JP5535497B2 - Transdermal patch - Google Patents

Description

  The present invention relates to a transdermal absorption patch.

  For example, transdermal patches are known that gradually absorb drugs such as nicotine and fentanyl from the skin to improve nicotine dependence and inflammation in the affected area.

  As such a transdermal absorption patch, for example, an adhesive layer containing a drug is known (see, for example, Patent Document 1).

  However, in the transdermal absorption patch described in Patent Document 1, the drug functions as a plasticizer for the pressure-sensitive adhesive layer, the adhesiveness of the pressure-sensitive adhesive layer to the skin increases, and pain occurs when the patch is peeled off. There was a problem that a part of the adhesive remained on the skin (adhesive residue). In addition, it is difficult to control the amount of drug released by simply containing it.

  In order to solve such a problem, a transdermal absorption patch composed of a drug storage layer for storing a drug and an adhesive layer is known (for example, see Patent Document 2).

  However, in the transdermal absorption patch described in Patent Document 2, the adhesive properties of the adhesive layer change over time due to the migration of the drug and other components constituting the drug storage layer to the adhesive layer. It was difficult to obtain a stable sticking property over time.

Japanese Patent No. 2837337 Japanese Patent No. 2701951

  An object of the present invention is to provide a transdermal absorption patch that can suppress changes in adhesive properties over time and is excellent in sustained sustained release of drugs.

Such an object is achieved by the present inventions (1) to ( 6 ) below.
(1) A transdermal absorption patch used by being applied to the skin,
A multi-layered adhesive layer provided on the side to be adhered to the skin, and a drug storage layer provided on the opposite side of the adhesive layer to the surface to be adhered to the skin,
The drug storage layer contains a drug and a low molecular solid component,
The content of the low molecular solid component when the content of the drug in the drug storage layer is 1 is 0.5 to 20 by mass ratio,
The pressure-sensitive adhesive layer includes a first pressure-sensitive adhesive layer in contact with the drug storage layer, and a second pressure-sensitive adhesive provided on a surface of the first pressure-sensitive adhesive layer opposite to the surface in contact with the drug storage layer. A layer, and
The average thickness of the first pressure-sensitive adhesive layer is 10 to 200 μm,
The average thickness of the second pressure-sensitive adhesive layer is 10 to 200 μm,
The gel fraction of the first pressure-sensitive adhesive layer, Ri 65-95% der,
The probe adhesive value of the said 2nd adhesive layer is 3000-9000mN / 5mmphi, The transdermal absorption patch characterized by the above-mentioned.

( 2 ) The first pressure-sensitive adhesive layer is mainly composed of an acrylic pressure-sensitive adhesive,
In the above (1 ) , the acrylic pressure-sensitive adhesive comprises a main monomer component selected from an alkyl acrylate ester and an alkyl methacrylate ester, a copolymer mainly containing a functional group-containing monomer component, and a crosslinking agent. The transdermal absorption patch of description.

( 3 ) The functional group-containing monomer component is a carboxyl group-containing monomer,
The transdermal patch according to ( 2 ) above, wherein the crosslinking agent is an aziridine compound.

( 4 ) The transdermal patch according to any one of (1) to ( 3 ), wherein the drug is nicotine.

( 5 ) The drug storage layer is obtained by impregnating the drug and the low-molecular solid component into a substrate composed of a fibrous substance,
The number average molecular weight of the low molecular solid component is 100 to 20000,
The transdermal absorption patch according to any one of (1) to ( 4 ), wherein the low molecular solid component is at least one selected from the group consisting of a rosin resin, a terpene resin, and a petroleum resin.

( 6 ) The average thickness of the first pressure-sensitive adhesive layer is 20 to 60 μm,
The average thickness of the second pressure-sensitive adhesive layer is 20 to 60 μm,
The gel fraction of the first pressure-sensitive adhesive layer is 67 to 90%,
The gel fraction of the second pressure-sensitive adhesive layer is 40 to 75%,
When the gel fraction of the second pressure-sensitive adhesive layer is Y [%] and the gel fraction of the first pressure-sensitive adhesive layer is X [%], (1) to (1) to satisfy the relationship of X> Y ( 5 ) The transdermal absorption patch according to any one of ( 5 ).

  ADVANTAGE OF THE INVENTION According to this invention, while being able to suppress the change of the adhesive characteristic with time, the transdermal absorption patch excellent in the sustained sustained-release property of a drug can be provided. In particular, according to the present invention, when nicotine is used as a drug, it is possible to provide a transdermal absorption patch that is particularly excellent in stability over time of adhesive properties and particularly excellent in sustained release of nicotine.

It is sectional drawing which shows suitable embodiment of the transdermal absorption patch of this invention. FIG. 2 is a process diagram showing an example of a method for producing a transdermal absorption patch of the present invention. It is sectional drawing which shows other embodiment of the transdermal absorption patch of this invention. It is sectional drawing which shows other embodiment of the transdermal absorption patch of this invention.

Hereinafter, the present invention will be described in detail based on preferred embodiments.
FIG. 1 is a cross-sectional view showing a preferred embodiment of the transdermal absorption patch of the present invention.

  As shown in FIG. 1, a transdermal absorption patch 1 is provided on a support base 11, one surface side of the support base 11, a drug storage layer 12 containing a drug, the support base 11 and a drug. A bonding layer 13 provided between the storage layer 12 and bonding the support substrate 11 and the drug storage layer 12, and a first layer provided on the opposite side of the drug storage layer 12 from the support substrate 11. The pressure-sensitive adhesive layer 14, the second pressure-sensitive adhesive layer 15 provided on the surface of the first pressure-sensitive adhesive layer 14 on the side to be adhered to the skin, and the side of the second pressure-sensitive adhesive layer 15 to be adhered to the skin A release sheet 17 is provided on the surface.

  The support base 11 has a function of supporting a drug storage layer 12, a first pressure-sensitive adhesive layer 14, and a second pressure-sensitive adhesive layer 15 described later. Such a substrate preferably has flexibility (softness), has a curved surface followability at the time of application, and is suitable for cutting or punching at the time of processing.

  Such a supporting substrate 11 is not particularly limited. For example, polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate (PBT), and polyethylene naphthalate (PEN), polyethylene (PE), polypropylene (PP), and the like. Plastic films made of resins such as polyolefin, polyarylate, polyurethane, polycarbonate, polyamide, polyimide, ethylene vinyl acetate copolymer, polyvinyl chloride, polytetrafluoroethylene, silicone, polysulfone, nylon, polylactic acid, rayon, acrylic, Woven, knitted and non-woven fabrics can be used. Furthermore, a laminate sheet of a plastic film and a plastic film, a woven fabric, a knitted fabric, a nonwoven fabric, paper, or the like can be used.

  The average thickness of the support substrate 11 is preferably 2 to 4000 μm, and more preferably 10 to 300 μm.

  The drug storage layer 12 is bonded to one surface side of the support substrate 11 via a bonding layer 13 described later, and contains a drug and a low molecular solid component.

  The drug storage layer 12 has a function of gradually releasing the drug to the skin attached via the first adhesive layer 14 and the second adhesive layer described later.

  Examples of the drug constituting the drug storage layer 12 include nicotine, fentanyl, nitroglycerin and the like. Among the above, nicotine is a liquid, volatile, highly toxic drug, and has high solubility in water and organic solvents, so it controls the drug release rate when used as a transdermal patch. Although it is a difficult drug, the drug release rate can be easily controlled by using the transdermal absorption patch of the present invention.

  The content of the drug contained in the drug storage layer 12 is preferably 0.1 to 50% by mass, and more preferably 1 to 30% by mass.

  The low molecular weight solid component constituting the drug storage layer 12 is a component having high compatibility with the drug and having a function of controlling the sustained release of the drug. That is, the low-molecular solid component is a component capable of controlling the drug release rate by being compatible with the drug. By including such components, the drug can be released slowly over a long period of time at a relatively uniform rate.

  Such a low molecular weight solid component preferably has a number average molecular weight of 100 to 20000, more preferably 500 to 10,000, and even more preferably 500 to 3000. Thereby, the sustained release property of the drug can be controlled more reliably. The solid means a solid at room temperature.

  Examples of such low molecular solid components include rosin resins such as gum rosin, wood rosin, hydrogenated rosin and hydrogenated rosin glycerin ester, terpene resins such as α-pinene resin, β-pinene resin, and terpene phenol resin, Aliphatic (C5) petroleum resins, aromatic (C9) petroleum resins, alicyclic petroleum resins, petroleum resins such as coumarone / indene resins, styrenic resins, etc., one or two of these A combination of the above can be used. Among these, rosin-based resins can be suitably used from the viewpoint of safety to the skin and economy. In particular, rosin-based resins have high compatibility with nicotine, and can be suitably used for transdermal patches using nicotine as a drug.

  In the present invention, the content of the low-molecular solid component in the drug storage layer is 0.5 to 20 in terms of mass ratio when the content of the drug in the drug storage layer is 1. By setting it as such content, the sustained sustained-release property of the drug of a transdermal absorption patch can be made excellent. On the other hand, when the content of the low molecular solid component is less than the lower limit, it becomes difficult to continuously release the drug. On the other hand, when the content of the low molecular solid component exceeds the upper limit, a large amount of the low molecular solid component gradually moves toward the adhesive layer (first adhesive layer and second adhesive layer) described later. It will migrate and reduce the adhesive properties of the adhesive layer.

  As described above, the content of the low-molecular solid component in the drug storage layer 12 is 0.5 to 20 in terms of mass ratio when the content of the drug in the drug storage layer 12 is 1. Is more preferably from 10 to 10, and even more preferably from 2 to 10. Thereby, the sustained sustained release of the drug of the transdermal absorption patch can be made particularly excellent.

  Moreover, it is preferable that the drug storage layer 12 is formed by impregnating the above-described components into a substrate composed of a fibrous substance. As a result, the drug and the low-molecular solid component as described above can be effectively retained in the drug storage layer 12, and the sustained sustained release of the drug can be further improved. Examples of the method for impregnating the substrate with the above components include means such as coating, dipping, dropping, and spraying.

  Examples of the substrate composed of the fibrous material include woven fabric, knitted fabric, non-woven fabric, and paper. Among the above-mentioned, it is preferable to use a woven fabric. Thereby, while being able to hold | maintain a drug and a low molecular solid component more effectively in the drug storage layer 12, the sustained sustained-release property of a drug can be made more excellent.

  Moreover, as a material which comprises a fibrous substance, a polyester resin, a polyamide resin, an acrylic resin etc. are mentioned, for example.

  The fibrous material is preferably a porous hollow fiber (porous hollow fiber). As a result, the drug and the low molecular weight solid component as described above can be reliably held in the drug storage layer 12 (fiber hollow portion), and the sustained sustained release of the drug is particularly excellent. be able to. In this specification, the porous hollow fiber has pores on the outer wall surface of a hollow fiber having a hollow portion along the fiber axis direction, and at least a part of the pores are hollow fibers. The fiber which penetrates even to the part.

  When a porous hollow fiber is used as the fibrous material, the thickness of the single yarn is preferably 1 to 500 μm, and more preferably 3 to 250 μm.

  The porosity of the pores on the outer wall surface of the porous hollow fiber is preferably 0.1 to 70%, more preferably 1 to 60%.

  Moreover, it is preferable that the porosity of the hollow part of a porous hollow fiber is 3-90%, and it is more preferable that it is 5-80%.

  Further, the total of the pores of the porous hollow fiber and the void ratio of the hollow portion is preferably 10 to 95%, more preferably 20 to 85%.

  In the present specification, the porosity of the hollow portion and the porosity of the pore of the porous hollow fiber are calculated as the volume of the hollow portion of the porous hollow fiber and the volume of the pore with respect to the volume of the porous hollow fiber. . Here, the volume of the hollow part and the volume of the pores of the porous hollow fiber can be measured by a mercury intrusion method.

  The average thickness of the drug storage layer 12 is preferably 5 to 5000 μm, and more preferably 10 to 500 μm.

  In the present embodiment, the drug storage layer 12 is sealed with a bonding layer 13 and a first pressure-sensitive adhesive layer 14 described later, as shown in FIG. By sealing in this way, volatilization and deterioration of the drug in the drug storage layer 12 can be prevented, and the drug can be transferred to the skin more reliably.

  In addition to the above components, for example, a stabilizer, an antioxidant, a fragrance, a pH adjuster, and the like may be added to the drug storage layer 12 as necessary.

  The bonding layer 13 has a function of bonding the support base 11 and the drug storage layer 12 described above.

  The material constituting the bonding layer 13 is not particularly limited as long as it is a material capable of bonding the support substrate 11 and the drug storage layer 12, and examples thereof include a thermosetting adhesive, an adhesive, and a heat Adhesives such as plastic adhesives and hot melt adhesives, rubber adhesives, acrylic adhesives, silicone adhesives, and the like can be used.

  The average thickness of the bonding layer 13 is preferably 5 to 100 μm, and more preferably 10 to 50 μm.

  As shown in FIG. 1, the first pressure-sensitive adhesive layer 14 is provided on the surface of the drug storage layer 12 that is attached to the skin. That is, the first pressure-sensitive adhesive layer is formed in contact with the drug storage layer 12.

  Moreover, the 1st adhesive layer 14 is equipped with the function which permeate | transmits the medicine which has migrated from the drug storage layer 12 to the stuck skin side.

  The transdermal absorption patch of this embodiment is characterized in that the gel fraction of the first pressure-sensitive adhesive layer (the pressure-sensitive adhesive layer in contact with the drug storage layer) is 65 to 95%.

  By the way, in the conventional transdermal absorption patch, the adhesive properties of the pressure-sensitive adhesive layer change over time due to the transfer of the drug and other components constituting the drug storage layer to the pressure-sensitive adhesive layer. It was difficult to obtain a stable sticking property. In particular, the low molecular weight solid component contained in the drug storage layer of the transdermal absorption patch of the present invention has an excellent function of controlling the sustained release of the drug, but has a strong tendency as described above. In particular, there is a problem that the adhesive strength is increased, and pain or adhesive residue is generated when peeling off after being applied to the skin. This is presumably because the low molecular weight solid component acts as a tackifier in the pressure-sensitive adhesive layer and the adhesive force is increased.

  On the other hand, as in this embodiment, the gel fraction of the pressure-sensitive adhesive layer (first pressure-sensitive adhesive layer) in contact with the drug storage layer is within the predetermined range to solve the above problem. Can do. In other words, by setting the gel fraction of the pressure-sensitive adhesive layer (first pressure-sensitive adhesive layer) in contact with the drug storage layer within the above-mentioned predetermined range, the drug and low-molecular solid component are first extracted from the drug storage layer. Even if it shifts to the pressure-sensitive adhesive layer, it is possible to suppress the tackifying effect due to the drug or the low-molecular solid component and to prevent the adhesive force from increasing with time. As a result, it is excellent in the sustained release property of the drug, and the change in the adhesive property over time can be suppressed. In particular, in this embodiment, since the second pressure-sensitive adhesive layer is provided on the side of the first pressure-sensitive adhesive layer attached to the skin, it is possible to more reliably prevent the change in the adhesive property over time. At the same time, the drug can have excellent sustained release properties.

  When the gel fraction of the first pressure-sensitive adhesive layer is less than the lower limit value, it is not possible to suppress the tackifying effect due to the drug or the low-molecular solid component, and prevent the adhesive force from increasing with time. I can't. On the other hand, when the gel fraction of the 1st adhesive layer exceeds the said upper limit, the softness | flexibility (flexibility) of a 1st adhesive layer will fall and the sticking property to a curved surface will fall.

  As described above, in this embodiment, the gel fraction of the pressure-sensitive adhesive layer (first pressure-sensitive adhesive layer) in contact with the drug storage layer is 65 to 95%, more preferably 67 to 90%. 70 to 85% is more preferable. Thereby, the effect of this invention can be made more remarkable.

In the present invention, “gel fraction” refers to a value calculated as follows.
Wrapping about 300 mg of the pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer with a 380 mesh filter cloth, fastening the ends so that the gel content does not leak out, make a sample. The sample is weighed accurately and heated to reflux for 16 hours using a Soxhlet extractor with ethyl acetate as the solvent. After heating to reflux, weigh the fully dried sample precisely. The difference in weight of the sample before and after heating reflux is calculated by the following formula (I), and the gel fraction (%) is calculated.

Gel fraction (%) = (weight after heating reflux) / (weight before heating reflux) × 100 (I)
The pressure-sensitive adhesive constituting the first pressure-sensitive adhesive layer 14 is not particularly limited as long as the gel fraction of the first pressure-sensitive adhesive layer 14 falls within the above range, and for example, an acrylic pressure-sensitive adhesive and a urethane-based pressure-sensitive adhesive An adhesive, a polyester-based adhesive, a rubber-based adhesive, a silicone-based adhesive, or the like can be used. Among the above-mentioned, it is preferable to use an acrylic pressure-sensitive adhesive. Thereby, the gel fraction of the 1st adhesive layer 14 can be easily adjusted to the above ranges. Moreover, it can be set as the layer excellent in the permeability | transmittance of a drug.

  For example, when an acrylic pressure-sensitive adhesive is used as the pressure-sensitive adhesive, the main monomer component that provides tackiness, the comonomer component that provides adhesiveness and cohesion, and the functional group-containing monomer component for improving the crosslinking point and adhesion It can be composed of a polymer or a copolymer.

  As the main monomer component, for example, acrylic acid alkyl esters such as ethyl acrylate, butyl acrylate, amyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, cyclohexyl acrylate, benzyl acrylate, methoxyethyl acrylate, Examples include methacrylic acid alkyl esters such as butyl methacrylate, 2-ethylhexyl methacrylate, cyclohexyl methacrylate, and benzyl methacrylate.

  Examples of the comonomer component include methyl acrylate, methyl methacrylate, ethyl methacrylate, vinyl acetate, styrene, acrylonitrile, and the like.

  Examples of the functional group-containing monomer component include carboxyl group-containing monomers such as acrylic acid, methacrylic acid, maleic acid, and itaconic acid, 2-hydroxyethyl acrylate, hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and methacrylic acid. Examples thereof include hydroxyl group-containing monomers such as 2-hydroxypropyl and N-methylolacrylamide, acrylamide, methacrylamide, glycidyl methacrylate and the like.

  By including these components, the gel fraction of the first pressure-sensitive adhesive layer 14 can be easily adjusted in the above-described range.

  The material used for forming the first pressure-sensitive adhesive layer may contain a crosslinking agent. Examples of the crosslinking agent include an epoxy compound, an isocyanate compound, a metal chelate compound, and an aziridine compound.

  Moreover, in the material used for forming the first pressure-sensitive adhesive layer, various additives such as a plasticizer, a tackifier, and a stabilizer may be included as necessary.

  The average thickness of the first pressure-sensitive adhesive layer 14 (average thickness at the center in the drawing) is not particularly limited, but is preferably 10 to 200 μm, and more preferably 20 to 60 μm. Thereby, the fall of the adhesion characteristic with time can be prevented more effectively.

  The 2nd adhesive layer 15 is provided on the surface on the opposite side to the surface which contact | connects the drug storage layer of the 1st adhesive layer 14 mentioned above. That is, the 2nd adhesive layer 15 is provided in the side stuck on skin rather than the 1st adhesive layer 14. And the transdermal absorption patch 1 is stuck by making the surface on the opposite side to the surface which contact | connects the 1st adhesive layer 14 contact skin.

  The second pressure-sensitive adhesive layer 15 is not in direct contact with the drug storage layer 12 and has a small migration amount of the low-molecular solid component, so that the change in the adhesive force with time is small. Therefore, the adhesive property to the skin is not impaired over time, and good adhesive property can be maintained over a long period of time.

  When the gel fraction of the second pressure-sensitive adhesive layer 15 is Y [%] and the gel fraction of the first pressure-sensitive adhesive layer 14 is X [%], the relationship X> Y is satisfied. Is preferred. By satisfying such a relationship, even if the low molecular weight solid component of the drug storage layer 12 is transferred to the second pressure-sensitive adhesive layer 15 via the first pressure-sensitive adhesive layer 14, the transfer amount is small. Therefore, it is possible to more reliably suppress the change in the adhesive property over time. Moreover, the softness | flexibility of the 2nd adhesive layer 15 becomes favorable, and the sticking property to the curved surface of the transdermal absorption patch 1 improves.

  Specifically, the gel fraction of the second pressure-sensitive adhesive layer 15 is preferably 40 to 75%, more preferably 40 to 70%, and still more preferably 40 to 65%. By setting the gel fraction of the second pressure-sensitive adhesive layer 15 within such a range, the low molecular solid component of the drug storage layer 12 has migrated through the first pressure-sensitive adhesive layer 14. In addition, it is possible to provide a transdermal absorption patch 1 that can more reliably suppress an increase in adhesive strength over time and has a sticking characteristic that is stable over time. Moreover, the softness | flexibility of the 2nd adhesive layer 15 becomes favorable, and the sticking property to the curved surface of the transdermal absorption patch 1 can be made more favorable.

  As the adhesive constituting the second adhesive layer 15, it is preferable to use the same adhesive as the first adhesive layer 14 described above. Thereby, the adhesiveness of the 1st adhesive layer 14 and the 2nd adhesive layer 15 improves, and delamination etc. can be prevented. Moreover, the adhesiveness to skin can be made favorable.

  The probe tack value of the second pressure-sensitive adhesive layer (the pressure-sensitive adhesive layer located on the outermost layer) is preferably 3000 to 9000 mN / 5 mmφ, and more preferably 5000 to 8000 mN / 5 mmφ. By setting the probe tack value of the second pressure-sensitive adhesive layer within such a range, the adhesiveness to the skin can be improved.

  The average thickness of the second pressure-sensitive adhesive layer 15 (the average thickness in the center portion in the figure) is not particularly limited, but is preferably 10 to 200 μm, and more preferably 20 to 60 μm. Thereby, while being able to make the sticking property to skin favorable, the sustained-release property of a drug can be made favorable.

  Moreover, it is preferable that the sum total of the average thickness (average thickness of the center part in a figure) of the 1st adhesive layer 14 and the 2nd adhesive layer 15 mentioned above is 10-400 micrometers, 40- More preferably, it is 120 μm. Thereby, the sustained release property of the drug can be improved while more effectively preventing the deterioration of the adhesive property over time.

  The release sheet 17 has a function of protecting the sticking surface of the second pressure-sensitive adhesive layer 15 when the transdermal absorption patch 1 is not used.

As such a release sheet 17, a well-known thing can be used.
Next, an example of the manufacturing method of the transdermal absorption patch 1 mentioned above is demonstrated.
FIG. 2 is a process diagram showing an example of a method for producing a transdermal absorption patch of the present invention.

First, as shown in FIG. 2A, a release sheet 17 is prepared.
Next, a material for forming the second pressure-sensitive adhesive layer 15 is applied to the release surface of the release sheet 17 to form the second pressure-sensitive adhesive layer 15.

  Next, the material which forms the 1st adhesive layer 14 is apply | coated on the formed 2nd adhesive layer 15, and the 1st adhesive layer 14 is formed (refer FIG.2 (b)).

Next, a fibrous substrate is stuck on the formed first pressure-sensitive adhesive layer 14.
Next, the drug storage layer 12 is formed by impregnating the fibrous substrate with a material constituting the drug storage layer 12 such as a drug or a low-molecular solid component (see FIG. 2C).

  On the other hand, the support substrate 11 is prepared, and the material 13 ′ for forming the bonding layer 13 is applied on the support substrate 11 to form the bonding layer 13.

  Next, as shown in FIG. 2D, the surface on which the drug storage layer 12 is formed and the bonding layer 13 are opposed to each other.

  Thereafter, the bonding layer 13 and the drug storage layer 12 are pressure-bonded. At this time, the edge of the bonding layer 13 and the edge of the first pressure-sensitive adhesive layer 14 are in close contact with each other, and the drug storage layer 12 is sealed in the transdermal absorption patch 1.

  By the above, as shown in FIG.2 (e), the transdermal absorption patch 1 (transdermal absorption patch of this invention) is obtained.

  Thus, the transdermal absorption patch of the present invention can be produced by a simple production method and is economically excellent.

  As mentioned above, although the transdermal absorption patch of this invention was demonstrated, this invention is not limited to these.

  For example, in the above-described embodiment, the configuration having the support base material has been described, but the support base material may not be provided.

  In the above-described embodiment, the configuration in which the drug storage layer 12 is sealed with the bonding layer 13 and the first pressure-sensitive adhesive layer 14 has been described. However, the end (peripheral portion) of the drug storage layer 12 is sealed. It does not have to be.

Moreover, although embodiment mentioned above demonstrated the structure of two adhesive layers, as shown in FIG. 3, the structure of only one adhesive layer (1st adhesive layer 14) may be sufficient. As shown in FIG. 4, the pressure-sensitive adhesive layer may be composed of three layers (a first pressure-sensitive adhesive layer 14, a second pressure-sensitive adhesive layer 15, and a third pressure-sensitive adhesive layer 16). The pressure-sensitive adhesive layer may be composed of four or more layers. Among such single-layer or multi-layer pressure-sensitive adhesive layers, the gel fraction of at least one layer is 65 to 95%, more preferably 67 to 90%, and 70 to 85%. Further preferred. The probe tack value of the pressure-sensitive adhesive layer located on the outermost layer is preferably 3000 to 9000 mN / 5 mmφ, and more preferably 5000 to 8000 mN / 5 mmφ. Furthermore, it has a multilayer adhesive layer, and the gel fraction of at least one adhesive layer located on the drug storage layer side is higher than the gel fraction of the adhesive layer located on the outermost layer. Particularly preferred. By setting it as the thing of such a range, the transdermal patch with the effect mentioned above can be obtained.
Moreover, the manufacturing method of the transdermal absorption patch of this invention is not limited to the said method.

Next, specific examples of the transdermal absorption patch of the present invention will be described.
Example 1
First, butyl acrylate: 65 parts by mass, 2-ethylhexyl acrylate: 30 parts by mass, methacrylic acid: 2.9 parts by mass, dimethylacrylamide: 2.9 parts by mass, and N-vinylpyrrolidone: 2.8 The ethyl acetate solution (solid content: 50 mass%) of the copolymer with a mass part was prepared.

  Next, to the ethyl acetate solution of this copolymer: 100 parts by mass, a hexamethylene diethylene urea solution (aziridine-based cross-linking agent, solid content: 5% by mass): 2 parts by mass is added to form a second pressure-sensitive adhesive layer. Obtained material.

  On the other hand, a release liner made of polyethylene terephthalate (PET) as a release sheet (product name “SP-PET7511”, manufactured by Lintec Corporation) is prepared, and the second pressure-sensitive adhesive layer forming material is dried on its release surface. It apply | coated so that average thickness might be set to 30 micrometers, and the 2nd adhesive layer was formed. The gel fraction of the second pressure-sensitive adhesive layer was 51.0%.

  On the other hand, hexamethylene diethylene urea solution (aziridine-based cross-linking agent, solid content: 5% by mass): 10 parts by mass is added to 100 parts by weight of the ethyl acetate solution of the above-mentioned copolymer to form a first pressure-sensitive adhesive layer forming material. Got.

  Next, the obtained first pressure-sensitive adhesive layer-forming material was applied onto the second pressure-sensitive adhesive layer so that the average thickness after drying was 30 μm, thereby forming a first pressure-sensitive adhesive layer. The gel fraction of the first pressure-sensitive adhesive layer was 78.1%.

  Next, the formed first pressure-sensitive adhesive layer, the thickness of the single yarn is 18 μm, the porosity of the pores on the outer wall surface of the porous hollow fiber is 12%, the porosity of the hollow portion is 27%, and the overall porosity is A total of 39% porous hollow fiber woven fabric (circular shape with a diameter of 30 mm, mass 90 mg) was bonded. Next, a drug-containing liquid (nicotine: hydrogenated rosin glycerin ester having a number average molecular weight of 1300: mixture of acetone in a mass ratio of 1: 5: 1) is applied to the woven fabric so that the impregnation amount after drying is 105 mg. It was impregnated and dried at 70 ° C. for 4 minutes to form a drug storage layer.

  On the other hand, an average thickness: 50 μm PET film (manufactured by Toray Industries, Inc., trade name “Lumirror”) as a supporting substrate was prepared.

  On this support substrate, a bonding layer forming material (the copolymer: 100 parts by weight of a hexamethylene diethylene urea solution (aziridine-based crosslinking agent, solid content: 5% by mass): 2 parts by mass) It apply | coated so that the average thickness after drying might be set to 40 micrometers, and the joining layer was formed.

  Thereafter, the formed bonding layer and the drug storage layer were pressure-bonded and cut into a circular shape having a diameter of 36 mm so that the drug storage layer was located at the center, to obtain a transdermal absorption patch.

(Example 2)
As a second pressure-sensitive adhesive layer forming material, hexamethylene diethylene urea solution (aziridine-based cross-linking agent, solid content: 5% by mass): 7.5 parts by mass is added to 100 parts by weight of the above-described copolymer ethyl acetate solution: A transdermal absorption patch was produced in the same manner as in Example 1 except that the above was used. The gel fraction of the second pressure-sensitive adhesive layer was 72.5%.

(Example 3)
As the first pressure-sensitive adhesive layer forming material, hexamethylene diethylene urea solution (aziridine-based cross-linking agent, solid content: 5% by mass): 7.5 parts by mass is added to 100 parts by weight of the above-described copolymer ethyl acetate solution: A transdermal absorption patch was produced in the same manner as in Example 1 except that the above was used. The gel fraction of the first pressure-sensitive adhesive layer was 72.5%.

Example 4
First, butyl acrylate: 65 parts by mass, 2-ethylhexyl acrylate: 30 parts by mass, methacrylic acid: 2.9 parts by mass, dimethylacrylamide: 2.9 parts by mass, and N-vinylpyrrolidone: 2.8 The ethyl acetate solution (solid content 50%) of the copolymer with a mass part was prepared.

  Next, a hexamethylene diethylene urea solution (aziridine-based cross-linking agent, solid content: 5% by mass): 10 parts by mass is added to 100 parts by weight of the ethyl acetate solution of the copolymer to form a first pressure-sensitive adhesive layer. Obtained material.

  Meanwhile, a release liner made of PET (trade name “SP-PET7511”, manufactured by Lintec Corporation) as a release sheet is prepared, and the average thickness after drying the first pressure-sensitive adhesive layer forming material on the release surface is It apply | coated so that it might become 60 micrometers, and the 1st adhesive layer was formed. The gel fraction of the first pressure-sensitive adhesive layer was 78.1%.

  Next, the formed first pressure-sensitive adhesive layer, the thickness of the single yarn is 18 μm, the porosity of the pores on the outer wall surface of the porous hollow fiber is 12%, the porosity of the hollow portion is 27%, and the overall porosity is A total of 39% porous hollow fiber woven fabric (circular shape with a diameter of 30 mm, weight 90 mg) was bonded. Next, a drug-containing liquid (nicotine: hydrogenated rosin glycerin ester having a number average molecular weight of 1300: mixture of acetone in a mass ratio of 1: 5: 1) is applied to the woven fabric so that the impregnation amount after drying is 105 mg It was impregnated and dried at 70 ° C. for 4 minutes to form a drug storage layer.

  On the other hand, an average thickness: 50 μm PET film (manufactured by Toray Industries, Inc., trade name “Lumirror”) as a supporting substrate was prepared.

  On this support base material, a bonding layer forming material (ethyl acetate solution of the above copolymer: 100 parts by weight, hexamethylene diethylene urea solution (aziridine-based crosslinking agent, solid content: 5% by mass): 2 parts by mass is added. And a bonding layer was formed so that the average thickness after drying was 40 μm.

  Thereafter, the formed bonding layer and the drug storage layer were pressure-bonded and cut into a circular shape having a diameter of 36 mm so that the drug storage layer was located at the center, to obtain a transdermal absorption patch.

(Example 5)
As the first pressure-sensitive adhesive layer forming material, hexamethylene diethylene urea solution (aziridine-based cross-linking agent, solid content: 5% by mass): 7.5 parts by mass is added to 100 parts by weight of the above-described copolymer ethyl acetate solution: A transdermal absorption patch was produced in the same manner as in Example 4 except that the above was used. The gel fraction of the first pressure-sensitive adhesive layer was 72.5%.

(Example 6)
What added 5 mass parts of hexamethylene diethylene urea solutions (aziridine type crosslinking agent, solid content: 5 mass%) to 100 mass parts of ethyl acetate solution of the said copolymer as a 1st adhesive layer formation material A transdermal absorption patch was produced in the same manner as in Example 4 except that was used. In addition, the gel fraction of the 1st adhesive layer was 67.3%.

(Example 7)
As a drug-containing solution, a mixture of nicotine: terpene resin having a number average molecular weight of 1000: mass ratio of ethyl acetate: 1: 5: 5 was used, and the drying time was 70 ° C. for 8 minutes. A transdermal absorption patch was produced.

(Example 8)
Example 1 except that a liquid mixture of nicotine: aliphatic petroleum resin having a number average molecular weight of 800: ethyl acetate: mass ratio 1: 5: 5 was used as the drug-containing liquid, and the drying time was 70 ° C. for 8 minutes. In the same manner, a transdermal absorption patch was produced.

Example 9
As a drug-containing liquid, a mixture liquid of nicotine: number-average molecular weight 900 terpene phenol resin: ethyl acetate in a mass ratio of 1: 5: 5 was used, and the drying time was 70 ° C. for 8 minutes. Thus, a transdermal absorption patch was produced.

(Comparative Example 1)
What added 2 mass parts of hexamethylene diethylene urea solutions (aziridine-type crosslinking agent, solid content: 5 mass%) to 100 mass parts of ethyl acetate solution of the said copolymer as a 1st adhesive layer formation material A transdermal absorption patch was produced in the same manner as in Example 4 except that was used. In addition, the gel fraction of the 1st adhesive layer was 51.0%.

  Table 1 summarizes the gel fraction of each adhesive layer, the average thickness of each layer, and the content of the drug (nicotine) in the transdermal patches prepared in the above Examples and Comparative Examples.

  The content of the drug contained in the transdermal patches of each Example and each Comparative Example was measured as follows.

  30 mL of ethyl acetate was placed in a 50 mL glass container, and one percutaneous absorption patch of each Example and each Comparative Example was placed therein, and shaken for 20 minutes to extract the drug. 1 mL of the extract was added to 10 mL of methanol and stirred, quantified by high performance liquid chromatography, and the drug content was measured.

<Evaluation>
[Change in probe tack over time]
Using the transdermal absorption patches of each Example and each Comparative Example immediately after production, and the respective transdermal absorption patches of each Example and each Comparative Example that were packaged in aluminum and left in an environment of 40 ° C. for 6 weeks, A probe tack test defined by the Material Testing Association (ASTM D2979) was performed, the probe tack value was measured four times under the following conditions, and the average value was taken as the measured value. In addition, the rate of change was calculated.

Test conditions:
Measurement environment: 23 ° C., 65% RH, probe: 5 mmφ (made of stainless steel), probe speed: 100 mm / second, adhesion time: 1 second, adhesion load: 100 g.

[Drug release test]
The drug release profile from the transdermal patch of each Example and each Comparative Example was measured as follows according to the paddle over disk method described in the US Pharmacopoeia.

  Set 500 mL of phosphate buffer solution of pH 7.4 in the specified dissolution tester, and fix the transdermal patches of each Example and each Comparative Example to the specified disk with the sticking surface facing up. The drug release rate after 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after the initial drug content was tested by high performance liquid chromatography. Measured with

[Sensory test of adhesive strength]
The percutaneous absorption patches of each Example and each Comparative Example immediately after production and each Example and each Comparative Example's percutaneous absorption patch that were packaged in aluminum and left in an environment of 40 ° C. for 6 weeks were applied to the skin. Then, the degree of peeling when each transdermal absorption patch was peeled off after 24 hours was evaluated according to the following three criteria.
A: Little pain was felt when peeling.
○: Pain was felt to some extent, but was acceptable.
X: Pain was strongly felt when peeling.
These results are shown in Table 2.

  As is apparent from Table 2, the transdermal absorption patch of the present invention was excellent in sustained sustained release of the drug. Further, the transdermal absorption patch of the present invention had stable adhesive properties over time. On the other hand, satisfactory results were not obtained with the transdermal patches of each comparative example.

DESCRIPTION OF SYMBOLS 1 Transdermal absorption patch 11 Support base material 12 Drug storage layer 13 Joining layer 13 'Material 14 1st adhesive layer 15 2nd adhesive layer 16 3rd adhesive layer 17 Release sheet

Claims (6)

A transdermal absorption patch used by being applied to the skin,
A multi-layered adhesive layer provided on the side to be adhered to the skin, and a drug storage layer provided on the opposite side of the adhesive layer to the surface to be adhered to the skin,
The drug storage layer contains a drug and a low molecular solid component,
The content of the low molecular solid component when the content of the drug in the drug storage layer is 1 is 0.5 to 20 by mass ratio,
The pressure-sensitive adhesive layer includes a first pressure-sensitive adhesive layer in contact with the drug storage layer, and a second pressure-sensitive adhesive provided on a surface of the first pressure-sensitive adhesive layer opposite to the surface in contact with the drug storage layer. A layer, and
The average thickness of the first pressure-sensitive adhesive layer is 10 to 200 μm,
The average thickness of the second pressure-sensitive adhesive layer is 10 to 200 μm,
The gel fraction of the first pressure-sensitive adhesive layer, Ri 65-95% der,
The probe adhesive value of the said 2nd adhesive layer is 3000-9000mN / 5mmphi, The transdermal absorption patch characterized by the above-mentioned. The first pressure-sensitive adhesive layer is mainly composed of an acrylic pressure-sensitive adhesive,
The acrylic pressure-sensitive adhesive, according to claim 1 in which comprises a copolymer as a main main monomer component selected from acrylic acid alkyl esters and methacrylic acid alkyl esters, and the functional group-containing monomer component, a crosslinking agent A transdermal absorption patch. The functional group-containing monomer component is a carboxyl group-containing monomer,
The transdermal patch according to claim 2 , wherein the crosslinking agent is an aziridine compound. The transdermal absorption patch according to any one of claims 1 to 3 , wherein the drug is nicotine. The drug storage layer is obtained by impregnating the drug and the low-molecular solid component on a substrate composed of a fibrous substance,
The number average molecular weight of the low molecular solid component is 100 to 20000,
The transdermal patch according to any one of claims 1 to 4 , wherein the low-molecular solid component is at least one selected from the group consisting of a rosin resin, a terpene resin, and a petroleum resin. The average thickness of the first pressure-sensitive adhesive layer is 20 to 60 μm,
The average thickness of the second pressure-sensitive adhesive layer is 20 to 60 μm,
The gel fraction of the first pressure-sensitive adhesive layer is 67 to 90%,
The gel fraction of the second pressure-sensitive adhesive layer is 40 to 75%,
The second gel fraction of the pressure-sensitive adhesive layer Y [%], the gel fraction of the first adhesive layer when the X [%], claims 1 satisfy the relation: X> Y 5 The transdermal absorption patch according to any one of the above.

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