JP2018187353A - Transdermal absorption preparation precursor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a transdermal absorption preparation precursor capable of preserving, in a mutually separated state, constituent components of a transdermal absorption preparation, feared to cause an adverse influence when preserved in a mutually mixed state or contact state, and conveniently acquiring the transdermal absorption preparation having a given laminate structure when in use.SOLUTION: A transdermal absorption preparation precursor 50 contains: a release liner 10 containing one first valley fold part 1, one or two first mountain fold parts 2, and a first base line L1 and a second base line L2 at one side and the other side apart from the first valley fold part 1 as a line of demarcation and at an approximately equal distance from the first valley fold part 1, where at least one of the first base line L1 and the second base line L2 is a fold line of the first mountain fold part 2; and a drug-containing layer 3 having a center line laid on the first base line L1 and an adhesive layer 4 having a center line laid on the second base line L2, disposed on the release liner 10.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a percutaneous absorption-type preparation precursor for obtaining a percutaneous absorption-type preparation that achieves a high level of both storage stability of a drug and skin permeability of the drug, for example.

  Percutaneous absorption-type preparations are not only intended for the treatment of lesions on the skin surface and tissues directly under the skin application site by local absorption of the drug, but also when the drug is taken into the blood from subcutaneous blood vessels, It is used as a preparation expected to affect not only nearby tissues but also the whole body, and has been recognized as one of the drug delivery systems.

  By the way, the percutaneous absorption-type preparation often contains a drug penetration enhancer (skin permeability enhancer). There may be problems with the stability of the drug during storage. In addition, when a drug in a transdermal preparation is present in an amorphous state, it is difficult for the drug to maintain an amorphous state during storage of the transdermal preparation due to the presence of certain additives. Thus, drug precipitation may occur, causing problems such as uneven skin permeability and poor appearance.

  Patent Document 1 contains a true compartment containing the active substance in a completely crystallized form (aggregated solid state) and at least one liquid penetration enhancer in order to solve such problems. Accelerator compartments that are stored separately and combined with these compartments when applied to human skin, so that the active substance dissolves in the penetration enhancer and delivers the active substance (drug) in a supersaturated state A treatment system has been proposed.

Special table 2008-525334 gazette

  However, the transcutaneous treatment system of Patent Document 1 specifically impregnates a sheet (true compartment) in which an adhesive layer containing an active substance (drug) is formed on a support such as a plastic film. While the film is laminated and stored, the back (accelerator compartment) with the liquid surface penetration accelerator stored on it is made and stored, and the permeability of the liquid penetration accelerator is controlled during use. It is assembled into a multilayer structure (see FIGS. 1a-1bs) in which both are bonded via a plastic film (control film) to be applied to the skin, and two compartments must be made separately. Also, in order to achieve a system that enables delivery of the target active substance in a supersaturated state, it must be assembled so that the stacking position and close contact state of both compartments in the multilayer structure are in an appropriate position and state. In addition, the user (patient) himself is very complicated to assemble the system, and there are many cases where the user (patient) himself cannot assemble correctly.

  The present invention has been made in view of the circumstances as described above, and the components of the transdermal preparation that are likely to adversely affect each other when stored in a mixed state or in contact with each other. The object is to provide a percutaneous absorption-type preparation precursor that can be stored in a separated state and can easily obtain a percutaneous absorption-type preparation having a predetermined laminated structure when used.

  As a result of earnest research to solve the above problems, the present inventors have found that a predetermined percutaneous absorption type preparation to be produced on a release liner having valley folds and mountain folds formed at predetermined intervals. If the two layers that are stacked on each other are disposed separately, the components of the transdermal preparation, which are feared to adversely affect each other, can be stored separately from each other, It is found that a user (patient) can easily assemble a percutaneous absorption preparation having a predetermined laminated configuration without causing a positional shift of each layer by simply folding the release liner in a valley and a mountain at the time of use. The invention has been completed.

That is, the present invention is as follows.
[1] A release liner having one first valley fold and one or two first mountain folds, the first on one side and the other side separating from the first valley fold A release liner having a first reference line and a second reference line at substantially equal intervals from the valley fold, wherein at least one of the first reference line and the second reference line is a fold line of the first mountain fold; ,
A first layer having a planar shape disposed on the release liner so that the center line is located on the first reference line, and disposed so that the center line is located on the second reference line. A second layer having a planar shape,
A percutaneously absorbable preparation precursor, wherein the first layer and / or the second layer contains a drug.
[2] The transdermal preparation precursor according to [1], wherein one of the first layer and the second layer is a drug-containing layer, and the other is an adhesive layer.
[3] The percutaneously absorbable preparation precursor according to the above [2], wherein the pressure-sensitive adhesive layer contains an additive.
[4] The percutaneously absorbable preparation precursor according to [2] or [3] above, wherein a control layer is laminated on the adhesive layer.
[5] The transdermal preparation precursor according to [2] or [3] above, wherein the adhesive layer contains a drug.
[6] The percutaneously absorbable preparation precursor according to any one of the above [2] to [5], wherein a base material layer and / or a cover layer is laminated on the drug-containing layer.
[7] The second valley fold is provided at a position opposite to the first valley fold with the second reference line of the release liner interposed therebetween, and is opposite to the second reference line with the second valley fold interposed therebetween. Having a second mountain fold at the position,
The interval between the second valley fold and the second reference line is substantially equal to the interval between the second mountain fold and the second valley fold,
Any one of the above-mentioned [1] to [5], comprising a third layer having a planar shape disposed on the release liner so that the center line thereof is positioned on the fold line of the second mountain fold. A percutaneous absorption-type preparation precursor.
[8] The percutaneously absorbable preparation precursor according to the above [7], wherein the third layer is a cover layer.
[9] The percutaneously absorbable preparation precursor according to the above [7], wherein the third layer is a drug-containing layer.

In the percutaneously absorbable preparation precursor of the present invention, the “center line” refers to two areas that are substantially equal in area to the surface through the center point of the layer surface (ie, plane) when the layer is viewed from vertically above. This means a line that divides into
Further, “on the release liner” basically means the surface of the release liner that has been subjected to the release treatment.
In addition, the “reference line” in the “release liner” is a straight line that can be recognized at least visually or tactilely attached to the release liner by coloring or embossing when the reference line is not a fold line of a mountain fold. is there.

  According to the percutaneously absorbable preparation precursor of the present invention, the two layers that are laminated in the upper and lower directions constituting the percutaneously absorbable preparation can be separated and stored. Can be stored in a separate layer from the drug. For this reason, the stability of the drug during storage can be maintained. And when administering a drug by a percutaneous absorption-type preparation, the fold-folded portion formed on the release liner is folded in a fold, and the valley-folded portion is fold-folded, so that the percutaneous structure having a predetermined laminated structure can be easily obtained. Absorbable preparations can be assembled without causing misalignment in the planar direction of each layer. Therefore, for example, when a user (patient) himself administers a drug using a percutaneous absorption preparation, a percutaneous absorption preparation capable of obtaining the desired performance can be easily and reliably assembled and applied to the skin. Can do.

FIG. 1 (A) to FIG. 1 (C) are schematic views of an example of a percutaneously absorbable preparation precursor according to the first embodiment of the present invention, and FIG. 1 (D) shows the percutaneously absorbable preparation precursor. It is a schematic sectional drawing of the percutaneous absorption type formulation assembled using. FIG. 2 (A) to FIG. 2 (C) are schematic views of an example of a percutaneous absorption preparation precursor according to the second embodiment of the present invention, and FIG. 2 (D) shows the percutaneous absorption preparation precursor. It is a schematic sectional drawing of the percutaneous absorption type preparation assembled using, and FIG.2 (E) is the schematic which shows the state which stuck the percutaneous absorption type preparation of FIG.2 (D) to skin. FIG. 3 (A) to FIG. 3 (C) are schematic views of an example of a percutaneously absorbable preparation precursor according to the third embodiment of the present invention, and FIG. 3 (D) shows the percutaneously absorbable preparation precursor. It is a schematic sectional drawing of the percutaneous absorption type preparation assembled using, and FIG.3 (E) is the schematic which shows the state which stuck the percutaneous absorption type preparation of FIG.3 (D) on the skin. FIG. 4-1 (A) and FIG. 4-1 (B) are schematic views of an example of the fourth embodiment of the percutaneously absorbable preparation precursor of the present invention. FIG. 4-2 (A) and FIG. 4-2 (B) are schematic views of an example of the fourth embodiment of the percutaneously absorbable preparation precursor of the present invention. FIGS. 4-3 (A) and 4-3 (B) are schematic views of an example of the fourth embodiment of the transdermally absorbable preparation precursor of the present invention, and FIG. 4-3 (C) is the transdermal. It is the schematic of the percutaneous absorption type | mold preparation assembled using the absorption-type preparation precursor.

  The present invention will now be described with reference to preferred embodiments, but the detailed description and specific examples are merely exemplary in nature and in no way limit the invention, its application, or uses. It is not intended. In the following description, “substantially equal intervals” and “substantially equal intervals” mean that the two intervals should be equal in light of the object of the invention, and within the scope of achieving the object of the invention. If so, it is allowed even if the two intervals are slightly different.

1. First Embodiment FIG. 1 is a schematic view of an example of a first embodiment of the percutaneously absorbable preparation precursor of the present invention.
In the percutaneous absorption-type preparation precursor 50 of this embodiment, the release liner 10 has one first valley fold 1 and one first mountain fold 2, and the first valley fold 1 is separated as a boundary. The first reference line L1 and the second reference line L2 are provided at substantially equal intervals from the first valley fold part 1 on the one side and the other side, and the first mountain fold part 2 is located on the first reference line L1. The fold line is applied. Then, the drug-containing layer 3 having a planar shape is disposed on the release liner 10 so that the center line is positioned on the first reference line L1, and the center line is positioned on the second reference line L2. Thus, the adhesive layer 4 which has a planar shape is arrange | positioned (FIG. 1 (A)). The first reference line L2 is not a fold line at the mountain fold, but a straight line that can be recognized at least visually or tactilely on the release liner by coloring, embossing, or the like.

  If it is the percutaneous absorption type preparation precursor 50 of the first aspect, the drug-containing layer 3 and the pressure-sensitive adhesive layer 4 can be separated and stored. When the transdermal preparation is administered to the skin, the first mountain fold 2 is folded (FIG. 1B), and the first valley fold 1 is valley folded (FIG. 1 ( C)) When the release liner 10 is peeled off from the drug-containing layer 3 while the drug-containing layer 3 is superimposed on the pressure-sensitive adhesive layer 4, the laminated structure of the drug-containing layer 3 / the pressure-sensitive adhesive layer 4 is formed on the release liner 10. A percutaneous absorption-type preparation having is completed.

  After completely peeling off the release liner 10 from the drug-containing layer 3, the base material layer 5 can be laminated on the drug-containing layer 3, so that the base material layer 5 / the drug-containing layer 3 / the adhesive layer Thus, a percutaneously absorbable preparation (FIG. 1D) having a laminate structure of 4 can be obtained. Further, if the base material layer 5 is laminated in advance on the drug-containing layer 3 disposed on the release liner 10, the first mountain fold portion 2 is mountain-folded, the first valley fold portion 1 is valley-folded, By superposing the drug-containing layer 3 on the pressure-sensitive adhesive layer 4 and peeling off the release liner 10 from the drug-containing layer 3, the percutaneous absorption of the laminated structure of the base material layer 5 / drug-containing layer 3 / pressure-sensitive adhesive layer 4 is achieved. A mold preparation (FIG. 1D) can be obtained.

  In addition, before the first mountain fold 2 of the release liner 10 is folded, that is, during the storage period of the percutaneously absorbable preparation precursor, a protective layer (protective layer) is formed on the outermost surfaces of the drug-containing layer 3 and the adhesive layer 4. It is preferable to provide a release liner (not shown). That is, before the transdermal preparation is completed and the transdermal preparation is applied to the skin, the drug-containing layer 3 and the adhesive layer 4 should be protected with a protective layer (protective release liner). preferable.

  In the example of FIG. 1 (percutaneous absorption preparation precursor 50), the second reference line L2 is a straight line attached to the release liner 10 by coloring, embossing, etc., but instead of the straight line, the second reference line L2 is used. You may form the 1st mountain fold part 2 which the fold line applies to the line L2. By doing so, the release liner 10 can be easily peeled off from the percutaneous absorption-type preparation completed on the release liner 10 (that is, the release liner 10 can be easily peeled off after the state shown in FIG. 1C). The absorptive preparation can be more easily applied to the skin.

Release liner

  In the percutaneous absorption type preparation precursor of the present invention, the release liner 10 is not particularly limited, and polyester (for example, polyethylene terephthalate) that has been subjected to release treatment by applying a silicone release agent, a fluorine release agent, or the like. Etc.), plastic films such as polyvinyl chloride and polyvinylidene chloride, paper such as high-quality paper and glassine paper, or a laminate film obtained by laminating two or more selected from these. The release liner 10 is subjected to a predetermined bending process to form a valley fold and a mountain fold. The sheet may be bent by a known method, and examples thereof include methods described in JP-A-6-166463, JP-A-2006-282314, and the like. Sheet folding is a process of imparting a crease (bending crease) to the sheet. Usually, the fold line that becomes the top line of the mountain fold part and the fold line that becomes the bottom line of the valley fold part are formed on the processed sheet. It is formed.

  Although the thickness of the release liner 10 is not particularly limited, the ease of processing for forming the valley fold and the mountain fold, the mountain fold operation and the valley for completing the transdermal preparation on the release liner, From the viewpoint of ease of folding work, shape stability of the release liner during storage of the percutaneously absorbable preparation precursor, etc., it is generally about 10 to 200 μm, preferably about 25 to 100 μm. .

In general, the planar shape of the release liner 10 is preferably a rectangle shown in FIG. 1A from the viewpoint of ease of valley folding and mountain folding, but is not limited thereto. The plane area of the release liner 10 is determined in consideration of the plane area of the transdermal preparation to be produced, the number of layers constituting the transdermal preparation, and the like. In the case of a liner, it is preferably about 30 to 400 cm ² , but is not limited thereto.

  It should be noted that the release liner 10 has a valley fold portion and a mountain fold portion that are more flexible than other portions, and has a thickness so that the valley fold portion and the mountain fold portion can be easily folded. It may be thinned.

  Further, in the release liner 10, the interval between the first valley fold 1 and the first reference line L1, and the interval between the first valley fold 1 and the second reference line L2 (see FIG. 1). (See (A)) is determined according to the planar area of the transdermal preparation to be produced and is not particularly limited, but is generally selected from the range of 2 to 20 cm.

Drug-containing layer In the percutaneous absorption-type preparation precursor of the present invention, the drug-containing layer 3 usually contains a drug and a matrix polymer as essential components. Although the matrix polymer is not particularly limited, for example, when the drug-containing layer is a layer in which the drug exists in an amorphous state, the matrix polymer is preferably a polymer having a glass transition temperature of 30 ° C to 200 ° C. A polymer having a glass transition temperature of 30 ° C. to 200 ° C. is rigid, and migration and aggregation of the drug in the drug-containing layer is suppressed, and crystallization of the drug existing in an amorphous state is suppressed. The polymer having a glass transition temperature of 30 ° C to 200 ° C preferably has a glass transition temperature of 50 ° C to 200 ° C, and more preferably 60 ° C to 180 ° C.

  Here, the “glass transition temperature” refers to a temperature at which a phenomenon in which rigidity and viscosity rapidly decrease and fluidity increases when an amorphous solid is heated is observed. The glass transition temperature of the polymer can be measured by differential scanning calorimetry (DSC) or the like.

  Examples of the polymer having a glass transition temperature of 30 ° C. to 200 ° C. include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, and cellulose acetate; acrylic resins, methacrylic acid / methyl methacrylate copolymers ( Methacrylic acid copolymer S (“EUDRAGIT S100”), methacrylic acid copolymer L (“EUDRAGIT L100”), made by Evonik Rohm, methacrylic acid / ethyl acrylate copolymer (dry methacrylic acid copolymer LD (“Eudragit”) (EUDRAGIT) L100-55 ", manufactured by Evonik Rohm)), methyl methacrylate, butyl methacrylate, dimethacrylate Methylaminoethyl copolymer (aminoalkyl methacrylate copolymer E (“EUDRAGIT EPO”, manufactured by Evonik Rohm)), methyl methacrylate / ethyl acrylate / methacrylated trimethylammonioethyl ester copolymer (ammonioalkyl methacrylate copolymer ( "EUDRAGIT RSPO", EUDRAGIT RLPO, manufactured by Evonik Loam), ethyl acrylate / methyl methacrylate copolymer (ethyl acrylate / methyl methacrylate copolymer dispersion ("EUDRAGIT NE30D"), Acrylic polymers such as Evonik Rohm)); polyvinylpyrrolidone; vinylpyrrolidone / vinyl acetate Copolymer; Polycarbonate; Cycloolefin copolymer; Polyvinylcaprolactam / polyvinyl acetate / polyethylene glycol graft copolymer (“Soluplus” (manufactured by BASF)); Polyvinyl alcohol; Polyvinyl acetate and the like. Can be used.

  The drug contained in the drug-containing layer 3 is not particularly limited, and a drug that can be administered through the skin to a mammal such as a human, that is, a transdermally absorbable drug is preferable. Specific examples of such drugs include general anesthetics, antipsychotics, antidepressants, mood stabilizers, psychostimulants, hypnotics, anxiolytics, antidepressants, migraine drugs, Antiemetics, antipruritics, local anesthetics, muscle relaxants, autonomic agents, antispasmodics, antiparkinsonian drugs, corticosteroids, nonsteroidal anti-inflammatory drugs, analgesics / antipyretic drugs, antidementia drugs, antirheumatic drugs Antihistamines, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasoconstrictor drugs, vasodilators, antianginal drugs, respiratory stimulants, bronchodilators, bronchial asthma drugs, antitussive Drugs, expectorants, hormonal drugs, hematopoietic drugs, hemostatic drugs, antithrombotic drugs, gout / hyperuricemia drugs, diabetes drugs, hyperlipidemia drugs, antineoplastic drugs, immunosuppressive drugs, antibacterial drugs , Chemotherapeutic drugs, antifungal drugs, antiviral drugs, antiparasitic drugs, narcotics, smoking cessation supplements Medicine, and the like.

  The content of the drug in the drug-containing layer 3 varies depending on the type of drug, the age, sex, symptoms, etc. of the patient to which the intended percutaneously absorbable preparation is used. Is 30 to 95% by weight, preferably 50 to 90% by weight.

  The drug-containing layer 3 includes acetic acid, lactic acid, octanoic acid, levulinic acid, oleic acid, decanoic acid, citric acid, fumaric acid, maleic acid and other organic acids; monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, Organic bases such as triisopropanolamine, pyridine, arginine; vegetable oils such as olive oil, castor oil, coconut oil; animal oils such as liquid lanolin; dimethyldecyl sulfoxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, Surfactants such as organic solvents such as dimethyl lauryl amide, methyl pyrrolidone, dodecyl pyrrolidone, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester; adipic acid Plasticizers such as isopropyl, phthalate and diethyl sebacate; hydrocarbons such as squalane and liquid paraffin; fatty acid esters such as ethyl oleate, isopropyl palmitate, octyl palmitate, isopropyl myristate, isotridecyl myristate, and ethyl laurate Fatty acid esters of polyhydric alcohols such as glycerin fatty acid esters and propylene glycol fatty acid esters; linear aliphatic alcohols such as 1-dodecanol, 1-tetradecanol and 1-hexadecanol, 2-hexyl-1-decanol, 2 Additives such as branched aliphatic alcohols such as -octyl-1-dodecanol and 2-hexyl-1-tetradecanol can be blended. Any one of these additives may be used alone, or two or more thereof may be used in combination.

The drug-containing layer 3 has a planar shape. That is, it exists in an island shape on the surface (release treatment surface) of the release liner. The planar shape and planar area of the drug-containing layer 3 follow the planar shape (for example, approximately square, approximately rectangular, elliptical, circular, etc.) and planar area of a predetermined transdermal preparation to be produced. Accordingly, the planar area is generally selected from the range of 4 to 100 cm ² , but is not limited thereto. The thickness of the drug-containing layer 3 is appropriately set according to the type of drug to be contained, and is not particularly limited, but is generally 10 to 300 μm, preferably 50 to 200 μm.

Adhesive Layer The adhesive layer 4 in the percutaneous absorption preparation precursor of the present invention is a layer for adhering the percutaneous absorption preparation to the skin, and contains a pressure-sensitive adhesive polymer as a main component at room temperature (25 C.) a layer having skin adhesiveness.

  The pressure-sensitive adhesive polymer is not particularly limited, and examples thereof include acrylic polymers including (meth) acrylic acid ester polymers; styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, poly Rubber polymers such as isoprene, polyisobutylene, and polybutadiene; silicone polymers such as silicone rubber, dimethylsiloxane base, and diphenylsiloxane base; vinyl ether polymers such as polyvinyl methyl ether, polyvinyl ethyl ether, and polyvinyl isobutyl ether; Vinyl ester polymers such as polymers; carboxylic acid components such as dimethyl terephthalate, dimethyl isophthalate, and dimethyl phthalate; and polyhydric alcohol components such as ethylene glycol Ranaru ester-based polymer, and the like.

  When a rubber-based polymer is used for the pressure-sensitive adhesive polymer, it is preferable that the adhesive layer further contains a tackifier for improving the skin adhesiveness of the adhesive layer at room temperature. The tackifier includes, for example, petroleum resins (for example, aromatic petroleum resins, aliphatic petroleum resins, etc.), terpene resins, rosin resins, coumarone indene resins, styrene resins (for example, styrene resins, poly ( α-methylstyrene) and the like, and hydrogenated petroleum resins (for example, alicyclic saturated hydrocarbon resins and the like). The amount of the tackifier is usually 33 to 300% by weight, preferably 50 to 200% by weight, based on the total weight of the rubber-based polymer.

  Additives other than the tackifier that can be contained in the pressure-sensitive adhesive layer 4 include diffusion of a drug penetrating from the drug-containing layer 3 in the pressure-sensitive adhesive layer when the drug-containing layer 3 is in a laminated state. And a skin permeability enhancer that improves the skin property and promotes the skin permeability of the drug. Moreover, an excipient | filler, a crosslinking agent, a plasticizer, antioxidant, antiseptic | preservative, etc. can be mentioned.

  Examples of skin permeability enhancers include organic acids such as acetic acid, lactic acid, octanoic acid, levulinic acid, oleic acid, decanoic acid, citric acid, fumaric acid, maleic acid; monoethanolamine, diethanolamine, triethanolamine, diethanolamine, and the like. Organic bases such as isopropanolamine, triisopropanolamine, pyridine, arginine; vegetable oils such as olive oil, castor oil and coconut oil; animal oils such as liquid lanolin; dimethyldecyl sulfoxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethylformamide, Surface activity such as organic solvents such as dimethylacetamide, dimethyllaurylamide, methylpyrrolidone, dodecylpyrrolidone, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester Agents: Plasticizers such as diisopropyl adipate, phthalate ester, diethyl sebacate; hydrocarbons such as squalane and liquid paraffin; ethyl oleate, isopropyl palmitate, octyl palmitate, isopropyl myristate, isotridecyl myristate, ethyl laurate Fatty acid esters such as glycerin fatty acid esters and propylene glycol fatty acid esters; fatty acid esters of polyhydric alcohols such as 1-dodecanol, 1-tetradecanol, and 1-hexadecanol; 2-hexyl-1 -Branched aliphatic alcohols such as -decanol, 2-octyl-1-dodecanol, 2-hexyl-1-tetradecanol and the like.

  One or more skin permeation enhancers are used, and the content of the skin permeation enhancer in the adhesive layer is not particularly limited, but generally 10 to 70 wt. %, Preferably about 20 to 40% by weight based on the entire pressure-sensitive adhesive layer. When the content is less than 10% by weight, there is a possibility that sufficient skin permeation promoting effect of the drug may not be obtained, and conversely, when the content exceeds 70% by weight, the skin permeation promoting agent is formed on the pressure-sensitive adhesive layer surface. May bloom.

  In addition, the pressure-sensitive adhesive layer 4 is formed by physical crosslinking by radiation irradiation such as ultraviolet irradiation or electron beam irradiation, isocyanate compounds such as trifunctional isocyanate, organic peroxides, organic metal salts, metal alcoholates, metal chelate compounds, A cross-linked pressure-sensitive adhesive layer is obtained by performing a chemical cross-linking treatment using various cross-linking agents such as a functional compound (a polyfunctional external cross-linking agent or a monomer for polyfunctional internal cross-linking such as diacrylate or dimethacrylate). be able to.

  The pressure-sensitive adhesive layer 4 can contain a drug. The drug may be the same drug as the drug contained in the drug-containing layer 3 or a different drug. As an aspect in which the same drug as the drug contained in the drug-containing layer 3 is contained in the pressure-sensitive adhesive layer 4, for example, when a sufficient dose cannot be ensured only by the drug-containing layer 3, the drug in the drug-containing layer 3 There is an aspect in which a sufficient dose is secured with the drug in the adhesive layer 4. In the case where a drug different from the drug contained in the drug-containing layer 3 is contained in the pressure-sensitive adhesive layer 4, even if two drugs are concerned that the drug may interact or denature when contained in the same layer, With the transdermally absorbable precursor of the present invention, such two drugs can be stored without causing interaction or modification, and when these are actually administered, the transdermally absorbable preparation is formed on a release liner. Is completed (that is, the drug-containing layer 3 is laminated on the pressure-sensitive adhesive layer 4) and applied to the skin, so that two drugs can be administered simultaneously.

  The content of the drug in the pressure-sensitive adhesive layer 4 is appropriately set according to the type of drug, the purpose of administration, the drug content in the drug-containing layer 3 and the like, and is not particularly limited. It is about 1 to 40 weight% with respect to the whole.

  Although the thickness of the adhesive layer 4 is suitably set according to the kind etc. of adhesive used for an adhesive layer, generally it is 50-200 micrometers, Preferably it is 50-100 micrometers. If it is less than 50 μm, the adhesiveness to the skin may not be exhibited sufficiently. On the other hand, if the thickness exceeds 200 μm, the improvement in adhesiveness will reach its peak, which may increase the material cost.

Base Material Layer The base material layer 5 in the percutaneous absorption preparation precursor of the present invention is a layer that holds a drug-containing layer as a support in the completed percutaneous absorption preparation. The material of the base material layer is not particularly limited, but the drug contained in the drug-containing layer is lost from the back through the base material layer and does not cause a decrease in the content, that is, does not permeate the drug. Materials composed of materials are preferable, for example, polyester resins such as polyethylene terephthalate; polyamide resins such as nylon; olefin resins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, polyvinyl chloride, polyvinylidene chloride, ionomers Examples thereof include vinyl resins such as resins; acrylic resins such as ethylene-ethyl acrylate copolymers; fluorocarbon resins such as polytetrafluoroethylene; single films such as metal foils, and laminate films thereof. In addition, the thickness of a base material layer is 10 micrometers-200 micrometers normally, Preferably they are 15 micrometers-150 micrometers, More preferably, they are 20 micrometers-100 micrometers.

Furthermore, in order to improve the adhesiveness (anchoring property) between the base material layer 5 and the drug-containing layer 3, the base material is a non-porous film made of the above material and a laminate film made of a porous film, It is preferable to laminate so as to adhere the drug-containing layer. The porous film is not particularly limited as long as it improves the anchoring property between the base material layer and the drug-containing layer, and examples thereof include paper, woven fabric, nonwoven fabric, mechanically perforated film, and the like. In particular, paper, woven fabric, and non-woven fabric are preferable. The thickness of the porous film is preferably 10 μm to 100 μm in consideration of improvement in anchoring property and flexibility of the drug-containing layer. In the case of using a woven fabric or nonwoven fabric as the porous film, it is preferable in terms of anchoring improvement of the basis weight of ^{3g / m 2 ~50g / m 2} , and preferably ^5g / ^{m 2 ~30g} / m 2 .

Protective layer (protective release liner)
The percutaneous absorption-type preparation precursor of the present invention can be provided with a protective layer (protective release liner) for protecting the drug-containing layer 3 and the pressure-sensitive adhesive layer 4. The protective layer (protective release liner) is not particularly limited as long as a sufficiently light release property can be secured for the drug-containing layer 3 and the pressure-sensitive adhesive layer 4. Specific examples include plastic films such as polyester, polyvinyl chloride, polyvinylidene chloride, and polyethylene terephthalate that have been subjected to release treatment by applying silicone resin, fluororesin, etc., paper such as fine paper, glassine paper, or the like. A laminate film of high quality paper or glassine paper and polyolefin and the like can be mentioned. The thickness of the protective layer (release liner) is usually about 10 to 200 μm.

  The planar shape of the pressure-sensitive adhesive layer 4, the base material layer 5 and the protective layer (protective release liner) is basically the planar shape of the drug-containing layer 3 (for example, approximately square, approximately rectangular, elliptical, circular, etc.) Is the same. The size (planar area) is basically the same as that of the drug-containing layer 3. The pressure-sensitive adhesive layer 4, the base material layer 5, and the protective layer (protective release liner) may be slightly larger than the drug-containing layer 3. That is, it may be a size that protrudes in the range of about 20 mm or less from the peripheral edge of the entire circumference of the drug-containing layer 3, but the protruding length (dimension) is not limited to this.

2. Second Embodiment FIGS. 2 (A) to 2 (C) are schematic views of an example of the second embodiment of the percutaneous absorption type preparation precursor of the present invention, and FIG. 2 (D) is the percutaneous absorption type. FIG. 2E is a schematic cross-sectional view of a percutaneous absorption preparation assembled using a preparation precursor, and FIG. 2E is a schematic view showing a state where the percutaneous absorption preparation of FIG. 2D is attached to the skin. . In these drawings, the same reference numerals as those in FIGS. 1A to 1D denote the same or corresponding parts. Reference numeral 20 in FIG. 2E indicates the skin surface.

  The percutaneously absorbable preparation precursor of the second embodiment is different from the percutaneous absorbable preparation precursor 50 of the first embodiment in that a cover layer 6 is laminated on the drug-containing layer 3.

  In the example of FIG. 2 (percutaneous absorption type preparation precursor 51), the second reference line L2 is a straight line attached to the release liner 10 by coloring, embossing, etc., but the second reference line L2 is also the first reference line L2. You may form by the fold line of the 1-fold folding part 2. FIG. By doing so, the release liner 10 can be easily peeled off from the transdermal absorption preparation completed on the release liner 10, so that the operation of applying the transdermal absorption preparation to the skin can be performed more easily.

Cover Layer As shown in the percutaneous absorption preparation precursor 51 of the second embodiment, the cover layer 6 may be laminated on the drug-containing layer 3 in the percutaneous absorption preparation precursor of the present invention. . The cover layer 6 may have the function of the base material layer 5. Alternatively, the base material layer 5 may be laminated on the drug-containing layer 3 in advance, and the cover layer 6 may be further laminated on the base material layer 5.

  In the percutaneous absorption type preparation precursor of the present invention, the cover layer 6 is a layer for protecting the drug-containing layer 3, and in FIG. A planar shape having a size larger than that of the drug-containing layer 3 is formed in a substantially square sheet shape.

  In the percutaneous absorption-type preparation precursor of the present invention, the planar area of the cover layer 6 is not particularly limited as long as the drug-containing layer 3 can be coated. For example, the entire circumference of the drug-containing layer 3 is 0.5 cm or more from the periphery, The size which protrudes in the range of 5 cm or less is preferable.

  The material of the cover layer 6 is basically the same as the material of the base material layer. As the cover layer 6, for example, a single layer film or a laminate film made of resin, or a woven fabric or a non-woven fabric is used for these films. Further, a laminate can be used. Among them, one that does not hinder skin followability, that is, one that easily stretches according to the elongation of the skin surface is preferable. For example, polyethylene terephthalate, nylon, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyvinylidene chloride, Single-layer films and laminate films made from one or more thermoplastic resins selected from the group consisting of ionomer resins, ethylene-ethyl acrylate copolymers and polytetrafluoroethylene, and woven fabrics or What laminated the nonwoven fabric is used preferably.

  The fibers constituting the woven fabric or the nonwoven fabric are preferably resin fibers made of a thermoplastic resin or a thermosetting resin. Specific examples include olefin resin fibers such as polyethylene and polypropylene, polyester resin fibers such as polyethylene terephthalate, polyamide resin fibers such as nylon, and cellulose resin fibers. Any one of these resin fibers may be used alone, or two or more thereof may be used in combination.

  The thickness of the cover layer 6 is not specifically limited, For example, Preferably it is 10-200 micrometers, More preferably, it is 25-100 micrometers.

  As shown in FIG. 2 (E), the cover layer 6 is disposed so as to wrap the drug-containing layer 3 and the pressure-sensitive adhesive layer 4 with respect to the skin surface 20 in a state where the percutaneous absorption type preparation is applied to the skin. The Therefore, usually, the lower surface of the cover layer 6 (the surface in contact with the drug-containing layer 3 or the base material layer 5) is coated with an acrylic, rubber-based, silicone-based or other skin adhesive on at least the periphery.

  The cover layer 6 may be formed with a large number of through holes penetrating in the thickness direction, or the through holes may not be formed.

3. Third Embodiment FIGS. 3 (A) to 3 (C) are schematic views of an example of the third embodiment of the percutaneous absorption preparation precursor of the present invention, and FIG. 3 (D) is the percutaneous absorption type. FIG. 3 is a schematic cross-sectional view of a percutaneous absorption preparation assembled using a preparation precursor, and FIG. 3E is a schematic view showing a state where the percutaneous absorption preparation of FIG. 3D is affixed to the skin. . In these drawings, the same reference numerals as those in FIGS. 2A to 2E denote the same or corresponding parts.

  The transdermally absorbable preparation precursor of the third embodiment is different from the percutaneous absorbable preparation precursor 51 of the second embodiment in that a control layer 7 is laminated on the adhesive layer 4.

  In the example of FIG. 3 (percutaneous absorption type preparation precursor 52), the second reference line L2 is a straight line attached to the release liner 10 by coloring, embossing or the like, but instead of the straight line, the second reference line L2 is used. You may form the 1st mountain fold part 2 which the fold line applies to the line L2. By doing so, the release liner 10 can be easily peeled off from the transdermal absorption preparation completed on the release liner 10, so that the operation of applying the transdermal absorption preparation to the skin can be performed more easily.

Control Layer As shown in the percutaneous absorption preparation precursor 52 of the third embodiment, the control layer 7 may be laminated on the adhesive layer 4 in the percutaneous absorption preparation precursor of the present invention. .

  In the percutaneous absorption-type preparation precursor of the present invention, the control layer 7 is a pressure-sensitive adhesive from the surface of the drug-containing layer 3 by diffusion transfer of the drug contained in the drug-containing layer 3 in a predetermined percutaneous absorption-type preparation to be produced. This is a layer for controlling the release amount and release rate when released to the layer 4 and exhibits a barrier function against free diffusion.

  When a percutaneous absorption-type preparation with a layered structure in which a control layer is laminated on a drug-containing layer is stored, the migration and adsorption of the drug contained in the drug-containing layer proceeds to the control layer, affecting the drug release at the time of administration. Effect. However, in the transdermal preparation precursor of the present invention, the drug-containing layer 3 and the control layer 7 are separated on the release liner 10, and the drug-containing layer 3 and the control layer 7 are stored (stored) separately. Therefore, the migration / adsorption of the drug contained in the drug-containing layer to the control layer can be prevented. When the drug is administered to the skin, the control layer 7 is laminated on the drug-containing layer 3 on the release liner 10 to complete a percutaneous absorption preparation having a predetermined laminated structure. Regardless, stable drug release is obtained.

  Examples of the control layer 7 include paper, non-woven fabric, woven fabric, perforated plastic film, and the like, and any non-porous plastic film (for example, polyethylene film, polypropylene film, ethylene / ethylene film) can be used as long as it is made of a material that dissolves the drug. Vinyl acetate copolymer film). However, when a non-porous plastic film is used, the release rate of the drug from the drug-containing layer may decrease, and the effective utilization rate of the drug in the drug-containing layer may decrease. Therefore, it is preferable to use a porous plastic membrane, particularly a plastic porous membrane. Further, the thickness of the plastic porous membrane is not particularly limited, but it is preferable to use a thickness of 100 μm or less in order to reduce the uncomfortable feeling (stiff feeling) at the time of application to the skin surface.

  Specific examples of the plastic porous membrane include polyethylene, polypropylene, polytetrafluoroethylene, ethylene / vinyl acetate copolymer, vinyl acetate / vinyl chloride copolymer, plastic vinyl chloride, polyurethane, polyvinylidene chloride, polyester, and the like. The thing which consists of material of this is mentioned.

  The plastic porous membrane preferably has an average pore size of 0.01 to 2.0 μm from the viewpoint of drug release controllability. The porosity is generally 20 to 95%, but is not limited thereto.

  In the percutaneous absorption type preparation precursor of the present invention, the control layer 7 is laminated on the adhesive layer 4 to control the release amount and the release rate of the drug from the drug-containing layer 3. Is transdermally absorbed into the body and a percutaneous absorption type preparation that suppresses skin irritation caused by the drug can be easily obtained.

  The plane area of the control layer 7 is not particularly limited, and even if it is the same as the pressure-sensitive adhesive layer 4, the pressure-sensitive adhesive layer protrudes within the range of 3 cm or less from the periphery of the pressure-sensitive adhesive layer 4 over the entire circumference of the pressure-sensitive adhesive layer 4. The planar area larger than the planar area of 4 or the planar area smaller than the planar area of the pressure-sensitive adhesive layer 4 may be used.

  The thickness of the control layer 7 is preferably 1 μm or more and 100 μm or less from the viewpoint of good drug release.

4). Fourth Embodiment FIGS. 4-1 (A), 4-1 (B), FIG. 4-2 (A), FIG. 4-2 (B), FIG. 4-3 (A) and FIG. 4-3 (B) ) Is a schematic view of an example of the fourth embodiment of the percutaneous absorption type preparation precursor of the present invention, and FIG. 4-3 (C) is a percutaneous absorption assembled using the percutaneous absorption type preparation precursor. It is a schematic sectional drawing of a type | mold formulation. In these drawings, the same reference numerals as those in FIGS. 2A to 2E denote the same or corresponding parts.

  The percutaneously absorbable preparation precursor 53 of this embodiment further includes a second valley fold portion 8 and a second mountain fold portion 9 in the release liner 10 with respect to the percutaneous absorbable preparation precursors of the first to third embodiments. In addition, the three layers included in a predetermined percutaneous absorption preparation to be manufactured (percutaneous absorption preparation to be completed) can be separately disposed on the release liner 10. In the release liner 10, the second valley fold 8 is formed at a position opposite to the first valley fold 1 with the second reference line L 2 interposed therebetween, and the second reference fold 8 is sandwiched between the second valley fold 8. The second mountain fold 9 is further provided at a position opposite to the line L2, and the distance between the second valley fold 9 and the second reference line L2 is such that the second mountain fold 9 and the second valley fold 8 are. It is set as the structure substantially equal to the space | interval. In the percutaneous absorption type pharmaceutical precursor 53 of this embodiment, the second reference line L2 is a straight line that can be recognized at least visually or tactilely by coloring or embossing.

  If it is the percutaneously absorbable preparation precursor 53 of this embodiment, the drug-containing layer 3 and the adhesive layer 4 can be separated and stored (FIG. 4A (A)). When the transdermal absorption preparation is administered to the skin, the first mountain fold 2 is folded (FIG. 4B), and the first valley fold 1 is valley-folded (see FIG. 4). 4-2 (A)) When the release liner 10 is peeled from the drug-containing layer 3 while the drug-containing layer 3 is superimposed on the pressure-sensitive adhesive layer 4, the drug-containing layer 3 is laminated on the pressure-sensitive adhesive layer 4 ( FIG. 4-2 (B)). Thereafter, the second mountain fold 9 is folded (FIG. 4-3 (A)), the second valley fold 8 is valley-folded (FIG. 4-3 (B)), and the cover layer 6 is formed into the drug-containing layer. When the release liner 10 is peeled off from the cover layer 6 while being stacked on the cover 3, the cover layer 6 is laminated on the drug-containing layer 3 and has a laminated structure of cover layer 6 / drug-containing layer 3 / adhesive layer 4. A transdermal preparation is completed (FIG. 4-3 (C)).

  In the transdermal preparation precursor 53 of the above example, there is one drug-containing layer 3, but a drug-containing layer may be disposed under the cover layer 6 (see FIG. 2A). (Refer to the state where the drug-containing layer 3 is covered with the cover layer 6). Alternatively, a drug-containing layer may be provided in place of the cover layer 6. By doing so, it is possible to assemble a percutaneous absorption preparation having a single drug-containing layer on the release liner, or a percutaneous absorption preparation consisting of a laminate of two drug-containing layers. Accordingly, transdermal preparations having different drug contents can be easily obtained. If the adhesive layer 4 also contains a drug, three patterns of transdermal absorption preparations having different drug contents can be obtained easily.

  In the percutaneous absorption type preparation precursor of the embodiment described above, information indicating the order of mountain fold and valley fold is not attached to the release liner. Assembling of the absorption-type preparation can be performed more reliably and efficiently. Such information can include, for example, at least letters and symbols that can be recognized visually or by touch, or combinations thereof.

  The method for producing the percutaneous absorption type preparation precursor of the present invention is not particularly limited. For example, on the release liner prepared separately from the release liner formed with the reference line, the mountain fold portion, and the valley fold portion for the precursor. It can be produced by forming layers (drug-containing layer, pressure-sensitive adhesive layer, etc.) to be included in the target percutaneous absorption type preparation precursor, and transferring those layers to a release liner for the precursor.

  The percutaneous absorption-type preparation precursor of the present invention can also be made into a package enclosed in a package together with a description that describes the order of folding and valley folding of the release liner.

  EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited by the following examples, and appropriate modifications are made within a range that can meet the above and the following purposes. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention. In the following, “parts” means “parts by weight” unless otherwise specified.

[Example 1]
(Preparation of tramadol octanoate)
Tramadol hydrochloride and sodium octanoate were dissolved in ultrapure water so as to have an equimolar amount, and ethyl acetate was further added and stirred. The ethyl acetate layer was collected using a separatory funnel and washed with ultrapure water. Ethyl acetate was removed from the washed ethyl acetate layer using an evaporator, methanol was added, and the solvent was removed. The residue after removal of the solvent was dried using a vacuum pump for about 16 hours to obtain tramadol octanoate crystals.

(Preparation of acrylic copolymer)
Under an inert gas atmosphere, 95 parts of 2-ethylhexyl acrylate, 5 parts of acrylic acid and 0.2 part of azobisisobutyronitrile were solution polymerized in ethyl acetate at 60 ° C. to obtain an ethyl acetate solution of the above copolymer. Was prepared.

(Manufacture of transdermal drug product precursors)
20 parts of methacrylic acid / methyl methacrylate copolymer ("Eudragit L100" (Evonik Rohm Co., Ltd.), glass transition temperature: 150 ° C) and 80 parts of tramadol octanoate are kneaded while being heated using a biaxial melt extruder. And extruded to obtain a mixture. An appropriate amount of the mixture is placed on a release-treated surface of a PET liner (thickness = 75 μm), further covered with a PET film (thickness = 25 μm), and a sheet having a mixture thickness of 250 μm using a heating press. After compression molding to form a shape, a square area of 10 mm ² (length 32 mm × width 32 mm, R = 5.3 mm) obtained by applying arcs with a radius of 5.3 mm to the four corners is punched into a drug. The 1st laminated body containing a content layer was obtained.

Next, 34.7 parts (as a solid content) of an ethyl acetate solution of an acrylic copolymer, 65 parts of isopropyl myristate, and trifunctional isocyanate (“Coronate HL” (manufactured by Nippon Polyurethane Industry Co., Ltd.)) as a crosslinking agent 3 parts (as a solid content) was added to an appropriate amount of ethyl acetate, and sufficiently mixed and stirred to dissolve uniformly to obtain a coating solution. The obtained coating solution was applied to the release-treated surface of the PET liner 1 (thickness = 75 μm) so that the thickness after drying was about 100 μm and dried, and further the PET liner 2 was applied to the adhesive surface. After bonding the peel-treated surfaces of (thickness = 75 μm), the plane area obtained by applying arcs with a radius of 5.3 mm to the four corners is 10 cm ² (length 32 mm × width 32 mm, R = 5.3 mm). Punched into a substantially square, a second laminate including a skin adhesive layer was obtained.

Prepare a paper liner (thickness: 100 μm) having a rectangular shape with a long side of 16 cm and a short side of 6 cm. The position where the long side of the release liner is divided into two equal parts is defined as the first valley fold. A position 4 cm away from the fold (the fold line) toward one short side is from the first mountain fold (= first reference line) and from the first valley fold (the fold line) to the other short side. The position separated by 4 cm was taken as the second reference line.
After removing the PET release liner of the first laminate, the drug-containing layer was bonded to the release-treated surface of the paper liner so that the center line of the drug-containing layer and the first reference line were aligned. Next, after peeling off the PET release liner 2 of the second laminate, the skin adhesive layer is bonded to the release treatment surface of the paper liner so that the center line of the skin adhesive layer matches the second reference line, A percutaneous absorption-type preparation precursor I was obtained.

(Evaluation of drug status)
The percutaneous absorption-type preparation precursor I was stored at room temperature, and the drug-containing layer at the time when 1 day, 2 days, 1 month, 6 months, and 8 months had elapsed after storage was visually and polarized microscope (DP71 OLYMPUS) Observed at. As a result, it was confirmed that no drug crystals were observed in the drug-containing layer at any storage time, and the film was amorphous.

(Operability evaluation)
In the percutaneous absorption-type preparation precursor I, after peeling the PET release liner 1 covering the skin adhesive layer, the first mountain fold is folded and a part of the drug-containing layer is peeled from the paper release liner. While folding the paper release liner at the first valley fold, the drug-containing layer is laminated on the skin adhesive layer so that the first reference line (= the fold line of the first mountain fold) is aligned with the second reference line As a result, a transdermally absorbable preparation was obtained.

  It was confirmed that the obtained percutaneously absorbable preparation precursor I was able to prevent drug crystallization by maintaining the drug in the drug-containing layer in an amorphous state even when stored for 8 months at room temperature. It was done. Further, in the operability evaluation, the percutaneous absorption-type preparation precursor I can be easily laminated without causing any misalignment between the drug-containing layer and the skin adhesive layer (displacement of the pasting position). The percutaneous absorption type preparation could be easily obtained.

DESCRIPTION OF SYMBOLS 1 1st valley fold part 2 1st mountain fold part 3 Drug content layer 4 Adhesive layer L1 1st reference line L2 2nd reference line 10 Release liner 50-53 Transdermal absorption type formulation precursor

Claims (9)

A release liner having one first valley fold and one or two first mountain folds, the first valley folds on one side and the other side separating from the first valley fold A release liner having a first reference line and a second reference line at substantially equidistant positions from each other, and at least one of the first reference line and the second reference line being a fold line of the first mountain fold,
A first layer having a planar shape disposed on the release liner so that the center line is located on the first reference line, and disposed so that the center line is located on the second reference line. A second layer having a planar shape,
A percutaneously absorbable preparation precursor, wherein the first layer and / or the second layer contains a drug.   The transdermal preparation precursor according to claim 1, wherein one of the first layer and the second layer is a drug-containing layer, and the other is an adhesive layer.   The transdermal preparation precursor according to claim 2, wherein the pressure-sensitive adhesive layer contains an additive.   The percutaneous absorption-type preparation precursor according to claim 2 or 3, wherein a control layer is laminated on the adhesive layer.   The transdermal absorption preparation precursor according to claim 2 or 3, wherein the adhesive layer contains a drug.   The percutaneously absorbable preparation precursor according to any one of claims 2 to 5, wherein a base material layer and / or a cover layer is laminated on the drug-containing layer. It has a second valley fold at a position opposite to the first valley fold across the second reference line of the release liner, and is located at a position opposite to the second reference line across the second valley fold. Has two folds,
The interval between the second valley fold and the second reference line is substantially equal to the interval between the second mountain fold and the second valley fold,
The transdermal absorption according to any one of claims 1 to 5, further comprising a third layer having a planar shape disposed on the release liner so that a center line thereof is positioned on a fold line of the second mountain fold. Mold formulation precursor.   The transdermal preparation precursor according to claim 7, wherein the third layer is a cover layer.   The transdermal preparation precursor according to claim 7, wherein the third layer is a drug-containing layer.