JPH0912450A - Pasting agent - Google Patents

Abstract

PURPOSE: To obtain a pasting agent having high percutaneous absorptivity and percutaneous stability of indomethacin in a pasting base agent, having excellent antiphlogistic and analgesic action and high safety to the skin. CONSTITUTION: This pasting agent contains a pasting base material, indomethacin in the amount of 0.1-2wt.% of the total base agent, 1-10wt.% crotamiton and 0.5-30wt.% a 4-6C dihydric alcohol (e.g.; 1,3-butylene glycol). The pasting base agent is pasted on a substrate to obtain the objective pasting agent. In this case, a tacky adhesive used in the pasting base agent is made of water-based, an acrylic-based, rubber-based, a silicone resin-based, etc., and has an adhesive strength capable of fixing on the surface of skin at a normal temperature for a long time. Percutaneous absorptivity of indomethacin conventionally inferior to the absorptivity is increased and its pharmacological action is exhibited at the maximum. In the case of oral administration, indomethacin inducing adverse effect such as digestive organs disease can be effectively percutaneously administrated directly to a patient part.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a patch containing indomethacin in a patch base, and more specifically, it has a high transdermal absorption rate of indomethacin, has an excellent anti-inflammatory and analgesic action, and is particularly safe for the skin. And a patch with high stability of indomethacin over time.

[0002]

2. Description of the Related Art Indomethacin has hitherto been used for treating rheumatoid arthritis, degenerative joint inflammation and the like in the orthopedic field, and its excellent effects have been recognized. However, on the other hand, it has been regarded as a problem that side effects such as digestive disorders occur when administered orally.

As means for solving this point, various external preparations such as liquid preparations, ointments and poultices containing indomethacin have been developed in recent years, and indomethacin can be directly applied to the skin.

However, since indomethacin is insoluble in water, it cannot be sufficiently transdermally absorbed by simply mixing the powder with an adhesive base. Therefore, it is necessary to mix indomethacin in a dissolved state in the base. However, when monohydric alcohols such as ethyl alcohol, isopropyl alcohol, and butyl alcohol are used as the solvent, the lower alcohols are easily miscible with water, resulting in extremely low solubility of indomethacin in the base. There is a problem. Moreover, if an attempt is made to use a lower alcohol as a solvent in the base to add an amount of indomethacin that is expected to have a pharmacological effect, the lower alcohol must be added in an extremely high concentration, which is preferable in terms of safety to the skin. Absent. Furthermore, indomethacin has a problem in terms of pharmacological effect, safety, and product in addition to the fact that it is easily decomposed by reacting with water or glycerin usually contained in a patch base and has poor stability.

[0005] The present invention has been made in view of the above circumstances,
A patch containing indomethacin as the active ingredient, which has a high transdermal absorption rate of indomethacin, high stability over time, and can effectively exert the pharmacological effect of indomethacin even after long-term storage, and has high safety to the skin. The purpose is to provide.

[0006]

Means and Action for Solving the Problems The present inventors have
As a result of diligent research to improve the transdermal absorption rate and the temporal stability of indomethacin by stably blending indomethacin in a patch to the adhesive patch, the patch has indomethacin and crotamiton and 4 to 6 carbon atoms. It has been found that the above-mentioned object can be achieved by blending together with a dihydric alcohol.

That is, when the present inventors have blended indomethacin with a dihydric alcohol having 4 to 6 carbon atoms and crotamiton in a patch base, they serve as a good solvent for indomethacin and are immiscible with water. Is formulated in a dissolved state, the transdermal absorbability of indomethacin is enhanced, and a patch base having a high anti-inflammatory and analgesic effect is obtained by the synergistic action of indomethacin, the above dihydric alcohol, and crotamiton, and in particular, skin irritation Further, the inventors have found that a patch base having good stability over time of indomethacin can be obtained, and have completed the present invention.

The present invention will be described in more detail below. The patch according to the present invention contains indomethacin in combination with crotamiton and a dihydric alcohol having 4 to 6 carbon atoms, which enhances the transdermal absorbability and stability of indomethacin. is there.

Here, the content of indomethacin is 0.1 to 2% (weight%, the same applies hereinafter) of the whole base material, especially 0.3 to
It is preferably set to 1%. When the content of indomethacin is less than 0.1%, a sufficient pharmacological effect cannot be obtained, and when it exceeds 2%, a sufficient pharmacological effect can be obtained, but it is not preferable in terms of skin irritation.

As the dihydric alcohol having 4 to 6 carbon atoms,
1,3-butylene glycol, dipropylene glycol, 3-methyl-1,3-butylene glycol, 2-methyl-2,4-pentanediol and the like can be mentioned, and one of these can be used alone or two or more can be used. It can be used in combination. The amount of the dihydric alcohol blended is preferably 0.5 to 30% of the total amount of the base, and particularly 1 to 20%.
Is preferred. If the content of dihydric alcohol is less than 0.5%, the effect of promoting percutaneous absorption is not sufficient.
If it exceeds%, the viscosity of the base material may be extremely reduced, which may cause a problem in terms of manufacturability. If the carbon number is 7 or more, the effect of promoting percutaneous absorption cannot be obtained.

In the present invention, crotamiton is further blended, whereby the transdermal absorbability and temporal stability of indomethacin are enhanced by the combined use with the above dihydric alcohol.

The content of crotamiton is preferably 1 to 10%, more preferably 2 to 5%. If the amount of crotamiton blended is less than 1%, sufficient stability cannot be ensured, and if it exceeds 10%, oil may precipitate and this may cause a problem as a product.

The patch of the present invention can be obtained by applying a patch base to a support. In this case, the pressure-sensitive adhesive used for the patch base is such that the patch is applied to the skin surface at room temperature. It is sufficient as long as it has an adhesive force that can be fixed for a certain period of time, and is not particularly limited, and for example, a water-based, acrylic-based, rubber-based, or silicone-resin-based adhesive can be used.

When prepared as a poultice having an aqueous pressure-sensitive adhesive, the composition is not particularly limited, and any composition can be used, such as polyacrylic acid, polyacrylic acid salt,
Polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, carboxyvinyl copolymer, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose salt, hydroxypropyl cellulose, sodium alginate, gelatin, pectin, polyethylene oxide, methyl vinyl ether / maleic anhydride. Copolymer, one or more kinds of water-soluble polymer substances such as carboxymethyl starch (1 to 15% of the total amount of the base material), kaolin, bentonite, montmorillonite, titanium oxide, zinc oxide, aluminum hydroxide , One or more kinds of inorganic powder such as silicic acid anhydride (0 to 10% of the total amount of the base material), propylene glycol, glycerin, sorbitol, sodium pyrrolidone carboxylic acid, It can be used such as a mixture in an appropriate ratio one or more humectants (0-20% of the total amount usually base) and water, such as sodium.

In this case, such an aqueous pressure-sensitive adhesive contains a metal ion-crosslinking type hydrogel base, particularly polyacrylic acid and polyacrylic acid salt, and further contains sodium carboxymethyl cellulose and / or alkali metal alginate. A non-gelatin base can be preferably used.
That is, the water-containing gel base of the above composition has a strong adhesive force, and also has a high water content, and is excellent in shape retention property. Therefore, by using this water-containing gel base, when indomethacin is blended, this effective The ingredients are efficiently absorbed by the skin. The hydrogel base having the above composition is one in which a base having an arbitrary pH can be obtained by changing the compounding ratio of polyacrylic acid and polyacrylic acid salt. In this case, polyacrylic acid is used. The compounding ratio of the polyacrylic acid salt and the polyacrylic acid salt is preferably 1: 9 to 8: 2. When the polyacrylic acid weight is less than 1/10 of the polyacrylic acid-polyacrylic acid weight, sufficient adhesion to the skin is obtained. May not be obtained, and when it is more than 8/10 of the weight of polyacrylic acid-polyacrylic acid salt, sufficient thickening may not be carried out and the plaster may drip. Further, when the water-containing gel base consisting of the above components is metal-crosslinked with a polyvalent metal salt, examples of the polyvalent metal salt include calcium chloride, magnesium chloride, aluminum chloride, potassium alum, ammonium alum, iron alum, aluminum sulfate and sulfuric acid no. Soluble salts of ferric iron, magnesium sulfate, EDTA-calcium, EDTA-aluminum, EDTA-magnesium, stannous chloride, calcium hydroxide, ferric hydroxide, aluminum hydroxide, calcium carbonate, magnesium carbonate, calcium phosphate, stearin Magnesium acid, aluminum stearate, calcium citrate, barium sulfate,
One or more selected from barium hydroxide, aluminum allantoinate, aluminum acetate, aluminum glycinal, stannous hydroxide, slightly soluble or sparingly soluble salts such as α-stannic acid, and the rate of crosslinking reaction E as a regulator
An organic acid, an organic acid salt, an organic base or the like having a chelating or coordinating ability with respect to metal ions such as DTA-2 sodium, citric acid, tartaric acid, urea and ammonia may be added.

In the acrylic pressure-sensitive adhesive, because of its adhesiveness, a (co) polymer of a (meth) alkyl alkyl ester obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid, and / Or a copolymer of the above-mentioned (meth) acrylic acid alkyl ester and other functional monomer is preferably used.

Examples of the (meth) acrylic acid ester include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate. , Stearyl acrylate, methyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-methacrylic acid
Examples include ethylhexyl, isooctyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate. Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, and a monomer having an amino group. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, monoalkyl maleic acid esters such as butyl maleate, maleic acid, coumaric acid and crotonic acid. Maleic anhydride also provides the same (co) polymerization component as maleic acid. Examples of the monomer having an amide group include acrylamide, dimethyl acrylamide, alkyl (meth) acrylamide such as diethyl acrylamide, butoxymethyl acrylamide,
Examples include alkyl ether methylol (meth) acrylamides such as ethoxymethyl acrylamide, diacetone acrylamide, and vinylpyrrolidone. Examples of the monomer having an amino group include dimethylamino acrylate. Copolymerizable monomers other than the above and vinyl acetate,
Examples thereof include styrene, α-methylstyrene, vinyl chloride, acrylotolyl, ethylene, propylene and butadiene, and these may be copolymerized. As the rubber-based pressure-sensitive adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer and the like are used. As the silicone resin adhesive, silicone rubber such as polyorganosiloxane is used.

Further, in the present invention, polybutene, latex, vinyl acetate emulsion, acrylic resin are added to the base material in addition to the above-mentioned components as necessary to adjust the physical properties of the paste (flexibility, tackiness, shape retention, etc.). High molecular substances such as emulsions, various polyvalent metal salts as cross-linking gelling agents, organic cross-linking agents such as dialdehyde starch, lanolin, liquid paraffin, vegetable oil, lard, beef tallow, higher alcohols as stable compounding ingredients of active ingredients , Higher fatty acids, activators and the like may be added appropriately. Further, if necessary, various compounding agents, for example, tackifiers such as rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene phenol resin; liquid polybutene, mineral oil, liquid polyisoprene, liquid polyacrylate, etc. Plasticizer, filler anti-aging agent, are added.

In the present invention, since the pKa of indomethacin is 4.5, the p-type adhesive composition is p.
It is preferable to use a weakly acidic one having H of 4 to 6.5, which increases the proportion of non-dissociated indomethacin molecules, so that the transdermal absorption rate of indomethacin is further increased and the storage stability is also improved. .

As the support for the patch, a support usually used for patches is used. Examples of the material of such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride. , Aluminum, etc. These are used, for example, as a single layer sheet (film) or a laminated body of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics.

The pressure-sensitive adhesive composition of the present invention can be produced according to a conventional method. For example, an aqueous poultice is prepared by kneading the above-mentioned components into a paste, which is applied to the above-mentioned support, and if necessary. It is obtained by coating a facing such as a polyethylene film. Further, for example, in the case of an acrylic, rubber or silicone pressure-sensitive adhesive composition, a pressure-sensitive adhesive layer containing a drug and a surfactant is formed on the surface of the support to obtain a patch. To form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam emulsion coating method can be used. Among them, the solvent coating method is preferably used. To form the pressure-sensitive adhesive layer by the solvent coating method, for example, the pressure-sensitive adhesive is diluted with an appropriate solvent, and a drug, a surfactant, a fatty acid ester and, if necessary, a compounding agent are uniformly mixed to obtain an adhesive layer. The obtained solution is applied to the surface of the support and dried. Instead of directly applying the solution to the surface of the support, the solution may be applied onto a release paper coated with a silicone resin or the like, dried and then brought into close contact with the support. Such release paper is used to protect the adhesive surface of the adhesive until the time of use. Even in coating methods other than the solvent coating method, it is recommended to dispose a release paper to protect this surface after forming the pressure-sensitive adhesive layer. The thickness of the pressure-sensitive adhesive layer also varies depending on the purpose of use, but is usually 30 to 200 μm. 30μ
If it is less than m, the required amount of the drug cannot be contained and the adhesiveness is insufficient. When it exceeds 200 μm, the drug contained in the pressure-sensitive adhesive layer near the support does not sufficiently diffuse, and the drug release property decreases.

[0022]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to stably add indomethacin, which was conventionally difficult to be stably mixed in a dissolved state, to the patch base, and in addition, the transdermal absorption rate of indomethacin is high, and its pharmacological action. Is what can be maximized. Moreover, according to the present invention, indomethacin, which causes side effects such as digestive disorders when administered orally, can be efficiently transdermally administered directly to the affected area, and in this respect also contributes to the safety of treatment. is there.

[0023]

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Examples and Comparative Examples] The components shown in Tables 1 to 3 were mixed and stirred by a Henschel mixer according to a conventional method, and this was uniformly coated on a non-woven fabric at 100 g / m ² to form a polyethylene film. Was applied to produce a patch.

[Experiment 1] Blood Concentration Measurement of Indomethacin A group of 10 Wistar male rats weighing 140 to 160 g was used for the experiment. Rats had their abdomens shaved the day before the experiment. On the day of the experiment, a patch having a size of 3 × 5 cm was applied to the shaved portion and the animal was raised in an individual cage. 1, 2,
Blood was collected from the rats under ether anesthesia 6 times after 3, 4, 6 and 8 hours. The blood was immediately centrifuged, and the plasma component was collected and subjected to high performance liquid chromatography analysis.
The blood concentration of indomethacin was calculated from a predetermined calibration curve, and the area under blood concentration (AUC) was calculated using blood concentration analysis software.

[Experiment 2] Carrageenin paw edema test A group of 10 Wistar male rats weighing 140 to 160 g was used as a group, and the paw volume of the right hind limb of each rat was measured by a volume differential meter, followed by a 1% carrageenin suspension. 0.1 ml is subcutaneously injected into the foot pad. The patch is applied to the right hind limb 4 hours before the injection of the inflammatory agent, the foot volume of the right hind limb after injection is measured with the above meter, and the edema rate and each patch are applied from the difference between the foot volume before and after injection according to the following formula. The edema suppression rate of the drug was determined. The patch applied during the test was covered with a black cloth bag from the rat head to the forelimbs so that the rat did not bite or lick. Further, for comparison, the same test was performed on a control group to which no patch was applied 4 hours before injection. Edema rate (%) = [(Vt−Vn) / Vn] × 100 Vn: foot volume before carrageenin injection Vt: foot volume 4 hours after carrageenin injection Edema inhibition rate (%) = [(Ec−Et) / Ec )] × 10
0 Ec: average edema rate of control group Et: average edema rate of patch application group

[Experiment 3] Stability test After each patch was manufactured, each patch was stored at 60 ° C. for 3 weeks, and the residual amount of indomethacin immediately after storage was determined.

[Experiment 4] Patch Test The patch of each of the Examples and Comparative Examples was applied to the upper arm of 20 healthy males and their skin irritation was examined by a 24-hour closed patch test. ○: No stimulation ×: Stimulation

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3]

Table 4 shows the above results. As can be seen from Table 4, the patches according to the present invention (Examples 1 to 9)
Had a good drug absorption through the skin, a good stability, a very high efficacy, and no skin irritation.

[0033]

[Table 4]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location A61K 47/16 A61K 47/16 E

Claims (2)

[Claims] 1. An adhesive patch containing indomethacin, characterized in that crotamiton and a dihydric alcohol having 4 to 6 carbon atoms are used in combination. 2. The dihydric alcohol having 4 to 6 carbon atoms is 1,3-butylene glycol, dipropylene glycol, 3-methyl-1,3-butylene glycol, 2-
The patch according to claim 1, which is one kind or two or more kinds selected from methyl-2,4-pentanediol.