JP4584620B2 - Anti-inflammatory analgesic topical - Google Patents

Description

  The present invention relates to an external preparation excellent in stability, containing an anti-inflammatory analgesic. Specifically, the present invention effectively suppresses an esterified product formation reaction in an external preparation containing an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule and an additive having a hydroxyl group in the molecule. It is related with the external preparation excellent in stability, and the esterification inhibitor.

  Various studies have been conducted on the treatment using so-called tapes containing anti-inflammatory drugs in oil-based adhesives, and many non-aqueous patches have been developed. L-Menthol is widely used as an active ingredient absorption promoter, as one of the medicinal ingredients, and as a cooling agent. However, when an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule is used as an anti-inflammatory analgesic, an l-menthol ester is produced by reaction with l-menthol during long-term storage, and the amount of the main drug is reduced. There was a problem with the stability of the active ingredient, such as a decrease.

  Examination of technology to suppress esterification reaction in non-aqueous patches for external use in systems where such anti-inflammatory drugs having a carboxyl group (or salt thereof) and l-menthol coexist in the molecule So far, for example, a technique for blending a fatty acid metal salt (Patent Document 1), a technique for blending a metal oxide (Patent Document 2), etc. have been proposed, and some of them have been put into practical use. Yes.

Japanese Patent No. 3238409 JP 2002-226366 A

Since non-aqueous patches undergo manufacturing processes such as heating and drying, the preparation is in a dry state, and the equilibrium of the esterification reaction between the carboxyl group (or salt thereof) and the hydroxyl group is likely to be biased toward the ester production side. .
Therefore, the present invention provides an esterified product formation reaction (dehydration condensation reaction) between an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule and an additive having a hydroxyl group in the molecule (for example, l-menthol). ) Is an issue.

  The present invention relates to an external preparation comprising an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule, an additive having a hydroxyl group in the molecule, and a metal hydroxide.

  The present invention also includes an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule and an additive having a hydroxyl group in the molecule, characterized by comprising a metal hydroxide. The esterified product formation reaction inhibitor in the external preparation which becomes.

  An external preparation of the present invention containing the esterified product formation reaction inhibitor of the present invention comprising a metal hydroxide, in particular, a nonaqueous external patch, an anti-inflammatory drug having a carboxyl group (or a salt thereof), Since the esterification reaction with an additive having a hydroxyl group in the molecule, such as l-menthol, is effectively suppressed, the storage stability of the preparation is significantly improved.

The external preparation of the present invention, in particular, the nonaqueous external patch is composed of a support, an adhesive layer, and a release film.
The adhesive layer of the patch of the present invention comprises at least an anti-inflammatory drug having a carboxyl group (or a salt thereof), an additive having a hydroxyl group in the molecule such as l-menthol, a metal hydroxide and a rubber system. It is composed of an adhesive base.

Examples of the anti-inflammatory drug having a carboxyl group (or a salt thereof) include ibuprofen, indomethacin, ketoprofen, diclofenac, piroxicam, felbinac, flurbiprofen, loxoprofen, and pharmaceutically acceptable salts thereof. .
An appropriate amount of the anti-inflammatory drug having a carboxyl group (or a salt thereof) is mixed depending on the purpose.
Examples of the additive having a hydroxyl group in the molecule include menthols typified by l-menthol and polyethylene glycol.

Examples of the metal hydroxide include one or more selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, and the like.
The compounding amount of the metal hydroxide is preferably 0.01 to 3% as the concentration in the adhesive layer. If it is less than 0.01%, there is almost no blending effect. On the other hand, if it exceeds 3%, there is a disadvantage that the dispersion of the metal oxide powder becomes non-uniform or a pre-process for uniform mixing is required.
In addition, the mass ratio of the anti-inflammatory drug having a carboxyl group (or a salt thereof) and the metal hydroxide is preferably in the range of 1: 0.1 to 10.

  Additives having a hydroxyl group in the molecule, that is, menthols such as l-menthol, for example, are blended according to the percutaneous absorption rate of the target drug or the expected refreshing feeling. Although not constant, generally 0.5 to 10% is preferable. If it is less than 0.5%, the effect of enhancing transdermal absorption is insufficient, and the sustainability of the refreshing feeling is not sufficient. Moreover, since skin irritation is recognized when it exceeds 10%, it is unpreferable.

The rubber-based adhesive base of the adhesive layer of the patch of the present invention means an adhesive composition mainly composed of natural or synthetic rubber. The pressure-sensitive adhesive composition is composed of natural and / or synthetic rubber, a tackifier resin, a softener, and an additive depending on the purpose.
Synthetic rubber used for the rubber-based adhesive base of the adhesive layer of the patch of the present invention includes polyisoprene, polyisobutylene, polybutadiene, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, styrene -Although 1 type, or 2 or more types selected from a butadiene rubber and a styrene-isoprene rubber are mentioned, a styrene-isoprene-styrene block copolymer is more preferable.
The ratio of natural and / or synthetic rubber to the entire rubber-based adhesive base is preferably 10 to 40% by mass.

  The tackifying resin used in the rubber-based adhesive base of the adhesive layer of the patch of the present invention is not particularly limited as long as it is generally used. For example, polyterpene resin, rosin ester resin, hydrogenated rosin ester resin An alicyclic saturated hydrocarbon resin, a terpene phenol resin, a petroleum resin, or the like is preferably used. The proportion of the tackifying resin in the entire rubber-based adhesive base is preferably 10 to 30% by mass.

  The softener used for the rubber-based adhesive base of the adhesive layer of the patch of the present invention is not particularly limited as long as it is generally used. For example, liquid paraffin, polybutene, liquid polyisobutylene, animal and vegetable oils, etc. Preferably used. The proportion of the softening agent in the entire rubber-based adhesive is preferably 30 to 70% by mass.

Additives according to the purpose used for the rubber-based adhesive base of the adhesive layer of the patch of the present invention are drugs, absorption promoters, fillers, antioxidants, solubilizers (solubilizers), ultraviolet absorber , Fragrances, pigments, etc.
Drugs mentioned here are those that are added in anticipation of synergistic therapeutic effects in addition to anti-inflammatory drugs. An agent, an essential oil component, and other components (for example, plant extract, tocopherol acetate, etc.) are meant.

The thickness of the adhesive layer of the patch of the present invention is preferably 20 to 300 μm.
As the support of the patch of the present invention, synthesis of polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, polyamide, polyester, nylon, cellulose derivative, polyurethane, etc. A resin film, a sheet, a sheet-like porous body, a sheet-like foam, a woven fabric, a knitted fabric, a nonwoven fabric, paper, or a laminate thereof can be used. Among them, those having elasticity such as a knitted fabric are preferable in terms of securing the adhesiveness of the patch to the skin. Moreover, what has self-supporting property is preferable at the point of the handleability of a patch.

  As the release film of the patch of the present invention, a sheet-like material made of polyester, polypropylene, polyethylene, paper, or a laminate thereof is preferably subjected to a release treatment (silicon coating or the like).

The metal hydroxide has a function of adjusting the pH environment in the adhesive layer. In addition, as a larger factor, metal hydroxide can capture moisture by chemical reaction and can also capture moisture by adsorbing water molecules. Is prevented, and water molecules are taken into the adhesive layer, so that it is considered that the chemical equilibrium of the adhesive layer is prevented from shifting to the esterification side.
Since the metal hydroxide used in the present invention generally has a lower hardness than the metal oxide, there is a risk that the mixer such as a mixer may be worn or damaged as in the case of compounding the metal oxide. Since there is no possibility of contamination due to metal powder or the like during mixing, it is also an advantage.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

The nonaqueous external patch of the present invention was prepared at the following blending ratio (mass%).
Diclofenac sodium 1
Crotamiton 5
l-Menthol 3
Aluminum hydroxide 2
Styrene-isoprene-styrene block copolymer (SIS) 14
Polyisobutylene (PIB) 14
Liquid paraffin 30.5
Alicyclic petroleum resin 30.5

<Preparation method>
(1) Diclofenac sodium was mixed with crotamiton.
(2) SIS, PIB, liquid paraffin, alicyclic petroleum resin, and aluminum hydroxide were heated and kneaded.
(3) (1) and l-menthol were added to (2) and mixed uniformly.
(4) (3) was spread on a liner, the support was laminated, and cut into an appropriate size to obtain a patch.

Comparative Example Non-aqueous patch for external use was prepared at the following blending ratio (mass%).
Diclofenac sodium 1
Crotamiton 5
l-Menthol 3
Aluminum hydroxide None Styrene-isoprene-styrene block copolymer (SIS) 14
Polyisobutylene (PIB) 14
Liquid paraffin 31.5
Alicyclic petroleum resin 31.5

<Preparation method>
(1) Diclofenac sodium was mixed with crotamiton.
(2) SIS, PIB, liquid paraffin, and alicyclic petroleum resin were heated and kneaded.
(3) (1) was added to (2) and mixed uniformly.
(4) (3) was spread on a liner, the support was laminated, and cut into an appropriate size to obtain a patch.

Test example 1
Seven patches each of Example 1 and Comparative Example 1 were packaged in a seronium packaging material, stored at 40 ° C. and 75% relative humidity, removed every month, and the content of diclofenac sodium was quantified by HPLC.
FIG. 1 is a graph showing the initial storage as 100%.
From FIG. 1, it can be seen that Example 1 is clearly superior to Storage Example 1 in terms of storage stability.

The nonaqueous external patch of the present invention was prepared at the following blending ratio (mass%).
Diclofenac sodium 1
PEG-4000 5
l-Menthol 3
Aluminum hydroxide 2
Styrene-isoprene-styrene block copolymer (SIS) 14
Polyisobutylene (PIB) 14
Liquid paraffin 30.5
Alicyclic petroleum resin 30.5

<Preparation method>
(1) Diclofenac sodium was dispersed in an appropriate amount of liquid paraffin (2) SIS, PIB, liquid paraffin, alicyclic petroleum resin, and aluminum hydroxide were heated and kneaded.
(3) (1) and l-menthol were added to (2) and mixed uniformly.
(4) (3) was spread on a liner, the support was laminated, and cut into an appropriate size to obtain a patch.

The nonaqueous external patch of the present invention was prepared at the following blending ratio (mass%).
Diclofenac sodium 1
l-Menthol 3
Aluminum hydroxide 2
Styrene-isoprene-styrene block copolymer (SIS) 14
Polyisobutylene (PIB) 14
Liquid paraffin 33
Alicyclic petroleum resin 33

<Preparation method>
(1) Diclofenac sodium was dispersed in an appropriate amount of liquid paraffin.
(2) SIS, PIB, liquid paraffin, alicyclic petroleum resin, and aluminum hydroxide were heated and kneaded.
(3) (1) and l-menthol were added to (2) and mixed uniformly.
(4) (3) was spread on a liner, the support was laminated, and cut into an appropriate size to obtain a patch.

  The external preparation of the present invention can be widely used in the pharmaceutical field as an external preparation containing an anti-inflammatory drug and having excellent stability.

The result measured about the storage stability of the diclofenac sodium in the nonaqueous external patch of Example 1 and Comparative Example 1 is shown.

Claims (9)

A nonaqueous external patch comprising an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule, an additive having a hydroxyl group in the molecule, and a metal hydroxide. The external patch according to claim 1, wherein the mass ratio of the anti-inflammatory drug having a carboxyl group (or a salt thereof) and the metal hydroxide is in the range of 1: 0.1 to 10. The external patch according to claim 1 or 2, wherein the metal hydroxide is one or more selected from the group consisting of aluminum hydroxide, potassium hydroxide, calcium hydroxide and sodium hydroxide. The anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule is selected from the group consisting of ibuprofen, indomethacin, ketoprofen, diclofenac, piroxicam, felbinac, flurbiprofen, loxoprofen, and pharmaceutically acceptable salts thereof. The external patch according to any one of claims 1 to 3, which is one or more selected.   An ester in an external preparation comprising an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule and an additive having a hydroxyl group in the molecule, characterized by comprising a metal hydroxide Compound formation inhibitor. The esterified product formation reaction inhibitor according to claim 5 , wherein the mass ratio of the anti-inflammatory drug having a carboxyl group (or a salt thereof) and the metal hydroxide is in the range of 1: 0.1 to 10. The esterified product formation reaction inhibitor according to claim 5 or 6 , wherein the metal hydroxide is one or more selected from the group consisting of aluminum hydroxide, potassium hydroxide, calcium hydroxide and sodium hydroxide. . The anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule is selected from the group consisting of ibuprofen, indomethacin, ketoprofen, diclofenac, piroxicam, felbinac, flurbiprofen, loxoprofen, and pharmaceutically acceptable salts thereof. The esterified product formation reaction inhibitor according to any one of claims 5 to 7 , which is one or more selected. The esterified product formation reaction inhibitor according to any one of claims 5 to 8 , wherein the external preparation is a nonaqueous external patch.

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