JP2764183B2 - Medical patch - Google Patents

Description

The present invention relates to a medicinal patch containing metoprolol and / or a salt thereof which is excellent in percutaneous absorption and storage stability.

(B) Prior art Metoprolol (tartaric acid) is a β ₁ -receptor blocker used for the treatment of hypertension and angina.

Metoprolol is usually administered orally as a tablet containing tartrate as the main drug, but due to the so-called first-pass effect, a considerable amount of the absorbed drug is metabolized at the initial stage, and the bioavailability is far from high. .

Therefore, a method of transdermal administration by a patch is proposed, but a transdermal preparation in which metoprolol or a salt thereof is prescribed has not been disclosed in development.

(C) Problems to be Solved by the Invention In the case of a salt form of metoprolol such as metoprolol tartrate contained in a tablet, even if the storage stability is good, the metoprolol is not required to be retained in either a hydrophilic or lipophilic base. The distribution of the drug from the agent to the skin is considered to be low.

On the other hand, when metoprolol (meaning free base) is contained in a tape based on a relatively high lipophilic rubber or acrylic polymer, the drug is distributed from the base to the skin. Is relatively high, but there are problems such as poor storage stability.

(D) Means for Solving the Problems The present inventors have solved the above-mentioned problems, have good transdermal absorbability of metoprolol and / or a salt thereof, and have improved storage stability to be effective in treating patients. The following findings were obtained as a result of intensive studies on patches that exhibited significant effects.

That is, the exposed surface of the pressure-sensitive adhesive layer containing metoprolol and / or a salt thereof has a pH of 7 to 11.5, and the pressure-sensitive adhesive layer contains (i) metoprolol and an acidic substance; Salts and basic substances, (ii
i) When any one of metoprolol and a salt of metoprolol is contained, metoprolol and / or its salt in the preparation can be easily transferred to the skin surface, and the stratum corneum as a barrier layer can be easily formed. It was found that it could penetrate into water.

Further, in the case where the pressure-sensitive adhesive layer contains metoprolol in a salt form, since the substance forming a salt with metoprolol is an acidic substance, it is not always necessary to coexist an acidic substance in the pressure-sensitive adhesive layer. In such a case, it has been found that the addition of a basic substance improves the transdermal absorbability of the salt.

 The present invention has been completed based on the above findings.

That is, the medical patch of the present invention is a medical patch in which a pressure-sensitive adhesive layer is laminated on a flexible support,
The exposed surface of the pressure-sensitive adhesive layer has a pH of 7 to 11.5, and the pressure-sensitive adhesive layer contains one of the following components.

(I) Metoprolol and acidic substances.

(Ii) Metoprolol salts and basic substances.

(Iii) metoprolol and salts of metoprolol.

 Hereinafter, the present invention will be described in detail.

The pressure-sensitive adhesive layer used in the present invention is a layer for containing and holding metoprolol and / or a salt thereof as a medicinal ingredient, and is not particularly limited as long as it is a layer formed of an adhesive that adheres to the skin surface. However, acrylic pressure-sensitive adhesives listed below are preferred from the viewpoint of adhesion to the skin and stability.

Among these pressure-sensitive adhesives, those having low skin irritation and good drug solubility, especially alkyl (meth) acrylate and alkyl (meth) acrylate having an ether bond in the molecule. And a pressure-sensitive adhesive made of a copolymer of a monomer with a copolymerizable monomer other than these.

Examples of the acrylic pressure-sensitive adhesive include butyl (meth) acrylate, pentyl (meth) acrylate, hexyl (meth) acrylate, heptyl (meth) acrylate, and octyl (meth) acrylate. (Meth) acrylic acid such as ester, nonyl (meth) acrylate, decyl (meth) acrylate, undecyl (meth) acrylate, dodecyl (meth) acrylate, tridecyl (meth) acrylate Examples thereof include one or more polymers of an alkyl ester, and a copolymer of one or more of the esters with a monomer copolymerizable therewith.

Examples of the copolymerizable monomer include carboxyl group-containing monomers such as (meth) acrylic acid, itaconic acid, crotonic acid, maleic acid, maleic anhydride, and fumaric acid;
Sulfoxyl group-containing monomers such as styrenesulfonic acid, allylsulfonic acid, sulfopropyl acrylate, (meth) acryloyloxynaphthalenesulfonic acid, acrylamidomethylpropanesulfonic acid, and acryloyloxybenzenesulfonic acid, hydroxyethyl (meth) acrylate, Hydroxyl group-containing monomers such as hydroxypropyl (meth) acrylate, (meth)
Acrylamide, dimethyl (meth) acrylamide, N
Amide group-containing acrylic monomers such as -butylacrylamide, tetramethylbutylacrylamide, N-methylol (meth) acrylamide, (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic Acid dimethylaminoethyl ester, alkylaminoalkyl group-containing acrylic monomers such as (meth) acrylic acid tret-butyl ester, (meth) acrylic acid methoxyethyl ester,
(Meth) acrylic acid ethoxyethyl ester, (meth)
Ether bond in the molecule such as butoxyethyl acrylate, tetrahydrofurfuryl (meth) acrylate, methoxydiethylene glycol (meth) acrylate, methoxydiethylene glycol (meth) acrylate, methoxypolypropylene glycol (meth) acrylate Functional monomers such as alkyl acrylates having a vinyl group, vinyl monomers such as N- (meth) acryloylamino acid, acrylic monomers such as urethane, urea and isocyanate esters of acrylic acid, and (meth) Acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylpiperazine, vinylpiperadone, vinylpyrimidine, vinylpyrrole, vinylimidazole, vinyl Le caprolactam, vinyl oxazole, vinyl thiazole, vinyl morpholine, styrene, alpha-methyl styrene, bis (N, N'-dimethylaminoethyl) vinyl monomers, such as maleate and the like.

In the present invention, the alkyl (meth) acrylate and the copolymerizable monomer include various isomers in which the alkyl portion is linear and branched, and various isomers and derivatives in which the position of the substituent is different. Includes

The blending ratio of the monomer copolymerizable with the alkyl (meth) acrylate in the acrylic pressure-sensitive adhesive should be 50 to 99/1 to 50 by weight. Desirable. When an alkyl (meth) acrylate having an ether bond in the molecule is used from the viewpoint of skin irritation and the like, the alkyl (meth) acrylate and the (meth) acryl having an ether bond in the molecule are used. Acid alkyl ester, the compounding ratio of the other copolymerizable monomer is a polymerization ratio of 40-80 / 59-10 /
Desirably, it is 1 to 40.

Other pressure-sensitive adhesives include, for example, rubber materials such as silicone rubber, polyisobutylene rubber, polyisoprene rubber, styrene-butadiene (or isoprene) -styrene block copolymer rubber, acrylic rubber, natural rubber, polyvinyl Alkyl ethers, polyvinyl acetate, partially saponified polyvinyl acetate, polyvinyl alcohol, vinyl polymers such as polyvinylpyrrolidone,
Cellulose derivatives such as methylcellulose, carboxymethylcellulose and hydroxypropylcellulose, polysaccharides such as pullulan, dextrin and agar, polyurethane elastic bodies and polyester elastic pairs can also be used.

In addition, when using the pressure-sensitive adhesive, if there is a possibility of causing a glue residue phenomenon on the applied skin surface after application to the skin due to insufficient cohesion and causing contamination of the skin surface, the skin adhesive property is reduced. Appropriate chemical cross-linking treatment (such as copolymerization of a cross-linkable monomer and addition of an external cross-linking agent) and physical cross-linking treatment (irradiation with ionizing radiation such as an electron beam or ultraviolet cross-linking) so as not to impair. Desirably, it is applied to the composition.

The content of metoprolol and / or a salt thereof as a medicinal ingredient used in the present invention is not particularly limited as long as it exhibits the pharmacological effect.
0.1 to 50% by weight, preferably 1 to 40% by weight, 20 to 3000 μg / cm ² per unit area, preferably 100 to
It is desirable to be 2000 μg / cm ² .

In the present invention, as a support for supporting the pressure-sensitive adhesive layer containing the metoprolol and / or a salt thereof and further a pH adjusting substance, for example, a plastic film,
Non-woven fabric, woven fabric, paper, metal foil, foam film, or a combination thereof.

In the medical patch of the present invention, the exposed surface of the above-mentioned pressure-sensitive adhesive layer has a pH of 7 to 11.5, and the pressure-sensitive adhesive layer contains (i) metoprolol and an acidic substance;
The transdermal absorbability of metoprolol and / or its salt and its storage stability by containing any one of the salt of metoprolol and a basic substance, and (iii) the salt of metoprolol and metoprolol. This is desirable because it improves for the reasons described below.

By the way, this base does not contain water, so that the acidic substance and / or the basic substance contained in the pressure-sensitive adhesive layer is different from the generally-known pH adjuster.

The acidic substance is not particularly limited as long as it is a substance that is pharmaceutically acceptable in view of safety, but it is preferable to use an organic acid, and particularly preferable to use an organic carboxylic acid. Specific examples include organic carboxylic acids such as citric acid, succinic acid, tartaric acid, maleic acid, fumaric acid, salicylic acid, and lactic acid.

Further, as the above-mentioned basic substance, a substance having a stronger base than metoprolol is preferably used, and particularly, a base performance within a pharmaceutically acceptable range is preferable from the viewpoint of safety.

Specific examples include inorganic substances such as sodium hydroxide and potassium hydroxide, or amines such as triethanolamine, diethanolamine, triisopropanolamine, and diisopropanolamine, or amino acids such as arginine. In view of the above, triethanolamine or arginine is preferred.

The content of the acidic substance and / or the basic substance is 0.1 to 10 per mol of metoprolol and / or a salt thereof.
Mol, preferably 0.5 to 5 mol.

Meanwhile, in the medical patch of the present invention, it is necessary to adjust the pH of the exposed surface of the pressure-sensitive adhesive layer by coexisting with an acidic substance and / or a basic substance so that the pH is in the range of 7 to 11.5. However, by adjusting the pH of the exposed surface in this way, transdermal absorption of metoprolol and / or its salt is further improved, and storage stability is further improved.

In this case, the surface pH is defined as a value when distilled water is dropped on the surface of the pressure-sensitive adhesive layer and the pH of the dropped water becomes equilibrium.

When the surface pH is less than 7, metoprolol does not sufficiently transfer to the skin surface, while when the surface pH exceeds 11.5, the skin irritation becomes significant.

(E) Action The reason why the transdermal absorbability and storage stability of the medical patch of the present invention are improved is not clear, but is considered as follows.

That is, by causing metoprolol and / or a salt thereof and an acidic substance and / or a basic substance to coexist in the pressure-sensitive adhesive layer, metoprolol and / or a salt thereof and further an acidic substance and / or a basic substance and a pressure-sensitive adhesive Some kind of intermolecular force acts between components and functional groups. This intermolecular force is different from that in solution in terms of the mode or magnitude of the interaction between molecules, and there are various forces such as a force that does not occur in solution and a force that is weaker than in solution. It is considered that the storage stability is good as in a tape preparation containing only metoprolol, and the transdermal absorbability is good as in a tape preparation containing only metoprolol free base.

By the way, in the medical patch of the present invention, when the pressure-sensitive adhesive layer contains metoprolol in the form of a salt, since the substance forming a salt with metoprolol is an acidic substance, the storage stability of metoprolol is good. It is. However, it is necessary to make a basic substance coexist in the pressure-sensitive adhesive layer in order to improve transdermal absorbability as in a preparation containing only metoprolol free base.

(F) Example Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto, and various modifications are possible. In addition, "parts" in the text indicates parts by weight.

Example 1 A four-necked flask was charged with 55 parts of 2-ethylhexyl acrylate, 30 parts of methoxyethyl acrylate, 15 parts of vinyl acetate, and 0.3 part of azobisisobutyronitrile. The polymerization reaction was started by raising the temperature to 63 ° C., the reaction temperature was controlled while adding 125 parts of ethyl acetate dropwise, and the reaction was continued for 10 hours.
The mixture was aged at 2 ° C. for 2 hours to obtain an acrylic copolymer solution (the copolymer solution thus obtained is hereinafter simply referred to as a copolymer solution (A)).

Metoprolol tartrate and ethanolamine were added and mixed to the obtained copolymer solution (A) such that the contents after drying were 20% by weight and 9% by weight, respectively, and then placed on a 75 μm-thick polyester release liner. Drug content is 1600 μg /
It was applied to a thickness of cm ² and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a medical patch of the present invention.

Example 2 95 parts of 2-ethylhexyl acrylate, 5 parts of acrylic acid, and 0.2 part of benzoyl peroxide were charged into a four-necked flask, and heated to 62 to 65 ° C under an inert gas atmosphere to carry out a polymerization reaction. The reaction was started for 8 hours by controlling the reaction temperature while dropping 125 parts of ethyl acetate.
For 2 hours to obtain a copolymer solution (B).

The content of the resulting copolymer solution (B) after drying metoprolol tartrate and sodium hydroxide was 30% each.
%, 6% by weight, and mixed to a thickness of 75μ.
2,000 m on polyester release liner
The solution was applied to a concentration of μg / cm ² and dried to form a pressure-sensitive adhesive layer.

Next, the pressure-sensitive adhesive layer was formed by laminating an ethylene-vinyl acetate copolymer (vinyl acetate content: 28% by weight) to a thickness of 50 μm.
Transfer to the vinyl acetate copolymer side to obtain a medical patch of the present invention.

Example 3 25 parts of VISTANEX MML-80 (viscosity average molecular weight 990,000), H
IMOL-4H (viscosity average molecular weight 40,000) A polyisobutylene solution (solid content 25% by weight) obtained by dissolving 75 molecular weights in hexane has a content of 5% by weight each of metoprolol tartrate and L-arginine after drying, 1% by weight, mixed, and applied on a 75 μm-thick polyester release liner so that the drug content is 800 μg / cm ² .
After drying, a pressure-sensitive adhesive layer was formed.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 30 μm polyethylene film support to obtain a medical patch of the present invention.

Example 4 Metoprolol and salicylic acid were added to the copolymer solution (A) obtained in Example 1 so that the content after drying was 20% by weight and 3% by weight, respectively, and mixed. Drug content on release liner is 1600μg /
It was applied to a thickness of cm ² and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a medical patch of the present invention.

Example 5 In the copolymer solution (A) obtained in Example 1, the content of metoprolol, succinic acid, and triethanolamine after drying was 20% by weight, 8% by weight, and 10% by weight, respectively. The mixture was added, mixed, applied to a 75 μm-thick polyester release liner so that the drug content was 2000 μg / cm ^2, and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a medical patch of the present invention.

Example 6 Metoprolol and metoprolol tartrate were added to the copolymer solution (A) obtained in Example 1 so that the content after drying was 20% by weight and 10% by weight, respectively, and mixed. The composition was applied on a polyester release liner so that the drug content was 2000 μg / cm ^2, and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a medical patch of the present invention.

Comparative Example 1 Metoprolol tartrate was added to and mixed with the copolymer solution (A) obtained in Example 1 so that the content after drying was 30% by weight, and the mixture was placed on a 75 μm-thick polyester release liner. It was applied to a drug content of 1600 μg / cm ² and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a patch.

Comparative Example 2 Metoprolol was added and mixed with the copolymer solution (A) obtained in Example 1 so that the content after drying was 20% by weight, and the drug was placed on a 75 μm-thick polyester release liner. It was applied to a content of 1600 μg / cm ² and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a patch.

Comparative Example 3 The copolymer solution (A) obtained in Example 1 had a content of each of metoprolol tartrate and tartaric acid after drying of 20.
% By weight and 4% by weight.
1600μ of drug content on polyester release liner
g / cm ² and dried to form a pressure-sensitive adhesive layer.

Next, the pressure-sensitive adhesive layer was formed by laminating an ethylene-vinyl acetate copolymer (vinyl acetate content: 28% by weight) to a thickness of 50 μm.
It was transferred to the vinyl acetate copolymer side to obtain a patch.

Comparative Example 4 Metoprolol and triethanolamine were added to the copolymer solution (B) obtained in Example 2 so that the content after drying was 20% by weight and 5% by weight, respectively, and mixed. Was applied so that the drug content was 2000 μg / cm ^2, and dried to form a pressure-sensitive adhesive layer.

Next, the pressure-sensitive adhesive layer was formed by laminating an ethylene-vinyl acetate copolymer (vinyl acetate content: 28% by weight) to a thickness of 50 μm.
It was transferred to the vinyl acetate copolymer side to obtain a patch.

Comparative Example 5 The content of metoprolol, succinic acid, and triethanolamine in the copolymer solution (A) obtained in Example 1 after drying was adjusted to 20% by weight, 8% by weight, and 0.1% by weight, respectively. The mixture was added, mixed, applied to a 75 μm-thick polyester release liner so that the drug content was 2000 μg / cm ^2, and dried to form a pressure-sensitive adhesive layer.

Next, the above-mentioned pressure-sensitive adhesive layer was transferred onto a 9 μm-thick polyester film support to obtain a patch.

Surface pH measurement test Examples 1 to 6 and Comparative Example 1 obtained as described above
Cut out the patches of ~ 5 in a circular shape of 12 mmφ, drop 0.1 ml of distilled water on the surface of the pressure-sensitive adhesive layer exposed by peeling off the liner, and measure the pH value at which the dropped water has almost reached equilibrium did. To reach near equilibrium here means that the value has not changed for more than 30 seconds.

 Table 2 shows the results.

Rabbit skin transfer test Examples 1 to 6 and Comparative Example 1 cut out to a size of 30 mmφ
After applying the patches of Nos. To 5 to the skin surface of the rabbit back for 8 hours, the patch was peeled off, the remaining metoprolol tartrate or metoprolol tartrate was extracted with methanol, and the apparent transfer rate to the skin surface was calculated from the initial content (hereinafter, referred to as "metoprolol"). Simply the skin transfer rate).

 Table 2 shows the results of these tests.

The surface pH was the average of four samples in each of the examples and comparative examples, and the skin transfer rate was the average of three samples in each of the examples and comparative examples.

Beagle Dog Plasma Concentrations The preparations obtained in Examples 1, 2, 5 and Comparative Examples 1 and 2 were cut out so that the total dose was 50 mg, and attached to the back of the Beagle dog. , 3,4,6,9,12,15,24,36,48 hours later, metoprolol plasma concentration was measured by HTLC.

The number of animals was 3 per group. The average value is shown in FIG.

Stability of the formulation Patches obtained in Examples 1-6 and Comparative Examples 1-5,
After storing at a temperature of 50 ° C. for 1, 2, or 3 months, a 30 mmφ section was cut out, the remaining metoprolol was extracted with methanol, and the residual ratio to the initial content was calculated.

 The result is shown in FIG.

FIG. 1 shows that Examples 1, 2, and 5 have higher plasma concentrations than Comparative Example 1 and are stable over a long period of time.

In addition, it can be seen from FIG. 2 that the Example has better stability of metoprolol than Comparative Examples 2 and 4.

From the above results, it can be seen that the transdermal absorbability and the stability are both good in the examples, but none of the comparative examples satisfy both properties.

(G) Effect of the Invention The medical patch of the present invention is a medical patch in which a pressure-sensitive adhesive or the like is laminated on a flexible support,
The exposed surface of the pressure-sensitive adhesive layer has a pH of 7 to 11.5, and the pressure-sensitive adhesive layer contains (i) metoprolol and an acidic substance, (ii) a salt and a basic substance of metoprolol, (ii)
i) It contains either metoprolol or a salt of metoprolol, and the pH of the exposed surface of the pressure-sensitive adhesive layer is adjusted to 7 to 11.5. In addition, both properties of storage stability are improved, and as a result, it has effects such as being extremely effective in treating hypertension, angina and the like.

[Brief description of the drawings]

FIG. 1 is a characteristic diagram showing the time-dependent change in the plasma concentration of metoprolol when Examples 1 and 2 and Example 5 and Comparative Examples 1 and 2 were applied to the back of a beagle dog, and FIG. 6
FIG. 6 is a characteristic diagram showing storage stability when Comparative Examples 1 to 5 are stored at a temperature of 50 ° C.

Claims (1)

(57) [Claims] 1. A medical patch comprising a pressure-sensitive adhesive layer laminated on a flexible support, wherein the exposed surface of the pressure-sensitive adhesive layer has a pH of 7 to 11.5, and A medical patch, wherein the pressure-sensitive adhesive layer contains any one of the following components. (I) Metoprolol and acidic substances. (Ii) Metoprolol salts and basic substances. (Iii) metoprolol and salts of metoprolol.