylene glycol 3 parts
(Product name: 1,3-butylene glycol, Daicel Chemical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, polyisobutylene, butyl rubber, liquid paraffin and terpene resin were heated and melted to obtain a uniform state, and then loxoprofen sodium, benzoic acid and butylene glycol were added to obtain a uniform melt. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 11).

Example 12
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 3 parts (2) Styrene-isoprene-styrene block copolymer 15 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) Styrene-butadiene-styrene block copolymer 10 parts
(Product name: Clayton D-1101, JSR Clayton
Elastomer)
(4) 35 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Terpene resin 13 parts
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) Hydrogenated rosin ester 20 parts
(Product name: KE311, Arakawa Chemical Industries)
(7) 2 parts of acetic acid
(Product name: Acetic acid, Showa Denko)
(8) 2 parts isopropanol
(Product name: Isopropyl alcohol, Nippon Petrochemical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, liquid paraffin, terpene resin and hydrogenated rosin ester are heated and melted to a uniform state, and then loxoprofen sodium, acetic acid and isopropanol are added. A uniform melt was obtained. Next, this melt was spread on a polyethylene terephthalate film so as to have a thickness of 100 μm using a doctor knife coating machine to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 12).

Example 13
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 2 parts (2) Natural rubber 31 parts (3) Polyisobutylene 5 parts
(Product name: Opanol B100, BASF)
(4) 10 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) 30 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) 2 parts salicylic acid
(Product name: salicylic acid, API Corporation)
(7) 20 parts of polyethylene glycol
(Product name: Macrogoal 400, Sanyo Chemical Industries)

(Manufacturing method)
Natural rubber, polyisobutylene, liquid paraffin and terpene resin were dissolved in a solvent (toluene / hexane) to obtain a uniform state, and then a mixture of sodium loxoprofen, salicylic acid and polyethylene glycol was added to obtain a uniform solution. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 13).

Example 14
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 8 parts (2) Isoprene rubber 27 parts
(Product name: IR-2200, Nippon Zeon)
(3) 5 parts of polyisobutylene
(Product name: Opanol B100, BASF)
(4) 22 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Terpene resin 9 parts
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) Hydrogenated rosin ester 24 parts
(Product name: KE311, Arakawa Chemical Industries)
(7) Adipic acid 3 parts
(Product name: Adipic acid, Asahi Kasei Chemicals)
(8) Concentrated glycerin 2 parts
(Product name: Concentrated glycerin, Japanese fat and oil)

(Manufacturing method)
Dissolve isoprene rubber, polyisobutylene, liquid paraffin, terpene resin and hydrogenated rosin ester in a solvent (toluene / hexane) to make it uniform, and then add a mixture of loxoprofen sodium, adipic acid and concentrated glycerin, and dissolve evenly It was a thing. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 14).

Example 15
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 5 parts (2) Natural rubber 30 parts (3) Polyisobutylene 5 parts
(Product name: Opanol B100, BASF)
(4) 19 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) Hydrogenated rosin ester 40 parts
(Product name: KE311, Arakawa Chemical Industries)
(6) Tartaric acid 1 part
(Product name: L-tartaric acid, Showa Kako)

(Manufacturing method)
Natural rubber, polyisobutylene, liquid paraffin and hydrogenated rosin ester were dissolved in a solvent (toluene / hexane) to obtain a uniform state, and then a mixture of loxoprofen sodium and tartaric acid was added to obtain a uniform dissolved product. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 15).

Example 16
An external patch was produced by the following composition and production method.

(Composition) Weight parts (1) Loxoprofen sodium 3 parts (2) Isoprene rubber 28 parts
(Product name: IR-2200, Nippon Zeon)
(3) 4 parts of polyisobutylene
(Product name: Opanol B100, BASF)
(4) 21 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) 40 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) Citric acid 1 part
(Product name: Citric acid, Showa Kako)
(7) 3 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Dissolve isoprene rubber, polyisobutylene, liquid paraffin and terpene resin in a solvent (toluene / hexane), add l-menthol and bring to a homogeneous state, then add a mixture of loxoprofen sodium and citric acid, did. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 16).

Example 17
An external patch was produced by the following composition and production method.

(Composition) Weight part (1) Loxoprofen sodium 5 parts (2) Styrene-isoprene-styrene block copolymer 20 parts
(Product name: Clayton D-1107cp, JSR Clayton
Elastomer)
(3) Isoprene rubber 20 parts
(Product name: IR-2200, Nippon Zeon)
(4) 30 parts liquid paraffin
(Product name: High Call M-352, Kaneda)
(5) 20 parts of terpene resin
(Product name: YS Resin PX1150N, Yasuhara Chemical)
(6) 5 parts of l-menthol
(Product name: l-menthol, Ogi Pharmaceutical)

(Manufacturing method)
Styrene-isoprene-styrene block copolymer, isoprene rubber, liquid paraffin and terpene resin are dissolved in a solvent (toluene / hexane), l-menthol is added to obtain a uniform state, loxoprofen sodium is added, and uniform dissolution is performed. It was a thing. Next, this dissolved material was spread on a polyethylene terephthalate film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a paste layer. Thereafter, the plaster layer was bonded to a stretchable nonwoven fabric. And it cut | judged to the desired magnitude | size and obtained the external patch (this invention product 17).

  All of the products 5 to 17 of the present invention are excellent in the solubility and release of loxoprofen sodium, and are excellent in stability with little decrease in the content thereof.

  As described above, it comprises a support, a paste layer and a release liner, and contains an acidic drug or an alkali salt as an active ingredient in the paste layer, and a rubber elastomer and a terpene as a base component of the paste layer Patch for topical use containing a base resin and / or hydrogenated rosin ester improves the solubility of the drug in the paste layer, the release of the drug from the paste layer, and the decrease in the drug content in the paste layer It was. Therefore, the external patch of the present invention is a non-aqueous external patch that has a better release of loxoprofen sodium than the conventional aqueous external patch and can obtain a sufficient bioavailability. It is very useful as a patch containing salt as an active ingredient.

It is the graph which showed the time transition behavior of the loxoprofen sodium cumulative release rate from the external use patch of this invention products 1-4 in the discharge | release test of Test Example 2, and the comparative products 1-2.

Claims (14)

  In an external patch comprising a support, a paste layer and a release liner, and containing an acidic drug or an alkali salt thereof as an active ingredient in the paste layer, a rubber elastomer and a terpene as a base component of the paste layer A patch for external use characterized by containing an epoxy resin and / or a hydrogenated rosin ester.   The external patch according to claim 1, wherein the acidic drug or an alkali salt thereof is a propionic acid anti-inflammatory analgesic.   The external patch according to claim 2, wherein the propionic acid anti-inflammatory analgesic is loxoprofen sodium.   The rubber-based elastomer is one or two selected from styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-butadiene rubber, polyisobutylene, polybutene, butyl rubber, natural rubber and isoprene rubber. The external patch according to any one of claims 1 to 3, wherein the patch is one or more species.   The content of the rubber elastomer in the plaster layer is 15 to 50% by mass, and the content of the terpene resin and / or hydrogenated rosin ester is 10 to 40% by mass. Item 5. A patch for external use according to item 4.   The external patch according to any one of claims 1 to 5, further comprising an organic acid as a base component in the plaster layer.   The content of the acidic drug or the alkali salt thereof in the plaster layer is 0.5 to 10% by mass, and the content of the organic acid is 0.1 to 10 times the content of the acidic drug or the alkali salt thereof. The external patch according to claim 6, wherein the external patch is mass-fold.   The content of the terpene resin and / or hydrogenated rosin ester in the plaster layer is 10% by mass to 40% by mass, and the content of the organic acid is the content of terpene resin and / or hydrogenated rosin ester The external patch according to claim 6 or 7, wherein the external patch is 1/40 mass times to 1/2 mass times.   The external patch according to any one of claims 6 to 8, wherein the organic acid is a carboxylic acid having 2 to 18 carbon atoms.   The carboxylic acid having 2 to 18 carbon atoms is one or more selected from acetic acid, lactic acid, tartaric acid, citric acid, malic acid, isostearic acid, oleic acid, adipic acid, benzoic acid and salicylic acid. The external patch according to claim 9.   The external patch according to any one of claims 1 to 10, further comprising a dissolving agent as a base component in the plaster layer.   The external patch according to claim 11, wherein the dissolving agent is acidic or neutral.   One or two acidic or neutral solubilizers selected from ethanol, octyldodecanol, isopropanol, propylene glycol, propylene glycol stearate, concentrated glycerin, butylene glycol, polyethylene glycol and esters or ethers thereof The patch for external use according to claim 12, which is as described above.   1 or 2 or more types of ester of acidic or neutral solubilizer selected from isopropyl myristate, octyldodecyl myristate, myristyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate and isopropyl palmitate The external patch according to claim 13, wherein the patch is for external use.

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