WO2010073326A1

WO2010073326A1 - Percutaneous absorption preparation

Info

Publication number: WO2010073326A1
Application number: PCT/JP2008/073487
Authority: WO
Inventors: 康慈川原; 徹古賀; 春奈八巻; 亨子林
Original assignee: ニチバン株式会社
Priority date: 2008-12-24
Filing date: 2008-12-24
Publication date: 2010-07-01
Also published as: WO2010074182A1; JPWO2010074183A1; WO2010074183A1; JPWO2010074182A1; JP4660858B2

Abstract

Provided is a percutaneous absorption preparation comprising a support having provided thereon an adhesive layer. An adhesive composition for forming the adhesive layer contains an adhesive mainly composed of an acrylic adhesive formed of a resin obtained by polymerization using an acrylic ester and/or a methacrylic ester having no carboxyl group in the molecule as a main monomer, a basic drug, silica particles and a polyhydric alcohol fatty acid ester. The polyhydric alcohol fatty acid ester is contained in an amount of from 15 to 40% by mass of the total mass of the adhesive composition. The percutaneous absorption preparation enables the addition of a permeation accelerator in a large amount without decreasing a cohesive force of the adhesive and also satisfies basic performance required for a percutaneous absorption preparation such that drug bioavailability is increased and the adhesive remaining on the skin or being sticky on the skin is improved.

Description

Transdermal preparation

The present invention relates to a novel percutaneous absorption-type preparation, and more particularly to a percutaneous absorption-type preparation excellent in both skin permeability and skin adhesion of a drug.

The percutaneous absorption type preparation is attracting attention as a dosage form that can eliminate problems inherent to the oral administration method, that is, a large dose due to the first-pass effect in the liver, and can maintain a stable blood concentration. Particularly in the present age of aging societies, it is attracting attention as a dosage form that facilitates administration of various drugs to patients who have difficulty swallowing.
On the other hand, because the skin is the largest organ in the human body and is also an important tissue that protects the body from foreign substances such as chemical substances and bacteria from the outside world, drugs and the like are not easily passed through as foreign substances. There are a limited number of drugs that can be provided as absorption-type preparations.
Therefore, as a means to promote the skin permeation of drugs, study of permeation enhancers using chemical substances (such as low molecular weight compounds), iontophoresis to promote percutaneous absorption of ionic drugs by electric energy, Various methods such as sonophoresis using ultrasonic waves (introduction of ultrasonic waves) have been studied.

In order to improve the percutaneous absorption promotion effect of the drug, it is desirable to increase the content in the pressure-sensitive adhesive layer. However, if added in a large amount, the coagulation force of the pressure-sensitive adhesive is reduced. Occurs.
If an acrylic pressure-sensitive adhesive using a cross-linking agent is used as the pressure-sensitive adhesive, the molecular weight can be controlled. Therefore, although a certain level of cohesion can be maintained even when a permeation accelerator is added, a cross-linking agent is generally used. In a rubber-based adhesive or a silicone-based adhesive that is not used, the amount of permeation accelerator used is limited.
For this reason, in the case of using such an adhesive, conventionally, it has been necessary to examine the formulation of a reservoir type formulation, etc., rather than increasing the addition amount of the permeation enhancer.

The aforementioned acrylic pressure-sensitive adhesive, that is, the acrylic copolymer used in the pressure-sensitive adhesive, can control the cohesive force by controlling the molecular weight using a crosslinking agent by using a monomer having a carboxyl group. In this way, a product using an adhesive called an organogel to which a large amount of isopropyl myristate as an oil component is added has been put on the market (Flandre Tape S, Toei Aiyo Co., Ltd.).
However, acrylic pressure-sensitive adhesives using a monomer having a carboxyl group (eg, acrylic acid) as a copolymer react with (bond to) the carboxyl group when a basic drug is added. It is known to prevent drug release from.
Therefore, when using the adhesive which has acrylic acid (monomer which has a carboxyl group), adding a lot of drugs is performed (refer patent document 1).
Moreover, use of polyhydric alcohol fatty acid ester as a permeation accelerator has been reported (see Patent Document 2).
JP-A-6-145051 JP-A-8-040937

As described above, when a basic drug is used, since the carboxyl group contained in the acrylic adhesive reacts with the basic drug, it is necessary to increase the amount of the drug added, and the bioavailability is increased. There was a problem of lowering.
Therefore, in order to efficiently use a basic drug in a transdermal absorption-type preparation, it can be said that it is preferable to prepare a pressure-sensitive adhesive using a monomer that does not contain a carboxyl group. Since it cannot be used, it is difficult to control the cohesive force, and as a result, it is difficult to add a large amount of permeation accelerator.
In addition, polyhydric alcohol fatty acid esters, like other accelerators, make it difficult to maintain cohesive force, so that there is a problem that it is difficult to add a large amount to the pressure-sensitive adhesive layer.

The present invention makes it possible to add a large amount of permeation enhancer without reducing the above-mentioned problems, that is, the cohesive force of the adhesive, improve the bioavailability of the drug, and apply the adhesive to the skin. It is an object of the present invention to provide a percutaneous absorption preparation that satisfies the basic performance required as a percutaneous absorption preparation, such as improving the residue and stickiness of the skin.

Therefore, the present inventors combined a pressure-sensitive adhesive obtained by using a (meth) acrylic acid ester having no carboxyl group in the molecule with silica particles, thereby making it difficult to produce polyhydric alcohol fatty acid esters. It has been found that a large amount can be added to the pressure-sensitive adhesive layer. In addition, it has been found that even when a monomer having a carboxyl group is used for the pressure-sensitive adhesive, the basic drug can be efficiently released from the pressure-sensitive adhesive layer by controlling the amount of the monomer used. Based on these findings, the present invention has been completed that provides a percutaneously absorbable preparation that enables sustained drug release and is excellent in both skin permeability and skin adhesion of the drug.

That is, the present invention relates to a transdermal preparation having a pressure-sensitive adhesive layer on a support, wherein the pressure-sensitive adhesive composition forming the pressure-sensitive adhesive layer comprises an acrylate ester having no carboxyl group in the molecule as a main monomer, and And / or containing a pressure-sensitive adhesive mainly composed of an acrylic pressure-sensitive adhesive made of a resin obtained by polymerization, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester, The present invention relates to a percutaneous absorption type preparation which is contained in a proportion of 15 to 40% by mass relative to the total mass of the pressure-sensitive adhesive composition.

In the percutaneous absorption type preparation, the acrylic pressure-sensitive adhesive comprises a resin obtained by polymerizing a monomer having a carboxyl group in addition to an acrylic ester and / or a methacrylic ester, and the monomer having a carboxyl group is a monomer. The molar ratio a / b between the molar number a of the basic drug and the molar number b of the monomer having a carboxyl group is 1.0 or more. It is desirable that there is.
The polyhydric alcohol fatty acid ester is preferably propylene glycol monolaurate, and is preferably contained in a proportion of 20 to 35% by mass with respect to the total mass of the pressure-sensitive adhesive composition.

Furthermore, it is desirable that the silica particles have an average particle size of 5 μm or less.
The acrylic pressure-sensitive adhesive is more preferably an acrylic acid-2-ethylhexyl / methacrylic acid-2-ethylhexyl / methacrylic acid dodecyl copolymer.
The basic drug is preferably in the form of a salt of tamsulosin or in the form of a free base.

According to the present invention, by combining the pressure-sensitive adhesive obtained by using an acrylic ester and / or methacrylic ester having no carboxyl group in the molecule with silica particles, without reducing the cohesive force of the pressure-sensitive adhesive, A large amount of polyhydric alcohol fatty acid ester which is a permeation accelerator can be added to the pressure-sensitive adhesive layer. And thereby, the adhesion to the skin can be improved and the percutaneous absorption of the drug into the skin can be promoted.
Even when a monomer having a carboxyl group is used for the pressure-sensitive adhesive, by controlling the amount used, the pressure-sensitive adhesive can be suppressed without increasing the amount of the drug added by suppressing the reaction between the basic drug and the carboxyl group. Efficient release of drug from the layer can be achieved.
Furthermore, by making the size of the particulate silica used smaller than a certain value, the cohesive force (adhesiveness) of the adhesive is made more suitable as a percutaneous absorption type preparation, and the adhesive is applied to the skin. It can be made into the formulation which improved the residue and the stickiness of the skin.
With such a configuration, the percutaneous absorption preparation of the present invention enables sustained drug release, is excellent in both skin permeability and skin adhesion of the drug, and has the basic performance required as a percutaneous absorption preparation. It is a satisfactory transdermal preparation.

The percutaneous absorption type preparation of the present invention is a percutaneous absorption type preparation in which a pressure-sensitive adhesive layer is provided on the surface of a support, and a release liner is usually bonded to the pressure-sensitive adhesive layer so as to cover the entire surface thereof. Next, each component of the present invention and its function will be further described.
In the present invention, “adhesive layer total mass standard” means an adhesive, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester, and other components (crosslinking agent, accelerator, antioxidant, filler, etc. )) Based on the total mass of the pressure-sensitive adhesive layer. However, the total mass of the reference pressure-sensitive adhesive layer does not include the organic solvent used for dilution.

1) Pressure-sensitive adhesive layer The pressure-sensitive adhesive layer, which is a constituent element of the transdermally absorbable preparation of the present invention, contains a pressure-sensitive adhesive, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester as essential components.
Further, if desired, it may further contain other additives as described below which are generally used in the pressure-sensitive adhesive layer of the transdermal preparation.

(1) Adhesive The adhesive contained in the adhesive layer of the transdermally absorbable preparation of the present invention is formed by polymerizing an acrylic acid ester and / or methacrylic acid ester having no carboxyl group in the molecule as a main monomer. An acrylic adhesive made of resin is used as the main adhesive.

Examples of the (meth) acrylic acid ester having no carboxyl group in the molecule include n-butyl (meth) acrylate, n-hexyl (meth) acrylate, n-octyl (meth) acrylate, (meth) 2-ethylhexyl acrylate, isooctyl (meth) acrylate, isononyl (meth) acrylate, n-decyl (meth) acrylate, isodecyl (meth) acrylate, dodecyl (meth) acrylate, octadecyl (meth) acrylate Etc.
These (meth) acrylic acid esters can be used singly or in combination of two or more.
Among them, a copolymer obtained by using three kinds of esters of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate is preferably used as the acrylic pressure-sensitive adhesive.

In addition to the (meth) acrylic acid ester having no carboxyl group, a monomer having a carboxyl group may be used as a monomer.
Examples of the monomer having a carboxyl group include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, itaconic acid and monobutyl maleate.

When the monomer having a carboxyl group is used, the polymerization ratio is 5% or less with respect to the total number of moles of monomers used. In this case, the basic drug described later is used so that the molar ratio [number of moles of basic drug a] / [number of moles b of monomer having a carboxyl group] is 1.0 or more.

The acrylate copolymer can be generally synthesized by radical polymerization. Examples of the polymerization method include a solution polymerization method, an emulsion polymerization method, a bulk polymerization method, and the like, but a solution polymerization method is preferable because good adhesive properties can be obtained.
In the polymerization reaction, a radical polymerization initiator is added at a ratio of about 0.1 to 1% by mass with respect to the total monomer mass, and the mixture is stirred for several hours to several tens of hours at a temperature of about 40 to 90 ° C. in a nitrogen stream. And do it. Examples of the polymerization initiator used here include organic peroxides such as benzoyl peroxide and lauroyl peroxide, and azo initiators such as azobisisobutyronitrile.

It is desirable that the intrinsic viscosity of the adhesive is 1.0 to 3.0. The intrinsic viscosity is measured according to the Japanese Pharmacopoeia Viscosity Measurement Method Method 1.

(2) Basic drug The basic drug contained in the adhesive layer of the transdermal preparation of the present invention is not particularly limited. For example, antipyretic anti-inflammatory analgesics (butorphanol tartrate, perisoxal citrate, etc.) Local anesthetics (such as lidocaine, procaine, and their hydrochlorides), dysuria drugs (such as tamsulosin), antiallergic drugs (such as ketotifen fumarate), bronchodilators (salmeterol), serotonin receptor antagonist antiemetics And narcotic analgesics (fentanyl citrate, etc.).
These drugs may be used alone or in combination of two or more.

Among the above basic drugs, it is desirable to use tamsulosin. Tamsulosin is present in the pressure-sensitive adhesive layer in the form of a free base or salt, and when present in the form of a salt, a basic additive is added to convert part or all of the drug into the free base form. It is desirable to use it later.
Tamsulosin salts include pharmacologically acceptable salts such as inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, or organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid and lactic acid. These acid addition salts can be used and in particular the hydrochloride salt, ie tamsulosin hydrochloride, is clinically useful.
Examples of basic additives used to convert a part or all of the drug into the free base form include potassium hydroxide, sodium hydroxide, acetate, monoethanolamine, diethanolamine, diisopropanolamine, And trishydroxymethylaminomethane.

The amount of the basic drug contained in the pressure-sensitive adhesive layer of the percutaneous absorption type preparation of the present invention can be appropriately changed depending on the kind of drug and the purpose of administration, but is usually 0 based on the total mass of the pressure-sensitive adhesive layer. It is desirable that the content be 1 to 20% by mass, preferably 1 to 10% by mass.
As described above, when a monomer having a carboxyl group is used as the monomer constituting the acrylic pressure-sensitive adhesive, the molar ratio a / b between the number of moles a of the basic drug and the number of moles b of the monomer having a carboxyl group. The amount of basic drug used is adjusted so as to be 1.0 or more.

(3) Silica particles The silica particles contained in the pressure-sensitive adhesive layer of the transdermal preparation of the present invention preferably have an average particle size of 5 μm or less.
The content of the silica particles depends on the content of a later-described polyhydric alcohol fatty acid ester which is a liquid component, but is preferably 1 to 20% by mass, more preferably 1 to 10% by mass based on the total mass of the pressure-sensitive adhesive layer. It is desirable to be.

(4) Polyhydric alcohol fatty acid ester Examples of the polyhydric alcohol fatty acid ester contained in the adhesive layer of the transdermal preparation of the present invention include propylene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, and fatty acid ester such as sho. It is preferable to use propylene glycol fatty acid ester.
Specific examples of the propylene glycol fatty acid ester include propylene glycol monolaurate, propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol monooleate and the like, among which propylene glycol monolaurate is preferable.
The content of the polyhydric alcohol fatty acid ester is 15 to 40% by mass, preferably 20 to 35% by mass, based on the total mass of the pressure-sensitive adhesive layer.

(5) Other additives In the adhesive layer of the transdermal preparation of the present invention, in addition to the above components, a solubilizer, a pharmaceutically acceptable permeation enhancer, a filler, an oxidation agent An inhibitor or the like can be further included.
In the acrylic adhesive used for the adhesive layer of the transdermal preparation of the present invention, when a monomer having a carboxyl group is used, various crosslinking agents are further added for the purpose of increasing the cohesive strength of the adhesive. Can be added.
Examples of the crosslinking agent include polyfunctional isocyanate compounds, polyfunctional epoxy compounds, and polyvalent metal salts.

2) Support The transdermal preparation of the present invention is a mixture (adhesive) obtained by blending an adhesive, a basic drug, silica particles, a polyhydric alcohol fatty acid ester, and other additives as required. Is coated on a suitable release liner, a suitable support is laminated thereon, and if necessary, it is cut into a suitable size to obtain a final product.
The support is appropriately selected according to the purpose in consideration of flexibility, stretchability, thickness, and the like in consideration of followability to the affected area and self-supporting property at the time of application.
As such a support, paper such as impregnated paper, coated paper, fine paper, craft paper, Japanese paper and glassine paper, polyester film, polyethylene film, polypropylene film, polyvinyl chloride film, polycarbonate film, polyurethane film, cellophane film, etc. And non-woven fabrics made of plastic films, foams, polyester fibers, polyethylene fibers and polypropylene fibers, fabric base materials such as woven fabrics and knitted fabrics, and laminates thereof. Among these, nonwoven fabrics, woven fabrics, and knitted fabrics are preferable in terms of stretchability, and plastic films having transparency in terms of usability are preferable.
The thickness of the support used is preferably 10 μm to 1000 μm, more preferably 10 μm to 700 μm for nonwoven fabrics, woven fabrics and knitted fabrics. In the case of a plastic film, the thickness is preferably 5 μm to 200 μm, more preferably 5 μm to 100 μm.
In addition, it is desirable that the support is used alone or in the form of a laminate in which two or more of the nonwoven fabric, woven fabric, knitted fabric and plastic film are bonded.

3) Release liner The release liner used in the transdermal preparation of the present invention is appropriately selected according to the purpose in consideration of easy release from the pressure-sensitive adhesive layer, air permeability, water permeability and flexibility. . Preferably, a film made of a polymer material such as polyethylene, polypropylene and polyester is used, and the film surface can be treated with silicon or fluorocarbon in order to enhance the peelability.

4) Production method of percutaneous absorption type preparation When the pressure-sensitive adhesive used in the pressure-sensitive adhesive layer of the percutaneous absorption type preparation of the present invention, that is, the acrylate copolymer is synthesized by the aforementioned solution polymerization method, acrylic acid is polymerized after the polymerization. It will be obtained as a solution containing an ester copolymer. Since this solution can be used as it is or diluted with a suitable organic solvent and used as the “acrylic adhesive solution” for the production of the transdermal preparation of the present invention, it is preferable to use the solution coating method.
In the solution coating method, first, a solution to which an acrylic pressure-sensitive adhesive, a basic drug, silica particles, a polyhydric alcohol fatty acid ester, and other additives as necessary are added is prepared. An organic solvent is added to this solution as a diluent to adjust the concentration appropriately.
Examples of the organic solvent used here include n-hexane, toluene, ethyl acetate, acetone, and methyl ethyl ketone. The concentration of the adhesive component in the diluted solution diluted with these organic solvents is preferably 10 to 50% by mass, More preferably, it is 20 to 40% by mass.
Next, the solution (diluent) containing each component is stirred and dissolved and dispersed uniformly. The solution thus obtained is uniformly applied on, for example, a release liner (silicone-treated polyester film) using a coating machine such as a knife coater, comma coater or reverse coater.
After the application, the organic solvent is volatilized by holding for about 30 seconds to 10 minutes in a dry heat atmosphere maintained at a temperature of about 40 ° C to 130 ° C. The drying conditions are appropriately selected depending on the type of organic solvent used and the thickness of the pressure-sensitive adhesive to be applied.
A transdermal absorption preparation (patch) can be obtained by laminating a support on the surface of the pressure-sensitive adhesive layer obtained by the above method. Depending on the type of the support, after the pressure-sensitive adhesive layer is formed on the support, a release liner may be laminated on the surface of the pressure-sensitive adhesive layer.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

[Each component used]
The detail of each component, such as an adhesive used in the Example and the comparative example, is as follows.
<Adhesive>
・ Acrylic adhesive (1)
100 parts by mass of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and methacryldodecyl mixed at a molar ratio of 1: 8: 1, 0.5 parts by mass of lauroyl peroxide as a polymerization initiator, and acetic acid Polymerization was performed by a conventional solution polymerization method at a concentration of 35% in ethyl to obtain an acrylic pressure-sensitive adhesive (1). The intrinsic viscosity of the obtained pressure-sensitive adhesive was 2.0.
・ Acrylic adhesive (2)
100 parts by mass of 2-ethylhexyl acrylate and acrylic acid mixed at a molar ratio of 95.0%: 5.0%, 0.5 parts by mass of lauroyl peroxide as a polymerization initiator, and 33% in ethyl acetate The acrylic pressure-sensitive adhesive (2) was obtained by polymerization using a conventional solution polymerization method.
・ Acrylic adhesive (3)
100 parts by mass of 2-ethylhexyl acrylate and acrylic acid mixed at a molar ratio of 97.5%: 2.5%, 0.5 parts by mass of lauroyl peroxide as a polymerization initiator, and 33% in ethyl acetate The acrylic pressure-sensitive adhesive (3) was obtained by polymerization using a conventional solution polymerization method.
・ Acrylic adhesive (4)
100 parts by weight of 2-ethylhexyl acrylate and acrylic acid mixed at a molar ratio of 98.7%: 1.3%, 0.5 parts by weight of lauroyl peroxide as a polymerization initiator, and 33% in ethyl acetate The acrylic pressure-sensitive adhesive (4) was obtained by polymerization by a conventional solution polymerization method.
・ Acrylic adhesive (5)
100 parts by mass of 2-ethylhexyl acrylate and acrylic acid mixed at a molar ratio of 90.4%: 9.6%, 0.5 parts by mass of lauroyl peroxide as a polymerization initiator, and 33% in ethyl acetate The acrylic pressure-sensitive adhesive (5) was obtained by polymerization using a conventional solution polymerization method.
Rubber adhesive Styrene / isoprene / styrene block copolymer (SIS5002, JSR Corp.) 49.5% by mass, hydrogenated rosin ester (Pine Crystal KE-311, Arakawa Chemical Industries Ltd.) 49.5% by mass %, Dibutylhydroxytoluene (BHT-F, Kirin Foodtech Co., Ltd.) 1.0 mass% was used to obtain a rubber-based pressure-sensitive adhesive.
<Basic drug>
-Tamsulosin: Tamsulosin free base-Salmeterol: Salmeterol free base-Ketotifen fumarate: Ketotifen fumarate <silica particles>
-Light silicic acid anhydride (1): Aerosil 200 (average particle size: about 0.012 μm, Nippon Aerosil Co., Ltd.)
-Light anhydrous silicic acid (2): Silicia 350 (average particle size: 3.9 μm, Fuji Silysia Chemical Ltd.)
Hydrous silicon dioxide: Pyrosphere C1510 (average particle size: 10 μm, Fuji Silysia Chemical Ltd.)
<Polyhydric alcohol fatty acid ester>
・ Propylene glycol monolaurate: Riquemar PL-100 (RIKEN Vitamin Co., Ltd.)
<Others>
・ Monoethanolamine: Special reagent grade (Kanto Chemical Co., Inc.)
・ Polyisocyanate: Coronate HL (Nippon Polyurethane Industry Co., Ltd.)

<Example 1>
The percutaneous absorption type preparation of Example 1 was obtained by the following composition and production method.
(composition)
1. Acrylic adhesive (1) 52.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 8.0% by mass
(Manufacturing method)
After weighing the above components, the total solid content was adjusted to 20% by mass in the ethyl acetate solution and stirred until uniform.
It was applied on a 75 μm single-sided silicon-treated PET (polyethylene terephthalate) film (film binder 75E-0010 No. 23, Fujimori Kogyo Co., Ltd.) so that the coating amount of the pressure-sensitive adhesive layer after drying was 25 g / m ² . Dry at 110 ° C. for 3 minutes.
Next, a 25 μm PET film (Lumirror S10, Toray Industries, Inc.) was bonded to one side of the pressure-sensitive adhesive layer to obtain a percutaneous absorption type preparation.

<Example 2>
The amount of propylene glycol monolaurate was 25% by mass, and each component was made the following composition accordingly, and the percutaneous absorption type preparation of Example 2 was obtained by the same production method as Example 1.
(composition)
1. Acrylic adhesive (1) 65.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 25.0% by mass
4). Tamsulosin 5.0% by mass

<Example 3>
Propylene glycol monolaurate was used in an amount of 20% by mass, and as a result, each component had the following composition, and the percutaneous absorption type preparation of Example 3 was obtained by the same production method as Example 1.
(composition)
1. Acrylic adhesive (1) 72.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 20.0% by mass
4). Tamsulosin 3.0% by mass

<Example 4>
The transdermal absorption preparation of Example 4 was obtained in the same manner as in Example 1 except that the silica particles were changed to light anhydrous silicic acid (2) and the same composition as in Example 1 was used. It was.
(composition)
1. Acrylic adhesive (1) 57.0% by mass
2. Light anhydrous silicic acid (2) 10.0% by mass
3. Propylene glycol monolaurate 25.0% by mass
4). Tamsulosin 8.0% by mass

<Example 5>
The transdermal absorption preparation of Example 5 was obtained in the same manner as in Example 1 using the same components as in Example 1 except that the pressure-sensitive adhesive was changed to acrylic pressure-sensitive adhesive (2). It was.
(composition)
1. Acrylic adhesive (2) 57.0% by mass
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 8.0% by mass

<Example 6>
The transdermal absorption preparation of Example 6 was obtained in the same manner as in Example 1 except that the pressure-sensitive adhesive was changed to an acrylic pressure-sensitive adhesive (3) and using the following composition. It was.
(composition)
1. Acrylic adhesive (3) 60.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 5.0% by mass

<Example 7>
A transdermal absorption preparation of Example 7 was obtained by the same production method as in Example 1 using the same components as in Example 1 except that the pressure-sensitive adhesive was changed to an acrylic pressure-sensitive adhesive (4). It was.
(composition)
1. Acrylic adhesive (2) 60.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 5.0% by mass

<Example 8>
A percutaneously absorbable preparation of Example 8 was obtained in the same manner as in Example 1 except that salmeterol was used as the basic drug and the same components as in Example 1 were used.
(composition)
1. Acrylic adhesive (1) 55.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Salmeterol 5.0% by mass

<Example 9>
The basic ingredient was ketotifen fumarate, and the same ingredients as in Example 1 were used except that monoethanolamine was used as a basic additive used when converting part or all of the drug into the free base form. Using the following composition, the transdermal absorption preparation of Example 9 was obtained in the same manner as in Example 1 except that the coating amount of the pressure-sensitive adhesive layer after drying was 40 g / m ^2. It was.
(composition)
1. Acrylic adhesive (1) 47.5% by mass
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Monoethanolamine 2.5% by mass
5). Ketotifen fumarate 10.0% by mass

<Comparative Example 1>
A percutaneous absorption type preparation of Comparative Example 1 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 62.0 mass%
2. Propylene glycol monolaurate 30.0% by mass
3. Tamsulosin 8.0% by mass

<Comparative example 2>
A percutaneous absorption type preparation of Comparative Example 2 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (5) 59.5% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 10.0% by mass

<Comparative Example 3>
A percutaneous absorption type preparation of Comparative Example 3 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (5) 54.5% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 15.0% by mass

<Comparative example 4>
A percutaneous absorption type preparation of Comparative Example 4 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (2) 60.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 5.0% by mass

<Comparative Example 5>
A rubber-based adhesive was used as the adhesive, and the percutaneous absorption type preparation of Comparative Example 5 was obtained using the following composition and production method.
(composition)
1. Rubber adhesive 65.0% by mass
2. Propylene glycol monolaurate 30.0% by mass
3. Tamsulosin 5.0% by mass
(Manufacturing method)
After weighing the above components, the total solid content was adjusted to 50% by mass in the toluene solution and stirred until uniform.
It was applied on a 75 μm single-sided silicon-treated PET (polyethylene terephthalate) film (film binder 75E-0010 No. 23, Fujimori Kogyo Co., Ltd.) so that the coating amount of the pressure-sensitive adhesive layer after drying was 25 g / m ² . Dry at 110 ° C. for 3 minutes.
Next, a 25 μm PET film (Lumirror S10, Toray Industries, Inc.) was bonded to one side of the pressure-sensitive adhesive layer to obtain a percutaneous absorption type preparation.

<Comparative Example 6>
A percutaneous absorption type preparation of Comparative Example 6 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 85.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Tamsulosin 5.0% by mass

<Comparative Example 7>
Using the following composition, the percutaneous absorption preparation of Comparative Example 7 was obtained by the same production method as in Example 1.
(composition)
1. Acrylic adhesive (1) 75.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 10.0% by mass
4). Tamsulosin 5.0% by mass

<Comparative Example 8>
A percutaneous absorption type preparation of Comparative Example 8 was obtained by the same production method as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (5) 60.0 mass%
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Salmeterol 5.0% by mass

<Comparative Example 9>
A percutaneous absorption type preparation of Comparative Example 9 was obtained in the same manner as in Example 1 except that the following composition was used and the coating amount of the pressure-sensitive adhesive layer after drying was 40 g / m ² .
(composition)
1. Acrylic adhesive (5) 57.0% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Monoethanolamine 2.5% by mass
5). Ketotifen fumarate 10.0% by mass

<Comparative Example 10>
A percutaneous absorption type preparation of Comparative Example 10 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 57.0% by mass
2. Hydrous silicon dioxide 10.0% by mass
3. Propylene glycol monolaurate 25.0% by mass
4). Tamsulosin 8.0% by mass

[Evaluation test method]
The percutaneous absorption preparations of the above Examples and Comparative Examples were tested according to the following evaluation test methods to evaluate the skin permeability of the basic drug, the adhesion of the percutaneous absorption preparation and the adhesion during sweating.
(1) Skin Permeability Test Method The percutaneous absorption preparations obtained in Examples and Comparative Examples were punched out to 1.77 cm ² , and a Franz-type diffusion cell and a hairless mouse (7 weeks old, male) abdominal excised skin The skin permeation test was conducted according to the following procedure.
Saline or pH 7.4 phosphate buffer (32 ° C) is used as the receiver solution, and 1 mL of the receiver solution is collected every sampling time (2, 3, 4 hours) set in advance from the start of the test. The same amount of new receiver solution was filled.
The same amount of methanol was added to the collected receiver solution to remove impurities, and then the drug concentration was measured by HPLC to calculate the cumulative permeation amount. Each specimen was tested three times to obtain an average value.
For Examples 1 to 7 and Comparative Examples 1 to 7, the drug utilization rate after 48 hours was determined as [(cumulative permeation amount at 48 hours) / (drug content per unit area) × 100]. Calculated as The drug content per unit area was calculated from (application amount) × (drug concentration).
The obtained results are shown in Tables 1 to 4 and FIGS.

(2) Adhesiveness of the preparation (normal / perspiration)
The adhesiveness of the obtained transdermally absorbable preparations of Examples and Comparative Examples was evaluated based on the following criteria using a finger tack method. Further, the adhesive residue (residue residue) was also evaluated.
○: Extremely well attached △: Well attached: ×: Not very sticky Also, a healthy adult in which the percutaneous absorption preparations of Examples and Comparative Examples were punched out to 10 cm ² and adhered to the skin inside the forearm was adjusted to room temperature of 40 ° C. After staying in the room for 10 minutes and sweating, the adhesion state of the preparation was evaluated based on the following criteria. Furthermore, the stickiness of the skin was evaluated.
◯: The entire surface is attached Δ: Floating is observed at the edge portion ×: Floating is observed at half or more of the surface XX: Dropped The results obtained are shown in Tables 5 and 6.

[Evaluation test results]
(1) Skin permeability The evaluation results of tamsulosin (free base) skin permeability are shown in Tables 1 and 2, and FIGS.
As can be seen from the results shown in Table 1 and FIG. 1, Example 1 and Example 2 using the acrylic pressure-sensitive adhesive (1) showed that the monomer having a carboxyl group (relative to the total number of moles of monomers used). Compared with Comparative Example 2 using an acrylic adhesive (5) made of a resin polymerized using 9.6% and Comparative Example 5 using a rubber adhesive, it shows a continuously high cumulative permeation amount. In addition, it showed a high drug utilization rate and a value that was recognized to be sufficient for exerting the drug effect.
In Example 3, the drug content was as low as 3%, and the cumulative permeation amount was lower than that in Example 1 and Example 2. However, Comparative Example 2 and Comparative Example 5 far exceeded the drug content in Example 3. As a result, the drug permeability was much higher.
On the other hand, Comparative Example 6 in which propylene glycol monolaurate was not blended and Comparative Example 7 in which the blending amount was as low as 10% showed extremely low skin permeability compared to Example 2 having the same tamsulosin concentration.

In addition, as can be seen from the results shown in Table 2 and FIG. 2, even when a polymer prepared using a monomer having a carboxyl group is used as the acrylic pressure-sensitive adhesive, the total moles of the monomer using the monomer having a carboxyl group are used. In Examples 5 to 7 using the acrylic pressure-sensitive adhesives (2) to (4) used at a ratio of 5% or less based on the number, the cumulative permeation amount was lower than that in Example 1. Even in this case, the effect as a percutaneous absorption type preparation could be expected sufficiently.
On the other hand, Comparative Example 2 and Comparative Example 3 using an acrylic pressure-sensitive adhesive (5) containing a polymer obtained by polymerizing a monomer having a carboxyl group (9.6% based on the total number of moles of monomers used) Only a very low skin permeability was exhibited compared to the above examples.
Further, even in the acrylic pressure-sensitive adhesive (2) used in a proportion of 5% with respect to the total number of moles of the monomer using a carboxyl group-containing monomer, the molar ratio of tamsulosin and the monomer having a carboxyl group is 1. The comparative example 4 which is less than 0 resulted in a low skin permeability as compared with the above examples.

Similarly, as shown in Table 3 and FIG. 3 (when salmeterol is used as a basic drug) and Table 4 and FIG. 4 (when ketotifen fumarate is used), a basic drug other than tamsulosin was used. Even in the case, Example 8 and Example 9 using the acrylic pressure-sensitive adhesive (1) showed a higher cumulative permeation amount than Comparative Examples 8 and 9 using the acrylic pressure-sensitive adhesive (5).

(2) Adhesiveness of the preparation (normal / perspiration)
As shown in Table 5 below, the preparations of Examples 1 to 4 showed no adhesive residue, and showed sufficient adhesiveness and adhesiveness as a transdermal preparation.
In addition, good adhesion was maintained even during sweating, and no skin stickiness after peeling was observed.

On the other hand, as shown in Table 6, in the preparation of Comparative Example 1, although good results were obtained with respect to adhesion, adhesive residue and stickiness of the skin during sweating were recognized. This seems to be because propylene glycol monolaurate, which is a liquid component, could not be sufficiently retained, and the cohesive strength of the adhesive was reduced.
Although the preparation of Comparative Example 2 gave good results with respect to adhesiveness, as described above, the cumulative permeation amount and the drug utilization rate showed low values, which were insufficient for exhibiting medicinal effects.
In the preparation of Comparative Example 5 using a rubber-based adhesive, it was difficult to maintain adhesiveness by adding a large amount of propylene glycol monolaurate, the finger tack was not suitable, and the preparation fell off due to sweating.
Further, Comparative Example 10 using hydrous silicon dioxide having a large particle size as silica particles (filler) is insufficient in the effect of improving the cohesive force, and the adhesive remains slightly and the skin becomes sticky after peeling during sweating. Admitted.

[Summary of evaluation results]
As described above, Comparative Example 1 which does not contain silica particles obtained results excellent in drug skin permeability, but left a problem in skin adhesion.
In Comparative Examples 2, 3, 8, and 9 using the pressure-sensitive adhesive in which the amount of the monomer having a carboxyl group used was larger than the amount specified in the present invention (5% or less), the skin permeability of the drug was significantly reduced. Even in the preparation (Comparative Example 4) using the pressure-sensitive adhesive in which the amount of the monomer having a carboxyl group is used in the amount specified in the present invention (5% or less), the molar amount of the drug used is the molar amount of the monomer. When it was less, the skin permeability and drug utilization rate of the drug decreased.
Moreover, when rubber-based adhesive was used, when 30% of propylene glycol monolaurate was contained, the result showed that adhesive force hardly developed (Comparative Example 5).
Furthermore, when propylene glycol monolaurate, which is a permeation enhancer, was not used, or when used in a small amount, even if used, the result was that the drug hardly permeated the skin (Comparative Examples 6 and 7). .
And when the thing which exceeds the magnitude | size (5 micrometers or less) prescribed | regulated by this invention for the particle diameter of the silica particle to contain was used, it resulted in lacking in skin adhesion somewhat (comparative example 10).

On the other hand, Examples 1 to 9, which are the transdermally absorbable preparations of the present invention, all have excellent drug skin permeability and excellent skin adhesiveness. As a result, it was confirmed that they have excellent characteristics.

FIG. 1 is a graph showing the results of cumulative permeation amounts of transdermal preparations of Examples 1 to 3 and Comparative Examples 1, 2 and 5 to 7 containing tamsulosin (free base). FIG. 2 is a graph showing the results of cumulative permeation amounts of transdermal preparations of Examples 1, 3, and 5 to 7 and Comparative Examples 2 to 4 containing tamsulosin (free base). FIG. 3 is a graph showing the results of cumulative permeation amounts of the transdermal preparations of Example 8 and Comparative Example 8 containing salmeterol (free base). FIG. 4 is a graph showing the results of cumulative permeation amounts of the transdermal preparations of Example 9 and Comparative Example 9 containing ketotifen fumarate.

Claims

In a transdermal preparation having a pressure-sensitive adhesive layer on a support, the pressure-sensitive adhesive composition forming the pressure-sensitive adhesive layer is an acrylic acid ester and / or methacrylic acid ester having no carboxyl group in the molecule as a main monomer. Containing a pressure-sensitive adhesive mainly composed of an acrylic pressure-sensitive adhesive made of polymerized resin, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester,
A percutaneously absorbable preparation comprising the polyhydric alcohol fatty acid ester in a proportion of 15 to 40% by mass with respect to the total mass of the pressure-sensitive adhesive composition.
The acrylic pressure-sensitive adhesive comprises a resin obtained by polymerizing a monomer having a carboxyl group in addition to an acrylic ester and / or a methacrylic ester,
The monomer having a carboxyl group is contained in a proportion of 5% or less with respect to the total number of moles of monomers,
The molar ratio a / b between the number of moles a of the basic drug and the number of moles b of the monomer having a carboxyl group is 1.0 or more.
The transdermally absorbable preparation according to claim 1.
The transdermal system according to claim 1 or 2, wherein the polyhydric alcohol fatty acid ester is propylene glycol monolaurate and is contained in a proportion of 20 to 35% by mass with respect to the total mass of the pressure-sensitive adhesive composition. Absorption formulation.
The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the silica particles have an average particle size of 5 µm or less.
The transdermal preparation according to claim 1, wherein the acrylic pressure-sensitive adhesive is 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer.
The transdermal preparation according to any one of claims 1 to 5, wherein the basic drug is in the form of a salt of tamsulosin or in the form of a free base.