WO2018199015A1

WO2018199015A1 - Transdermally absorbable preparation and method for producing same

Info

Publication number: WO2018199015A1
Application number: PCT/JP2018/016441
Authority: WO
Inventors: 宏史更田; 英範澤田; 川村　尚久
Original assignee: ニプロ株式会社
Priority date: 2017-04-26
Filing date: 2018-04-23
Publication date: 2018-11-01
Also published as: JPWO2018199015A1

Abstract

This transdermally absorbable preparation is provided with a support, a reservoir layer containing rotigotine or a salt thereof, an adhesive layer containing a rubber-based adhesive, and a release liner, in the stated order. While having skin permeability equivalent to that of commercial transdermally absorbable preparations containing rotigotine, the present invention makes it possible to, e.g., provide higher adhesiveness than in these preparations and/or maintain the stability of the rotigotine or salt thereof without containing sulfite. This makes it possible in this transdermally absorbable preparation to prevent detachment from the skin of a patient and/or prevent induction of skin hypersensitivity in the patient, and to properly administer rotigotine or a salt thereof to the patient.

Description

Transdermal preparation and method for producing the same

The present invention relates to a transdermal preparation and a method for producing the same, and more particularly to a transdermal preparation containing rotigotine or a salt thereof as an active ingredient and a method for producing the same.

Rotigotine has a D3 / D2 / D1 dopamine receptor agonistic action and is an active ingredient of a pharmaceutical agent useful for the treatment of Parkinson's disease and moderate to advanced idiopathic restless legs syndrome (restless leg syndrome). Rotigotine is used, for example, in a dosage form of a transdermal preparation comprising an adhesive layer containing rotigotine between a support and a liner. In Japan, “New Pro (registered trademark) patch” is used. Is commercially available under the trade name "Non-patent Document 1".

As percutaneous absorption preparations containing such rotigotine, Patent Documents 1 to 4 describe rotigotine and polyvinylpyrrolidone as two types of adhesives (for example, an acrylic pressure-sensitive adhesive and a silicone-based pressure sensitive adhesive). A so-called micro-reservoir type preparation technique dispersed in an adhesive layer composed of

However, in these percutaneous absorption preparations described in Patent Documents 1 to 4, the silicone-based pressure-sensitive adhesive constituting the adhesive layer does not have sufficient adhesiveness, so that the application to the skin is not necessarily satisfactory. It's hard to say.

On the other hand, Patent Document 5 discloses a so-called matrix-type preparation technique using a rubber adhesive containing a rosin resin and a rubber adhesive component in order to suppress crystal precipitation derived from rotigotine. Furthermore, Patent Document 6 discloses a so-called matrix-type preparation technique using a rubber adhesive and using mercaptobenzimidazole or sulfite as a production inhibitor of a decomposition product of rotigotine.

However, it is pointed out that the percutaneous absorption preparations described in Patent Documents 5 and 6 have insufficient skin permeability of rotigotine. The sulfite is a compound that may induce skin hypersensitivity (sulfite hypersensitivity). In view of more patient applications, it is desirable to avoid the use of the compounds in transdermal formulations as much as possible.

For this reason, development of a new transdermal absorption preparation containing rotigotine which can be replaced with a conventional preparation is desired.

Special table 2002-509878 Special table 2004-536054 gazette Special table 2010-532390 Special table 2016-500086 gazette JP 2014-177428 A JP 2013-079220 A

The present invention has an object to solve the above-mentioned problems, and the object of the present invention is, for example, a skin that is better applied to the skin by improving the adhesive force as compared with conventional rotigotine commercially available preparations. Disclosed is a transdermal preparation and a method for producing the same, having excellent characteristics such as improving the stability of rotigotine or a salt thereof as an active ingredient, which can avoid the concern of inducing hypersensitivity (sulfite hypersensitivity). There is.

The present invention provides a support;
A reservoir layer containing rotigotine or a salt thereof and a substrate;
A pressure-sensitive adhesive layer containing a rubber-based adhesive; and a release liner;
In this order.

In one embodiment, the reservoir layer has a film-like layer structure.

In one embodiment, the release liner has a siliconized surface.

In one embodiment, the rubber adhesive is polyisobutylene, polybutene, polyisoprene, styrene / isoprene / styrene block copolymer, styrene / butadiene / styrene block copolymer, butyl rubber, styrene / butadiene rubber and natural rubber. And at least one rubber compound selected from the group consisting of:

In a further embodiment, the rubber adhesive is polyisobutylene.

In one embodiment, the reservoir layer further contains dibutylhydroxytoluene.

In a further embodiment, the total content of dibutylhydroxytoluene is 0.01 mg to 4 mg.

In one embodiment, the reservoir layer does not contain sulfite.

In one embodiment, a portion of the rotigotine or salt thereof has migrated from the reservoir layer into the adhesive layer and is 80% to 99.9% by weight of the total content of the rotigotine or salt thereof. % Remains in the reservoir layer.

The present invention is also a method for producing a transdermally absorbable preparation,
The method includes a step of laminating a support; a reservoir layer containing rotigotine or a salt thereof and a substrate; an adhesive layer containing a rubber-based adhesive; and a release liner in this order.

In one embodiment, in the laminating step, the adhesive layer does not contain the rotigotine or a salt thereof.

In one embodiment, in the laminating step,
The total weight of the reservoir layer is 5 g / m ² to 50 g / m ² ;
When the total weight of the rubber-based adhesive contained in the adhesive layer and the base material contained in the reservoir layer is 100, the ratio of the weight of the rotigotine or salt thereof contained is 5 to 50, Then, the reservoir layer and the adhesive layer are laminated so that the weight ratio of the adhesive layer is 100 to 1000 when the weight of the reservoir layer is 100.

The present invention also provides a support;
A reservoir layer comprising rotigotine or a salt thereof, a substrate and dibutylhydroxytoluene;
An adhesive layer; and a release liner;
In this order.

In one embodiment, the reservoir layer has a film-like layer structure.

In one embodiment, the total content of dibutylhydroxytoluene is 0.01 mg or more and 4 mg or less.

In one embodiment, the adhesive layer contains a rubber-based adhesive and the release liner has a siliconized surface.

In a further embodiment, the rubber adhesive is polyisobutylene.

The present invention is also a method for producing a transdermally absorbable preparation,
A method comprising a step of laminating a support; a reservoir layer comprising rotigotine or a salt thereof, a substrate, and dibutylhydroxytoluene; an adhesive layer; and a release liner in this order.

In one embodiment, in the laminating step,
The total weight of the reservoir layer is 5 g / m ² to 50 g / m ² ;
When the total weight of the adhesive base contained in the adhesive layer and the substrate contained in the reservoir layer is 100, the weight ratio of the rotigotine or a salt thereof is 5 to 50, and the reservoir layer The reservoir layer and the adhesive layer are laminated so that the weight ratio of the adhesive layer when the weight is 100 is 100 to 1000.

According to the present invention, high adhesiveness to the skin can be maintained for a long time. This makes it possible to avoid loss of opportunity to allow the desired amount of rotigotine or a salt thereof to permeate through the skin by being easily removed after the preparation is applied to the skin.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing an example of a transdermally absorbable preparation of the present invention, in which (a) is a perspective view of the transdermally absorbable preparation, and (b) is an AA direction of the preparation shown in (a) It is sectional drawing. It is a figure which shows the example of the manufacturing method of the percutaneous absorption type formulation of this invention, Comprising: It is a schematic diagram for demonstrating the lamination | stacking procedure which comprises the said formulation.

Hereinafter, the present invention will be described in detail. In addition, this invention is not limited only by the following, This invention can have various embodiment as long as the objective is achieved.

FIG. 1 shows an example of a transdermal absorption preparation of the present invention. As shown to (a) of FIG. 1, the percutaneous absorption type formulation 100 of this invention is a patch which has the external appearance of predetermined shapes, such as a rectangle. In one embodiment of the present invention shown in FIG. 1, the transdermally absorbable preparation 100 includes a support 110, a reservoir layer 120, an adhesive layer 130, and a release liner 140 in this order ((( b)).
The size of the transdermally absorbable preparation of the present invention is not necessarily limited, but has an area of, for example, 2 cm ² to 50 cm ² , or 3 cm ² to 50 cm ² . More specifically, the percutaneous absorption type preparation 100 has a surface (sticking surface) having an area of, for example, 5 cm ² , 10 cm ² , 15 cm ² , 20 cm ² , 30 cm ² , 40 cm ² , preferably four corners It has the appearance of a round-shaped rectangle (for example, a square).

Here, the term “in this order” used in the present specification represents only the order in which the support, the reservoir layer, the adhesive layer, and the release liner included in the transdermally absorbable preparation of the present invention are arranged. Unless otherwise specified, within the range that does not impair the operation and effect of the present invention, one member constituting the support, reservoir layer, adhesive layer, or release liner and the other members constituting them This includes the case where another member (for example, a layer) is disposed between the members.

1 (b), the transdermal preparation 100 of the present invention has a structure in which a support 110, a reservoir layer 120, an adhesive layer 130, and a release liner 140 are laminated in this order. Such a laminated structure has a simple structure as compared with, for example, microreservoir type percutaneous absorption preparations described in Patent Documents 1 to 4, and can be manufactured more easily. .

The support 110 supports the reservoir layer 120 and the adhesive layer 130 in the percutaneously absorbable preparation, and covers the reservoir layer 120 so that a patient or the like does not directly touch the reservoir layer 120.

The structure and material of the support 110 are not particularly limited as long as they are generally used in the field of transdermal absorption preparations. Examples of the structure of the support 110 include fabrics such as woven fabrics, nonwoven fabrics, and knitted fabrics, films, and sheets. Examples of the material constituting the support include thermoplastic resins such as polypropylene, polyethylene, polybutylene, polyethylene terephthalate, and polyurethane, or fiber materials (for example, filaments), regenerated fibers such as rayon, natural fibers such as cotton, and Examples thereof include pulp fibers such as paper. A nonwoven fabric made of polyethylene terephthalate is preferably used for the support 110 because it is widely used in the technical field and is easily available.

The thickness of the support 110 is not necessarily limited, but is, for example, 10 μm to 80 μm.

In the present invention, the reservoir layer 120 is provided between the support 110 and the adhesive layer 130. Further, in the embodiment shown in FIG. 1B, the reservoir layer 120 is provided so that one surface is in contact with the support 110 and the other surface is in contact with the adhesive layer 130.

The reservoir layer 120 contains rotigotine or a salt thereof and a base material. Furthermore, the reservoir layer preferably has a film-like layer structure. Such a layer structure is clearly distinguished from a reservoir employed in a microreservoir type percutaneous absorption preparation described in, for example, Patent Documents 1 to 4.

Rotigotine is represented by the chemical name of (6S) -6- [propyl [2- (thiophen-2-yl) ethyl] amino] -5,6,7,8-tetrahydronaphthalen-1-ol, D3 / D2 / D1 has a dopamine receptor agonist activity and is used as an active ingredient for treating, for example, Parkinson's disease and moderate to high idiopathic restless legs syndrome (restless leg syndrome). Rotigotine is composed of an amorphous form or a crystalline polymorph of type I or type II. The rotigotine used in the present invention is preferably an amorphous body. Rotigotine is also preferably present in a dissolved state in the base material of the transdermal preparation of the present invention.

Rotigotine salts include both inorganic salts and organic salts as long as they are pharmaceutically acceptable. An example of such a rotigotine salt is rotigotine hydrochloride.

Here, in the transdermally absorbable preparation 100 of the present invention, most of rotigotine or a salt thereof is mainly contained in the reservoir layer 120, but a part thereof is transferred from the reservoir layer 120 to the adhesive layer 130 as described later. Exists in a migrated state. For this reason, in the present invention, the content of rotigotine or a salt thereof is selected on the basis of the total amount in one transdermal preparation (that is, the amount contained in the entire transdermal preparation). In the present invention, the content of rotigotine or a salt thereof is determined depending on whether the therapeutic purpose (that is, the transdermal preparation of the present invention is Parkinson's disease or moderate to highly idiopathic restless legs syndrome). Although it is not necessarily limited, it is selected from the range of 0.5 mg to 20 mg per transdermal preparation, for example. More specifically, in the present invention, the content of rotigotine or a salt thereof is determined according to a commercially available rotigotine preparation (for example, “New Pro® Patch” marketed in Japan and “NEUPRO” marketed in the United States. Content similar to “PATCH”) (eg 2.25, 4.5, 6.75, 9, 13.5 and 18 mg) may be employed.

In the reservoir layer 120, the base material plays a role of holding the rotigotine or a salt thereof.

The substrate is not particularly limited as long as it is generally used in the field of percutaneous absorption preparations. For example, a hydrophilic or water-soluble substrate can be suitably selected. Examples of materials constituting the substrate include gelatin, agar, polyvinyl alcohol, polyvinylpyrrolidone, propylene carbonate, carboxymethylcellulose, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, sodium alginate, maleic anhydride Copolymers and carrageenans, and combinations thereof are mentioned. These materials can be used in combination so as to have a viscosity suitable for production, for example. For example, when a combination of polyvinyl pyrrolidone and hydroxypropyl cellulose is employed, 10 to 200 parts by weight of hydroxypropyl cellulose is mixed with 100 parts by weight of polyvinyl pyrrolidone. By combining polyvinyl pyrrolidone and hydroxypropyl cellulose at such a ratio, the non-crystalline property of rotigotine can be preferably stably maintained during the production of the transdermal absorption preparation of the present invention.

The reservoir layer 120 may contain an antioxidant. The antioxidant can act as a production inhibitor that suppresses the production of degradation products mainly derived from rotigotine or a salt thereof contained in the reservoir layer 120. Examples of such antioxidants include sulfites such as dibutylhydroxytoluene, sodium pyrosulfite, sodium bisulfite, sodium sulfite, and potassium pyrosulfite, and phenolic antioxidants such as mercaptobenzimidazole, butylhydroxyanisole, and propyl gallate. Oxidizing agent, L-ascorbic acid, L-ascorbic acid palmitic acid ester, ascorbic acid and its ester derivatives such as sodium isoascorbate, sodium edetate, citric acid, potassium dicycloisocyanurate, soybean lecithin, thymol, tocopherol and the like Examples include ester derivatives, 1,3-butylene glycol, benzotriazole and monothioglycerin, and combinations thereof.

On the other hand, in one embodiment of the present invention, from the viewpoint of avoiding induction of skin hypersensitivity (sulfite hypersensitivity), as an antioxidant added to the reservoir layer 120, sodium pyrosulfite, sodium bisulfite, sodium sulfite And does not contain sulfites such as potassium pyrosulfite. Furthermore, in a further embodiment of the present invention, the reservoir layer 120 contains, for example, dibutylhydroxytoluene instead of the sulfite as the antioxidant.

In the percutaneous absorption preparation of the present invention, for example, when dibutylhydroxytoluene is used as an antioxidant, the total content of dibutylhydroxytoluene is, for example, 4 mg or less, preferably 0.01 mg or more per preparation. 4 mg or less. Alternatively, when the total of the weight of the reservoir layer 120 and the weight of the adhesive layer 130 is 100%, the total content of the dibutylhydroxytoluene is preferably 0.01% by weight to 1% by weight, more preferably 0.00%. 05 wt% to 0.5 wt%. Alternatively, the total content of the dibutylhydroxytoluene, based on unit area of the formulation, preferably ^{0.00025mg / cm 2 ~ 0.8mg / cm} 2, more preferably 0.001mg ^/ cm 2 ~ 0.05mg ^/ cm ² .

Furthermore, the reservoir layer 120 may contain other components in addition to the rotigotine or a salt thereof and a base material, and an antioxidant contained as necessary. Examples of other components that may be contained in the reservoir layer 120 include inorganic powders, surfactants, crosslinking agents, crosslinking control agents, adhesion enhancers, pH adjusters, cooling agents, water-soluble polymer compounds. , Preservatives, pigments, and humectants, and combinations thereof. The amount of the other components contained in the reservoir layer 120 is not particularly limited, and an appropriate content can be selected by those skilled in the art.

The thickness of the reservoir layer 120 is not necessarily limited, but is, for example, 5 μm to 50 μm.

In the present invention, the adhesive layer 130 is provided between the reservoir layer 120 and the release liner 140. Further, in the embodiment shown in FIG. 1B, the adhesive layer 130 is provided so that one surface is in contact with the reservoir layer 120 and the other surface is in contact with the release liner 140.

The adhesive layer 130 serves to deliver rotigotine or a salt thereof contained in the reservoir layer 120 to the patient's body through the patient's skin by directly attaching the exposed surface of the release liner 140 to the patient's skin. Fulfill.

In the present invention, the adhesive layer 130 contains an adhesive base. Examples of the adhesive substrate include rubber adhesives, acrylic adhesives, silicone adhesives, and adhesives composed of combinations thereof. The rubber adhesive is not particularly limited as long as it is generally used in the field of percutaneous absorption preparations. For example, polyisobutylene, polybutene, polyisoprene, styrene / isoprene / styrene block copolymer Styrene-butadiene-styrene block copolymers, butyl rubber, styrene-butadiene rubber and natural rubber, and combinations thereof. Specific examples of the acrylic adhesive include isobornyl acrylate, tetrahydrofurfuryl acrylate, 2-hydroxy-3-phenoxypropyl acrylate, butoxyethyl acrylate, lauryl acrylate, stearyl acrylate, benzyl acrylate, hexyl diglycol acrylate, Monofunctional (meth) acrylates such as 2-hydroxyethyl acrylate, 2-ethylhexyl acrylate, cyclohexyl acrylate, phenoxyethyl acrylate, dicyclopentadiene acrylate, polyethylene glycol acrylate, polypropylene glycol acrylate, nonylphenoxyethyl cellosolve acrylate, and polyethylene glycol diacrylate , Neopentyl glycol diacrylate , Tri triacrylate, polyfunctional (meth) acrylates such as pentaerythritol triacrylate, and combinations thereof. Specific examples of silicone-based adhesives include organopolysiloxanes, diorganopolysiloxanes, and organohydrogenpolysiloxanes, and combinations thereof. In the present invention, it is preferable that a rubber adhesive is selected as the pressure-sensitive adhesive substrate for the pressure-sensitive adhesive layer 130 because of its high adhesive strength to the skin.

The adhesive layer 130 does not contain the above rotigotine or a salt thereof before the reservoir layer 120 is laminated. However, as shown in FIG. 1B, after the reservoir layer 120 is laminated on the adhesive layer 130, a part of rotigotine or a salt thereof contained in the reservoir layer 120 gradually moves to the adhesive layer 130, and Spread. For this reason, the content of rotigotine or a salt thereof in the adhesive layer 130 increases with time for a certain period after being laminated with the reservoir layer 120, and is then used in a stable state. Thus, in a state where the transfer of rotigotine or a salt thereof to the adhesive layer 130 is finally stable, the transdermal preparation 100 of the present invention is preferably 80% by weight of the total content of rotigotine or a salt thereof. ˜99.9 wt% stays in the reservoir layer 120, or preferably 0.1 wt% to 20 wt% of the total content of rotigotine or a salt thereof stays in the adhesive layer 130.

In the present invention, the adhesive layer 130 is used in the earliest possible time from the viewpoint of shortening the time required from the production of the transdermal preparation to the start of use with respect to the transfer of rotigotine or a salt thereof from the reservoir layer 120. In addition, it preferably has the property of reaching the saturation amount of rotigotine or a salt thereof. The time required for the saturation amount in the adhesive layer 130 can be varied by adjusting the concentration of rotigotine or a salt thereof previously added to the reservoir layer 120 and the weight of each layer set in the reservoir layer 120 and the adhesive layer 130. is there. For example, when the support 110, the reservoir layer 120, the adhesive layer 130, and the release liner 140 constituting the transdermal preparation 100 of the present invention are laminated, the total weight of the reservoir layer 120 is preferably 5 g / The ratio of the weight of rotigotine or a salt thereof when m ² to 50 g / m ² and the total weight of the rubber-based adhesive contained in the adhesive layer 130 and the base material contained in the reservoir layer 120 is 100 If the ratio of the weight of the adhesive layer 130 is preferably 100 to 1000 when the weight of the reservoir layer 120 is 100, one of rotigotine or a salt thereof added to the reservoir layer 120 is preferable. Can be transferred and diffused to the adhesive layer 130 earlier, and the content of rotigotine or a salt thereof in the adhesive layer 130 can be saturated in a shorter time. It is possible to raise up to the amount.

In addition, the adhesive layer 130 may contain a plasticizer as appropriate from the viewpoint of improving moldability. The plasticizer is not particularly limited as long as it is generally used in the field of transdermal absorption preparations. For example, petroleum oil (paraffinic process oil, naphthenic process oil, aromatic process oil, etc.) ), Liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, isopropyl linoleate, etc.), vegetable oils (olive oil, camellia oil, castor oil, tall oil, peanut oil, etc.), liquid rubber (Liquid polyisobutylene, liquid polybutene, liquid polyisoprene, etc.), glycerin, chlorobutanol, vinyl acetate resin, dimethylpolysiloxane / silicon dioxide mixture, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, pyrrolidones, phytostero Le, propylene glycol, polyethylene glycol, glycerin polysorbate 80 (TM) and monostearate, and combinations thereof. The plasticizer is appropriately selected depending on the type of the pressure-sensitive adhesive substrate used in the pressure-sensitive adhesive layer 130. For example, when polyisobutylene (rubber adhesive) is selected as the pressure-sensitive adhesive substrate, it is easily available and polyisobutylene. It is preferable to use isopropyl myristate as a plasticizer because it has a high affinity with the styrene. The amount of the plasticizer contained in the adhesive layer 130 is not particularly limited, and an appropriate content can be selected by those skilled in the art.

Furthermore, the adhesive layer 130 may contain other components in addition to the adhesive and the plasticizer contained as necessary. Examples of other components that may be included in the adhesive layer 130 include inorganic powders, surfactants, crosslinking agents, crosslinking control agents, adhesion enhancers, pH regulators, cooling agents, water-soluble polymer compounds. , Preservatives, pigments, and humectants, and combinations thereof. The amount of other components contained in the adhesive layer 130 is not particularly limited, and an appropriate content can be selected by those skilled in the art.

The thickness of the adhesive layer 130 is not necessarily limited, but is, for example, 30 μm to 70 μm.

The release liner 140 constitutes one outermost layer of the transdermal preparation 100 of the present invention. Further, in the embodiment shown in FIG. 1B, the release liner 140 is provided so that one surface is in contact with the adhesive layer 130.

The release liner 140 serves to protect the adhesive layer 130 until the adhesive layer 130 is directly applied to the patient's skin.

The material constituting the release liner 140 is not particularly limited as long as it is generally used in the field of percutaneous absorption preparations. For example, paper, resin films such as polystyrene, polyethylene terephthalate and polypropylene, or Sheet.

The release liner 140 that can be in direct contact with the adhesive layer 130 may have a release surface that has been subjected to a surface treatment such as silicone treatment or embossing in order to improve the peelability from the adhesive layer 130. In particular, in the percutaneous absorption preparations described in Patent Documents 1 to 4, since a silicone pressure sensitive adhesive is used for the adhesive layer, a surface treatment with silicone having high affinity with the silicone pressure sensitive adhesive was performed. There was also a problem that a release liner could not be used. However, in the present invention, for example, when the adhesive layer 130 contains a rubber adhesive as described above, the release liner 140 having a silicone-treated release surface can be positively used. Since the silicone-treated release liner is easily available, the percutaneous absorption type preparation of the present invention can be more easily produced.

The transdermal preparation of the present invention is laminated so that a support; a reservoir layer containing rotigotine or a salt thereof and a substrate; an adhesive layer containing an adhesive substrate; and a release liner are arranged in this order. It is manufactured by.

For such production, means generally employed in the field of transdermal preparations can be used.

An example of a more specific method for producing the transdermal preparation of the present invention will be described below with reference to FIG.

In the first production method of the present invention, first, on the release liner 140, the above-mentioned pressure-sensitive adhesive base material (for example, a rubber-based adhesive) and a solvent (for example, an organic solvent such as heptane) for forming the pressure-sensitive adhesive layer 130; In the release liner 140 and the pressure-sensitive adhesive layer 130, a solution containing a plasticizer and / or other components added as necessary is spread, and then the solvent is removed from the spread solution and dried. A laminated body 150 is produced ((1- (a) in FIG. 2)).

On the other hand, on the support 110, a substrate for constituting the reservoir layer 120, rotigotine or a salt thereof and a solvent (for example, an organic solvent such as acetone or methanol), an antioxidant added as necessary, and / or Alternatively, a solution containing other components is spread, the solvent is removed from the spread solution, and drying is performed, so that a laminate 160 including the reservoir layer 120 and the support 110 is produced (FIG. 2 (1- (b))).

Thereafter, the laminated body 150 and the laminated body 160 are arranged so that the exposed surface of the adhesive layer 130 and the exposed surface of the reservoir layer 120 of each laminated body face each other ((1- (c1) in FIG. 2)). They are pasted together ((1- (c2) in FIG. 2)). Thereafter, it may be cut into a desired size and shape as necessary.

Thus, the percutaneous absorption type preparation 100 of the present invention can be produced.

Alternatively, in the second production method of the present invention, first, on the release liner 140, the above-mentioned pressure-sensitive adhesive substrate (for example, rubber adhesive) and a solvent (for example, an organic solvent such as heptane) for forming the pressure-sensitive adhesive layer 130 ) And an antioxidant and / or other components added as necessary, and then the solvent is removed from the spread solution and dried, whereby the release liner 140 and the adhesive are adhered. A laminate with the layer 130 is manufactured ((2- (a) in FIG. 2)).

Next, on the exposed surface of the pressure-sensitive adhesive layer 130 of the obtained laminate, a base material for forming the reservoir layer 120, rotigotine or a salt thereof and a solvent (for example, an organic solvent such as acetone or methanol), and as necessary A reservoir layer 120 is further laminated on the adhesive layer 130 by spreading a solution containing the added antioxidant and / or other components, removing the solvent from the spread solution, and drying. ((2- (b) in FIG. 2)).

Thereafter, the support 110 is arranged on the exposed surface of the reservoir layer 120 of the obtained laminate and laminated ((2- (c) in FIG. 2)).

Thus, the percutaneous absorption preparation 100 of the present invention may be produced.

Alternatively, in the third production method of the present invention, first, on the support 110, a substrate for forming the reservoir layer 120, rotigotine or a salt thereof and a solvent (for example, an organic solvent such as acetone or methanol), A solution containing an antioxidant and / or other components added as necessary is spread, and the solvent is removed from the spread solution and dried, whereby the reservoir layer 120, the support 110, (3- (a) in FIG. 2) is produced.

Next, on the exposed surface of the reservoir layer 120 of the obtained laminate, the above-mentioned adhesive base material (for example, rubber-based adhesive) and a solvent (for example, an organic solvent such as heptane) for forming the adhesive layer 130 are necessary. The adhesive layer 130 is laminated on the reservoir layer 120 by spreading a solution containing a plasticizer and / or other components added according to the conditions, and then removing the solvent from the spread solution and drying. ((3- (b) in FIG. 2)).

Thereafter, the release liner 140 is disposed on the exposed surface of the adhesive layer 130 of the obtained laminate and laminated ((3- (c) in FIG. 2)).

Referring to FIG. 1B again, the transdermal preparation 100 of the present invention peels the release liner 140 from the adhesive layer 130, and exposes the exposed surface of the adhesive layer 130 to the patient's skin (for example, shoulder, upper arm, Normal skin of any of abdomen, flank, buttocks, and thighs). After the adhesive layer 130 is applied to the skin, the rotigotine or a salt thereof that has migrated from the reservoir layer 120 to the adhesive layer 130 and has been diffused is distributed on the skin surface, and further diffuses in the skin and migrates from subcutaneous to blood. . In addition, when the rotigotine or a salt thereof is distributed on the skin surface, a new rotigotine or a salt thereof is provided from the reservoir layer 120 to the adhesive layer 130 in the adhesive layer 130 having a reduced concentration of rotigotine or a salt thereof. .

Thus, transdermal delivery of rotigotine or a salt thereof from the transdermal preparation 100 of the present invention to a patient becomes possible.

As described above, the transdermally absorbable preparation 100 of the present invention includes the reservoir layer 120 that contains and holds rotigotine or a salt thereof in addition to the adhesive layer 130 that directly contacts the patient's skin. are categorized.

In general, a transdermal preparation is a preparation in which when a patient applies the preparation to the skin, the active ingredient is distributed from the preparation to the skin surface, further diffuses in the skin, and finally moves from the subcutaneous to the blood. It is. In the field of percutaneous absorption type preparations, unless there are special circumstances, those skilled in the art are assumed to adopt the matrix type disclosed in Patent Documents 5 and 6 having a simpler structure. On the other hand, in the past, reservoir-type transdermal preparations (including the microreservoir type of Patent Documents 1 to 4) are based on the special circumstances that it is desired to increase the time for drug distribution from the preparation to the matrix type. It is only adopted as an application of the formulation. For example, if it is desired to increase the distribution of the active ingredient from the formulation to the skin surface (ie skin permeability), the person skilled in the art will select a matrix type that can contain more active ingredient in the adhesive layer in contact with the skin It is assumed that

In contrast, the percutaneous absorption type preparation of the present invention surprisingly shows better skin permeability than the matrix type. Therefore, the percutaneous absorption type preparation of the present invention is useful in that it exceeds the conventional matrix type preparation.

Furthermore, in the transdermally absorbable preparation of the present invention of the present invention, it is essential that sulfite is contained as an antioxidant in order to suppress the decomposition of rotigotine or a salt thereof as in the conventional matrix-type preparation. Not in. That is, when dibutylhydroxytoluene is used as an antioxidant in place of the sulfite, compared with a conventional matrix-type preparation containing rotigotine or a salt thereof, there is a concern of developing skin hypersensitivity. Can be released.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1
A rotigotine transdermal preparation (E1) was prepared as follows using the formulation shown in Table 1.

A solution was prepared by dissolving 16 g of polyisobutylene and 4 g of isopropyl myristate in 90 mL of heptane. Next, this solution was spread on a release liner (silicone-treated polyethylene terephthalate film; thickness 75 μm) so as to be about 5 mg / cm ² (thickness 50 μm), and the solvent was removed at 70 ° C. for 15 minutes. By removing and drying, a laminate (E1a) of a release liner / adhesive layer was obtained.

On the other hand, a solution prepared by dissolving 1.8 g rotigotine, 1.8 g polyvinylpyrrolidone, 0.8 g hydroxypropylcellulose and 0.02 g dibutylhydroxytoluene in 10 mL acetone and 40 mL methanol was about 1 mg / cm ² (thickness 11 μm). By spreading on a nonwoven fabric of a support (a polyethylene terephthalate film laminated with a nonwoven fabric made of polyethylene terephthalate; thickness 12 μm), removing the solvent at 70 ° C. for 15 minutes and drying. A film type reservoir layer / support laminate (E1b) was obtained.

The release liner / adhesive layer laminate (E1a) obtained above and the film-type reservoir layer / support laminate (E1b) were exposed to the exposed surface of the adhesive layer and the exposed film-type reservoir layer of each laminate. The rotigotine transdermal preparations (E1) having the formulations shown in Table 1 were prepared by pasting them so that the surfaces face each other and then cutting them into squares of appropriate size.

(Comparative Example 1)
An existing commercial preparation (New Pro (registered trademark) patch 4.5 mg, manufactured by Otsuka Pharmaceutical Co., Ltd .; (area 10 cm ² )) was used as the rotigotine transdermal absorption preparation (C1) of Comparative Example 1.

(Comparative Example 2)
A rotigotine transdermal preparation (C2) was prepared as follows using the formulation shown in Table 2.

A solution was prepared by dissolving 1.8 g rotigotine, 0.02 g dibutylhydroxytoluene, 17.7 g polyisobutylene and 4.9 g isopropyl myristate in 10 mL acetone and 100 mL heptane. Next, this solution was spread on a long release liner (silicone-treated polyethylene terephthalate film; thickness: 75 μm) so as to be about 6 mg / cm ² (thickness: 61 μm). By removing the solvent in a minute and drying, a release liner / adhesive layer laminate (C2a) was obtained.

The exposed surface of the nonwoven fabric side of the support (polyethylene terephthalate film laminated with a nonwoven fabric made of polyethylene terephthalate; thickness 12 μm) on the exposed surface of the adhesive layer of the release liner / adhesive layer laminate (C2a) obtained above. Were then cut into appropriate square sizes to prepare a rotigotine transdermal preparation (C2) having the formulation shown in Table 2.

(Comparative Example 3)
A rotigotine transdermal preparation (C3) was prepared in the following manner using the formulation shown in Table 3.

Rotigotine 1.8 g, dibutylhydroxytoluene 0.02 g, acrylic adhesive (acrylic adhesive described in WO2014 / 34939 (adhesive containing an acrylic copolymer containing diacetone acrylamide as a component) I)); hereinafter also referred to as MAS; solid content 38%) A solution in which 17.7 g and 4.9 g of isopropyl myristate were dissolved in 63 mL of ethyl acetate was prepared. Next, this solution was spread on a long release liner (silicone-treated polyethylene terephthalate film; thickness 75 μm) so as to be about 6 mg / cm ² (thickness 61 μm). The release liner / adhesive layer laminate (C3a) was obtained by removing the solvent in 15 minutes and drying.

The exposed surface on the nonwoven fabric side of the support (polyethylene terephthalate film laminated with a nonwoven fabric made of polyethylene terephthalate; thickness 12 μm) on the exposed surface of the adhesive layer of the release liner / adhesive layer laminate (3Ca) obtained above. Were then cut into squares of appropriate size to produce a rotigotine transdermal absorption preparation (C3) having the formulation shown in Table 3.

(Comparative Example 4)
The release liner of Comparative Example 1 was peeled off, and a newly prepared silicone-treated polyethylene terephthalate film (thickness 75 μm) was bonded to a new release liner to prepare a rotigotine transdermal absorption preparation (C4).

(Experimental example 1: Adhesive strength evaluation test)
The percutaneously absorbable preparations (E1) and (C1) obtained in Example 1 and Comparative Example 1 were affixed to Yucatan micropig-excised skin (female, 5 months old), and a 2 kg roller from above each preparation. Was reciprocated once and pressed. After pressure bonding, after 1 minute (immediately after application) and 24 hours later, the adhesive strength tester was used to peel off the preparation at a speed of 300 ± 30 mm per minute, and the load until each preparation was completely peeled off was measured as the adhesive strength. . The measurement was performed 3 times for each preparation and each time, and the average value ± standard deviation was calculated. Table 4 shows the obtained results.

As shown in Table 4, the preparation (E1) obtained in Example 1 shows higher adhesiveness immediately after the application than the preparation (C1) of Comparative Example 1, and is applied to the patient's skin. It turns out that it was hard to drop off.

(Experimental example 2: Observation of crystal formation state)
The percutaneously absorbable preparations (E1), (C1), (C2) and (C3) obtained in Example 1 and Comparative Examples 1 to 3 were cut into 2.5 cm ² pieces, and these test pieces were wrapped in aluminum. The sample was packaged with a material and stored at 5 ° C., 25 ° C. and 40 ° C. for 1 month or 3 months, and the state of crystal formation of rotigotine contained in each test piece after storage was observed visually and with a polarizing microscope. The observation at the start of storage was similarly performed.

For each observation, the test piece in which no crystal was observed was represented by ○, and the test piece in which the crystal was observed was represented by ×. The results obtained are shown in Table 5.

As shown in Table 5, in the test piece prepared from the preparation (C2) of Comparative Example 2, the precipitation of crystals was confirmed at 1 month or 3 months after storage at any temperature except for the result at the start of storage. . Therefore, the preparation (C2) of Comparative Example 2 does not need to undergo the skin permeation test of Experimental Example 3 described later, and the skin permeability is the preparations (E1) and (C1) of Example 1, Comparative Examples 1 and 3. And it turns out that it is inferior compared with (C3).

(Experimental Example 3: Skin Permeation Test)
The hairless mouse-extracted skin (purchased from Japan SLC Co., Ltd.) was set in a vertical diffusion cell with the dermis side facing the receiver. Next, 1.2 mL of 0.05 mol / L McIlvine buffer (pH 7.4) was added as a receiver solution to the receiver, and the preparations of Example 1 and Comparative Examples 1 and 3 (E1) were used as donors on the stratum corneum side. , 1.77 cm ² test pieces prepared from (C1) and (C3) were attached. Thereafter, over 24 hours, 0.6 mL of the receiver solution was collected from the receiver every predetermined time, and the rotigotine concentration in the receiver solution was measured by the HPLC method. In addition, after collecting 0.6 mL of receiver solution every predetermined time, 0.6 mL of new 0.05 mol / L McIlvine buffer solution was replenished to the receiver. This measurement and operation was performed 6 times for each test piece.

The cumulative amount of skin permeation over 24 hours was calculated as “average value ± standard deviation” by adding the rotigotine concentrations measured at each time point. The calculated results are shown in Table 6.

As shown in Table 6, the cumulative skin permeation amount of the test piece obtained from the preparation (E1) of Example 1 was equivalent to the permeation amount of Comparative Example 1. On the other hand, the cumulative skin permeation amount of the test piece obtained from the preparation (C3) of Comparative Example 3 was significantly lower than that of Example 1 and Comparative Example 1. Thus, when the results obtained in Experimental Examples 1 and 3 are combined, the preparation (E1) obtained in Example 1 is equivalent to the existing commercial preparation (C1) of Comparative Example 1 in terms of skin permeability. It can be seen that the film has more excellent adhesiveness.

(Experimental example 4: confirmation of peelability)
With respect to the percutaneously absorbable preparations (E1) and (C4) obtained in Example 1 and Comparative Example 4, when the respective release liners were peeled off, the release liner of the preparation (E1) of Example 1 was easily Although it peeled off, it was difficult to peel off the release liner of the preparation (C4) of Comparative Example 4.

(Experimental example 5: Measurement of content ratio (%) of all related substances)
The preparations (E1) and (C1) obtained in Example 1 and Comparative Example 1 were stored at 60 ° C. (humidity 75%) in the dark. The amount of total related substances of rotigotine in each preparation at each time point after the start of storage, 0.25, 0.5, 1 and 2 months after the start of storage was measured by HPLC (UV254 nm), and the relative ratio to the rotigotine content As the content rate (%) of the total related substances. The results obtained are shown in Table 7.

As shown in Table 7, the content ratio of the total related substances of rotigotine in the preparation (E1) obtained in Example 1 changed at a lower value than the preparation (C1) in Comparative Example 1 as the storage period increased. I understand that it was.

According to the present invention, while having a skin permeability equivalent to that of a commercially available percutaneous absorption preparation containing rotigotine, for example, it can provide higher adhesiveness compared to the preparation, and / or The stability of rotigotine or a salt thereof can be maintained without containing a sulfite. As a result, the transdermally absorbable preparation of the present invention can prevent detachment from the patient's skin and / or induce the patient's skin hypersensitivity and appropriately administer rotigotine or a salt thereof to the patient. Become. Therefore, the transdermally absorbable preparation of the present invention is useful in the preparation of a preparation used for the treatment of Parkinson's disease and moderate to high idiopathic restless legs syndrome (restless leg syndrome).

DESCRIPTION OF SYMBOLS 100 Percutaneous absorption type preparation 110 Support body 120 Reservoir layer 130 Adhesive layer 140 Release liner 150,160 Laminated body

Claims

Support;
A reservoir layer containing rotigotine or a salt thereof and a substrate;
A pressure-sensitive adhesive layer containing a rubber-based adhesive; and a release liner;
Are provided in this order.
The transdermal absorption preparation according to claim 1, wherein the reservoir layer has a film-like layer structure.
The transdermal preparation according to claim 1 or 2, wherein the release liner has a surface treated with silicone.
The rubber adhesive is selected from the group consisting of polyisobutylene, polybutene, polyisoprene, styrene / isoprene / styrene block copolymer, styrene / butadiene / styrene block copolymer, butyl rubber, styrene / butadiene rubber and natural rubber. The percutaneous absorption preparation according to any one of claims 1 to 3, wherein the preparation is at least one rubber compound.
The transdermal preparation according to claim 4, wherein the rubber adhesive is polyisobutylene.
The transdermal absorption preparation according to any one of claims 1 to 5, wherein the reservoir layer further contains dibutylhydroxytoluene.
The transdermal preparation according to claim 6, wherein the total content of dibutylhydroxytoluene is 0.01 mg or more and 4 mg or less.
The transdermal preparation according to any one of claims 1 to 7, wherein the reservoir layer does not contain sulfite.
A part of the rotigotine or a salt thereof is transferred from the reservoir layer into the adhesive layer, and 80% to 99.9% by weight of the total content of the rotigotine or a salt thereof is in the reservoir layer. The percutaneous absorption type preparation according to any one of claims 1 to 8, which is retained.
A method for producing a transdermally absorbable preparation, comprising:
A method comprising: laminating a support; a reservoir layer containing rotigotine or a salt thereof and a substrate; an adhesive layer containing a rubber-based adhesive; and a release liner in this order.
The method according to claim 10, wherein in the laminating step, the adhesive layer does not contain the rotigotine or a salt thereof.
In the lamination step,
The total weight of the reservoir layer is 5 g / m 2 to 50 g / m 2 ;
The ratio of the weight of the rotigotine or salt thereof contained when the total weight of the rubber-based adhesive contained in the adhesive layer and the base material contained in the reservoir layer is 100 is 5 to 50, The method according to claim 11, wherein the reservoir layer and the adhesive layer are laminated so that the weight ratio of the adhesive layer is 100 to 1000 when the weight of the reservoir layer is 100.