JPH0692843A - Percutaneous plaster - Google Patents

Abstract

(57) [Summary] [Purpose] To provide a transdermal patch, which has excellent transdermal absorbability and adhesion to the skin and can continuously supply medicinal components for a long time. [Structure] An acrylic pressure-sensitive adhesive layer containing 3-pentanoylcyclobenzaprine as a medicinal component is provided on a support, and the acrylic pressure-sensitive adhesive has a single amide bond in the molecule with an alkyl acrylate ester. And a copolymer having a monomer as a main constituent.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a transdermal patch,
In particular, the present invention relates to a percutaneous absorption patch containing 3-pentanoylcyclobenzaprine as a medicinal component, having an excellent muscle relaxant effect, and capable of being supplied through keratinous skin.

[0002]

2. Description of the Related Art As a powerful muscle relaxant useful for the treatment of skeletal muscle hyperactivity, for example, JP-A-53-56648 discloses 3-pentanoylcyclobenzaprine. However, since the administration method is oral administration by tablets or the like, parenteral administration by sterile aqueous solution, oily solution or suspension, or rectal administration by suppositories, there is a problem in sustaining the blood concentration of the drug, There is a problem that the drug must be administered 2-3 times a day to obtain a sufficient drug effect.

[0003]

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems, and its purpose is to provide excellent transdermal absorbability and adhesion to the skin, and to maintain a medicinal component for a long time. The present invention is to provide a transdermal absorption patch that can be supplied as a product.

[0004]

The transdermal patch of the present invention comprises a support, on which an acrylic pressure-sensitive adhesive layer containing 3-pentanoylcyclobenzaprine as a medicinal component is provided. The agent is characterized by being composed of a copolymer having an acrylic acid alkyl ester and a monomer having an amide bond in the molecule as main constituent components, and thereby the above object is achieved.

The present invention will be described in detail below. The medicinal component used in the transdermal patch of the present invention is 3-pentanoylcyclobenzaprine {N, N, which is useful for the treatment of muscle relaxation.
-Dimethyl 3- [3- (1-oxopentyl) -5H-
Dibenzo [a, d] cycloheptene-5-ylidene] propanamine} (see JP-A-53-56648).

The acrylic pressure-sensitive adhesive used in the transdermal patch of the present invention is a copolymer having (meth) acrylic acid alkyl ester and a monomer having an amide bond in the molecule as main constituents. Consists of.

As the above-mentioned (meth) acrylic acid alkyl ester, those obtained by reacting an alkyl alcohol having 1 to 18 carbon atoms with (meth) acrylic acid are preferable. Further, when the alcohol has more than 18 carbon atoms, the resulting pressure-sensitive adhesive tends to become hard due to the hydrophobic interaction between the side chains.

Examples of the (meth) acrylic acid alkyl ester include methyl acrylate, ethyl acrylate, butyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, lauryl acrylate, methyl methacrylate, ethyl methacrylate, Examples thereof include butyl methacrylate and 2-ethylhexyl methacrylate.

Examples of the monomer having an amide bond in the molecule used in the present invention include acrylamide, methyl acrylamide, ethyl acrylamide, butyl acrylamide, octyl acrylamide, dimethyl acrylamide, diethyl acrylamide, dibutyl acrylamide and ethoxymethyl acrylamide. , (Meth) acrylamides such as butoxymethylacrylamide, diacetoneacrylamide, methacrylamide, methylmethacrylamide, ethylmethacrylamide, butylmethacrylamide, dimethylmethacrylamide, dimethylaminopropylmethacrylamide; vinylpyrrolidone and the like.

The amount of the monomer having an amide bond constituting the above-mentioned copolymer is appropriately determined by the amount of 3-pentanoylcyclobenzaprine contained in the acrylic pressure-sensitive adhesive layer. Since the compatibility with noylcyclobenzaprine becomes poor and the adhesiveness of the acrylic pressure-sensitive adhesive decreases when the amount increases, it is usually 1 to 50 in the copolymer.
It is contained in the proportion of mol%. When the amount of 3-pentanoylcyclobenzaprine is large, it is preferable to increase the amount of the above-mentioned monomer.

In the above copolymer, in addition to the above components, for example, vinyl esters such as vinyl acetate and vinyl butyrate;
Styrene, α-methylstyrene, acrylonitrile, vinyl chloride, ethylene, propylene and other α-olefins; butadiene, isoprene and other dienes; (meth)
Acrylic acid; hydroxyethyl (meth) acrylate,
Monomers such as (meth) acrylic acid hydroxyalkyl ester such as hydroxypropyl (meth) acrylate may be contained. The content of these monomers is preferably 50 mol% or less in the copolymer.

It is preferable that the above copolymer further contains a polyfunctional monomer. By copolymerizing such a polyfunctional monomer, a slight cross-linking occurs between the copolymers, and the internal cohesive force of the obtained pressure-sensitive adhesive increases. Therefore, the adhesive does not remain on the skin when the transdermal absorption patch attached to the skin is peeled off, and the so-called stringing phenomenon of the adhesive does not occur. Moreover, the drug release and skin irritation are not adversely affected.

The polyfunctional monomer is preferably a compound having two or more (meth) acrylic acid ester groups in one molecule, such as di (meth) acrylate and tri (meth) acrylate.

Examples of such compounds include ethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, butylene glycol di (meth). ) Acrylate, hexane glycol di (meth) acrylate, neopentyl glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate and the like.

In addition, compounds having two or more vinyl groups in one molecule such as divinylbenzene and divinyltoluene; diallyl phthalate, diallylmaleate, diallyl adipate, diallyl glycolate, triallyl isocyanurate, diethylene glycol bisallyl carbonate. Compounds having two or more allyl groups in one molecule such as methylenebisacrylamide can also be used.

One or more of these polyfunctional monomers are added during the polymerization of the acrylic pressure-sensitive adhesive and are copolymerized with other monomer components. The amount of the polyfunctional monomer used is 1 × 10 ⁻³ to 1 mol% in all monomer components (including the polyfunctional monomer) used for the polymerization of the acrylic pressure-sensitive adhesive. preferable. When the amount used is less than 1 × 10 ⁻³ mol%, the effect of improving the internal cohesive force due to crosslinking is small, and
If the amount is excessive, gelation occurs during the polymerization reaction, making it difficult to produce a pressure-sensitive adhesive, which is not preferable.

In the present invention, in order to prepare an acrylic pressure-sensitive adhesive, a monomer having an amide bond in the molecule and, if necessary, a polyfunctional monomer are added to the above alkyl acrylate ester. Then, the polymerization reaction is carried out by an ordinary method. Examples of the form of the polymerization reaction include solution polymerization, bulk polymerization, emulsion polymerization, suspension polymerization and the like.
In the above polymerization reaction, azobis compounds, peroxide compounds and the like, which are commonly used in radical polymerization reactions, are preferably used as a catalyst.

In the present invention, the blending amount of 3-pentanoylcyclobenzaprine with respect to the acrylic pressure-sensitive adhesive is not particularly limited, but if it is too small, sufficient medicinal effect cannot be obtained.
If the amount is too large, the compatibility with the pressure-sensitive adhesive becomes poor. Therefore, it is usually preferable to be 1 to 30% by weight of the total weight of the components constituting the acrylic pressure-sensitive adhesive layer.

In the present invention, in order to improve the stability of 3-pentanoylcyclobenzaprine over time, magnesium oxide may be added to the acrylic pressure-sensitive adhesive layer. The blending amount varies depending on the content of 3-pentanoylcyclobenzaprine, but if the blending amount increases, the tackiness of the acrylic pressure-sensitive adhesive layer decreases, so that the amount equal to or less than the weight of 3-pentanoylcyclobenzaprine is used. Generally, 30% by weight or less of the total weight of the components constituting the acrylic pressure-sensitive adhesive layer is preferable.

In addition to the above components, the acrylic pressure-sensitive adhesive layer may further contain polyethylene glycol, ethylene glycol, polypropylene glycol, if necessary.
Glycols such as propylene glycol; fatty acid esters such as isopropyl myristate, diethyl sebacate, octyl stearate; dimethyl sulfoxide; dimethylformamide; N-methylpyrrolidone; polyether synthetic oil; medium chain fatty acid triglyceride; squalene, squalane; water Absorption promoters such as

The support used in the present invention is not particularly limited, and examples thereof include polyethylene, ethylene-vinyl acetate copolymer, soft polyvinyl chloride, polyvinylidene chloride, polyester, nylon, urethane,
A flexible film such as acrylic or a laminated film thereof is preferably used. Further, breathable materials such as non-woven fabric and spandex are also preferably used.

The transdermal patch of the present invention comprises mixing an acrylic pressure-sensitive adhesive, a medicinal component, 3-pentanoylcyclobenzaprine, and magnesium oxide, if necessary, and then applying this on a support. Is obtained by

In order to mix these components constituting the acrylic pressure-sensitive adhesive layer, for example, a method of adding 3-pentanoylcyclobenzaprine to an organic solvent solution of the acrylic pressure-sensitive adhesive and mixing them; A method in which 3-pentanoylcyclobenzaprine or the like is added and heated to melt and mix the pressure-sensitive adhesive (hot melt method) and the like are used.

As a method for forming the acrylic pressure-sensitive adhesive layer on the support, a method of directly applying the above mixture onto the support; a method of applying the mixture onto a release paper such as silicon and then transferring onto the support. , Etc. are used. The thickness of the formed pressure-sensitive adhesive layer is not particularly limited, but is usually 30 μm.
m to 1000 μm is preferable, more preferably 40 μm
˜200 μm.

The thickness of the acrylic pressure-sensitive adhesive layer is required depending on the concentration of 3-pentanoylcyclobenzaprine in the pressure-sensitive adhesive (solution) to be applied and per unit area of the transdermal patch. It is appropriately determined depending on the amount of pentanoylcyclobenzaprine.

[0026]

EXAMPLES The present invention will be described below with reference to examples. Example 1 [Preparation of patch for percutaneous absorption] After preparing an ethyl acetate solution of a copolymer consisting of 30% by mole of 2-ethylhexyl methacrylate, 61% by mole of butyl acrylate and 9% by mole of diacetone acrylamide, this copolymer was prepared. 10 parts by weight of 3-pentanoylcyclobenzaprine and 5 parts by weight of magnesium oxide were added to 100 parts by weight (in terms of solid content) and uniformly mixed to obtain a mixed solution. This blended solution was applied to one side of an ethylene-vinyl acetate copolymer film so as to have a thickness after drying of 50 μm and dried to form an acrylic pressure-sensitive adhesive layer to prepare a transdermal patch.

[Performance Evaluation of Percutaneous Absorption Patch] The above-prepared transdermal absorption patch was cut into a circular shape having a size of 50 cm ² and applied to the abdomen of a hair-removed rat. (1) Adhesion to the skin After 24 hours from application, the presence or absence of peeling is visually observed, and peeling is considered to be 10% or less of the total area, and peeling exceeding 10% of the total area is regarded as defective. The results are shown in Table 1. (2) Measurement of blood concentration The concentration of the medicinal component in rat blood was measured at regular intervals (3, 8, 12 and 24 hours) after application, and the results are shown in Table 1. The blood concentration was measured by gas chromatography using a sample obtained by separating blood collected after a predetermined time from plasma, extracting with n-hexane and centrifuging.

Example 2 52.98 mol% butyl acrylate, 32 mol% 2-ethylhexyl methacrylate, 10 mol% 2-ethylhexyl acrylate, 5 diacetone acrylamide
After preparing a solution of 100 parts by weight of a copolymer consisting of 1% hexane glycol dimethacrylate and 0.02 mol% of ethyl acetate in ethyl acetate, 10 parts by weight of 3-pentanoylcyclobenzaprine was added and mixed uniformly. A mixed solution was obtained. After this mixed solution was applied on one side of an ethylene-vinyl acetate copolymer film so that the thickness after drying was 50 μm and dried to prepare a transdermal patch having an acrylic pressure-sensitive adhesive layer formed, The same performance evaluation as in Example 1 was performed, and the results are shown in Table 1.

Example 3 69.003 mol% of 2-ethylhexyl acrylate,
After preparing an ethyl acetate solution containing 100 parts by weight of a copolymer consisting of 30 mol% of vinylpyrrolidone and 0.007 mol% of 1,6 hexaneglycol dimethacrylate, 10 parts by weight of 3-pentanoylcyclobenzaprine was homogenized. To obtain a blended solution. This blended solution was applied to an ethylene-vinyl acetate copolymer film so as to have a thickness after drying of 50 μm and dried to prepare a transdermal patch having an acrylic pressure-sensitive adhesive layer, and The same performance evaluation as in Example 1 was performed, and the results are shown in Table 1.

[0030]

[Table 1]

[0031]

EFFECTS OF THE INVENTION Since the present invention is constituted as described above, it is excellent in transdermal absorbability and adhesion to the skin, and can be used for muscle relaxation in which the medicinal effect can be continued for a long time with one application. It is possible to provide a percutaneous absorption patch.

Claims (1)

[Claims] 1. An acrylic pressure-sensitive adhesive layer containing 3-pentanoylcyclobenzaprine as a medicinal component is provided on a support, and the acrylic pressure-sensitive adhesive forms an amide bond in the molecule with an alkyl acrylate ester. A percutaneous absorption patch, comprising a copolymer containing a monomer as a main constituent.