JPH03120213A - Percutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorption preparation having excellent bond strength to the skin and sustained release of drug by laminating a drug- containing base layer and a drug-containing tacky agent layer to one side of a supporting film and distributing a drug unevenly in the vicinity of the interface thereof. CONSTITUTION:A base layer containing a drug in a dispersed state of solid and a tacky agent layer containing a drug in a molten state are successively laminated to one side of a supporting film such as nonwoven fabric having drug impermeability to prepare the objective substance. The drug contained in the base layer is unevenly dispersed by recrystallizing the drug at the interface between the base layer and the tacky agent layer or on the surface in the vicinity of the interface. The base layer is obtained by immersing a base comprising the base layer in a solution having dissolved a drug, spraying the solution and retaining the solution on the base or thermally melting the drug and coating the base with the drug. An acrylic polymer containing >=50wt.% (meth)acrylic ester is preferably used as the tacky agent.

Description

[Detailed description of the invention] <Industrial application field> The present invention relates to meridional absorption preparations.

<Prior Art> In recent years, many meridional absorption preparations for administering drugs into living bodies through the skin or mucous membranes have been proposed, and among these, patch-type meridional absorption preparations that are easy to handle have been attracting attention.

-M-type patch-type preparations include a drug-containing adhesive layer on one side of the support film, such as acrylic, rubber, etc.
It has a layer of adhesive such as silicone adhesive. Further, the drug contained in the adhesive layer is usually contained in an amount that is less than the saturation solubility in the adhesive. This is because even if an excessive amount of drug is contained, the crystal particles will have a large particle size, and the excess drug will not be effectively utilized.

On the other hand, various methods have been proposed to increase the longitudinal absorption of drugs and improve their pharmacological effects, such as increasing the thickness of the adhesive layer in which the drug is dissolved, or increasing the size of the preparation. ing.

However, both of these methods are not only uneconomical, but also may give the user an unnecessary sense of discomfort.

To overcome these drawbacks, recently proposed formulations employ drug-permeable wall materials, microcapsules, or hollow fibers as drug storage layers (Japanese Patent Application Laid-Open No. 1986-1999). Publication No. 154122, Japanese Unexamined Patent Publication No. 61-29391
Publication No. 1). In this preparation, the drug is gradually released from the storage layer, diffuses into the adhesive layer adjacent to the core layer, and is finally continuously administered to the skin or mucosal surface to which the preparation is applied. The drug can be contained in the storage layer in an amount exceeding the saturation solubility, and the drug does not cause discomfort to the user.

However, it requires complicated steps to formulate a drug, and requires a great deal of effort and cost to select the combination of storage layer material and drug.

Furthermore, a laminated type preparation consisting of a backing layer, a drug storage layer, a microporous membrane, and an adhesive layer, in which the adhesive layer contains undissolved giant drug particles has also been proposed (U.S. Pat. Specification No. 4201211). The adhesive layer of this formulation is made of an inert liquid such as mineral oil that has poor ability to dissolve drugs;
It is coated and formed by mixing an adhesive component such as polyisobutylene and drug powder under high shear stress, and contains drug particles dispersed in a suspended state.

However, since the drug particles are applied in a suspended state, the drug has the disadvantage that it is dispersed non-uniformly in the adhesive layer. It is difficult to form an adhesive layer with a small thickness.

In addition, as another method, the amount of drug contained in the adhesive is 1.2 times or more than the saturation concentration, and the drug is recrystallized in the adhesive. A thin and small-sized preparation whose portion contributes to the pharmacological effect has been developed (Japanese Patent Application Laid-Open No. 185713/1983). Although this preparation contains the drug relatively uniformly, some of the crystalline particles of the drug also precipitate on the skin application surface, so a large amount of the drug may be released during initial release. In addition, when crystal particles are continuously formed, a drug release path is formed by dissolving the drug crystals in the adhesive, making sustained release impossible and leaving room for improvement in terms of sustained release. .

Furthermore, Japanese Patent Application Laid-open No. 119421/1983 discloses a multilayered preparation consisting of a backing member, a drug storage layer, and an adhesive layer. The formulation process for this formulation is relatively simple, and drug release can be controlled. However, the release of the drug in this formulation is only affected by the diffusion of the drug in the adhesive layer and its distribution to the skin, and sustained release requires the diffusion of the drug in the reservoir layer and the interaction between the reservoir layer and the adhesive layer. It is required that the distribution speed between the two is rapid. In particular, the distribution of the drug to the adhesive layer has a large effect on the supply of the drug to the adhesive layer, and in order to release the drug from the adhesive layer and quickly supply the drug to the adhesive layer, It is preferable to bring the drug itself into contact with the adhesive layer, and providing a storage layer is rather inefficient from the standpoint of sustained drug release.

<Problems to be Solved by the Invention> The present invention has been made to solve the above-mentioned drawbacks of conventional formulations, and its purpose is to make the drug present in a dissolved state on the skin application side, and to The object of the present invention is to provide a meridional absorption preparation that effectively contributes to the pharmacological effects of most of the drugs contained in the drug.

Another objective is to provide a meridional absorption preparation that can continuously supply a drug and that contains a large amount of the drug.

Means for Solving the Problems> As a result of intensive studies to achieve the above object, the present inventors have discovered a method of laminating a drug-containing base material layer and a drug-containing adhesive layer, and placing a drug near the interface. The inventors have discovered that a unevenly distributed preparation can achieve the above object, and have completed the present invention.

That is, the longitudinal absorption preparation of the present invention has a drug-containing base layer and a drug-containing adhesive layer laminated in sequence on one side of a substantially non-drug-transferable support film. The drug is contained in a solid dispersed state, and the drug is unevenly distributed at the interface with the adhesive layer and the surface layer near the interface.
Moreover, the adhesive layer is characterized in that the drug is contained in a dissolved state.

The support film used in the meridional absorption preparation of the present invention is made of a material that is substantially non-drug-transferable, and provides self-supporting properties to the preparation, as well as loss of drug in the drug-containing layer due to volatilization or migration. The function is to prevent Specifically, films or sheets made of plastics such as polyethylene, polypropylene, polyacrylic, polyurethane, polyester, polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, polyamide, and ethylenic copolymers, or laminated films of these, and rubber. and/or porous synthetic resin film or sheet, fibrous film such as nonwoven fabric, woven fabric, paper, etc.
Alternatively, it is made of a sheet, metal foil, or the like, and a metal vapor-deposited material on the surface of these films or sheet-like materials, with a thickness of 500 μm or less, preferably 5 to 150 μm. One example is crm.

The drug-containing base layer provided on one side of the support film functions as a drug storage layer provided to gradually release the drug from the meridional absorption preparation of the present invention. Contained in a solid dispersed state.

Further, the drug is unevenly distributed at the interface with the adhesive layer, which will be described later, and in the surface layer near the interface, and a portion of the drug is buried in the adhesive layer. The above-mentioned base material is not particularly limited as long as it has poor reactivity with drugs and can stably hold drugs, but in recent years, non-woven fabrics and woven fabrics, which are less irritating to the skin and are used in many wound tapes, etc. Fiber aggregates such as cloth and knitted cloth are preferably employed.

The base material layer containing the above-mentioned drug in a solid dispersed state can be produced, for example, by the following method.

A drug solution is prepared by dissolving the drug in a solvent in advance, and the base material constituting the base layer is immersed in the solution, or the solution is sprayed on the base material to retain the drug solution, and then the drug solution is dried.
Alternatively, the base material layer can be obtained by melting the drug with heat and applying it to the base material.

An adhesive layer for application to the skin is laminated on such a base layer, and this adhesive layer also contains the same type of drug as the drug contained in the base layer in a dissolved state. The drug in a dissolved state contained in the adhesive layer improves the initial release properties of the drug and rapidly absorbs the drug to the effective blood concentration range when the meridional absorption preparation of the present invention is applied to the skin surface. It is usually contained in a range of 0.5 to 40% by weight, and is contained so as to be below the saturation solubility of the drug in the adhesive. When the amount of drug increases and the drug is contained in the adhesive layer in a solid dispersed state without being dissolved, the dissolved drug recrystallizes using this drug as a core, and the drug is precipitated over the entire adhesive layer. As a result, drugs may precipitate on the surface of the adhesive layer on the adhesive side, impairing skin adhesion, and after being applied to the skin, a large amount of the drug on the surface may be absorbed into the body over time, causing side effects. Yes, not desirable.

As the adhesive used in the present invention, a homopolymer and/or copolymer adhesive mainly composed of rubber and/or synthetic resin is used.

Such adhesives have a glass transition temperature of 10 to -
70°C, more preferably in the range of -25 to -60°C. Adhesives with a glass transition temperature of more than -110°C will be hard, and the diffusion mobility of the drug in the adhesive will decrease. , skin adhesion becomes poor. On the other hand, −
If the temperature is lower than 70°C, the adhesive will be soft and have poor cohesive properties, resulting in poor oral shape retention and the phenomenon of adhesive residue occurring when the preparation is removed from the skin, causing physical irritation to the skin. It's not good because it starts to give. Specifically, rubbers such as styrene-isoprene (or butadiene)-styrene blank copolymer comb, styrene-butadiene rubber, polybutene rubber, polyisoprene rubber, butyl rubber, silicone rubber, natural rubber, synthetic isoprene rubber, etc. Poly(meth)acrylic,
Synthetic resins such as polyvinyl ether, polyurethane, polyester, polyamide, and ethylenic copolymers are included, and by adding compounding agents such as tackifying resins, liquid rubber, and softeners, glass can be made. The transition temperature can be adjusted.

In the practice of the present invention, the adhesive which is also preferred for practical use includes at least 5 acrylic esters or methacrylic esters having an alkyl group having an average number of carbon atoms of 4 or more.
Acrylic polymers containing 0% by weight or more are preferred. Such polymers have relatively little irritation to the skin and have excellent drug solubility and stable retention.

The acrylic polymer also includes a copolymerizable functional monomer and/or a copolymer with a vinyl ester motumer, in which case the functional monomer is 20% by weight.
The amount of vinyl ester monomer is preferably 0.5 to 10% by weight, and the vinyl ester monomer is 40% by weight or less, preferably 5% by weight.
Each of them is blended in a range of 30% by weight and subjected to a copolymerization reaction. The above functional monomer can change the cohesiveness of the copolymer depending on the number of parts added, and the hydrophilicity of the copolymer depending on the type of monomer, and the vinyl ester monomer can improve the drug solubility of the copolymer. It is something.

Examples of the (meth)acrylic acid alkyl ester, functional monomer, and vinyl ester monomer include the following.

[(meth)alkyl esul] n-butyl (meth)acrylate, amyl (meth)acrylate, n-hexyl (meth)acrylate, 2-(meth)acrylate
Ethyl butyl, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, tridecyl (meth)acrylate, etc.

[1st Blood] (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, 2-methoxyethyl (meth)acrylate, ( 2-ethoxyethyl meth)acrylate, butoxyethyl (meth)acrylate, (meth)acrylamide, dimethyl(meth)acrylamide,
Dimethylaminoethyl (meth)acrylate, t-butylaminoethyl (meth)acrylate, (meth)acrylonitrile, vinylpyrrolidone, vinylimidazole, etc.

[Vinyl ester monomer] Vinyl acetate, vinyl propionate, etc.

Further, the adhesive layer has a thickness of 5 to 500 pm, preferably 1
Lamination is performed in a range of 0 to 300 μm. If the thickness is too thin, skin adhesion will be poor; if it is too thick, the lag time will be long when the drug is released to the skin surface due to dissolution of the solid drug in the solid base layer and diffusion movement in the adhesive layer. Therefore, the desired sustained release properties may not be achieved.

The drugs used in the meridional absorption preparation of the present invention are not particularly limited as long as they are absorbed longitudinally into the body and exert a pharmacological effect, such as corticosteroids, analgesic anti-inflammatory agents, hypnotic sedatives, and tranquilizers. drugs, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial substances, antifungal agents, vitamin preparations, coronary vasodilators, antihistamines, antitussives, sex hormones, anti-rock drugs, etc. One or more drugs can be selected depending on the therapeutic purpose.

In the present invention, the base material layer and/or the adhesive layer may contain fillers such as finely powdered silica, titanium white, calcium carbonate, etc. for the purpose of increasing weight, promoting longitudinal absorption, shaping, etc.
Longitudinal absorption enhancers known per se such as polyhydric alcohols, sulfoxides, amides, adipates, sebacates, laurates, salicylic acid, urea, allantoin,
Excipients such as lactose, cyclodextrin, cellulose powder (generally mixed with the drug before use), and other compounding agents such as emollients and antipruritics are added to the
It can be added in amounts up to % by weight.

The exposed surface of the adhesive layer of the longitudinal absorption preparation of the present invention is preferably covered with a separator treated with a known silicone-based or fluorine-based release agent to protect the surface until use. .

<Effects of the Invention> As described above, the meridional absorption preparation of the present invention is formed by laminating a base layer containing a drug in a solid dispersed state and an adhesive layer containing a drug in a dissolved state. Thereafter, the drug is quickly transferred and absorbed from the adhesive layer to the skin surface, and the amount of the drug decreased in the adhesive layer is replenished by dissolution and diffusion of the solid drug dispersed in the base material layer. Therefore, the pharmacological effect is sustained and sustained release properties are imparted.

In addition, the drug contained in the base material layer is unevenly distributed at or near the interface with the adhesive layer, so the drug for replenishment is wasted (it is used effectively, but compared to conventional products) This increases the effective utilization rate.

The uneven distribution of the drug described above can be easily achieved by recrystallizing the drug contained in the base material layer near the interface with the adhesive layer, and this uneven distribution causes the drug to be on the surface of the adhesive layer. Precipitation can be prevented, and excellent skin adhesion can be maintained and sustained release properties can be provided.

<Examples> Examples of the present invention will be shown below and explained in more detail.

Example 1 A monomer mixture consisting of 95 parts by weight of 2-ethylhexyl acrylate and 5 parts by weight of acrylic acid was polymerized in a conventional manner to obtain an adhesive solution.

Add isosorbide dinitrate to this adhesive solution so that the solid content concentration after drying is 7% by weight, dissolve it, apply it on the separator so that the thickness after drying becomes 40 μm, and dry to form the adhesive layer. Formed. Note that the content of isosorbide dinitrate in this layer was 300 μg/d.

On the other hand, a solution of isosorbide dinitrate solution (20% by weight, solvent: ethyl acetate) was sprayed onto the nonwoven surface of a support film in which a polypropylene nonwoven fabric was previously provided on a 12 μm thick polyester film, and then dried at 90° C. for 5 minutes. The content of isosorbide dinitrate at this time is 6
It was 90 μg/ctj.

The above-mentioned adhesive layer was laminated on the nonwoven fabric surface of the support film thus obtained to obtain a longitudinal absorption preparation of the present invention.

Comparative Example 1 Isosorbide dinitrate was added to the adhesive solution obtained in Example 1 so that the solid content concentration after drying was 20% by weight, dissolved, and placed on a separator so that the thickness after drying was 40 μm. A pressure-sensitive adhesive layer was formed by coating and drying, and a 12 μm thick polyester film as a support film and the pressure-sensitive adhesive layer were laminated to obtain a longitudinal absorption preparation. The content of isosorbide dinitrate in the adhesive layer is 1200 pg/
It was d.

Example 2 A monomer mixture consisting of 50 parts by weight of 2-ethylhexyl acrylate, 25 parts by weight of 2-methoxyethyl acrylate, and 25 parts by weight of vinyl acetate was polymerized in a conventional manner to obtain an adhesive solution.

Indomethacin was added to this adhesive solution so that the solid content concentration after drying was 4% by weight, dissolved, and applied onto the separator so that the thickness after drying was 40 pm, and dried to form an adhesive layer. . Note that the content of indomethacin in this layer was 160 μg/d.

On the other hand, a solution of indomethacin (7% by weight, solvent: ethyl acetate) was sprayed onto the nonwoven surface of the support film used in Example 1, and then dried at 100° C. for 5 minutes. The content of indomethacin at this time was 260 μg/−.

The above-mentioned adhesive layer was laminated on the nonwoven fabric surface of the support film thus obtained to obtain a longitudinal absorption preparation of the present invention.

Comparative Example 2 Indomethacin was added to the adhesive solution obtained in Example 1 so that the solid content concentration after drying was 10% by weight, dissolved, and applied on a separator so that the thickness after drying was 40 μm. It was dried to form an adhesive layer, and a 12 μm thick polyester film as a support film and the adhesive layer were laminated to obtain a longitudinal absorption preparation. Note that the content of indomethacin in the adhesive layer was 410 μg/cA.

The longitudinal absorption preparations obtained in each of the above Examples and Comparative Examples were
After cutting into cm squares and storing at 40°C for 24 hours, the height measurements showed that no drug particles (crystals) were deposited on the surface of the adhesive layer on the separator side, and that no drug particles (crystals) were precipitated on the surface of the adhesive layer on the separator side and in the vicinity of the interface between the adhesive layer and the nonwoven fabric. existed in layers. On the other hand, in the comparative height measurement, drug particles (crystals) were observed to be deposited on the entire adhesive layer, and some were also deposited on the surface of the adhesive layer on the separator side, resulting in a rough surface.

Moreover, the longitudinal absorption preparations obtained in each of the above Examples and Comparative Examples are ? Cl1l angle (Example 1 and Comparative Example 1), 4 cm
The samples were cut into squares (Example 2 and Comparative Example 2), and a drug elution test from each preparation was conducted, and the results are shown in the drawings. The test conditions are as follows.

Test solvent: 800 J of distilled water Detection method: UV (three wavelength measurement) Isosorbide dinitrate 230 ns, 260 nw + indomethacin 254 ns, 285 ru++ As is clear from the drawing, each measured value has a higher sustained release property of the drug than a comparative product. This is something that is noticeable.

[Brief explanation of drawings]

The drawing is a graph showing the results of a drug dissolution test from the meridional absorption preparations obtained in Examples and Comparative Examples.

Claims (1)

[Claims] A drug-containing base layer and a drug-containing adhesive layer are sequentially laminated on one side of a support film that is substantially non-drug-transferable, and the base layer contains the drug in a solid dispersed state. A meridian-absorbing preparation characterized in that the drug is unevenly distributed at the interface with the adhesive layer and in the surface layer near the interface, and the drug is contained in the adhesive layer in a dissolved state.