JPS60193920A - Pharmaceutical preparation of drug for endermic administration - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation wherein clonidine useful as an antihypertensive and a remedy for tonsilitis is provided with stability with time, obtained by blending a drug-containing layer comprising an acrylic polymer as a base material with clonidine or its hydrochloride and citric acid or succinic acid. CONSTITUTION:A drug-containing layer comprising an acrylic polymer having a glass transition temperature of -70--10 deg.C, having pressure-sensitive adhesiveness at normal temperature, is blended with clonidine (chemical name: 2,6-dichloro-N-2-imidazolidinylidenebenzeneamine) and/or its hydrochloride, citric acid and/or succinic acid, and laminated to a substrate material, to give pharmaceutical preparation of drug for endermic administration. Stability of clonidine is improved by addition of citric acid and/or succinic acid, reduction in content can be prevented for a long period, and a sufficient amount of the drug to remedy diseases can administered from the skin to the body. An amount of citric acid, etc. added is preferably 1-4wt% based on the polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical preparation for transdermal administration in which clonidine and/or its hydrochloride is administered into the body through the skin. The present invention relates to a pharmaceutical preparation for transdermal administration, which allows clonidine and/or its hydrochloride to be absorbed through the skin surface, and which has been given stable stability over time.

In recent years, instead of oral administration or injection administration of drugs, transdermal administration has been attracting attention for the purpose of prolonging pharmacological effects and reducing side effects. There is a transition from pharmaceuticals to systemic drugs such as heart disease treatments, but it is extremely difficult to prevent the content of the medicinal ingredient from decreasing due to changes in the drug formulation over time and to maintain stable drug content over a long period of time. Met. Transdermal absorption preparations using clonidine and/or its hydrochloride, which are transdermal absorbable systemic drugs, are found in JP-A-54-20129 and JP-A-57-150614. Although these drugs can fully satisfy the objectives in terms of controlling the release rate and pharmacological effects, they are still insufficient in terms of long-term drug stability.

The present inventors have conducted extensive research to solve the above problems, and have found that by incorporating citric acid and/or succinic acid together with clonidine and/or its hydrochloride into an acrylic polymer, drug stability can be improved. The inventors have discovered a scale that improves the medicinal properties and prevents the content of medicinal ingredients from decreasing over a long period of time, leading to the present invention.

That is, the present invention provides a pharmaceutical formulation for transdermal administration, in which clonidine and/or its hydrochloride is stably incorporated into the formulation without causing a decomposition reaction, and the drug is administered transdermally into the body. and the glass transition temperature is from 170℃ to 110℃
In a pharmaceutical formulation in which a drug-containing layer and a carrier are laminated together, the drug-containing layer is made of an acrylic polymer having pressure-sensitive adhesive properties at room temperature, and citric acid and/or succinic acid are essential components in the drug-containing layer. The present invention relates to a pharmaceutical preparation for transdermal administration, characterized in that it contains clonidine and/or its hydrochloride.

The carrier constituting the pharmaceutical preparation for transdermal administration of the present invention is not limited as long as it supports a drug-containing layer based on an acrylic polymer layer, such as polyolefin, polyurethane, polyvinyl alcohol, polyester, etc. Examples include plastic films or sheets such as vinylidene chloride, polyamide, ethylene-vinyl acetate copolymer, rubber and/or synthetic resin foamed films or/sheets, metal foils, papers, nonwoven fabrics, woven fabrics, or laminates thereof. However,
Preferably, it has sufficient flexibility to follow the curvature of the skin surface to which it is applied.

The acrylic polymer used in the present invention has a glass transition temperature (Tg) of -70°C to -10°C and has pressure-sensitive adhesive properties at room temperature. These are homopolymers containing (meth)acrylic acid alkyl ester as the main monomer, copolymers with other copolymerizable monomers, and mixtures of these polymers.

Examples of (meth)acrylic acid alkyl esters in which the alkyl group has 4 or more carbon atoms include (meth)acrylic acid butyl ester, (meth)acrylic acid pentyl ester, (
(meth)acrylic acid hexyl ester, (meth)acrylic acid heptyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic acid decyl ester, (meth)acrylic acid dodecyl ester, (meth)acrylic acid dodecyl ester Examples include acrylic acid stearyl ester, and the above monomers include those in which the alkyl group is linear or branched, and two or more of the above Rff1 forms may be used in combination. The desired amount and type of these main component monomers can be arbitrarily selected from among the monomers listed in 1. I can do it.

In addition, monomers copolymerizable with the main component monomer include:
For example, carboxyl group-containing monomers such as (meth)acrylic acid, maleic acid, maleic anhydride, and crotonic acid, and hydroxyl group-containing fJ it forms such as (meth)acrylic acid hydroxyethyl ester and (meth)acrylic acid hydroxypropyl ester. , (meth)acrylamide, (
Functional monomers such as amide or amino group-containing monomers such as meth)acrylic acid dimethylaminoethyl ester and (meth)acrylic acid diethylaminoethyl ester, nitrile group-containing monomers such as acrylonitrile, and vinyl acetate. , vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylimidazole, (meth)acrylic acid methoxyethyl ester, (meth)acrylic acid ethoxyethyl ester, (meth)acrylic acid butoxyethyl ester, etc., and the desirable usage amount of these The type thereof can be arbitrarily selected from the above monomers in an amount of 50% by weight or less based on the total monomers used when cleaving the acrylic polymer, depending on the purpose.

Clonidine and its hydrochloride used in the present invention are drugs that have the effect of reducing central sympathetic nerve tonus, and are used for the prevention or treatment of hypertension, migraine, and the like. Furthermore, the term "clonidine" used in the specification of the present invention is a common name and generally refers to 2,6-dichloro-N-2-imidazolidinylidenebenzenamine.

The amount of the drug added is preferably 1 to 25% by weight, preferably 2 to 10% by weight, based on the acrylic polymer.

Citric acid and/or succinic acid used in the present invention is a component for suppressing the decomposition reaction of clonidine and/or its hydrochloride contained in a pharmaceutical preparation for transdermal administration and stably containing it. The amount used is in the range of 0.1 to 5% by weight, preferably 1 to 4% by weight, based on the acrylic polymer. If it is less than 0.1% by weight, it is difficult to obtain the desired effect, and if it is less than 5% by weight, % or more, there is hardly any effect of increasing the amount, and it is also undesirable from the viewpoint of skin irritation. Furthermore, the cohesive force of the acrylic polymer is significantly reduced, and there is a possibility that adhesive residue may be left on the skin surface to which it is applied.

Furthermore, clonidine and/or
Or, in order to release more of its hydrochloride, glycols such as propylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, N-methyl-2-pyrrolidone, N-methylpyrrolidine-N-oxide, salicylic acid, One or more auxiliary agents such as urea, dimethyl sulfoxide, dimethylbormamide, diethyl sebacate, ethyl alcohol, and various surfactants can be added, but
Considering the balance of skin adhesion and cohesiveness, it is desirable that these additives be added in an amount of 0.5 to 20% by weight based on the acrylic polymer.

As mentioned above, the pharmaceutical preparation for percutaneous administration of the present invention suppresses the decomposition of clonidine and/or its hydrochloride contained therein by incorporating citric acid and/or succinic acid, and is stable for a long period of time. Clonidine and/or its hydrochloride are administered into the body through the applied skin surface in an amount sufficient to cure the disease.

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to these, and can be applied in various ways without departing from the technical idea. In addition, parts in the following text mean parts by weight.

Example 1 55 parts of 2-ethylhexyl acrylate, 15 parts of 2-ethoxyethyl acrylate, and 30 parts of vinyl acetate were placed in a flask under an inert gas atmosphere, and 0.2 parts of benzoyl peroxide was added as a polymerization initiator. was added to initiate polymerization. The internal temperature was controlled at 58 to 62°C by adjusting the stirring speed and external temperature and dropping ethyl acetate, and the polymerization reaction was carried out for about 12 hours to form an acrylic polymer (Tg-3
0°C) solution was obtained.

Clonidine and succinic acid were added and mixed to the obtained acrylic polymer solution, and the coating thickness after drying was 5.
It was coated and dried to a thickness of 0 μm, and transferred onto the treated surface of a polyethylene film that had undergone surface oxidation treatment to obtain a pharmaceutical preparation for transdermal administration. The clonidine content and succinic acid content in the obtained pharmaceutical preparation for transdermal administration were each 7.5.
% by weight, 2.5% by weight, and when applied to the applied skin surface, a sufficient amount of clonidine was released to treat hypertension. Furthermore, the stability of clonidine is shown in Table 1.

Example 2 90 parts of acrylic acid 2-ethylhexyl ester and 10 parts of N-vinyl-2-pyrrolidone were placed in a flask under an inert gas atmosphere, and 0.3 parts of azobisisobutyronitrile was added as a polymerization initiator. Polymerization was started. Polymerization was carried out for 8 hours by controlling the internal temperature at 57 to 60°C in the same manner as in Example 1 to obtain an acrylic polymer (Tg = -41°C)
A solution was obtained.

Clonidine and citric acid were added and mixed to the obtained acrylic polymer solution, coated on a release liner so that the coating thickness after drying was 60 μm, dried, and transferred onto a polyurethane film for transdermal application. A pharmaceutical formulation for administration was obtained. The clonidine content and citric acid content in the obtained pharmaceutical preparation for transdermal administration were 5% by weight and 2% by weight, respectively, and when applied to the skin surface, a sufficient amount of clonidine was released to treat hypertension. It was observed. Furthermore, the stability of clonidine is shown in Table 1.

Example 3 95 parts of acrylic acid 2-ethylhexyl ester and 5 parts of acrylic acid were charged into a flask under an inert gas atmosphere,
0.3 part of azobisisobutyronitrile was added as a polymerization initiator to initiate polymerization.

In the same manner as in Example 1, the internal temperature was controlled at 58 to 62°C and polymerization was carried out for 8 hours to obtain an acrylic polymer (Tg = -4
3°C) solution was obtained.

Clonidine hydrochloride, citric acid, and succinic acid were added and mixed to the obtained acrylic polymer solution, and this was coated and dried on a release liner so that the coating thickness after drying was 40 μm. A pharmaceutical formulation for transdermal administration was obtained by transfer onto a polymer film (vinyl acetate content: 22%).

The clonidine hydrochloride content, citric acid and succinic acid content in the obtained pharmaceutical formulation for transdermal administration were each 10% by weight,
When applied to the applied skin surface, a sufficient amount of clonidine hydrochloride was released to treat blood pressure. Furthermore, the stability of clonidine hydrochloride is shown in Table 1.

Comparative Examples 1 to 3 Comparative Examples 1 to 3 correspond to Examples 1 to 3, except that succinic acid, citric acid, citric acid, and succinic acid were removed from each example, and the other operations were the same as in each example. The desired pharmaceutical formulation for transdermal administration was obtained.

Table 1 The residual rate of clonidine or its hydrochloride in Table 1 is determined by cutting the pharmaceutical formulations for transdermal administration obtained in the Examples and Comparative Examples of the present invention at 50°C for 3 months into regular shapes. (n=
10) methanol extraction was performed and quantification was performed using high performance liquid chromatography.

In addition, the residual rate was calculated using the following formula.

Content after storage at 50°C for 3 months Survival rate (%) = xlOO Content immediately after formulation

Claims (1)

[Claims] (1) In a pharmaceutical formulation in which a drug-containing layer and a carrier are laminated, the drug-containing layer is made of an acrylic polymer having a glass transition temperature of 170°C to 110°C and has pressure-sensitive adhesive properties at room temperature,
A pharmaceutical preparation for transdermal administration, characterized in that the drug-containing layer contains citric acid and/or succinic acid and clonidine and/or its hydrochloride as essential ingredients.