WO2017131034A1

WO2017131034A1 - Transdermal absorption pharmaceutical-preparation

Info

Publication number: WO2017131034A1
Application number: PCT/JP2017/002553
Authority: WO
Inventors: 智史天野; 昭雄竹内; 小林　弘明; 隆夫黒川; 真美子山▲崎▼; 栗林　満; 啓太本村
Original assignee: 久光製薬株式会社
Priority date: 2016-01-28
Filing date: 2017-01-25
Publication date: 2017-08-03
Also published as: TW201726119A; JP6556873B2; TWI710381B; JPWO2017131034A1

Abstract

Disclosed is a transdermal absorption pharmaceutical-preparation comprising: a drug reservoir layer having a first and a second primary surface and containing a drug; an adhesive agent layer disposed on the first primary surface of the drug reservoir layer and containing a silicone adhesive agent which includes a polyorganosiloxane; and a support formed such as to cover the side surfaces and the second primary surface of the drug reservoir layer. The silicon adhesive agent content is 20 mass% or greater relative to the total mass of the adhesive layer, and the moisture permeability of the transdermal absorption pharmaceutical-preparation overall is 20 g/m²·24hr to 314 g/m²·24 hr.

Description

Transdermal absorption preparation

The present invention relates to a percutaneous absorption preparation containing a drug and a silicone adhesive.

In recent years, there has been an increasing demand not only for transdermally absorbable preparations for administering drugs over a short period of time, but also for transdermally absorbable preparations that can administer drugs to living bodies efficiently and stably for a long period of time. Has been.

For example, Patent Document 1 discloses the structure of a transdermally absorbable preparation comprising a drug reservoir layer, a drug permeation layer and a support. This transdermally absorbable preparation can absorb the drug percutaneously through the drug permeation layer without bringing the drug reservoir layer into direct contact with the skin.

WO2010 / 095537

However, although the percutaneous absorption preparation such as the structure described in Patent Document 1 has a structure in which the drug reservoir layer is not in direct contact with the skin, the drug released from the percutaneous absorption preparation when applied to the skin for a long period of time. May cause skin irritation.

Therefore, an object of the present invention is to provide a percutaneous absorption preparation in which drug-induced skin irritation caused by long-term application is reduced.

As a result of intensive studies, the inventors have made the pressure-sensitive adhesive layer contain a silicone pressure-sensitive adhesive containing polyorganosiloxane in an amount of 20% by mass or more with respect to the total mass of the pressure-sensitive adhesive layer, so the, ^20g / m 2 · 24hr or more, by a 314g ^/ m 2 · 24hr within the range, it is possible to make the percutaneous absorption preparation having a suitable sustained release and skin permeation persistence of drug, As a result, the inventors have found that the above problems can be solved.

That is, the transdermally absorbable preparation according to one embodiment of the present invention has first and second main surfaces, and is provided on a drug reservoir layer containing a drug and on the first main surface side of the drug reservoir layer. A transdermal absorption preparation comprising a pressure-sensitive adhesive layer containing a silicone pressure-sensitive adhesive containing polyorganosiloxane, and a support formed so as to cover a side surface of the drug reservoir layer and the second main surface. The content of the silicone pressure-sensitive adhesive is 20% by mass or more with respect to the total mass of the pressure-sensitive adhesive layer, and the moisture permeability of the transdermal absorption preparation as a whole is 20 g / m ² · 24 hr or more, 314 g / m ^2. Provide a transdermally absorbable preparation that is 24 hr or less.

The pressure-sensitive adhesive layer may further contain a pressure-sensitive adhesive base containing one or more compounds selected from the group consisting of a styrene-isoprene-styrene block copolymer (SIS), a tackifier resin, and a plasticizer. You may contain 80 mass% or less of the said adhesive base with respect to the total mass of an adhesive layer. The drug reservoir layer may contain ethyl cellulose. The content of ethyl cellulose in the drug reservoir layer may be 40 to 99% by mass with respect to the total mass of the drug reservoir layer. The drug reservoir layer may contain an acrylic base. The content of the acrylic base in the drug reservoir layer may be 40 to 99% by mass with respect to the total mass of the drug reservoir layer. The support may contain a polyethylene terephthalate (PET) knitted fabric or an ethylene vinyl acetate copolymer film.

The transdermally absorbable preparation according to the present invention has appropriate sustained release of the drug and long-term skin permeation, and can reduce drug-derived skin irritation caused by long-term application.

One embodiment of the present invention has first and second main surfaces, a drug reservoir layer containing a drug, and provided on the first main surface side of the drug reservoir layer, and includes polyorganosiloxane A percutaneously absorbable preparation comprising a pressure-sensitive adhesive layer containing a silicone pressure-sensitive adhesive, and a support formed to cover the side surface of the drug reservoir layer and the second main surface. content, the is 20 mass% or more relative to the total weight of the adhesive layer, the moisture permeability of the whole percutaneous absorption preparation is ^20g / m 2 · 24hr or more, or less 314g ^/ m 2 · 24hr, through It is a skin-absorbing preparation.

Percutaneous absorption preparation according to an embodiment of the present invention, the moisture permeability of the whole percutaneous absorption preparation is ^20g / m 2 · 24hr or more, or less 314g ^/ m 2 · 24hr. The lower limit of moisture permeability as the whole transdermally absorbable preparation is not particularly limited, and may be 25, 30, 35, 40, or 100 g / m ² · 24 hr. The upper limit value of moisture permeability as the whole transdermally absorbable preparation is not particularly limited, and may be 150, 200, 250, or 300 g / m ² · 24 hr.

The drug reservoir layer is a layer containing a drug to be administered transdermally.
The area of the drug reservoir layer can be arbitrarily set in consideration of the drug amount, the application time, etc., but is, for example, in the range of 3 to 150 cm ² , preferably in the range of 10 to 100 cm ² , and in the range of 10 to 50 cm ² . A range is more preferred. The thickness of the drug reservoir layer is not particularly limited, but is preferably 25 to 1000 μm from the viewpoint that it can contain an amount of drug capable of exerting a sufficient therapeutic effect over the application period of the preparation, ease of production, strength of the preparation, etc. 50 to 500 μm is more preferable, and 75 to 250 μm is more preferable.

The drug is not particularly limited as long as it is transdermally administrable, but the more easily the drug causes skin irritation, the more easily the skin irritation reducing effect of the present invention is exhibited. Examples of drugs that are relatively susceptible to skin irritation include oxybutynin, asenapine, bisoprolol, risperidone, nicotine, and citalopram. Other non-steroidal anti-inflammatory drugs such as indomethacin, ketoprofen, methyl salicylate, glycol salicylate, diclofenac sodium, flurbiprofen, felbinac, meloxicam and loxoprofen sodium, estradiol, norethisterone And hormonal drugs such as estriol, antihistamines such as ketotifen, anti-Alzheimer drugs such as memantine, rivastigmine, donepezil, galantamine, sertraline, fluoxetine, paroxetine, antidepressants such as fluvoxamine, gastric ulcer drugs such as teprone, tolterodine, And overactive bladder drugs such as solifenacin, bronchodilators such as tulobuterol, Parkinson's disease drugs such as rotigotine, and metoprolol Antihypertensive drugs, and the like. The drug may be selected from the group consisting of, for example, oxybutynin, asenapine, bisoprolol, citalopram, diclofenac sodium, memantine, rivastigmine, donepezil, galantamine, fluoxetine, paroxetine, tolterodine, and rotigotine.

The drug contained in the drug reservoir can be contained in the drug reservoir in a dissolved state, a saturated state, a supersaturated crystal state, or a dispersed state.
The lower limit of the content of the drug contained in the drug reservoir layer is not particularly limited, and may be 1, 5, 10, 15, 20, 30, or 40% by mass with respect to the total mass of the drug reservoir layer. When it is at least the above lower limit, sufficient skin permeability of the drug is easily obtained. The upper limit of the content of the drug contained in the drug reservoir layer is not particularly limited, and may be 50, 60, 70, 80, or 85 mass% with respect to the total mass of the drug reservoir layer. When the amount is not more than the above upper limit value, sufficient strength for maintaining the shape of the drug reservoir layer is easily secured. The content of the drug contained in the drug reservoir layer may be, for example, 1 to 90% by mass and 15 to 85% by mass with respect to the total mass of the drug reservoir layer.

The drug reservoir layer may contain ethyl cellulose. Since the drug reservoir contains ethyl cellulose, the drug reservoir maintains cohesiveness even when exposed to perspiration at the skin application site, environmental moisture, etc., and can reduce skin irritation due to swelling and destruction. . The lower limit of the content of ethylcellulose contained in the drug reservoir layer is not particularly limited, and may be 20, 25, 30, 35, 40, or 50 mass% with respect to the total mass of the drug reservoir layer. It is easy to maintain the cohesiveness of a drug reservoir layer as it is above the lower limit. The upper limit value of the content of ethyl cellulose contained in the drug reservoir layer is not particularly limited, and may be 70, 80, 90, 95, or 99 mass% with respect to the total mass of the drug reservoir layer. The content of ethyl cellulose contained in the drug reservoir layer may be, for example, 40 to 99% by mass with respect to the total mass of the drug reservoir layer.

The drug reservoir may contain an acrylic base. Because the drug reservoir contains an acrylic base, the drug reservoir maintains cohesiveness and reduces skin irritation due to swelling and destruction even when exposed to sweat at the skin application site and moisture in the environment. Can do. The lower limit value of the content of the acrylic base contained in the drug reservoir layer is not particularly limited, and may be 20, 25, 30, 35, 40, or 50 mass% with respect to the total mass of the drug reservoir layer. It is easy to maintain the cohesiveness of a drug reservoir layer as it is above the lower limit. The upper limit of the content of the acrylic base contained in the drug reservoir layer is not particularly limited, and may be 70, 80, 90, 95, or 99 mass% with respect to the total mass of the drug reservoir layer. The content of the acrylic base contained in the drug reservoir layer may be, for example, 40 to 99% by mass with respect to the total mass of the drug reservoir layer.

As the acrylic base contained in the drug reservoir, a homopolymer or copolymer of (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms, or the above (meth) acrylic acid alkyl ester and other A copolymer with a functional monomer is preferably used. In addition, (meth) acryl means acryl or methacryl.

As the acrylic base contained in the drug reservoir layer, an acrylate copolymer is preferable. The acrylate copolymer may be selected from the group consisting of an acrylate copolymer having no functional group, an acrylate copolymer having a hydroxy group, an acrylate copolymer having a carboxy group, and combinations thereof.

Examples of the acrylate copolymer having no functional group include Duro-tak (registered trademark, Henkel Corporation) 87-9900, Duro-tak (registered trademark) 87-9301, GELVA (registered trademark) GMS 3083, and the like. It is done.
Examples of the acrylate copolymer having a hydroxy group include hydroxyalkyl acrylates such as 2-hydroxyethyl acrylate. The hydroxyalkyl acrylate may be further substituted with a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or the like. Examples of the acrylate copolymer having a hydroxy group include Duro-tak (registered trademark) 87-2516, GELVA (registered trademark) GMS 788, GELVA (registered trademark) GMS 737, and the like.
Examples of the acrylate copolymer having a carboxy group include acrylic acid-containing acrylate copolymers. The monomer component copolymerized with acrylic acid is not particularly limited as long as it can be copolymerized with acrylic acid. Examples thereof include acrylic acid esters such as methyl acrylate and 2-ethylhexyl acrylate; Examples include acrylic acid amides such as acid morpholine amide; vinyl acetate; vinyl alcohol; styrene. The monomer component copolymerized with acrylic acid may be one kind alone, or two or more kinds. Examples of the acrylate copolymer having a carboxy group include Duro-tak (registered trademark) 87-2194, Duro-tak (registered trademark) 87-2852, GELVA (registered trademark) GMS 753, and the like.

The drug reservoir layer may contain components other than the drug and ethyl cellulose as long as the coagulability of the drug reservoir layer can be maintained. Examples of other components include, but are not limited to, drug stabilizers, plasticizers, solubilizers, transdermal absorption enhancers, and fats and oils.

The stabilizer is not particularly limited as long as it is a compound that has been confirmed to have a stabilizing action in a transdermal absorption preparation, and examples thereof include tocopherols, ascorbic acids, dibutylhydroxytoluene, sodium hydrogen sulfite, and ethylenediaminetetraacetate. It is done.

The plasticizer is not particularly limited as long as it is a compound in which a plasticizing action is recognized in the transdermal preparation, and examples thereof include liquid paraffin, liquid polybutene, liquid polyisoprene, and esterified oils.

The solubilizing agent is not particularly limited as long as it is a compound having a dissolving action on a drug, and the percutaneous absorption enhancer is not particularly limited as long as it is a compound having an absorption promoting action in a transdermal absorption preparation. Examples of the solubilizer and absorption promoter include fatty acids having 6 to 20 carbon chains, aliphatic alcohols, fatty acid esters, fatty acid amides, fatty acid ethers, aromatic organic acids, aromatic alcohols, and aromatic organic acids. Esters, aromatic organic acid ethers (which may be saturated or unsaturated, and may be cyclic, linear or branched), lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpenes Compounds, Azone, Azone derivatives, Pyrothiodecane, Glycerin fatty acid esters, Propylene glycol fatty acid esters, Sorbitan fatty acid esters (Span), Polysorbate (Tween), Polyethylene glycol fatty acid esters, Polyoxyethylene cured Castor oil (HCO), polyoxy Chi alkylene alkyl ethers, sucrose fatty acid esters and vegetable oil, and the like. Specifically, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, diethyl sebacate, glycerol monocaprate, glycerol monolaurate, glycerol monooleate, sorbitan monolaurate, propylene glycol monolaurate, polyoxyethylene Examples include lauryl ether, pyrothiodecane, and isopropyl myristate.

The pressure-sensitive adhesive layer is a layer that is provided on the first main surface side of the drug reservoir layer that is in contact with the skin, and serves to prevent the drug reservoir layer from directly contacting the skin.
The area of the pressure-sensitive adhesive layer is not particularly limited as long as it is equal to or larger than the area of the drug reservoir layer, but is preferably wider than the drug reservoir layer in order to securely fix the support covering the drug reservoir layer. The thickness of an adhesive layer is not specifically limited, It can set arbitrarily.

The pressure-sensitive adhesive layer contains a silicone pressure-sensitive adhesive containing polyorganosiloxane. When the pressure-sensitive adhesive layer contains a silicone pressure-sensitive adhesive containing polyorganosiloxane, the moisture permeability of the transdermally absorbable preparation is increased.
As the polyorganosiloxane, commercially available products such as BIO-PSA 7-4202 and BIO-PSA 7-4302 manufactured by Dow Corning can be used.
The lower limit value of the polyorganosiloxane content in the silicone pressure-sensitive adhesive is not particularly limited, and may be 40, 50, 60, 70, 80, or 90% by mass. The upper limit of the content of polyorganosiloxane in the silicone pressure-sensitive adhesive is not particularly limited, and may be 80, 90, 95 or 100% by mass.
Content of a silicone adhesive is 20 mass% or more with respect to the total mass of an adhesive layer. The lower limit of the content of the silicone pressure-sensitive adhesive may be 30, 35, or 40% by mass with respect to the total mass of the pressure-sensitive adhesive layer. The upper limit of content of a silicone adhesive is not specifically limited, It may be 60, 70, 80, 90 or 100 mass% with respect to the total mass of an adhesive layer.

The pressure-sensitive adhesive layer may further contain a pressure-sensitive adhesive base containing one or more compounds selected from the group consisting of a styrene-isoprene-styrene block copolymer, a tackifying resin, and a plasticizer in addition to the silicone pressure-sensitive adhesive. More preferably, it further contains an adhesive base containing two or more compounds selected from the group consisting of a styrene-isoprene-styrene block copolymer, a tackifier resin and a plasticizer, and a styrene-isoprene-styrene block. It is further preferable to further contain an adhesive base containing a copolymer, a tackifying resin and a plasticizer. By further containing the above adhesive base, the permeation persistence of the transdermally absorbable preparation can be enhanced.

The lower limit of the content of the styrene-isoprene-styrene block copolymer in the adhesive base is not particularly limited, and may be 1, 5, 10 or 20% by mass with respect to the total mass of the adhesive base. Further, the upper limit of the content of the styrene-isoprene-styrene block copolymer in the adhesive base is not particularly limited, and is 60, 70, 80, 90, or 95% by mass with respect to the total mass of the adhesive base. It's okay.
The tackifying resin is not particularly limited as long as it is a compound having an effect of improving the adhesive strength. For example, alicyclic saturated hydrocarbon resin (for example, Alcon P-100 of Arakawa Chemical Industries), rosin derivative (for example, rosin) Rosin glycerin ester, hydrogenated rosin and hydrogenated rosin glycerin ester), terpene resin (for example, Clearon P-125 of Yashara Chemical), aliphatic hydrocarbon resin (for example, Quinton B170 of Nippon Zeon), maleic resin, etc. Can be mentioned. The lower limit value of the content of the tackifying resin in the adhesive base is not particularly limited, and may be 5, 10, 20, 30, or 40% by mass with respect to the total mass of the adhesive base. Moreover, the upper limit of content of the tackifying resin in the said adhesive base is not specifically limited, It may be 60, 70, 80, 90, or 95 mass% with respect to the total mass of an adhesive base.
The plasticizer is as described above. The lower limit of content of the plasticizer in the said adhesive base is not specifically limited, It may be 1, 5, 10 or 20 mass% with respect to the total mass of the said adhesive base. Moreover, the upper limit of content of the plasticizer in the said adhesive base is not specifically limited, It may be 60, 70, 80, 90, or 95 mass% with respect to the total mass of an adhesive base.

The lower limit of content of the said adhesive base is not specifically limited, It may be 5, 10, 20, 30 or 40 mass% with respect to the total mass of an adhesive layer. Moreover, the upper limit of content of the said adhesive base is not specifically limited, It may be 60, 70, 80, 90, or 95 mass% with respect to the total mass of an adhesive layer.
When the pressure-sensitive adhesive base is included, the ratio of the content of the silicone pressure-sensitive adhesive and the pressure-sensitive adhesive base in the pressure-sensitive adhesive layer may be 1: 4 to 7: 3, or 3: 7 to 7: 3. . When the ratio is in the above range, the skin permeation persistence tends to be enhanced while maintaining good moisture permeability of the transdermally absorbable preparation.

The pressure-sensitive adhesive layer may further contain a (meth) acrylic acid ester copolymer. Examples of the (meth) acrylic acid ester copolymer include C4-C20 alkyl ester of (meth) acrylic acid and (meth) acrylic acid hydroxy C4-C20 alkyl ester as main monomers. Copolymerized monomers of (meth) acrylic acid ester copolymers include C4 to C20 alkyl esters of (meth) acrylic acid, (meth) acrylic acid hydroxy C4 to C20 alkyl esters, (meth) acrylic acid, vinyl acetate and vinyl. Examples include pyrrolidone and the like.

The pressure-sensitive adhesive layer may contain components other than the pressure-sensitive adhesive and the pressure-sensitive adhesive base. The other components are not particularly limited as long as they are generally used for transdermally absorbable preparations, and examples thereof include stabilizers.

The support is a layer that holds the drug reservoir layer.
The area of a support body is not specifically limited, It can set arbitrarily. The thickness of the support is not particularly limited, but is, for example, 1 to 3000 μm, preferably 1 to 1000 μm, more preferably 50 to 500 μm, and further preferably 100 to 250 μm.

The support is made of a sheet having a property that does not swell due to migration of a drug or the like in the drug reservoir layer. Examples of the material for the support include polyester (such as PET), polyolefin (such as polyethylene and polypropylene), and polyurethane.
Examples of the properties of the support include films, nonwoven fabrics, woven fabrics, knitted fabrics, and porous sheets. When the support is cloth-like, it may be subjected to water repellent treatment. This is because the water repellent treatment of the support tends to reduce the moisture in the environment absorbed by the drug reservoir and reduce swelling of the drug reservoir. Examples of the water repellent treatment include silicone water repellent, fluororesin water repellent, paraffin wax water repellent, zirconium compound water repellent, ethylene urea water repellent, methylolamide water repellent and aliphatic. Treatment with a water repellent or the like can be mentioned.
As the support material and properties, a laminate film of PET film and PET nonwoven fabric (hereinafter referred to as PET / nonwoven fabric laminate film), a polyurethane film, and an ethylene vinyl acetate copolymer film are preferable, and a water-repellent treated PET knitted fabric Is more preferable. The support may be selected, for example, from the group consisting of a water-repellent treated PET knitted fabric, an ethylene vinyl acetate copolymer film, a PET / nonwoven fabric laminate film, a polyurethane nonwoven fabric, a polyurethane film, and a PET film. Further, from the viewpoint of increasing the moisture permeability of the transdermally absorbable preparation, the support is selected from the group consisting of a water-repellent treated PET knitted fabric, an ethylene vinyl acetate copolymer film, a polyurethane nonwoven fabric, and a polyurethane film. It is preferable. Furthermore, from the viewpoint of preventing the back-through of the drug, the support is more preferably a PET knitted fabric or an ethylene vinyl acetate copolymer film subjected to a water repellent treatment. Here, the back-through of the drug refers to a phenomenon in which the drug escapes from the support side due to moisture brought from the external environment.

The transdermally absorbable preparation of the present invention may be further covered with a cover material, or the cover material may be further laminated.

The cover material is composed of a support and an adhesive layer laminated on one side. Cover materials include those that cover the transdermally absorbable preparation of the present invention and are fixed to the skin, and those that are further laminated on the transdermally absorbable preparation. The cover material can be used, for example, to maintain the state of the percutaneously absorbable preparation during the administration period of the drug and to protect the percutaneously absorbable preparation from moisture (such as a shower) brought from the external environment.

The support of the cover material is preferably provided with appropriate strength, moisture permeability, water resistance, and the like, and is preferably selected from polyester (PET, etc.), polyolefin (polyethylene, polypropylene, etc.) and polyurethane.

Examples of the properties of the support of the cover material include films (preferably urethane films), non-woven fabrics, woven fabrics, knitted fabrics, porous sheets, and the like, but sweat generated when a percutaneous absorption preparation is applied to the skin. From the point of promoting the volatilization of moisture such as, it is preferably a cloth shape, more preferably a knitted fabric. When the support is in the form of a cloth, it may be subjected to water repellent treatment in order to improve its waterproofness. Examples of the water repellent treatment include silicone water repellent, fluororesin water repellent, paraffin wax water repellent, zirconium compound water repellent, ethylene urea water repellent, methylolamide water repellent and aliphatic. Treatment with a water repellent or the like can be mentioned.

In the case where the adhesive layer of the cover material covers the percutaneously absorbable preparation and is fixed to the skin, it has an adhesive property for fixing the percutaneously absorbable preparation to the skin and is further laminated on the percutaneously absorbable preparation. In this case, it has adhesiveness for adhering to the transdermally absorbable preparation. It is preferable that the cover material has further excellent moisture permeability.

Examples of the adhesive base contained in the adhesive layer of the cover material include an acrylic adhesive, a silicone adhesive, and a rubber adhesive. As an acrylic adhesive, what contains a (meth) acrylic acid ester copolymer is mentioned, for example. Examples of the (meth) acrylic acid ester copolymer include C4-C20 alkyl ester of (meth) acrylic acid and (meth) acrylic acid hydroxy C4-C20 alkyl ester as main monomers. Copolymerized monomers of (meth) acrylic acid ester copolymers include C4 to C20 alkyl esters of (meth) acrylic acid, (meth) acrylic acid hydroxy C4 to C20 alkyl esters, (meth) acrylic acid, vinyl acetate and vinyl. Examples include pyrrolidone and the like.

Examples of the silicone pressure-sensitive adhesive include polydimethylsiloxane.
Examples of the rubber adhesive include polyisobutylene (PIB), polyisoprene, and styrene-isoprene-styrene block copolymer (SIS).

The pressure-sensitive adhesive layer of the cover material may contain components other than the pressure-sensitive adhesive. The other components are not particularly limited as long as they are generally used for transdermally absorbable preparations, and examples thereof include tackifier resins, plasticizers, and stabilizers.

The cover material is provided separately from the percutaneous absorption preparation, may be used in combination with the application of the percutaneous absorption preparation, or may be provided in a form bonded in advance to the percutaneous absorption preparation.

The pressure-sensitive adhesive layer of the transdermally absorbable preparation of the present invention or the pressure-sensitive adhesive layer of the cover material may be covered with a layer for protecting the pressure-sensitive adhesive layer until application to the skin, for example, a layer comprising a release liner. .

Release liners include, for example, films such as polyester (such as PET), polyvinyl chloride, polyvinylidene chloride, nylon and polyolefin (such as polyethylene and polypropylene), paper such as fine paper and glassine paper, fine paper or glassine paper, and polyolefin Laminating film or the like.
The release liner can be subjected to a wrinkle release treatment by applying a silicone resin, a fluororesin or the like to the surface in contact with the pressure-sensitive adhesive layer.
The release liner may be formed from a plurality of pieces. The release liner has a size that can cover at least the entire pressure-sensitive adhesive layer of the transdermal absorption preparation or the pressure-sensitive adhesive layer of the cover material, and may extend outward from each pressure-sensitive adhesive layer.

Examples of the basic production method of the transdermally absorbable preparation of the present invention include the following methods.

Example of production of transdermally absorbable drug Weighed and mixed drugs, etc., fluidized by a method such as adding or melting a solvent to form a sheet, then solidified by removing the solvent, etc., to an appropriate shape A drug reservoir is obtained by cutting. Next, the drug reservoir layer is heated and softened and bonded to the support.

After forming a pressure-sensitive adhesive layer containing a silicone pressure-sensitive adhesive on a release liner by a conventional method, a drug reservoir layer is laminated on the pressure-sensitive adhesive layer, and cut into an appropriate shape to obtain a transdermally absorbable preparation.

The sheet serving as the cover material can be obtained by forming a pressure-sensitive adhesive layer on a release liner by a conventional method, laminating a support on the pressure-sensitive adhesive layer, and cutting it into an appropriate shape.

When covering the percutaneously absorbable preparation with a cover material, the release liner is peeled off from the cover material sheet, and the support layer of the percutaneously absorbable preparation is joined to the adhesive surface of the adhesive layer of the exposed cover material sheet, Cut into an appropriate shape if necessary. Furthermore, when the adhesive layer of the transdermal absorption preparation is coated with a release liner, the release liner attached to the transdermal absorption preparation is peeled and removed as necessary, and the adhesive surface of the cover material sheet is instead removed with the release liner. After covering the side to form a sheet, it is cut into an appropriate shape.

[Test 1]
Comparison of base composition of adhesive layer Adhesive containing silicone-based adhesive containing polyorganosiloxane, styrene-isoprene-styrene block copolymer (SIS), tackifying resin and plasticizer as the base of the adhesive layer For the transdermally absorbable preparations (Examples 1 to 7 and Comparative Example 1) containing a base (hereinafter also referred to as “SIS-containing adhesive base”) at a predetermined ratio, moisture permeability and drug permeation persistence of the drug were measured. Compared.

Production of Examples 1 to 7 and Comparative Example 1 In the drug reservoir layer, 40% by mass of bisoprolol and 60% by mass of ethyl cellulose were weighed and dissolved by adding an appropriate amount of solvent (methanol) to obtain a coating solution. The coating liquid was applied onto the release liner, and the solvent was removed by drying to obtain a sheet having a thickness of 150 g / m ² . This sheet was cut into a circle (38 cm ² ) to obtain a drug reservoir. Each component in Table 1 was weighed, and an appropriate amount of solvent (toluene or ethyl acetate) was added and dissolved to obtain a coating solution. The coating liquid was applied onto the release liner, and the solvent was removed by drying to obtain a pressure-sensitive adhesive layer having a thickness of 75 g / m ² . The drug reservoir layer is bonded on the adhesive layer, the release liner of the drug reservoir layer is peeled and removed, and a support (water-repellent PET knitted fabric) is laminated on the exposed surface, with the drug reservoir layer approximately in the center. It was cut in (38cm ^2), whereby a transdermal absorption preparation was obtained.

Evaluation method (1) Moisture permeability test method The moisture permeability of the transdermally absorbable preparation is determined according to the moisture permeability test method (cup method) of the moisture-proof packaging material defined in JIS Z 0208: 1976. Relative humidity: Moisture permeation rate (MVTR) g / m ² · 24 hr at 90 ± 2% was measured.

Evaluation criteria of the moisture permeability test ◎: moisture permeability of ^40g / m 2 · 24hr or more = moisture permeability is high, irritation of the skin is almost no ○: moisture permeability of ^20g / m 2 · 24hr or more ~ ^40g / m 2 · 24hr Less than = moisture permeability is slightly high and skin irritation hardly occurs x: moisture permeability is less than 20 g / m ² · 24 hr = moisture permeability is low and skin irritation is likely to occur

(2) In vitro human skin permeation test method A percutaneous absorption preparation is applied to the stratum corneum side of a human skin piece (application area: 3 cm ² ), and hot water at 32 ° C. is circulated so that the skin dermis side is the receptor tank side. A piece of skin was attached to a warm flow-through diffusion cell. Next, the receptor bath was filled with phosphate buffered saline, and the solution was collected from the receptor bath every 168 hours up to 168 hours while replacing at a constant flow rate. The concentration of drug (bisoprolol) in the collected solution was measured by high performance liquid chromatography.

Next, the amount of drug permeated at each time was calculated from the measured concentration value, and the skin permeation rate (μg / cm ² / hr) of the drug at each time was determined. Further, as an index representing the permeation persistence of the drug, the skin permeation speed J _last after 168 hours was divided by the maximum skin speed J _max to calculate a J _last / J _max value. A large J _last / J _max value means that the drug permeation persistence is high.

Evaluation Criteria for In Vitro Human Skin Permeation Test ◎: J _last / J _max value is 0.60 or more ○: J _last / J _max value is 0.30 or more and less than 0.60 ×: J _last / J _max value is 0 Less than 30

Evaluation results of Examples 1 to 7 and Comparative Example 1

When the ratio of the silicone pressure-sensitive adhesive containing polyorganosiloxane in the pressure-sensitive adhesive layer was increased, the moisture permeability of the percutaneous absorption preparation tended to increase. Although the skin permeation persistence of the drug slightly decreased as the proportion of the silicone pressure-sensitive adhesive containing polyorganosiloxane increased, it maintained a sufficient value. The percutaneously absorbable preparations of Examples 1 to 7, particularly Examples 2 to 7, were good in both moisture permeability and persistence of the drug through the skin.

In addition, the percutaneous absorption preparation in which bisoprolol in the drug reservoir of Examples 1 and 4 was changed to oxybutynin, asenapine, citalopram, diclofenac sodium, memantine, rivastigmine, donepezil, galantamine, fluoxetine, paroxetine, tolterodine, and rotigotine, respectively. Both moisture permeability and drug permeation through the skin were good.

[Test 2]
Comparison of Support for Transdermal Absorption Formulation Percutaneous absorption formulation using water-repellent treated PET knitted fabric, ethylene vinyl acetate copolymer film, PET / nonwoven laminate film, polyurethane nonwoven fabric or polyurethane film as the support For (Examples 8 to 12), the moisture permeability was compared. Further, a PET knitted fabric subjected to water repellent treatment, a transdermal absorption preparation (Examples 8 to 9 and 29) using an ethylene vinyl acetate copolymer film or a PET film, and a percutaneous layer in which the support is not laminated. About the absorption preparation (comparative example 2), the fall-through prevention of the drug was compared.

Production of Examples 8 to 12, 29, and Comparative Example 2 The drug reservoir was obtained by weighing 40 mass% bisoprolol and 60 mass% ethyl cellulose and using the same method as described in Test 1. The pressure-sensitive adhesive layer was obtained by weighing out 100% by mass of a silicone-based pressure-sensitive adhesive containing polyorganosiloxane and by the same method as described in Test 1. The drug reservoir layer is bonded onto the adhesive layer, the release liner of the drug reservoir layer is peeled and removed, and the support of Table 3 is laminated on the exposed surface (Comparative Example 2 has no support laminate). Was cut into a circle (38 cm ² ) about the center to obtain a transdermal absorption preparation.

Evaluation criteria for moisture permeability test A: Moisture permeability is 40 g / m ² · 24 hr or more = High moisture permeability and skin irritation hardly occurs ○: Moisture permeability is 20 g / m ² · 24 hr or more to 40 g / m ² · 24 hr Less than = moisture permeability is slightly high and skin irritation hardly occurs x: moisture permeability is less than 20 g / m ² · 24 hr = moisture permeability is low and skin irritation is likely to occur

Evaluation results of Examples 8-12

It was found that the moisture permeability of the percutaneous absorption preparation using a PET knitted fabric (water repellent treatment), an ethylene vinyl acetate copolymer film, a polyurethane nonwoven fabric and a polyurethane film as a support was high.

(2) Test Method for Preventing Drug See-Through Prevention After immersing the support side of the transdermally absorbable preparations of Examples 8 to 9, 29 and Comparative Example 2 in 900 mL of water and allowing to stand for 15 minutes, the drug content in the water Was measured.

Evaluation Criteria for Prevention of Drug See-through: ○: No show-through of the drug from the support side was observed.
X: The strike-through of the drug from the support side was observed.

Evaluation results of Examples 8 to 9, 29 and Comparative Example 2

A percutaneous absorption preparation using a PET knitted fabric (water repellent treatment), an ethylene vinyl acetate copolymer film, and a PET film as a support was found to have a high tendency to prevent the drug from falling through.

[Test 3]
Comparison of Drug Reservoir The coagulability of the drug reservoir was compared for transdermally absorbable preparations (Examples 13 to 28) containing ethyl cellulose (EC), acrylic base or hydroxypropyl cellulose (HPC) in the drug reservoir.

Production of Examples 13 to 28 Each component in Table 6 was weighed and a drug reservoir was obtained by the same method as described in Test 1.

100% by mass of a silicone-based pressure-sensitive adhesive containing polyorganosiloxane (BIO-PSA 7-4202 / BIO-PSA 7-4302 = 50/50) was weighed, and the pressure-sensitive adhesive layer was obtained by the same method as described in Test 1 Got.

The drug reservoir layer is bonded onto the adhesive layer, the release liner of the drug reservoir layer is peeled and removed, a support (PET / nonwoven fabric laminate film) is laminated on the exposed surface, and the drug reservoir layer is approximately square ( 13.4 cm ² ) to obtain a transdermal absorption preparation.

Evaluation method of cohesiveness A gel sheet containing 2% by mass of agar was prepared, and the release liner of the adhesive layer of the transdermal absorption preparations of Examples 13 to 28 obtained above was peeled off, and the exposed adhesive surface was the gel sheet. The percutaneous absorption material was laminated on the gel sheet so as to be in contact with the gel sheet, and left standing for 24 hours. The percutaneously absorbable preparation was peeled from the gel sheet, and the water adhering to the adhesive surface of the percutaneously absorbable preparation was air-dried, and then the cohesiveness of the drug reservoir layer was evaluated by finger tack based on the following criteria.

Evaluation criteria for cohesiveness ○: The drug reservoir did not cohesively break Δ: The drug reservoir slightly coagulated

Evaluation results of Examples 13 to 28

In the percutaneous absorption preparations of Examples 21 to 23 containing HPC as a base of the drug reservoir layer, the drug reservoir layer swells with moisture, and the drug reservoir layer cohesively breaks when the transdermal absorption preparation is peeled from the gel sheet. There was a trend.
On the other hand, in the transdermal absorption preparations of Examples 13 to 20 containing ethylcellulose as the base of the drug reservoir and Examples 24 to 28 containing an acrylic base as the base of the drug reservoir, coagulation destruction of the drug reservoir Tended to be suppressed and cohesion was maintained. In particular, in the percutaneous absorption preparations of Examples 13 to 17, 19 to 20, and 24 to 28, the drug reservoir layer did not cohesively break and the cohesiveness was good.

Claims

A drug reservoir having a first and second major surface and containing a drug;
An adhesive layer that is provided on the first main surface side of the drug reservoir layer and contains a silicone adhesive containing polyorganosiloxane;
A support formed to cover a side surface of the drug reservoir and the second main surface;
A transdermally absorbable preparation comprising:
The content of the silicone adhesive is 20% by mass or more based on the total mass of the adhesive layer,
The percutaneous absorption preparation whose moisture permeability as a whole percutaneous absorption preparation is 20 g / m < 2 > * 24hr or more and 314g / m < 2 > * 24hr or less.
The warp according to claim 1, wherein the pressure-sensitive adhesive layer further contains a pressure-sensitive adhesive base containing one or more compounds selected from the group consisting of a styrene-isoprene-styrene block copolymer, a tackifier resin, and a plasticizer. Skin absorption preparation.
The transdermally absorbable preparation according to claim 2, wherein the content of the adhesive base is 80% by mass or less based on the total mass of the adhesive layer.
The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the drug reservoir layer contains ethyl cellulose.
The transdermally absorbable preparation according to claim 4, wherein the content of ethylcellulose is 40 to 99 mass% with respect to the total mass of the drug reservoir layer.
The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the drug reservoir layer contains an acrylic base.
The transdermally absorbable preparation according to claim 6, wherein the content of the acrylic base is 40 to 99 mass% with respect to the total mass of the drug reservoir layer.
The percutaneous absorption preparation according to any one of claims 1 to 7, wherein the support comprises a polyethylene terephthalate knitted fabric or an ethylene vinyl acetate copolymer film.