JPS5942314A - Material for external use - Google Patents

Abstract

PURPOSE:A material for external use containing a copolymer of an ether group- containing (meth)acrylic ester, (meth)acrylic acid alkyl ester, etc. and scopolamine(derivative), not crystallizing the drug, showing improved releasability, not causing a rash, etc. on the skin. CONSTITUTION:An adhesive containing 100pts.wt. copolymer consisting of 5- 75wt% (meth)acrylic ester(e.g., methoxyethyl acrylate) having an ether group in the molecule, 85-15wt% (meth)acrylic acid alkyl ester (e.g., n-butyl methacrylate) and 10-50wt% polar monomer (e.g., functional monomer such as meleic acid, etc., vinyl ester such as vinyl acetate, etc.), and 0.1-20pts.wt., preferably 0.5-15pts.wt. scopolamine(derivative), a parasympathetic depressant to be medicated for internal use, is directly or indirectly applied to a carrier such as a plastic film, cloth, nonwoven fabric, etc. Having improved initial releasability (time for reaching effective plasma concentration) in its application through adhesion and improved durability of action.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external member containing scopolamine or a scopolamine derivative that is made to be applied directly to the skin surface of the body.

Scopolamine or a scopolamine derivative is a parasympathetic nerve suppressant administered orally), and when administered by subcutaneous injection, it is used as an antispasmodic for symptoms such as alcohol delirium, narcotic state, and drug withdrawal symptoms. It also has a sedative effect on the central nervous system, and when administered in small doses, it acts as an antidepressant and is used as a prophylactic for nausea and vomiting caused by motion sickness.

Conventional administration methods mainly include oral administration and subcutaneous injection, and although these administration methods provide a satisfactory rapid action, they lack sustainability of action and can be used over a long period of time. If efficacy over a period of time is required, several administrations may be necessary. Furthermore, tablets may get stuck in the throat when taken, which is especially common among young children and the elderly.

In the case of injectable drugs, there is also the drawback that self-administration is not possible.

As a result of intensive research to solve the above problems, the present inventors have found that the problems can be solved by replacing the oral form of administration with transdermal administration. In transdermal administration system components using synthetic resin-based adhesives, the solubility of the scopolamine or scobolamine derivatives contained in the adhesive is extremely high due to its extremely high water permeability. Insufficient and limited time to release an effective amount of drug. Sub-2
If a large amount of drug is desired to be released within a predetermined period of time, there is a problem in that it is necessary to contain a large amount of an expensive drug. Furthermore, there is a problem that it lacks the ability to absorb sweat generated on the skin and has poor adhesion to the skin.

Therefore, the object of the present invention is to provide a patch that is fast enough to prevent the drug contained in the patch from crystallizing on the skin surface, and has a high water absorption capacity, so that the water becomes a route for the drug to reach the skin and is The present invention provides an external member that can release a large amount of drug within a certain amount of time.

That is, the present invention comprises a carrier and a drug-containing adhesive layer formed directly or indirectly on the carrier, and the adhesive layer has an ether group in its molecules. 5 to 75% by weight of (meth)acrylic ester with (meth)
The drug which is mainly composed of a copolymer consisting of 85 to 15% by weight of an acrylic acid alkyl ester and 10 to 50% by weight of a polar monomer and which is contained in the drug-containing patch is scopolamine or a scopolamine derivative. The present invention provides a member for external use.

The (meth)acrylic acid ester having an ether group in the molecule used in the present invention improves the solubility of the drug in the adhesive composition and releases a large amount of scopolamine or scopolamine derivatives within a limited time. An ester monomer having an ether bond in the functional alcohol moiety, such as tetrahydrofurfuryl acrylate, tetrahydrofurfuryl methacrylate, methoxypolyethylene glycol acrylate, methoxypolyethylene glycol methacrylate, ethoxydiethylene glycol acrylate, butoxydiethylene glycol acrylate, butylene glycol acrylate , butylene glycol methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, 3-ethoxypropyl acrylate, hydroxyethyl acrylate, ethoxyethyl methacrylate, butoxyethyl acrylate, butoxyethyl methacrylate, and the like.

Most of these ester monomers have a homopolymer glass transition temperature of -10 to -70°C, and have a free volume that allows the polymer segments to move freely at -ss at the operating temperature of external parts. In addition, this property, such as the electron-donating property of the ether bond, increases the diffusion and movement of the drug in the copolymer, and this together with the property that the monomer itself has high drug solubility. , it is possible to release more of the contained drug in a limited period of time.

The (meth)acrylic acid alkyl ester used in the present invention is a component that imparts tackiness, adhesion, and cohesiveness to the adhesive, and examples thereof include n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2- Ethyl butyl acrylate, isooctyl acrylate, 2
Examples include -ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.

(meth)acrylic acid ester fA+ having an ether group in the molecule and (meth)acrylic acid alkyl ester (
The blending ratio or % of Bl and the polar monomer (at) described below
fAt: (Bl: (C1=5~75:
85-15: 10-50 (weight t%), and (A) is 5
If the weight is less than <<, the drug may not be absorbed and dissolved, and even if mixed forcibly, there is a possibility that scopolamine or scopolamine derivatives will crystallize.・Dust, poor initial drug release, and rapid loss of drug efficacy. fAt
When the amount is 75% by weight or more, the drug is dissolved well and the initial release property is good, but the adhesion as an external member when applied directly to the skin is poor, which is not preferable.

In this way, the copolymer formed by copolymerizing (meth)acrylic acid ester and (meth)acrylic acid alkyl ester having an ether group in the molecule contains scopolymers to achieve a pharmaceutically effective concentration. A method for incorporating scopolamine or a scopolamine derivative into the above copolymer is to add and dissolve it in a (meth)acrylic acid ester or (meth)acrylic acid alkyl ester having an ether group in advance. Alternatively, scopolamine or a scopolamine derivative may be added and dissolved in the copolymer as an (aqueous) solution.

In the step of making the copolymer, (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate is used to improve the cohesion of the copolymer and to further increase the hydrophilicity. , functional monomers such as hydroxyethyl acrylate, acrylamide, and dimethylacrylamide, and polar monomers such as vinyl esters such as acrylonitrile, vinyl acetate, and vinyl propionate are copolymerized in a proportion of 10 to 50% by weight of K in the copolymer. 0 The addition of this polar monomer absorbs water on the skin and improves its adhesion to the skin, promotes the diffusion of the drug in the copolymer into the skin and improves release properties, and has the following auxiliary properties: Even if the agents are retained in the copolymer, the copolymer is plasticized and its tackiness does not decrease.

In addition, alcohols such as propylene glycol and diethylene glycol, and salicylic acid are used to release the drug more reliably from the adhesive, to enhance the medicinal efficacy of the released drug, or to achieve both of these functions. , urea, allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, diisopropyl adibate, diethyl sepacate, ethyl laurate, etc., may be added in consideration of the composition of the drug and its efficacy. Can be done.

The amount added is preferably 0.5 to 20 parts by weight per 100 parts by weight of the copolymer.

Scopolamine or scopolamine derivatives used in the present invention include scopolamine, scopolamine hydrobromide,
Examples include butyl scopolamine bromide and methyl scobonamine bromide, and the content in the adhesive layer can range from 0.1 to 20 parts by weight per 100 parts by weight of the copolymer. , preferably 0.5 to 15 parts by weight.

In addition, adhesives include plastic films, sheets or pieces,
It can be applied directly onto a carrier such as paper, non-woven fabric, cloth, or flexible metal foil, or through an undercoat material such as an adhesive composition mainly composed of rubber and/or synthetic resin, or the above-mentioned copolymer containing no drug. It is formed indirectly on the whole or in part, but the method for forming it is to prepare the drug-containing adhesive composition by emulsion polymerization, solution polymerization, etc., and then directly or directly onto the carrier. It goes without saying that the external member of the present invention may be coated and dried indirectly, or coated and dried on a release liner in advance to form a film, and then transferred onto a carrier. Although the patch contains a copolymer component, this component is not irritating to the skin, and care has been taken to ensure that dermatitis such as rash does not occur even when the patch is used for a long period of time. There is.

The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited to these Examples, and various modifications can be made without departing from the technical idea of the present invention. It is possible. Note that 1 in the middle of the text indicates parts by weight.

Example 1 A monomer mixture consisting of ss parts of 2-ethylhexyl acrylate, 30 parts of 2-methoxyethyl acrylate, and 15 parts of vinyl acetate was mixed with 0.0 parts of azobisisobutyronitrile.
Polymerization was carried out by raising the temperature to 65°C in ethyl acetate in the presence of 2 parts. After reaction for 8 hours, the temperature was raised to 80°C and aging for 2 hours to obtain an acrylic copolymer. A scopolamine hydrobromide aqueous solution adjusted to have a saturation solubility in 1 water is added to the copolymer solution and mixed, and coated on one side of a polyethylene phthalate film so that the thickness after drying is 40 μm, It was dried at 80° C. for 8 minutes to obtain an external member containing scopolamine hydrobromide.

The amount of scopolamine hydrobromide used in this example was set to 200 ttgl.
r, no crystal precipitation was observed, and the release of scopolamine hydrobromide when applied as a patch was also good, reaching an effective plasma concentration in about 30 minutes after application, and the effect lasted for about 12 hours. did. In addition, after peeling and removal, there were no lumps 17 on the applied skin surface.

Example 2 In the presence of 0.5 parts of ammonium persulfate as a polymerization initiator, 5 parts of an emulsifier,
Polymerization was carried out at 60 to 65°C in an aqueous solution of 150 parts of distilled water, and after 5 hours of reaction, the temperature was further raised to 80°C, aged for 2 hours, and methylscopolamine bromide was added and mixed to the copolymer aqueous solution to form a polyethylene film. The thickness after drying is 5 on one side of
It was coated to a thickness of 0 μm and dried at 80° C. for 10 minutes to obtain a member for external use containing methylscopolamine bromide.

The amount of methylscopolamine bromide used in this example was set at 500 parts g/cyd.

The solubility of methyl scopolamine bromide in the obtained external use member was good, and no precipitation was observed, and the release of methyl scopolamine bromide when applied by adhesive was also good, and it took approximately 20 minutes after application. Effective plasma concentrations were reached at 100 ml, and the effect lasted for approximately 12 hours.

In addition, there was no swelling on the applied skin surface after peeling and removal.

Example 3 50 parts of n-nonyl methacrylate, 1,000 parts of ethoxydiene
A monomer mixture consisting of 20 parts of 7 glycol and 30 parts of vinyl propionate was polymerized in the presence of 0.3 parts of benzoyl peroxide in toluene by raising the temperature to 65°C. After reaction for 8 hours, a further 80 The temperature was raised to .degree. C. and aged for 2 hours to obtain a compound solution.

Next, 10 parts of dimethyl sulfoxide and scopolamine prepared to have a saturation solubility in a water/ethanol (]/1) mixture were added to the copolymer solution and mixed. A desired external member containing scopolamine was obtained. In this example, the amount of scopolamine used was 200 parts g/1yrf.
It was set so that

The solubility of scopolamine in the obtained external use member was good, no crystal precipitation was observed, and the release of scopolamine when applied as an adhesive was good, reaching an effective plasma concentration in about 20 minutes after application. The effect lasted for about 20 hours. Furthermore, there was no rash on the continuous cortical surface after removal of the peel.

patent applicant Nitto Electric Industry Co., Ltd. Representative Sanbe Hijikata

Claims (1)

[Claims] It consists of a carrier and a drug-containing adhesive layer formed directly or indirectly on the carrier, and the adhesive layer is made of (meth)acrylic acid having an ether group in the molecule. 5-75% by weight of ester, 85-15% by weight of alkyl (meth)acrylic ester, and 10-50% by weight of polar monomer.
1. A member for external use, characterized in that the drug contained in the drug-containing adhesive layer is scopolamine or a scopolamine derivative.