WO2018199015A1 - Préparation absorbable par voie transdermique et son procédé de production - Google Patents

Préparation absorbable par voie transdermique et son procédé de production Download PDF

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Publication number
WO2018199015A1
WO2018199015A1 PCT/JP2018/016441 JP2018016441W WO2018199015A1 WO 2018199015 A1 WO2018199015 A1 WO 2018199015A1 JP 2018016441 W JP2018016441 W JP 2018016441W WO 2018199015 A1 WO2018199015 A1 WO 2018199015A1
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Prior art keywords
rotigotine
salt
adhesive layer
reservoir layer
adhesive
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PCT/JP2018/016441
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English (en)
Japanese (ja)
Inventor
宏史 更田
英範 澤田
川村　尚久
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ニプロ株式会社
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Priority to JP2019514485A priority Critical patent/JPWO2018199015A1/ja
Publication of WO2018199015A1 publication Critical patent/WO2018199015A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • “New Pro (registered trademark) patch” is used. Is commercially available under the trade name "Non-patent Document 1".
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the reservoir layer has a film-like layer structure.
  • the release liner has a siliconized surface.
  • 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.
  • the rubber adhesive is polyisobutylene.
  • the reservoir layer further contains dibutylhydroxytoluene.
  • the total content of dibutylhydroxytoluene is 0.01 mg to 4 mg.
  • the reservoir layer does not contain sulfite.
  • 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.
  • the adhesive layer does not contain the rotigotine or a salt thereof.
  • 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 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.
  • the reservoir layer has a film-like layer structure.
  • the total content of dibutylhydroxytoluene is 0.01 mg or more and 4 mg or less.
  • the adhesive layer contains a rubber-based adhesive and the release liner has a siliconized surface.
  • 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.
  • the rubber adhesive is polyisobutylene.
  • 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, 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.
  • the total weight of the reservoir layer is 5 g / m 2 to 50 g / m 2 ;
  • 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.
  • 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.
  • 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
  • FIG. 1 shows an example of a transdermal absorption preparation of the present invention.
  • the percutaneous absorption type formulation 100 of this invention is a patch which has the external appearance of predetermined shapes, such as a rectangle.
  • 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 .
  • 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).
  • 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.
  • 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.
  • 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 ⁇ m to 80 ⁇ m.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • a hydrophilic or water-soluble substrate can be suitably selected.
  • 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.
  • 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.
  • 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
  • ester derivatives 1,3-butylene glycol, benzotriazole and monothioglycerin, and combinations thereof.
  • the reservoir layer 120 contains, for example, dibutylhydroxytoluene instead of the sulfite as the 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.
  • 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%.
  • 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 .
  • 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 ⁇ m to 50 ⁇ m.
  • 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.
  • the adhesive layer 130 contains an adhesive base.
  • 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.
  • acrylic adhesive examples 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.
  • silicone-based adhesives include organopolysiloxanes, diorganopolysiloxanes, and organohydrogenpolysiloxanes, and combinations thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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, pyr
  • the plasticizer is appropriately selected depending on the type of the pressure-sensitive adhesive substrate used in the pressure-sensitive adhesive layer 130.
  • polyisobutylene rubber adhesive
  • 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.
  • the adhesive layer 130 may contain other components in addition to the adhesive and the plasticizer contained as necessary.
  • 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 ⁇ m to 70 ⁇ m.
  • 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.
  • 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.
  • a surface treatment such as silicone treatment or embossing in order to improve the peelability from the adhesive layer 130.
  • a surface treatment such as silicone treatment or embossing in order to improve the peelability from the adhesive layer 130.
  • a surface treatment with silicone having high affinity with the silicone pressure sensitive adhesive was performed.
  • a release liner could not be used.
  • 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.
  • the above-mentioned pressure-sensitive adhesive base material for example, a rubber-based adhesive
  • a solvent for example, an organic solvent such as heptane
  • 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)).
  • 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))).
  • 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.
  • the percutaneous absorption type preparation 100 of the present invention can be produced.
  • 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)).
  • 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
  • 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)).
  • 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)).
  • the percutaneous absorption preparation 100 of the present invention may be produced.
  • 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.
  • a solvent for example, an organic solvent such as acetone or methanol
  • the above-mentioned adhesive base material for example, rubber-based adhesive
  • a solvent for example, an organic solvent such as heptane
  • 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)).
  • 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)).
  • the percutaneous absorption preparation 100 of the present invention may be produced.
  • 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).
  • 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. .
  • 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.
  • transdermal delivery of rotigotine or a salt thereof from the transdermal preparation 100 of the present invention to a patient becomes possible.
  • 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.
  • 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.
  • 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.
  • reservoir-type transdermal preparations 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
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m) so as to be about 5 mg / cm 2 (thickness 50 ⁇ m), 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.
  • 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 ⁇ m).
  • a nonwoven fabric of a support a polyethylene terephthalate film laminated with a nonwoven fabric made of polyethylene terephthalate; thickness 12 ⁇ m
  • 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.
  • 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 ⁇ m) so as to be about 6 mg / cm 2 (thickness: 61 ⁇ m). By removing the solvent in a minute and drying, a release liner / adhesive layer laminate (C2a) was obtained.
  • acrylic adhesive acrylic adhesive described in WO2014 / 34939 (adhesive containing an acrylic copolymer containing diacetone acrylamide as a component)
  • MAS solid content 38%
  • the release liner / adhesive layer laminate (C3a) was obtained by
  • Comparative Example 4 The release liner of Comparative Example 1 was peeled off, and a newly prepared silicone-treated polyethylene terephthalate film (thickness 75 ⁇ m) was bonded to a new release liner to prepare a rotigotine transdermal absorption preparation (C4).
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 3 Skin Permeation Test
  • the hairless mouse-extracted skin purchased from Japan SLC Co., Ltd.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • Example 4 confirmation of peelability
  • 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.
  • 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.
  • 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).

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Abstract

Cette préparation absorbable par voie transdermique est pourvue d'un support, d'une couche réservoir contenant de la rotigotine ou d'un sel de celle-ci, d'une couche adhésive contenant un adhésif à base de caoutchouc, et d'une doublure détachable, dans l'ordre indiqué. Tout en ayant une perméabilité cutanée équivalente à celle de préparations commerciales absorbables par voie transdermique contenant de la rotigotine, la présente invention permet, par exemple, d'obtenir une adhésivité supérieure à celle de ces préparations et/ou de maintenir la stabilité de la rotigotine ou de son sel sans contenir de sulfite. Ceci permet dans cette préparation absorbable par voie transdermique d'empêcher le détachement de la peau d'un patient et/ou d'empêcher l'induction de l'hypersensibilité cutanée chez le patient, et d'administrer correctement de la rotigotine ou un sel de celle-ci au patient.
PCT/JP2018/016441 2017-04-26 2018-04-23 Préparation absorbable par voie transdermique et son procédé de production WO2018199015A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130281944A1 (en) * 2010-11-29 2013-10-24 Ratiopharm Gmbh Transdermal therapeutic system (tts) comprising rotigotine
WO2014051128A1 (fr) * 2012-09-28 2014-04-03 株式会社 ケイ・エム トランスダーム Timbre transdermique
WO2015177204A1 (fr) * 2014-05-20 2015-11-26 Lts Lohmann Therapie-Systeme Ag Système d'administration transdermique contenant de la rotigotine
JP2016500086A (ja) * 2012-11-22 2016-01-07 ウーツェーベー ファルマ ゲーエムベーハーＵｃｂ Ｐｈａｒｍａ Ｇｍｂｈ ロチゴチンの経皮投与のための複数日用のパッチ
US20160199316A1 (en) * 2013-06-14 2016-07-14 Tesa Labtec Gmbh Three-layer transdermal therapy system (tts)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130281944A1 (en) * 2010-11-29 2013-10-24 Ratiopharm Gmbh Transdermal therapeutic system (tts) comprising rotigotine
WO2014051128A1 (fr) * 2012-09-28 2014-04-03 株式会社 ケイ・エム トランスダーム Timbre transdermique
JP2016500086A (ja) * 2012-11-22 2016-01-07 ウーツェーベー ファルマ ゲーエムベーハーＵｃｂ Ｐｈａｒｍａ Ｇｍｂｈ ロチゴチンの経皮投与のための複数日用のパッチ
US20160199316A1 (en) * 2013-06-14 2016-07-14 Tesa Labtec Gmbh Three-layer transdermal therapy system (tts)
WO2015177204A1 (fr) * 2014-05-20 2015-11-26 Lts Lohmann Therapie-Systeme Ag Système d'administration transdermique contenant de la rotigotine

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Title
MATSUNAGA, KAYOKO: "Focusing on additive contact dermatitis of skin external agent", THE JOURNAL OF PRACTICAL PHARMACY, vol. 53, no. 11, 2002, pages 71 - 76 *

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