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WO2018155682A1 - Préparation transdermique contenant de la rivastigmine - Google Patents

Préparation transdermique contenant de la rivastigmine Download PDF

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Publication number
WO2018155682A1
WO2018155682A1 PCT/JP2018/006929 JP2018006929W WO2018155682A1 WO 2018155682 A1 WO2018155682 A1 WO 2018155682A1 JP 2018006929 W JP2018006929 W JP 2018006929W WO 2018155682 A1 WO2018155682 A1 WO 2018155682A1
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WO
WIPO (PCT)
Prior art keywords
less
rivastigmine
content
rubber
adhesive
Prior art date
Application number
PCT/JP2018/006929
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English (en)
Japanese (ja)
Inventor
智 川上
学 曽我部
大樹 柴田
靖 堀川
Original Assignee
帝國製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by 帝國製薬株式会社 filed Critical 帝國製薬株式会社
Priority to JP2019501861A priority Critical patent/JP7079015B2/ja
Publication of WO2018155682A1 publication Critical patent/WO2018155682A1/fr

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a transdermal preparation containing rivastigmine. More specifically, the present invention relates to a percutaneous absorption preparation that exhibits stable skin permeability of rivastigmine and is highly safe for the skin.
  • a disorder of the cholinergic nervous system in the brain has occurred. It is also known that the brain cholinergic nervous system can be activated by increasing acetylcholine in the brain with an inhibitor of acetylcholinesterase or butyrylcholinesterase. Rivastigmine is known as a drug having such an inhibitory action, and rivastigmine is used in clinical settings as a therapeutic agent that suppresses the progression of Alzheimer-type dementia. However, rivastigmine generally has strong side effects, and many reports of side effects such as liver dysfunction and gastrointestinal disorders have been made. In the case of an oral preparation containing rivastigmine, it is often difficult to take the oral preparation in patients with advanced symptoms. For patients with such advanced symptoms, transdermal preparations are suitable.
  • Rivastigmine has an amino group and a carbonyl group in the molecule, and may cause skin irritation by transdermal administration.
  • Rivastigmine has an amino group and a carbonyl group in the molecule, and may cause skin irritation by transdermal administration.
  • the adhesive is required to have a certain level of adhesive strength, but if the adhesive strength is too strong, local physical irritation may occur when the adhesive is peeled off.
  • Alzheimer-type dementia patients have many elderly people, and the skin of elderly people often has a reduced moisturizing function and the barrier function of the skin.
  • Non-patent Document 1 the main skin symptoms that occurred in domestic clinical trials were 37.7% erythema at the application site, 36.6% pruritus at the application site, 25.4% contact dermatitis at the application site, application site Edema of 11.1% and 4.8% of skin exfoliation at the application site have been reported (Non-patent Document 1).
  • the same skin symptom has developed even after marketing, and treatments such as reducing skin irritation by using a moisturizer together in the clinical setting have been made, and stable drug skin permeability and skin irritation Both reductions are desired.
  • Patent Document 1 discloses a patch in which skin irritation is reduced by blending rivastigmine into a patch base containing a thermoplastic elastomer and a non-volatile hydrocarbon oil.
  • Patent Document 2 discloses a patch in which rivastigmine is added to a patch base containing a styrene / isoprene / styrene block copolymer, a tackifier resin, and a plasticizer.
  • Patent Document 1 has no or only a very small amount of tackifying resin in the patch, so that the initial adhesive strength is weak, and the patch permeates through the skin by dropping or partially peeling. There is a risk that it may not be able to fully exhibit its properties.
  • Patent Document 2 since the skin irritation is improved by using a smaller amount of rivastigmine than before, there is a possibility that the skin irritation cannot be improved if the content of rivastigmine is increased.
  • the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a rivastigmine-containing transdermal absorption preparation that can continuously administer rivastigmine as an active ingredient over a long period of time and has low skin irritation. There is.
  • the configuration of the present invention is as follows.
  • Rivastigmine 5% or more, 30% or less
  • Rubber-based adhesive 10% or more and 60% or less
  • tackifier resin 30% or more and 70% or less
  • a transdermal absorption-type preparation characterized by not containing a plasticizer.
  • Rivastigmine 5% or more, 30% or less
  • Rubber adhesive 10% or more, 60% or less
  • Tackifying resin 30% or more, 70% or less
  • plasticizer more than 0%, less than 2%
  • the content of the rivastigmine is a (%)
  • the content of the rubber adhesive is b (%)
  • the content of the tackifying resin is c (%)
  • the following formula (1) The transdermal absorption preparation according to [4] or [5], which satisfies (2).
  • the rubber-based pressure-sensitive adhesive is at least one selected from the group consisting of styrene / isoprene / styrene block copolymer, polyisobutylene, styrene / butadiene / styrene block copolymer, and styrene-butadiene rubber.
  • the transdermally absorbable preparation according to any one of [6].
  • the tackifying resin is at least one selected from the group consisting of alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, rosin derivatives, and maleic resin.
  • the plasticizer is petroleum oil, squalane, squalene, vegetable oil, synthetic oil, liquid rubber, liquid fatty acid ester, diethylene glycol, polyethylene glycol, salicylate glycol, propylene glycol, dipropylene glycol, triacetin, triethyl citrate ,
  • rivastigmine containing a rivastigmine which is an active ingredient, can be continuously administered over a long period of time and has a low skin irritation property.
  • the rivastigmine-containing transdermal preparation of the present invention has a sufficient initial adhesive force when applied, rivastigmine is percutaneously absorbed into the body at a pharmacologically effective rate. Furthermore, when the content of rivastigmine in the adhesive layer is reduced, the plasticity of the adhesive layer is lowered, and when the preparation is peeled, an appropriate adhesive strength is obtained so that no local physical irritation is exhibited. As a result, an effective amount of the active ingredient can be continuously administered, and skin safety can be improved.
  • the rivastigmine-containing transdermal preparation of the present invention can continuously administer an effective amount of an active ingredient and can reduce skin irritation, so that the skin barrier function is lowered. It is extremely effective for improving QOL of Alzheimer type patients with many dementia patients.
  • rivastigmine 5% or more, 30% or less
  • rubber-based adhesive 10% or more, 60% or less
  • tackifying resin 30% or more
  • the content of rivastigmine is a (%)
  • the content of the rubber adhesive is b (%)
  • the content of the tackifying resin is c (%)
  • the following formula (1 ) And (2) are satisfied.
  • rivastigmine 5% or more, 30% or less
  • rubber-based adhesive 10% or more, 60% or less
  • tackifying resin 30% or more in mass%. 70% or less, and does not contain a plasticizer.
  • transdermally absorbable preparation of the present invention by mass%, rivastigmine: 5% or more, 30% or less, rubber-based adhesive: 10% or more, 60% or less, tackifying resin: 30% or more, 70% or less, and plasticizer: more than 0%, less than 2%.
  • the content of the liquid component in the adhesive layer is controlled to be a certain amount or less at the time of exfoliation of the preparation while controlling the content of the liquid component in the adhesive layer to be a certain value or less when the preparation is peeled off, the above problem is solved. I thought it could be solved.
  • rivastigmine which is the main ingredient, exists as a liquid component at room temperature in the adhesive layer containing the rubber-based adhesive and the tackifier resin, and surprisingly has a softening action on the adhesive layer. It has been found that it acts as a plasticizer. That is, rivastigmine acts as a plasticizer at the time of application of the drug to stably release the drug in order to exert initial adhesive strength, while rivastigmine is absorbed percutaneously at the time of release of the drug and the content in the adhesive layer It has been found that the peel force can be reduced because of the lowering of.
  • the transdermally absorbable preparation of the present invention is, in mass%, rivastigmine: 5% or more and 30% or less, rubber adhesive: 10% or more and 60% or less, and tackifying resin: 30%.
  • rivastigmine 5% or more and 30% or less
  • rubber adhesive 10% or more and 60% or less
  • tackifying resin 30%.
  • the transdermal absorbability and the initial adhesive strength can be improved. it can. Preferably it is 58 or more, More preferably, it is 60 or more, More preferably, it is 62 or more. On the other hand, if the value on the left side of the formula (1) becomes too large, the initial adhesive strength becomes too high, which may cause skin irritation during peeling.
  • the value on the left side of the formula (1) is preferably 90 or less, more preferably 80 or less, and still more preferably 70 or less.
  • the initial adhesive strength can be improved. it can. Preferably it is 0.90 or less, More preferably, it is 0.85 or less, More preferably, it is 0.80 or less. On the other hand, if the value on the left side of the formula (2) is too low, the preparation becomes too hard, and the initial adhesive strength may decrease.
  • the value on the left side of Formula (2) is preferably 0.16 or more, more preferably 0.3 or more, still more preferably 0.5 or more, and even more preferably 0.6 or more.
  • Rivastigmine is an active ingredient and exhibits a plasticizing action in the adhesive layer. This plasticizing action can improve adhesion at the time of sticking, and can easily exhibit a stable drug supply ability. Rivastigmine is preferably blended as a free form (free form), but may be blended as a salt if necessary.
  • the salt is not limited as long as it is a pharmaceutically acceptable salt.
  • a medically acceptable inorganic acid or organic acid such as hydrochloride, acetate, tartrate, oxalate, citrate, etc.
  • examples include acid addition salts.
  • the content of rivastigmine in the transdermal preparation of the present invention is grasped as% when the total amount of the adhesive layer is 100%, 5% or more, 30% or less. If the content of rivastigmine is less than 5%, the medicinal effect cannot be exerted, and further, the plasticizing action by rivastigmine is reduced and the initial adhesive force is insufficient, and the preparation may be peeled off or dropped during application.
  • rivastigmine is 7% or more, More preferably, it is 9% or more.
  • the content of rivastigmine exceeds 30%, an excessive amount of rivastigmine remains in the adhesive layer at the time of peeling of the preparation, so that the peel strength becomes too high and may cause skin irritation.
  • it is 20% or less, More preferably, it is 15% or less.
  • the amount of residual rivastigmine after 24 hours in the sticking residual test is preferably 10% to 60% of the initial amount of rivastigmine. More preferably, it is 10% or more and 50% or less.
  • the sticking remaining test may be carried out, for example, by sticking to the rabbit skin.
  • the rubber adhesive is used as the adhesive in the transdermal preparation of the present invention. Further, the rubber-based adhesive is suitable for enhancing the transdermal absorbability of rivastigmine as compared with an acrylic adhesive or the like. Rubber adhesives generally have lower self-adhesive strength than acrylic adhesives and so on, and thus can be expected to be effective in terms of contributing to a reduction in irritation due to a decrease in the content of rivastigmine. .
  • the rubber-based pressure-sensitive adhesive is preferably at least one selected from the group consisting of styrene / isoprene / styrene block copolymer, polyisobutylene, styrene / butadiene / styrene block copolymer, and styrene-butadiene rubber. These can be used alone or in combination of two or more. Of these, styrene / isoprene / styrene block copolymers are particularly preferred.
  • styrene / isoprene / styrene block copolymers examples include Clayton D-KX401CS and D-1161JP manufactured by JSR Kraton Elastomer Co., Ltd., Califlex TR-1107, TR-1111, TR-1112 and TR- manufactured by Shell Chemical Co., Ltd. 1117, JSR-5000, 5002, SR-5100 manufactured by Nippon Synthetic Rubber Co., Ltd., QUINTAC 3530, 3570C, 3421 manufactured by Nippon Zeon Co., Ltd., and the like.
  • polyisobutylene examples include Tetrax 3T manufactured by Shin Nippon Petrochemical Co., Ltd. and Opanol B150 manufactured by BASF Japan Co., Ltd.
  • styrene / butadiene / styrene block copolymer examples include Califlex TR-1101 manufactured by Shell Chemical Co., Ltd.
  • styrene-butadiene rubber examples include SBR1013H and SBR1502 manufactured by Nippon Synthetic Rubber Co., Ltd.
  • the content of the rubber-based pressure-sensitive adhesive (a single content when included alone, or a total amount thereof when including two or more) is 10% or more when the total amount of the pressure-sensitive adhesive layer is 100%. 60% or less. Considering formation of the adhesive layer and skin permeability, it is preferably 20% or more, more preferably 30% or more. On the other hand, if the content of the rubber adhesive exceeds 60%, sufficient transdermal absorbability may not be obtained. Preferably it is 55% or less, More preferably, it is 50% or less.
  • the tackifying resin in the percutaneous absorption type preparation of the present invention is not particularly limited as long as it can impart initial adhesive force to the preparation.
  • alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, terpene resin 1 or more selected from the group consisting of a rosin derivative, and a maleic resin can be used alone or in combination of two or more.
  • the tackifier resin is more preferably one or more selected from the group consisting of aliphatic hydrocarbon resins, rosin derivatives, and terpene resins. More preferably, it is a cyclic saturated hydrocarbon resin.
  • Examples of the alicyclic saturated hydrocarbon resin include Alcon P100 manufactured by Arakawa Chemical Industries, Ltd.
  • An example of the aliphatic hydrocarbon resin is Quinton B170 manufactured by Nippon Zeon Co., Ltd.
  • An example of the terpene resin is Clearon P-125 manufactured by Yashara Chemical Co., Ltd.
  • Examples of the rosin derivative include rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester, and rosin pentaerythritol ester.
  • the content of the tackifying resin (single content when included alone, and the total amount when including two or more) is 30% or more when the total amount of the adhesive layer is 100%, 70% or less.
  • the tackifying resin greatly affects the initial adhesive strength, and if it is less than 30%, the initial adhesive strength is weakened and the preparation may peel off or fall off during the application of the patch. Preferably it is 40% or more, more preferably 45% or more. On the other hand, if the content of the tackifying resin exceeds 70%, the preparation becomes too hard and sufficient initial adhesive strength cannot be obtained. Preferably it is 60% or less, More preferably, it is 55% or less.
  • a rubber-based adhesive is used as the adhesive.
  • a plasticizer is usually blended in order to increase the initial adhesive force.
  • the action of rivastigmine as a plasticizer in the adhesive layer is utilized, the physical properties of the patch and the initial adhesive force as the patch can be maintained without positively blending the plasticizer.
  • the adhesive when a large amount of plasticizer is blended in the adhesive layer, the adhesive itself maintains high adhesiveness due to the action of the plasticizer even when the patch is peeled off. For this reason, from the viewpoint of reducing skin irritation at the time of peeling of the patch, it is particularly preferable that the amount of the plasticizer in the adhesive layer is not excessive and that no plasticizer is contained.
  • the plasticizer content is more than 0% and less than 2%. It is preferable that it is a single content when it is contained alone, and a total content of these when two or more types are contained. Thereby, initial adhesive force can be improved, suppressing the skin irritation by a plasticizer.
  • the content of the plasticizer is more preferably 0.05% or more and 0.15% or less, further preferably 0.07% or more and 0.10% or less.
  • the plasticizer is preferably a liquid component that can soften the adhesive layer.
  • plasticizers include petroleum oils such as naphthenic process oil and aromatic process oil; squalane; squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil; synthetic oils such as silicone oil Liquid oil such as polybutene; liquid fatty acid esters such as oleyl oleate, isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; One or more selected from the group consisting of triethyl acid; crotamiton; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; glycerol; and polybuteneThese can be used alone or in combination of two or more. From the viewpoint
  • content of adhesives such as a rivastigmine, a rubber adhesive, and tackifying resin, is% with respect to the whole adhesion layer (excluding a support body and a peeling film) which added the additive, when adding the additive shown below. (Mass%) should be understood.
  • the percutaneous absorption preparation provided by the present invention contains an antioxidant, a filler, a water-soluble polymer, a cross-linking agent, an antiseptic and an ultraviolet absorber as long as it does not inhibit the action of the present invention. can do.
  • antioxidant 1 selected from the group consisting of tocopherol and its ester derivatives, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (hereinafter abbreviated as BHT), and butylhydroxyanisole More than species.
  • the filler is selected from the group consisting of calcium carbonate, magnesium carbonate, silicates such as aluminum silicate and magnesium silicate, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, and silicon dioxide. 1 type or more to be mentioned.
  • crosslinking agent amino resin, phenol resin, epoxy resin, alkyd resin, thermosetting resin such as unsaturated polyester, isocyanate compound, blocked isocyanate compound, organic crosslinking agent, and inorganic crosslinking agent such as metal or metal compound 1 type or more chosen from the group which consists of.
  • Examples of the preservative include one or more selected from the group consisting of ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.
  • Examples of the ultraviolet absorber include one or more selected from the group consisting of p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, amino acid compounds, dioxane derivatives, coumarin derivatives, imidazoline derivatives, and pyrimidine derivatives.
  • esters such as cetyl lactate that are solid at room temperature, purified lanolin, cholesterol, gum arabic, lecithin and the like can be blended.
  • the transdermal absorption preparation of the present invention is a transdermal absorption patch preparation containing at least a support layer, an adhesive layer, and a release film.
  • the first aspect has been described on the assumption that it is a matrix type patch, the percutaneous absorption type preparation of the present invention is not limited to this.
  • a stretchable or non-stretchable support can be used as the support for the transdermally absorbable preparation of the present invention.
  • the support include cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate (hereinafter abbreviated as PET), an aluminum sheet, and a composite material thereof.
  • the release film examples include a silicon film coated with a polyethylene film, a polyethylene terephthalate film, or a polypropylene film. Such a release film is preferable because it protects the adhesive layer until the percutaneously absorbable preparation is applied to the skin, suppresses the deterioration of rivastigmine, and can be easily peeled off.
  • the thickness of the pressure-sensitive adhesive layer is preferably 30 ⁇ m or more and 200 ⁇ m or less.
  • the sustained drug release is reduced.
  • it is 30 micrometers or more, More preferably, it is 50 micrometers or more.
  • the thickness of the adhesive layer exceeds 200 ⁇ m, not only will the cost increase, but the amount of drug per unit area in the adhesive layer will increase, and as a result, the drug concentration after time will be significantly higher than that at the beginning of application. Since it does not decrease, skin irritation during peeling increases.
  • it is 200 micrometers or less, More preferably, it is 150 micrometers or less.
  • the transdermally absorbable preparation of the present invention is, in the second aspect, in mass%, rivastigmine: 5% or more, 30% or less, rubber-based adhesive: 10% or more, 60% or less, and tackifying resin: 30%. As mentioned above, it contains 70% or less, and does not contain a plasticizer.
  • a rubber-based adhesive is used as the adhesive, but in the case of a patch based on a rubber-based adhesive, a plasticizer is usually blended.
  • the content of rivastigmine, rubber pressure-sensitive adhesive, and tackifying resin is controlled to a predetermined amount, and the action of rivastigmine as a plasticizer in the pressure-sensitive adhesive layer is used. Without this, the physical properties of the patch and the initial adhesive strength of the patch can be maintained.
  • the adhesive when a large amount of plasticizer is blended in the adhesive layer, the adhesive itself maintains high adhesiveness even when the patch is peeled off, but the adhesive layer does not contain a plasticizer. The skin irritation at the time of peeling of the patch can be reduced.
  • the content of rivastigmine, rubber-based adhesive, and tackifying resin in the adhesive layer is controlled so as to satisfy the following formulas (1) and (2) as in the first aspect. It is preferable to do.
  • Formula (1) a + c ⁇ 55 Specifically, by setting the value of the left side of the formula (1) consisting of the content a (%) of rivastigmine and the content c (%) of the tackifier resin to 55 or more, the transdermal absorbability and The initial adhesive strength can be improved. More preferably, it is 58 or more, More preferably, it is 60 or more, More preferably, it is 62 or more. On the other hand, if the value on the left side of the formula (1) becomes too large, the initial adhesive strength becomes too high, which may cause skin irritation during peeling.
  • the value on the left side of the formula (1) is preferably 90 or less, more preferably 80 or less, and still more preferably 70 or less.
  • the initial adhesive strength can be improved. More preferably, it is 0.90 or less, More preferably, it is 0.85 or less, More preferably, it is 0.80 or less.
  • the value on the left side of Equation (2) is preferably 0.16 or more, more preferably 0.3 or more, still more preferably 0.5 or more, and even more preferably 0.6 or more.
  • the transdermally absorbable preparation of the present invention is, in the third aspect, in mass%, rivastigmine: 5% or more and 30% or less, rubber adhesive: 10% or more, 60% or less, and tackifying resin: 30% or more. 70% or less, and plasticizer: more than 0%, less than 2%.
  • the effective amount of the active ingredient is increased. It can be administered continuously and skin irritation can be significantly suppressed. Furthermore, by adding more than 0% and less than 2% plasticizer to the adhesive layer, the initial adhesive force can be improved while suppressing skin irritation.
  • the content of the plasticizer (individual content when included alone, and the total amount when including two or more) is more than 0% when the total amount of the adhesive layer is 100%. Less than 2%. If it is this range, initial adhesive force can be improved, suppressing skin irritation. Preferably they are 0.05% or more and 0.15% or less, More preferably, they are 0.07% or more and 0.10% or less.
  • the transdermal preparation of the present invention can be produced by the following method.
  • a base composition containing a drug is thermally melted and applied to a release film or a support, and then bonded to the support or the release film to obtain a preparation (hot melt method).
  • a preparation component is obtained by dissolving an agent component in a solvent such as toluene, hexane, ethyl acetate and the like, and extending on a release film or a support to remove the solvent by drying, and then bonding it to the support or the release film.
  • Solvent method solvent method
  • Example 1 11.4 g of a styrene / isoprene / styrene block copolymer and 15.0 g of an alicyclic saturated hydrocarbon resin were mixed and dissolved in an appropriate amount of toluene to obtain an adhesive base solution. 4.3 g of rivastigmine was added to this adhesive base solution, and the adhesive solution obtained by stirring and mixing until uniform was spread on a release film (PET film), and the solvent was removed by drying to a thickness of 129 ⁇ m. An adhesive layer was formed. Next, a patch was obtained by laminating a support (PET film). Table 1 shows the content of each component.
  • Examples 2-4 Examples 2 to 4 were obtained by the same production method as Example 1, except that the content of each component was the content shown in Table 1, and the thickness of the adhesive layer was the thickness shown in Table 1. Table 1 shows the content of each component.
  • Comparative Examples 1 and 2 As Comparative Example 1, a commercially available tulobuterol-containing patch that is known to exhibit excellent initial adhesive strength among commercially available products as a once-daily patch preparation was used. As Comparative Example 2, a commercially available rivastigmine-containing patch (Ixeron (registered trademark) patch) having a rivastigmine content of 1.8 mg / cm 2 and containing an acrylic adhesive and a silicone adhesive was used.
  • Ixeron (registered trademark) patch having a rivastigmine content of 1.8 mg / cm 2 and containing an acrylic adhesive and a silicone adhesive was used.
  • Adhesion test 1 180 ° peel test To verify the initial adhesive strength of the patch, a 180 ° peel test was performed. First, the preparations of Example 1 and Comparative Example 1 were adjusted to a size of 10 mm in width and 50 mm in length, the release film was peeled off from the preparation, and cellophane tape was applied to the part from the end in the length direction to 5 mm to free end Was provided. Thereafter, the preparation was quickly pasted onto a stainless steel plate (SUS plate), and immediately passed over the preparation twice through a rubber roller having a mass of 850 g at a speed of 300 mm / min. Next, after leaving at room temperature for 1 minute, the free end was folded back to a 180 ° angle.
  • SUS plate stainless steel plate
  • Adhesion test 2 Probe tack test A probe tack test was conducted to examine the initial adhesive strength. First, the preparations of Example 1 and Comparative Example 1 were punched into a circle having a diameter of 14 mm. Subsequently, a double-sided tape was affixed on the sample stage, and the preparation was affixed with the release film facing up. Thereafter, the release film was peeled off from the preparation, and a stainless steel spherical probe (diameter 5 mm) was attached to the pressure-sensitive shaft attachment part, and then the sample stage was raised at a speed of 10 mm / min. Finally, the pressure-sensitive adhesive surface was brought into contact with the spherical probe with a force of 50 g, and after resting for 10 seconds, the force required to separate was measured to obtain a peeling force (g). The results are shown in Table 2.
  • Example 1 is an example that satisfies the requirements of the present invention, and the peel force in the adhesive test 1 (180 ° peel test) was almost the same as that of Comparative Example 1, but the adhesive test 2 (probe tack test). The peel strength at was higher than that of Comparative Example 1. From this, it was confirmed that the preparation of the present invention had excellent initial adhesive strength.
  • Examples 1 to 4 are examples that satisfy the requirements of the present invention.
  • the cumulative drug permeation amount 24 hours after the start of the test is larger than that of Comparative Example 2 and has a drug release property superior to that of Comparative Example 2.
  • Example 1 Rabbit skin primary irritation test
  • Example 4 a rabbit skin primary irritation test was conducted using 6 rabbits as a group. Each preparation was affixed to the back of the rabbit from which hair was removed at two sites, normal skin and damaged skin, for 24 hours, and the total score of erythema score and edema score after 1 hour and 48 hours after peeling was determined. Further, the total score was divided by the number (4) obtained from the number of applied sites (2) ⁇ the observation time point (2) to obtain the Primary Irritation Index (PI). The results are shown in Tables 5 and 6. Table 7 shows the safety evaluation criteria. Each preparation was peeled off after 24 hours, and it was confirmed that the preparations of Examples 1 and 4 were easier to remove than Comparative Example 2.
  • PI Primary Irritation Index
  • Examples 1 and 4 are examples that satisfy the requirements of the present invention, and were found to be preparations having lower skin irritation and higher safety than Comparative Example 2.
  • Table 8 shows other prescription examples of the preparation of the present invention. However, the present invention is not limited to these.

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Abstract

L'invention concerne une préparation transdermique contenant de la rivastigmine, qui est capable d'administrer en continu un principe actif qui est la rivastigmine pendant une longue période, et qui présente une faible irritation de la peau. Une préparation transdermique selon la présente invention contient, en % en masse, de 5 % à 30 % (inclus) de rivastigmine, de 10 % à 60 % (inclus) d'un adhésif en caoutchouc et de 30 % à 70 % (inclus) d'une résine tackifiante; et si a (%) est le contenu en rivastigmine, b (%) est la teneur en adhésif en caoutchouc et c (%) est la teneur en résine tackifiante, a, b et c satisfont aux formules (1) et (2). a + c ≥ 55 (1) b/c ≤ 1,00 (2)
PCT/JP2018/006929 2017-02-27 2018-02-26 Préparation transdermique contenant de la rivastigmine WO2018155682A1 (fr)

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JP2019501861A JP7079015B2 (ja) 2017-02-27 2018-02-26 リバスチグミン含有経皮吸収型製剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3656383A4 (fr) * 2017-07-19 2021-05-19 Teikoku Seiyaku Co., Ltd. Préparation de type à absorption percutanée contenant de la rivastigmine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008066115A1 (fr) * 2006-11-30 2008-06-05 Nipro Patch Co., Ltd. Patch cutané adhésif et procédé d'évaluation dudit patch cutané adhésif
US20120197221A1 (en) * 2011-01-28 2012-08-02 Jang Myoung Hwa Transepidermal drug delivery system containing rivastigmine
JP2012533632A (ja) * 2009-07-21 2012-12-27 マイラン・インコーポレーテッド ポリイソブチレンベース経皮パッチの連続製造方法
WO2014034939A1 (fr) * 2012-09-03 2014-03-06 ニプロパッチ株式会社 Patch cutané adhésif
JP2014508728A (ja) * 2010-12-24 2014-04-10 サムヤン バイオファーマシューティカルズ コーポレイション リバスティグミンを含有する経皮吸収製剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008066115A1 (fr) * 2006-11-30 2008-06-05 Nipro Patch Co., Ltd. Patch cutané adhésif et procédé d'évaluation dudit patch cutané adhésif
JP2012533632A (ja) * 2009-07-21 2012-12-27 マイラン・インコーポレーテッド ポリイソブチレンベース経皮パッチの連続製造方法
JP2014508728A (ja) * 2010-12-24 2014-04-10 サムヤン バイオファーマシューティカルズ コーポレイション リバスティグミンを含有する経皮吸収製剤
US20120197221A1 (en) * 2011-01-28 2012-08-02 Jang Myoung Hwa Transepidermal drug delivery system containing rivastigmine
WO2014034939A1 (fr) * 2012-09-03 2014-03-06 ニプロパッチ株式会社 Patch cutané adhésif

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3656383A4 (fr) * 2017-07-19 2021-05-19 Teikoku Seiyaku Co., Ltd. Préparation de type à absorption percutanée contenant de la rivastigmine
US12290501B2 (en) 2017-07-19 2025-05-06 Teikoku Seiyaku Co., Ltd. Rivastigmine-containing transdermal absorption preparation

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JPWO2018155682A1 (ja) 2020-01-16

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