JP2015098439A - Patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a patch which has a good feel and low skin irritation, while having a sufficient adhesiveness when placing it on the skin, and has good skin permeability of diclofenac or a salt thereof, and exhibits sufficient percutaneous absorption properties.SOLUTION: In a patch where an adhesive layer retaining a drug is formed on a support, the adhesive layer comprises a thermoplastic elastomer, more than 300 pts.wt. of liquid paraffin to 100 pts.wt. of the elastomer, and diclofenac or a salt thereof and a solubilizer thereof, and if the adhesive layer comprises a tackifier, the content thereof in the adhesive layer is 10 wt.% or less.

Description

  The present invention relates to a patch containing diclofenac or a salt thereof. More specifically, the present invention relates to a patch having high skin permeability of diclofenac or a salt thereof and good transdermal absorbability.

In order to achieve percutaneous absorption of a drug, the drug is mixed with an adhesive base or the like to form a patch. In recent years, a tape agent having higher adhesiveness is often used than a cataplasm containing a large amount of water as a constituent component in a patch. As the adhesive base of this tape agent, a lipophilic adhesive base such as rubber, acrylic or silicone is used. Among these, rubber-based adhesive bases are widely used because additives can be easily blended as compared with other adhesive bases (Patent Documents 1 to 3).
However, even in a patch using a rubber-based adhesive base, there is a problem that sufficient drug release cannot be secured or skin irritation caused by a tackifier usually added to the patch occurs. It was pointed out.
On the other hand, as a patch containing diclofenac or a salt thereof, a cataplasm or a tape using a rubber adhesive is already on the market (Non-patent Document 1). However, since existing tape preparations use a tackifier such as rosin ester, skin irritation may be increased, and patches that are more effective than existing patch preparations and tape preparations. Is required.

JP 2001-302502 A JP-A-9-291028 Japanese Patent Laid-Open No. 10-316559

Nabol tape Attached document

  An object of the present invention is to provide a patch having sufficient adhesiveness, low skin irritation, good skin permeability of diclofenac or a salt thereof, and sufficient transdermal absorption. .

  As a result of intensive research to solve the above problems, the present inventors have used a thermoplastic elastomer and a large amount of liquid paraffin as the adhesive base, so that no tackifier is contained. However, when it contains diclofenac or a salt thereof and a solubilizing agent, good skin permeability can be seen and sufficient percutaneous absorption can be achieved. The present inventors have found that a patch of diclofenac or a salt thereof exhibiting properties can be obtained, and the present invention has been completed.

That is, the gist of the present invention is as follows.
(1) A patch in which an adhesive layer for holding a drug is formed on a support, the adhesive layer comprising a thermoplastic elastomer, liquid paraffin, diclofenac exceeding 300 parts by weight relative to 100 parts by weight of the elastomer or A patch comprising the salt and a solubilizer, and may contain a tackifier, and the content in the adhesive layer is 10% by weight or less.
(2) The patch according to (1) above, wherein the content of liquid paraffin in the adhesive layer is 60% by weight or more.
(3) The patch according to (1) or (2) above, wherein the thermoplastic elastomer is a styrene block copolymer.
(4) The patch according to (3) above, wherein the styrenic block copolymer is a styrene-isoprene-styrene copolymer.
(5) The patch according to any one of (1) to (4), wherein the adhesive layer does not contain a tackifier.
(6) The patch according to any one of (1) to (5) above, which contains one or more selected from an amide solvent and a liquid organic acid as a solubilizer.
(7) The patch according to any one of (1) to (6) above, which contains an amide solvent and a liquid organic acid as a solubilizer.
(8) The patch according to any one of (1) to (7), wherein diclofenac is a hydroxyethylpyrrolidine salt.

  The patch of the present invention has sufficient adhesiveness when applied to the skin, has reduced skin irritation, has good skin permeability of diclofenac or a salt thereof, and has excellent transdermal absorbability.

It is the figure which compared and represented the transdermal absorbability of the patch which concerns on the Example of this invention, and the patch of a comparative example. Similarly, it is the figure which compared and represented the transdermal absorbability of the patch which concerns on the Example of this invention, and the patch of a comparative example.

In the patch of the present invention, an adhesive layer for holding a drug is formed on a support, and the adhesive layer comprises a thermoplastic elastomer, liquid paraffin, diclofenac or more than 300 parts by weight relative to 100 parts by weight of the elastomer. The salt and the solubilizer may be included, and a tackifier may be included, and the content in the adhesive layer is 10% by weight or less.
“Thermoplastic elastomer” used in the present invention is an elastomer that exhibits fluidity when softened and exhibits fluidity, and returns to a rubber-like elastic body when cooled. Urethane, acrylic, styrene, Various thermoplastic elastomers, such as an olefin type and a silicone type, are mentioned. Of these, styrene-based thermoplastic elastomers, particularly styrene-based block copolymers, are preferably used from the viewpoint of achieving sufficient tackiness and reducing skin irritation, both of which are the objects of the present invention.
Specific examples of the styrene block copolymer include a styrene-butadiene block copolymer, a styrene-butadiene-styrene block copolymer, a styrene-isoprene block copolymer, a styrene-isoprene-styrene block copolymer, and a styrene- Ethylene / butylene block copolymer, styrene-ethylene / butylene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutylene block copolymer, Examples include styrene-isobutylene-styrene block copolymers. In the above, “ethylene / butylene” represents a copolymer block of ethylene and butylene, and “ethylene / propylene” represents a copolymer block of ethylene and propylene. These styrene block copolymers may be used alone or in combination of two or more.
Among the above styrene block copolymers, in addition to achieving both adhesiveness and low skin irritation, styrene-isoprene-styrene block copolymers and styrene-isoprene blocks from the viewpoints of the availability and handling of patch products. One or more selected from the group consisting of copolymers are particularly preferably used.
For the purposes of the present invention, the styrene-isoprene-styrene block copolymer preferably has a styrene content of 5 wt% to 60 wt% in the copolymer and is 10 wt% to 50 wt%. Is more preferable. Moreover, the thing whose weight average molecular weights measured by the gel filtration chromatography are 20,000-500,000 is preferable, and what is 30,000-300,000 is more preferable. The styrene-isoprene block copolymer preferably has a styrene content in the copolymer of 5% to 50% by weight, more preferably 10% to 40% by weight. Moreover, the thing whose weight average molecular weights measured by the gel filtration chromatography are 10,000-500,000 is preferable, and what is 20,000-300,000 is more preferable.
As such a styrene-isoprene-styrene block copolymer or a styrene-isoprene block copolymer, a copolymer produced by a method known per se can be used, but a commercially available product satisfying the above characteristics, for example, “KRATON”. D "(manufactured by KRATON POLYMERS)," JSR SIS "(manufactured by JSR), and the like can also be used.

The “liquid paraffin” of the present invention is a colorless and odorless liquid mixture of alkanes having 20 or more carbon atoms, and a known commercially available one can be used and is not particularly limited. Those conforming to the standards prescribed in the Japanese Pharmacopoeia, the US Pharmacopoeia and the like can be preferably used.
As described above, in the present invention, liquid paraffin exceeding 300 parts by weight is blended with 100 parts by weight of the thermoplastic elastomer. As long as the ratio is satisfied, the specific blending amount of the thermoplastic elastomer and the liquid paraffin in the adhesive layer is not particularly limited, but in general, if the thermoplastic elastomer is too small, it is difficult to maintain the shape as an adhesive, and if the amount is too large Sufficient tackiness cannot be obtained. On the other hand, when the liquid paraffin is too small, sufficient tackiness cannot be obtained, and when it is too large, it is difficult to maintain the shape as an adhesive. Therefore, the upper limit of the liquid paraffin content does not exceed 1500 parts by weight because it affects the adhesiveness and elasticity of the preparation. In addition, 300 weight part-1000 weight part can be mentioned as a preferable quantity of a liquid paraffin with respect to 100 weight part of this elastomer.

The lower limit of the thermoplastic elastomer content is usually 5% by weight, preferably 8% by weight, more preferably 10% by weight. The upper limit is usually 25% by weight, preferably 20% by weight. The lower limit of the liquid paraffin content is usually 60% by weight, preferably 65% by weight, more preferably 70% by weight, and particularly preferably 75% by weight. The upper limit is usually 95% by weight, preferably 90% by weight.
In the patch of the present invention, by adopting the blending amount of the thermoplastic elastomer and the liquid paraffin as described above, good tackiness can be exhibited without adding a tackifier. As used herein, “tackifier” means a tackifier that is generally used in the field of patches, such as rosin resins, polyterpene resins, coumarone-indene resins, petroleum resins, terpene-phenol resins, fats. Examples thereof include cyclic saturated hydrocarbon resins.
From the viewpoint of reducing skin irritation and the like, in the present invention, the content of the tackifier in the adhesive layer is 10% by weight or less. It is preferably 5% by weight or less, more preferably 2% by weight or less, still more preferably 1% by weight or less, and most preferably does not contain a tackifier. Moreover, the content of a tackifier is also adjusted according to the addition amount and ratio of an elastomer and liquid paraffin from the relation with the adhesiveness of a preparation. From this viewpoint, the preferable content of the tackifier may be 0 to 5% by weight.

Diclofenac or a salt thereof of the present invention refers to diclofenac or a salt thereof used for percutaneous absorption. From the viewpoint of easy availability, a salt of diclofenac is preferably used. Examples of the salt of diclofenac include diclofenac sodium, diclofenac potassium, diclofenac diethylammonium and diclofenac hydroxyethylpyridine.
Of the diclofenac salts, diclofenac hydroxyethylpyridine and diclofenac sodium are preferable, and diclofenac hydroxyethylpyridine is more preferable from the viewpoint of solubility and dispersibility. The content of diclofenac or a salt thereof in the preparation is not particularly limited, but is preferably 0.1 to 10% by weight, more preferably 0.5 to 7% by weight.

In the patch of the present invention, a solubilizer is contained for the purpose of improving the transdermal absorbability of diclofenac or a salt thereof, the adhesiveness of the patch, and the drug stability in the patch.
Examples of the solubilizer include alcohol solvents, amide solvents, and liquid organic acids. Of these, one or more selected from amide solvents and liquid organic acids are preferred, and it is more preferred to use amide solvents and liquid organic acids in combination.

Examples of the “amide solvent” of the present invention include pyrrolidone such as N-methyl-2-pyrrolidone and 2-pyrrolidone; imidazolidinone such as 1,3-dimethyl-2-imidazolidinone; caprolactam such as ε-caprolactam. ; Formamide, N-methylformamide, N, N-dimethylformamide, acetamide, N-methylacetamide, N, N-dimethylacetamide, N-methylpropanamide and other alkaneamides; hexamethylphosphoric triamide and other phosphoramides, crotamiton Etc.
Of the amide solvents, N-methyl-2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide and crotamiton are preferable, and crotamiton is more preferable.

The “liquid organic acid” of the present invention refers to an organic acid that is liquid at room temperature and does not volatilize during production, storage, and pasting and remains in the adhesive layer. Accordingly, the liquid organic acid is a substance having a melting point at a temperature lower than normal temperature and a boiling point of preferably 150 ° C. or higher, more preferably 170 ° C. or higher. In the present invention, an organic acid having a certain degree of viscosity can also be used. The “liquid organic acid” of the present invention refers to one having a viscosity at 25 ° C. of 0.01 mPa · s to 1,000,000 mPa · s. “Normal temperature” refers to normal temperature (15 ° C. to 25 ° C.) according to the 16th revised Japanese Pharmacopoeia General Rules.
Examples of liquid organic acids include aliphatic monocarboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid (heptanoic acid), caprylic acid, and pelargonic acid (nonanoic acid); olein Aliphatic unsaturated monocarboxylic acids such as acid, linoleic acid, arachidonic acid and docosahexaenoic acid; hydroxycarboxylic acids such as lactic acid (DL-lactic acid or L-lactic acid and / or a mixture of D-lactic acid and anhydrous lactic acid); methoxy Examples thereof include liquid carboxylic acids substituted with alkoxy groups such as acetic acid; sulfonic acids such as methanesulfonic acid.
Of these liquid organic acids, lactic acid and oleic acid are preferably used, and lactic acid is particularly preferably used.

Examples of other solubilizers include alcohol solvents such as lauryl alcohol, isostearyl alcohol, 2-octyldodecanol, and other higher saturated aliphatic alcohols that are liquid at room temperature with about 12 to 20 carbon atoms; carbon such as oleyl alcohol. Higher unsaturated aliphatic alcohols that are liquid at room temperature of about several tens to 20; polyhydric alcohols that are liquid at room temperature such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, polyethylene glycol having a molecular weight of about 100 to 600, etc. Is mentioned.
Among them, polyhydric alcohols that are liquid at normal temperature such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, polyethylene glycol, etc. are preferable, ethylene glycol, propylene glycol, 1,3-butanediol, molecular weight of about 100 to 600 A diol that is liquid at room temperature such as polyethylene glycol is more preferable.

  The total addition amount of the solubilizer is not particularly limited, but it may contribute to improving the solubility and dispersibility of diclofenac or its salt in the adhesive, improving skin permeability, and affecting the adhesive properties. From the viewpoint, 10 parts by weight to 1000 parts by weight is preferable and 20 parts by weight to 500 parts by weight is more preferable with respect to 100 parts by weight of diclofenac or a salt thereof. Moreover, as content in an adhesion layer, it is 0.1 to 30 weight% normally, Preferably it is 0.2 to 20 weight%, More preferably, it is 0.5 to 15 weight%.

In the adhesive layer forming the patch of the present invention, general additives such as excipients, antioxidants, flavoring agents, coloring agents, surfactants and the like may be contained as optional components.
Examples of the excipient used in the present invention include silicon compounds such as silicic anhydride, light silicic anhydride, and hydrous silicic acid; cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; polyvinyl alcohol and the like Synthetic water-soluble polymers; aluminum compounds such as dry aluminum hydroxide gel and hydrous aluminum silicate; pigments such as kaolin and titanium oxide.
Examples of the antioxidant used in the present invention include dibutylhydroxytoluene, ascorbic acid, tocopherol, tocopherol acetate, butylhydroxyanisole, and 2-mercaptobenzimidazole.
Examples of the flavoring agent used in the present invention include d-camphor, dl-camphor, cinnamaldehyde, mint oil, dl-menthol, and l-menthol.
Examples of the colorant used in the present invention include yellow iron oxide, yellow ferric oxide, carbon black and the like.
Examples of the surfactant used in the present invention include cholesterol, glycerin fatty acid ester, sorbitan fatty acid ester and the like.

The patch of the present invention is prepared by spreading an adhesive layer having the above structure on a support.
In the present invention, the “support” is not particularly limited, and a general-purpose one can be used. For example, stretchable or non-stretchable woven fabrics such as polyethylene and polypropylene, non-woven fabrics, polyesters such as polyethylene, polypropylene, and polyethylene terephthalate, ethylene vinyl acetate copolymers, films such as vinyl chloride, and foaming properties such as urethane and polyurethane A support is mentioned. These may be used alone or may be a laminate of a plurality of types. Furthermore, in order to prevent static electricity from accumulating on the support, an antistatic agent may be contained in the woven fabric, non-woven fabric, film, etc. constituting the support. In order to obtain good anchoring properties with the adhesive layer, a nonwoven fabric or a woven fabric, or a laminate of these with a film can be used as the support. The thickness of the support is usually 10 μm to 100 μm for a film, preferably 15 μm to 50 μm, and is usually 50 μm to 2,000 μm, preferably 100 μm to porous sheets such as a woven fabric, a nonwoven fabric, and a foamable support. 1,000 μm.

  The patch of the present invention can also be provided with a release liner that is common in the field of patches. As the release liner, glassine paper, polyethylene, polypropylene, polyester, polyethylene terephthalate, polystyrene, aluminum film, foamed polyethylene film or foamed polypropylene film, or a laminate of two or more of the above can be used. Silicone-processed, fluororesin-processed, embossed, etc. can also be used. The thickness of the release liner is usually 10 μm to 200 μm, preferably 15 μm to 150 μm.

The patch of the present invention is, for example, a hot melt method in which a coating solution in which diclofenac or a salt thereof and various additives are dissolved or dispersed in a mixture of a thermoplastic elastomer and a liquid paraffin homogenized in a heated and melted state is applied, Alternatively, it can be produced by dissolving or dispersing in a solvent such as toluene to prepare a coating solution for forming an adhesive layer, applying the obtained coating solution to a support, and then drying. When a release liner is used, the release liner can be pressure-bonded to the adhesive layer and laminated. Or the said coating liquid may be apply | coated on a release liner, an adhesive layer may be formed on the surface of a release liner, and a support body may be pressure-bonded on the adhesive layer, and may then be bonded together. Application of the coating solution for forming the adhesive layer uses, for example, a conventional coater such as a roll coater, die coater, gravure roll coater, reverse roll coater, kiss roll coater, dip roll coater, bar coater, knife coater, spray coater, etc. Can be done. Diclofenac or adhesive layer containing a salt thereof, preferably from ^{10g / m 2 ~1000g / m 2} , more preferably from ^{20g / m 2 ~800g / m 2} .

  Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples, but the present invention is not limited to these.

Preparation of a patch containing diclofenac or a salt thereof Each sample was weighed so as to have the composition (w / w%) shown in Table 1 below, and a styrene-isoprene-styrene copolymer was added to liquid paraffin to obtain about 160 Dissolve by heating at ℃. The solution is cooled to 100 ° C., diclofenac or a salt thereof and other reagents are added and mixed and stirred to prepare an adhesive base.
The adhesive base is applied to a siliconized polyester film and adjusted to an amount of 200 g / m ² . A polyester nonwoven fabric is laminated on the surface of the adhesive base. This was cut into a desired size to obtain the desired patch.

  The patches prepared in Table 1 had good texture and skin adhesion characteristics.

(Comparative example 1) Commercially available diclofenac sodium salt tape agent Diclofenac sodium salt 1.0 w / w% contained in an adhesive base composed of styrene-isoprene-styrene copolymer, polyisobutylene, tackifier, liquid paraffin, etc. The patch to be used was used. The base weight was 214 g / m ² .

(Comparative Example 2) Commercially available diclofenac / hydroxyethylpyridine salt patch A patch containing 1.3 w / w% diclofenac / hydroxyethylpyridine salt in an aqueous base composed of water, a water-soluble polymer, a polyhydric alcohol, and the like. Using. The base weight was 1000 g / m ² .

(Comparative Example 3)
A patch was obtained in the same manner as in Example 1 according to the composition (w / w%) shown in Table 2 below.

(Test example) Percutaneous absorbability evaluation test of patch In accordance with a known method, the abdominal extract skin of male Wister rats (5 weeks old) was attached to a vertical Franz diffusion cell, and Example 1 and Comparative Examples 1 to Each of the three test patches was punched into a circular shape having a diameter of 1.0 cm, and applied to the rat skin of the diffusion cell (n = 3). On the receptor side, 10% ethanol physiological saline was used to quantify the amount of drug that permeates the rat skin after a certain time by HPLC.

  These results are shown in FIG. 1 (permeation amount of diclofenac 24 hours after application: the permeation amount of the commercially available diclofenac / sodium salt tape of Comparative Example 1 is 100, and the permeation amount of each patch is shown as a relative ratio) and FIG. 2 (permeation amount of diclofenac 24 hours after application: the permeation amount of the commercially available diclofenac / hydroxyethylpyridine salt patch of Comparative Example 2 was taken as 100, and the permeation amount of the patch of Example 1 was shown as a relative ratio) . As shown in FIG. 1, the patch of Example 1 of the present invention is diclofenac added to a conventional thermoplastic elastomer adhesive base compounding system in which a large amount of the existing diclofenac sodium salt tape of Comparative Example 1 and a tackifier are added. -It was shown that the skin permeability of diclofenac is superior to Comparative Example 3 in which hydroxyethylpyridine salt was added together with a solubilizer. Further, FIG. 2 shows that the patch of Example 1 of the present invention is superior in skin permeability of diclofenac to the existing diclofenac / hydroxyethylpyridine salt patch of Comparative Example 2.

  According to the present invention, it is possible to provide a patch having a good texture while having sufficient adhesiveness when applied to the skin, a good skin permeability of diclofenac or a salt thereof, and an excellent transdermal absorbability. .

Claims (8)

  A patch in which an adhesive layer for holding a drug is formed on a support, comprising a thermoplastic elastomer, more than 300 parts by weight of liquid paraffin, diclofenac or a salt thereof and a solubilizer thereof relative to 100 parts by weight of the elastomer. And the patch which may contain the tackifier and whose content in the adhesion layer is 10 weight% or less.   The patch according to claim 1, wherein the liquid paraffin content in the adhesive layer is 60% by weight or more.   The patch according to claim 1 or 2, wherein the thermoplastic elastomer is a styrene block copolymer.   The patch according to claim 3, wherein the styrenic block copolymer is a styrene-isoprene-styrene copolymer.   The patch according to any one of claims 1 to 4, wherein the adhesive layer does not contain a tackifier.   The patch according to any one of claims 1 to 5, comprising one or more selected from an amide solvent and a liquid organic acid as a solubilizer.   The patch according to claim 6, comprising an amide solvent and a liquid organic acid as a solubilizer.   The patch according to any one of claims 1 to 7, wherein diclofenac is a hydroxyethylpyrrolidine salt.

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