TW202440102A - Donepezil-containing transdermal formulation - Google Patents
Donepezil-containing transdermal formulation Download PDFInfo
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- TW202440102A TW202440102A TW112139958A TW112139958A TW202440102A TW 202440102 A TW202440102 A TW 202440102A TW 112139958 A TW112139958 A TW 112139958A TW 112139958 A TW112139958 A TW 112139958A TW 202440102 A TW202440102 A TW 202440102A
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- Prior art keywords
- donepezil
- weight
- percutaneous absorption
- preparation
- present
- Prior art date
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- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 title claims abstract description 164
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
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- 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
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- 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
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Abstract
Description
本發明是有關於一種經皮吸收製劑，其是關於具備支撐體與含有黏著基劑及藥物的黏著劑層之經皮吸收製劑，詳細而言，作為有效成分而含有的藥物，是作為用於失智症治療之多奈哌齊自由體的抗失智症治療劑。The present invention relates to a percutaneous absorption preparation, which is a percutaneous absorption preparation having a support and an adhesive layer containing an adhesive base and a drug. Specifically, the drug contained as an active ingredient is an anti-dementia therapeutic agent that is free form of donepezil for the treatment of dementia.
多奈哌齊具有乙醯膽鹼酯酶抑制作用，被廣泛用作抑制阿茲海默型失智症中失智症症狀的進展，即用作阿茲海默病的治療劑。已有報告指出，腦內膽鹼作動性神經系統的障礙之阿茲海默病中，多奈哌齊的各種乙醯膽鹼酯酶抑制劑，使其腦內乙醯膽鹼增加，並使腦內膽鹼作動性神經系統活性化。先前，已知實際使用的多奈哌齊的製劑以片劑、膠囊劑、糖漿劑或顆粒劑等的口服形式給藥。Donepezil has an acetylcholine esterase inhibitory effect and is widely used as a therapeutic agent for Alzheimer's disease to inhibit the progression of dementia symptoms in Alzheimer's disease. It has been reported that in Alzheimer's disease, which is a disorder of the choline-acting nervous system in the brain, various acetylcholine esterase inhibitors such as donepezil increase acetylcholine in the brain and activate the choline-acting nervous system in the brain. Previously, it is known that the preparations of donepezil actually used are administered orally in the form of tablets, capsules, syrups or granules.
但是，隨著症狀的進展，失智症患者在服藥上的課題可列舉：因吞嚥功能下降而使藥劑服用困難等。經皮吸收製劑即使在口服治療困難的情況下，可以容易地給藥，且由於貼附劑尚未獲得批准用於高度失智症，作為新的治療選擇而要求進行開發。 專利文獻1公開一種包含本發明的經皮吸收製劑之含多奈哌齊之經皮吸收製劑，但沒有記載本發明之用法及用量，也尚未證實與多奈哌齊的口服製劑之藥物動態的等效性及治療效果。 另外，專利文獻2記載多奈哌齊之經皮送達系統，其基本上是長期間給藥用的製劑(3日以上)，與本發明之一日一次給藥的經皮吸收製劑不同。 [先前技術文獻] [專利文獻] However, as symptoms progress, dementia patients face problems in taking medicines, such as difficulty taking medicines due to decreased swallowing function. Transdermal preparations can be easily administered even when oral treatment is difficult, and since patches have not yet been approved for use in advanced dementia, they are being developed as a new treatment option. Patent document 1 discloses a transdermal preparation containing donepezil that includes the transdermal preparation of the present invention, but does not describe the usage and dosage of the present invention, and has not yet confirmed the equivalence of the pharmacodynamics and therapeutic effect with the oral preparation of donepezil. In addition, Patent Document 2 describes a transdermal delivery system for donepezil, which is basically a preparation for long-term administration (more than 3 days), which is different from the transdermal absorption preparation for once-daily administration of the present invention. [Prior Technical Document] [Patent Document]
[專利文獻1]國際公開第2011/049038號 [專利文獻2]日本特表2019-522024號公報 [Patent Document 1] International Publication No. 2011/049038 [Patent Document 2] Japanese Patent Publication No. 2019-522024
[發明所欲解決之課題][The problem that the invention wants to solve]
因此，為了解決先前的問題，本發明的課題在於提供一種經皮吸收製劑，其表現出與多奈哌齊的口服製劑具有相同程度的藥物動態及治療效果。 [用以解決課題之手段] Therefore, in order to solve the previous problems, the subject of the present invention is to provide a percutaneous absorption preparation that exhibits the same degree of drug dynamics and therapeutic effects as the oral preparation of donepezil. [Means for solving the problem]
為了解決此課題，本發明者等進行致力研究的結果，發現可以提供一種經皮吸收製劑，其是具有包含多奈哌齊自由體之黏著劑層的經皮吸收製劑，其黏著劑層含有疏水性高分子及13.75~55mg的多奈哌齊自由體，將該經皮吸收製劑向患者1日1次給藥，藉此顯示與多奈哌齊鹽酸鹽的口服製劑相同程度的藥物動態。 特別是，關於將苯乙烯-異戊二烯-苯乙烯嵌段共聚物(以下，有時簡寫為「SIS」)作為主基劑的製劑(以下，有時簡寫為「SIS製劑」)，發現較佳為將氫化松香甘油酯用作黏著賦予樹脂，將液態石蠟用作塑化劑，從而完成了本發明。 To solve this problem, the inventors of the present invention have conducted intensive research and found that a percutaneous absorption preparation can be provided, which is a percutaneous absorption preparation having an adhesive layer containing free donepezil, wherein the adhesive layer contains a hydrophobic polymer and 13.75-55 mg of free donepezil. The percutaneous absorption preparation is administered to a patient once a day, thereby showing the same degree of drug dynamics as an oral preparation of donepezil hydrochloride. In particular, regarding a preparation using styrene-isoprene-styrene block copolymer (hereinafter, sometimes abbreviated as "SIS") as the main base (hereinafter, sometimes abbreviated as "SIS preparation"), it was found that it is preferable to use hydrogenated rosin glycerol ester as the adhesive imparting resin and liquid wax as the plasticizer, thereby completing the present invention.
亦即，本發明是有關於以下。 [1] 一種經皮吸收製劑，其是具有包含多奈哌齊自由體的黏著劑層，且用於治療失智症的經皮吸收製劑，其中，黏著劑層含有苯乙烯-異戊二烯-苯乙烯嵌段共聚物及13.75mg~55mg的多奈哌齊自由體，向患者1日1次給藥。 [2] 如[1]之經皮吸收製劑，其中前述黏著劑層進一步含有氫化松香甘油酯、液態石蠟及吸收促進劑。 [3] 如[2]之經皮吸收製劑，其中相對於黏著劑層的重量，苯乙烯-異戊二烯-苯乙烯嵌段共聚物的調配量為5~70重量%，氫化松香甘油酯的調配量為5~70重量%，液態石蠟的調配量為10~70重量%，以及吸收促進劑的調配量為0.01~30重量%。 [4] 如[2]之經皮吸收製劑，其中相對於黏著劑層的重量，苯乙烯-異戊二烯-苯乙烯嵌段共聚物的調配量為10~50重量%，氫化松香甘油酯的調配量為10~60重量%，液態石蠟的調配量為10~50重量%，以及吸收促進劑的調配量為1~10重量%。 [5] 如[2]之經皮吸收製劑，其中相對於黏著劑層的重量，苯乙烯-異戊二烯-苯乙烯嵌段共聚物的調配量為20~30重量%，氫化松香甘油酯的調配量為30~50重量%，液態石蠟的調配量為15~30重量%，以及吸收促進劑的調配量為3~8重量%。 [6] 如[1]~[5]中任一項之經皮吸收製劑，其中氫化松香甘油酯與多奈哌齊自由體的重量比，氫化松香甘油酯/多奈哌齊自由體=1.5~8，且 苯乙烯-異戊二烯-苯乙烯嵌段共聚物與液態石蠟的重量比，苯乙烯-異戊二烯-苯乙烯嵌段共聚物/液態石蠟=0.7~1.8。 [7] 如[1]~[5]中任一項之經皮吸收製劑，其中氫化松香甘油酯與多奈哌齊自由體的重量比，氫化松香甘油酯/多奈哌齊自由體=4~7，且 苯乙烯-異戊二烯-苯乙烯嵌段共聚物與液態石蠟的重量比，苯乙烯-異戊二烯-苯乙烯嵌段共聚物/液態石蠟=0.8~1.6。 [8] 如[1]~[5]中任一項之經皮吸收製劑，其包含13.75mg、27.5mg或55mg的多奈哌齊自由體。 [9] 如[6]之經皮吸收製劑，其包含13.75mg、27.5mg或55mg的多奈哌齊自由體。 [10] 如[7]之經皮吸收製劑，其包含13.75mg、27.5mg或55mg的多奈哌齊自由體。 [11] 如[1]~[10]中任一項之經皮吸收製劑，其中吸收促進劑為脂肪族醇。 [12] 如[1]~[5]中任一項之經皮吸收製劑，其中包含多奈哌齊自由體的黏著劑層之與皮膚接觸的面的面積為10~ 100cm 2。 [13] 一種失智症的治療方法，其包含將如[1]~[12]中任一項之經皮吸收製劑向患者給藥。 [14] 如[1]~[12]中任一項之經皮吸收製劑，其用於失智症的治療。 [15] 一種如[1]~[12]中任一項之經皮吸收製劑用於製備治療失智症之醫藥的用途。 [16] 一種經皮吸收製劑的用途，其是將如[1]~[12]中任一項之經皮吸收製劑用於失智症的治療。 [17] 如[1]~[12]中任一項之經皮吸收製劑，其中在釋放試驗中，在第3小時從製劑中的藥物釋放率為10~50%。 [18] 如[1]~[12]中任一項之經皮吸收製劑，其中在釋放試驗中，在第6小時從製劑中的藥物釋放率為30~70%。 [19] 如[1]~[12]中任一項之經皮吸收製劑，其中在釋放試驗中，在第9小時從製劑中的藥物釋放率為40%以上。 [發明的效果] That is, the present invention relates to the following. [1] A percutaneous absorption preparation having an adhesive layer containing free donepezil and for use in treating dementia, wherein the adhesive layer contains a styrene-isoprene-styrene block copolymer and 13.75 mg to 55 mg of free donepezil, and is administered to a patient once a day. [2] The percutaneous absorption preparation as described in [1], wherein the adhesive layer further contains hydrogenated rosin glycerol ester, liquid wax and an absorption enhancer. [3] The percutaneous absorption preparation of [2], wherein the amount of styrene-isoprene-styrene block copolymer is 5-70% by weight, the amount of hydrogenated rosin glycerol ester is 5-70% by weight, the amount of liquid wax is 10-70% by weight, and the amount of absorption enhancer is 0.01-30% by weight, relative to the weight of the adhesive layer. [4] The percutaneous absorption preparation of [2], wherein the amount of styrene-isoprene-styrene block copolymer is 10-50% by weight, the amount of hydrogenated rosin glycerol ester is 10-60% by weight, the amount of liquid wax is 10-50% by weight, and the amount of absorption enhancer is 1-10% by weight, relative to the weight of the adhesive layer. [5] The percutaneous absorption preparation of [2], wherein the amount of styrene-isoprene-styrene block copolymer is 20-30% by weight, the amount of hydrogenated rosin glycerol ester is 30-50% by weight, the amount of liquid wax is 15-30% by weight, and the amount of absorption enhancer is 3-8% by weight, relative to the weight of the adhesive layer. [6] The percutaneous absorption preparation of any one of [1] to [5], wherein the weight ratio of hydrogenated rosin glycerol ester to donepezil free body is hydrogenated rosin glycerol ester/donepezil free body = 1.5-8, and the weight ratio of styrene-isoprene-styrene block copolymer to liquid wax is styrene-isoprene-styrene block copolymer/liquid wax = 0.7-1.8. [7] The percutaneous absorption preparation of any one of [1] to [5], wherein the weight ratio of hydrogenated rosin glycerol ester to donepezil free body is hydrogenated rosin glycerol ester/donepezil free body = 4 to 7, and the weight ratio of styrene-isoprene-styrene block copolymer to liquid wax is styrene-isoprene-styrene block copolymer/liquid wax = 0.8 to 1.6. [8] The percutaneous absorption preparation of any one of [1] to [5], comprising 13.75 mg, 27.5 mg or 55 mg of donepezil free body. [9] The percutaneous absorption preparation of [6], comprising 13.75 mg, 27.5 mg or 55 mg of donepezil free body. [10] A percutaneous absorption preparation as described in [7], comprising 13.75 mg, 27.5 mg or 55 mg of free donepezil. [11] A percutaneous absorption preparation as described in any one of [1] to [10], wherein the absorption enhancer is a fatty alcohol. [12] A percutaneous absorption preparation as described in any one of [1] to [5], wherein the area of the surface of the adhesive layer containing free donepezil in contact with the skin is 10 to 100 cm2 . [13] A method for treating dementia, comprising administering the percutaneous absorption preparation as described in any one of [1] to [12] to a patient. [14] A percutaneous absorption preparation as described in any one of [1] to [12], which is used for the treatment of dementia. [15] A use of a percutaneous absorption preparation as described in any one of [1] to [12] for the preparation of a medicament for the treatment of dementia. [16] A use of a percutaneous absorption preparation as described in any one of [1] to [12] for the treatment of dementia. [17] A percutaneous absorption preparation as described in any one of [1] to [12], wherein in a release test, the drug release rate from the preparation at 3 hours is 10-50%. [18] A percutaneous absorption preparation as described in any one of [1] to [12], wherein in a release test, the drug release rate from the preparation at 6 hours is 30-70%. [19] A percutaneous absorption preparation as described in any one of [1] to [12], wherein in a release test, the drug release rate from the preparation at 9 hours is 40% or more. [Effects of the Invention]
根據本發明，可以提供表現出與多奈哌齊的口服製劑具有相同程度的藥物動態及治療效果之經皮吸收製劑。According to the present invention, a percutaneous absorption preparation can be provided which exhibits the same degree of pharmacodynamics and therapeutic effects as an oral preparation of donepezil.
藉由本發明提供之含多奈哌齊之經皮吸收製劑，可以使多奈哌齊自由體透過皮膚而有效率地吸收到循環血液中，並可以得到與口服製劑同等的治療效果。 因此，本發明為進行症狀之患者提供新的選擇的同時，假定使吞嚥功能下降之患者服藥容易，及從其可見性而提升服藥順從性，期待將減輕介護者的負擔。 The percutaneous absorption preparation containing donepezil provided by the present invention can allow free donepezil to be efficiently absorbed into the circulating blood through the skin, and can obtain the same therapeutic effect as the oral preparation. Therefore, the present invention provides a new option for patients with symptoms, and at the same time, it is assumed that it will make it easier for patients with decreased swallowing function to take medicine, and improve medication compliance due to its visibility, and it is expected to reduce the burden on caregivers.
以下，對本發明提供之含多奈哌齊之經皮吸收製劑進行更詳細的說明。Hereinafter, the transdermal absorption preparation containing donepezil provided by the present invention will be described in more detail.
在本說明書中，「含有」或「包含」用語，可以與「調配有」互換使用。另外，在本說明書中，「含量」及「調配量」可以互換使用。In this specification, the terms "contain" or "include" can be used interchangeably with "mixed with". In addition, in this specification, "content" and "mixed amount" can be used interchangeably.
本發明所謂的經皮吸收製劑是指，至少含有支撐體及黏著劑層(也稱為黏著組成物)的貼附劑，包含具有藥物儲藏層的儲存型的外用貼附劑及單層基材型的外用貼附劑。The percutaneous absorption preparation of the present invention refers to an adhesive patch containing at least a support and an adhesive layer (also referred to as an adhesive composition), including a storage type external patch having a drug storage layer and a single-layer base type external patch.
基材型的外用貼附劑具有自黏性，且具有效成分的黏著組成物可直接接著於皮膚，因此相較於儲存型的外用貼附劑，具有優異的接著性及藥劑的吸收性。 因此，對於以下本發明的經皮吸收製劑，主要以基材型的貼附劑作為實例進行說明，但本發明並不限於此。 The substrate-type external patch is self-adhesive, and the adhesive composition with active ingredients can be directly attached to the skin, so it has excellent adhesion and drug absorption compared to the storage-type external patch. Therefore, the following percutaneous absorption preparation of the present invention is mainly described using the substrate-type patch as an example, but the present invention is not limited to this.
本發明提供的經皮吸收製劑中，包含溶解有多奈哌齊自由體的黏著組成物。 通常，其為含有藥物(多奈哌齊自由體)的黏著劑層，及積層在其背面的支撐體所構成的形態。此黏著劑層較佳為具有能在皮膚表面24小時以上且在治療上沒問題之有效面積貼著的自黏性，但若在其困難的情況下，可以使用比藥物含有層的面積更大，且使用具有黏著力的片狀的蓋體。 The percutaneous absorption preparation provided by the present invention includes an adhesive composition in which free-body Donepezil is dissolved. Generally, it is a form consisting of an adhesive layer containing a drug (free-body Donepezil) and a support layered on the back thereof. The adhesive layer preferably has self-adhesiveness that allows it to adhere to an effective area on the skin surface for more than 24 hours without any problem in treatment, but if this is difficult, a cover body in the form of a sheet having an adhesive force and having a larger area than the drug-containing layer can be used.
多奈哌齊可以形成鹽，但在本發明的經皮吸收製劑中，使用多奈哌齊自由體(即不形成鹽之游離型的多奈哌齊)的形式。 本發明的經皮吸收製劑，藉由將多奈哌齊自由體溶解於黏著組成物中，可以不產生附著性問題且穩定地供給藥物。 此外，相對於黏著組成物全體的重量，其調配量為5~8重量%，較佳為6~7重量%。更佳地，本發明的經皮吸收製劑以包含13.75mg、27.5mg或55mg的多奈哌齊自由體的方式製造。 本發明的經皮吸收製劑中多奈哌齊的釋放性，由於根據基劑成分而受到影響，因此多奈哌齊的調配量也可以藉由藥物釋放試驗來決定。作為藥物釋放試驗，較佳為測定相對於水之釋放率的方法。例如，在以試驗液1000mL、試驗液溫度32±0.5℃、圓筒旋轉數50rpm實施的情況下，較佳為在試驗開始3小時後向水中的釋放率為10~50%，6小時後為30%~70%，9小時後為40%以上。 Donepezil can form a salt, but in the percutaneous absorption preparation of the present invention, the free form of donepezil (i.e., free-type donepezil that does not form a salt) is used. The percutaneous absorption preparation of the present invention can stably supply the drug without causing adhesion problems by dissolving the free form of donepezil in the adhesive composition. In addition, the formulation amount is 5 to 8% by weight, preferably 6 to 7% by weight, relative to the weight of the entire adhesive composition. More preferably, the percutaneous absorption preparation of the present invention is manufactured in a manner that contains 13.75 mg, 27.5 mg or 55 mg of the free form of donepezil. Since the release of donepezil in the percutaneous absorption preparation of the present invention is affected by the base component, the dosage of donepezil can also be determined by a drug release test. As a drug release test, a method of measuring the release rate relative to water is preferred. For example, when the test solution is 1000 mL, the test solution temperature is 32±0.5℃, and the cylinder rotation number is 50rpm, the release rate into water is preferably 10~50% 3 hours after the start of the test, 30%~70% after 6 hours, and 40% or more after 9 hours.
本發明的黏著組成物，含有疏水性的高分子作為具有自黏性的黏著組成物。 作為疏水性的高分子，沒有特別限定，但較佳為使用橡膠系高分子、丙烯酸系高分子或矽系高分子。 作為橡膠系的高分子，可列舉：苯乙烯-異戊二烯-苯乙烯嵌段共聚物、異戊二烯、聚異丁烯(以下，簡稱為「PIB」)、苯乙烯-丁二烯-苯乙烯嵌段共聚物(以下，簡稱為「SBS」)、苯乙烯-丁二烯橡膠(以下，簡稱為「SBR」)等，其中較佳為SIS。 The adhesive composition of the present invention contains a hydrophobic polymer as a self-adhesive adhesive composition. The hydrophobic polymer is not particularly limited, but preferably a rubber polymer, an acrylic polymer or a silicone polymer is used. The rubber polymer includes styrene-isoprene-styrene block copolymer, isoprene, polyisobutylene (hereinafter referred to as "PIB"), styrene-butadiene-styrene block copolymer (hereinafter referred to as "SBS"), styrene-butadiene rubber (hereinafter referred to as "SBR"), etc., among which SIS is preferred.
作為丙烯酸系高分子，只要是含有與2-乙基己酯丙烯酸酯、丙烯酸甲酯、丙烯酸丁酯、丙烯酸羥乙酯、2-乙基己酯甲基丙烯酸酯等所代表之(甲基)丙烯酸衍生物中至少一種進行共聚合者，則沒有特別限定。 具體而言，例如，在醫藥品添加物辭典2007(日本醫藥品添加劑協會編輯)中作為黏著劑而收錄之丙烯酸-丙烯酸辛酯共聚物、丙烯酸2-乙基己酯-乙烯基吡咯啶酮共聚物溶液、丙烯酸酯-乙酸乙烯酯共聚物、丙烯酸2-乙基己酯-甲基丙烯酸2-乙基己酯-甲基丙烯酸十二烷基酯共聚物、丙烯酸甲酯-丙烯酸2-乙基己酯共聚物樹脂乳液、丙烯酸樹脂烷醇胺液中所含有之丙烯酸系高分子等的黏著劑，亦可使用DURO-TAK丙烯酸系黏著劑系列(Henkel公司製造)、EUDRAGIT系列(樋口商會公司製造)等市售品。 As acrylic polymers, there are no particular limitations as long as they are copolymerized with at least one of (meth)acrylic acid derivatives represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate, etc. Specifically, for example, acrylic acid-octyl acrylate copolymer, 2-ethylhexyl acrylate-vinyl pyrrolidone copolymer solution, acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, methyl acrylate-2-ethylhexyl acrylate copolymer resin emulsion, acrylic acid resin alkanolamine liquid, etc., which are listed as adhesives in the Dictionary of Pharmaceutical Additives 2007 (edited by the Japan Pharmaceutical Additives Association). Commercially available products such as DURO-TAK acrylic adhesive series (manufactured by Henkel) and EUDRAGIT series (manufactured by Higuchi Shokai Co., Ltd.) can also be used.
作為矽系高分子的具體例，可列舉：聚有機矽氧烷等的矽橡膠。Specific examples of silicon-based polymers include silicone rubbers such as polyorganosiloxane.
該些疏水性高分子可以混合2種以上使用，且基於該些高分子的組成物全體的重量之調配量，考慮黏著劑層的形成及充分的透過性，其為5~70重量%，較佳為10~50重量%，進一步較佳為20~30重量%。The hydrophobic polymers may be mixed in two or more kinds and the amount thereof based on the total weight of the polymer composition is 5 to 70% by weight, preferably 10 to 50% by weight, and more preferably 20 to 30% by weight, in consideration of the formation of the adhesive layer and sufficient permeability.
本發明提供的經皮吸收製劑的黏著組成物，較佳為含有吸收促進劑，作為可使用的吸收促進劑，可列舉：脂肪酸酯、脂肪族醇、界面活性劑等。 具體而言，可列舉：月桂酸甲酯、月桂酸己酯、檸檬酸三乙酯、肉豆蔻酸異丙酯(以下簡稱IPM)、肉豆蔻酸肉荳蔻酯、肉豆蔻酸辛基十二烷酯、棕櫚酸十六烷酯、三乙酸甘油酯、乳酸十八醇酯、乳酸月桂酯、水楊酸甲酯、水楊酸二醇酯、水楊酸乙二醇酯、癸二酸二乙酯、癸二酸二異丙酯、中鏈脂肪酸三酸甘油酯、月桂基醇、硬脂醯基醇、異硬脂醯醇、肉荳蔻醇、油醇、鯨蠟醇(cetanol)、甘油單辛酸酯、甘油單月桂酸酯、甘油單油酸酯、單月桂酸山梨聚糖酯、山梨醇酐單油酸酯、單月桂酸蔗糖酯、聚山梨酸酯20、單月桂酸丙二醇酯、單月桂酸聚乙二醇酯、聚乙二醇單硬脂酸酯、聚月桂乙二醇(Lauromacrogol)、HCO-60、月桂酸二乙醇醯胺、N-甲基-2-吡咯啶酮、克羅他命酮(crotamiton)、二甲基亞碸等，但較佳為檸檬酸三乙酯、肉豆蔻酸異丙酯、乳酸十八醇酯、油醇、山梨醇酐單油酸酯、聚乙二醇單硬脂酸酯、聚月桂乙二醇(Lauromacrogol)、N-甲基-2-吡咯啶酮及三乙酸甘油酯。 The adhesive composition of the percutaneous absorption preparation provided by the present invention preferably contains an absorption enhancer. Usable absorption enhancers include: fatty acid esters, fatty alcohols, surfactants, etc. Specifically, the following can be cited: methyl laurate, hexyl laurate, triethyl citrate, isopropyl myristate (hereinafter referred to as IPM), myristyl myristate, octyldodecyl myristate, hexadecyl palmitate, triacetin, stearyl lactate, lauryl lactate, methyl salicylate, glycol salicylate, ethylene glycol salicylate, diethyl sebacate, diisopropyl sebacate, medium-chain fatty acid triglycerides, lauryl alcohol, stearyl alcohol, isostearyl alcohol, myristyl alcohol, oleyl alcohol, cetanol, glyceryl monocaprylate, glyceryl monolaurate, glyceryl monooleate, sorbitan monolaurate, sorbitan anhydride Monooleate, sucrose monolaurate, polysorbate 20, propylene glycol monolaurate, polyethylene glycol monolaurate, polyethylene glycol monostearate, lauromacrogol, HCO-60, lauric acid diethanolamide, N-methyl-2-pyrrolidone, crotamiton, dimethyl sulfoxide, etc., but the preferred ones are triethyl citrate, isopropyl myristate, octadecyl lactate, oleyl alcohol, sorbitan monooleate, polyethylene glycol monostearate, lauromacrogol, N-methyl-2-pyrrolidone and triacetin.
在該些中，較佳為選自由脂肪族醇(例如月桂醇、硬脂醇、異硬脂醇、肉荳蔻醇及油醇等)中的1種或2種以上進行調配。Among these, it is preferred to mix one or more selected from aliphatic alcohols (such as lauryl alcohol, stearyl alcohol, isostearyl alcohol, myristyl alcohol and oleyl alcohol).
此般的吸收促進劑，考慮到作為貼附製劑之主藥充份的透過性及發紅、浮腫等的皮膚刺激性等，基於黏著劑層的組成全體的重量，較佳為以0.01~30重量%程度進行調配，更佳為1~10重量%，進一步較佳為3~8重量%。Such absorption enhancers are preferably formulated at 0.01 to 30% by weight, more preferably 1 to 10% by weight, and even more preferably 3 to 8% by weight, based on the weight of the entire composition of the adhesive layer, taking into account sufficient permeability of the main drug of the patch preparation and skin irritation such as redness and swelling.
本發明提供的經皮吸收製劑中的黏著組成物可以含有塑化劑。作為可使用的塑化劑，可列舉：石油系油(例如，石蠟系加工處理油、環烷烴系加工處理油、芳香族系加工處理油等)；角鯊烷；角鯊烯；植物系油(例如，橄欖油、山茶油、妥爾油、花生油、蓖麻油)；矽油；二元酸酯(例如，鄰苯二甲酸二丁酯、鄰苯二甲酸二辛酯)；液態橡膠(例如，聚丁烯、液態異戊二烯橡膠)；液態脂肪酸酯類(肉豆蔻酸異丙酯、月桂酸己酯、癸二酸二乙酯、癸二酸二異丙酯)；二乙二醇；聚乙二醇；丙二醇；二丙二醇等。特別較佳為液態石蠟、液態聚丁烯或矽油。最佳為液態石蠟。The adhesive composition in the percutaneous absorption preparation provided by the present invention may contain a plasticizer. Examples of usable plasticizers include: petroleum oils (e.g., paraffin processing oils, cycloalkane processing oils, aromatic processing oils, etc.); squalane; squalene; plant oils (e.g., olive oil, camellia oil, tall oil, peanut oil, castor oil); silicone oil; dibasic acid esters (e.g., dibutyl phthalate, dioctyl phthalate); liquid rubbers (e.g., polybutene, liquid isoprene rubber); liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate); diethylene glycol; polyethylene glycol; propylene glycol; dipropylene glycol, etc. Liquid wax, liquid polybutene or silicone oil is particularly preferred. Liquid wax is the most preferred.
該些成分可以2種以上混合使用，此般的塑化劑，考慮到充分的皮膚透過性及維持作為貼附製劑之充分的凝集力，基於黏著劑層的組成全體之調配量，該些合計為10~70重量%，較佳為10~50重量%，進一步較佳為15~30重量%。These components can be used in combination of two or more. In view of sufficient skin permeability and maintaining sufficient cohesive force as an adhesive preparation, the total amount of plasticizers is 10-70% by weight, preferably 10-50% by weight, and further preferably 15-30% by weight, based on the overall composition of the adhesive layer.
為了調整製劑的黏著力，期望對本發明的黏著劑層調配黏著賦予樹脂。此外，黏著賦予樹脂之中也具有表現出溶解多奈哌齊自由體作用者，也用於調節貼附劑中多奈哌齊自由體的溶解性。 作為可使用的黏著賦予樹脂，可例舉：松香衍生物(例如，松香、松香甘油酯、氫化松香、氫化松香甘油酯、松香季戊四醇酯等)；脂環族飽和烴樹脂(例如，Arkon P100，荒川化學工業公司製)；脂肪族系烴樹脂(例如，Quintone B170，日本瑞翁公司製)；萜烯樹脂(例如Clearon P-125，Yasuhara Chemical公司製)、順丁烯二酸樹脂等。但考慮製劑的黏著性、製劑中的多奈哌齊自由體溶解性的情況下，特別較佳為氫化松香甘油酯。 In order to adjust the adhesive force of the preparation, it is desirable to formulate an adhesive resin for the adhesive layer of the present invention. In addition, there are also adhesive resins that have the effect of dissolving free bodies of donepezil, and they are also used to adjust the solubility of free bodies of donepezil in the patch. As the tackifier resin that can be used, there are: rosin derivatives (e.g., rosin, rosin glycerol ester, hydrogenated rosin, hydrogenated rosin glycerol ester, rosin pentaerythritol ester, etc.); alicyclic saturated hydrocarbon resins (e.g., Arkon P100, manufactured by Arakawa Chemical Industries, Ltd.); aliphatic hydrocarbon resins (e.g., Quintone B170, manufactured by Nippon Zeon Co., Ltd.); terpene resins (e.g., Clearon P-125, manufactured by Yasuhara Chemical Co., Ltd.), maleic acid resins, etc. However, considering the tackiness of the preparation and the solubility of donepezil free body in the preparation, hydrogenated rosin glycerol ester is particularly preferred.
此般的黏著賦予樹脂，考慮到作為貼附製劑之充分的黏著力及剝離時對皮膚的刺激性，基於黏著組成物的組成全體之調配量為5~70重量%，較佳為10~60重量%，進一步較佳為30~50重量%。Such an adhesive imparting resin is formulated in an amount of 5 to 70% by weight, preferably 10 to 60% by weight, and more preferably 30 to 50% by weight, based on the entire composition of the adhesive composition, in consideration of sufficient adhesiveness as an adhesive preparation and irritation to the skin during peeling.
本發明提供的含多奈哌齊之經皮吸收製劑，由於其為全身作用性的經皮吸收製劑，若保存中的主藥結晶化，將成為導致貼附時的多奈哌齊自由體的血中濃度降低的原因而不佳。因此，期望即使在長期保存條件下，製劑中不會生成多奈哌齊自由體的結晶。然而，由於本發明是調配有經皮吸收促進劑的製劑，因此難以在長期保存品中保持基劑的均勻性，擔憂因基劑的不均勻所致之主藥的結晶化。The percutaneous absorption preparation containing donepezil provided by the present invention is a percutaneous absorption preparation with systemic action. If the main drug crystallizes during storage, it will cause a decrease in the blood concentration of the free body of donepezil when applied, which is not desirable. Therefore, it is expected that crystals of the free body of donepezil will not be generated in the preparation even under long-term storage conditions. However, since the present invention is a preparation formulated with a percutaneous absorption enhancer, it is difficult to maintain the uniformity of the base in a long-term storage product, and there is a concern about crystallization of the main drug due to the non-uniformity of the base.
因此，在SIS製劑中，不僅將氫化松香甘油酯作為黏著賦予樹脂，也使其作為多奈哌齊自由體的溶解劑的功能，試圖增加多奈哌齊自由體的溶解性。當氫化松香甘油酯調配一定量以上時，由於觀察到多奈哌齊自由體的溶解性過高導致主藥釋放性降低，因此氫化松香甘油酯及多奈哌齊自由體必須以適當的重量比進行調配。Therefore, in the SIS formulation, hydrogenated rosin glycerol ester is not only used to impart adhesiveness to the resin, but also functions as a solvent for donepezil free body in an attempt to increase the solubility of donepezil free body. When hydrogenated rosin glycerol ester is formulated above a certain amount, it is observed that the solubility of donepezil free body is too high, resulting in a decrease in the release of the main drug. Therefore, hydrogenated rosin glycerol ester and donepezil free body must be formulated at an appropriate weight ratio.
根據本發明者等的研究，判明本發明的含多奈哌齊之經皮吸收製劑中，氫化松香甘油酯與多奈哌齊自由體的較佳重量比，氫化松香甘油酯/多奈哌齊自由體=1.5~8，更佳為4~7，進一步較佳為6~7。亦即，當氫化松香甘油酯/多奈哌齊自由體小於1.5時，由於製劑中的多奈哌齊自由體的溶解性低，因此擔憂在保存中之製劑中的主藥結晶化，並且，當大於8時，發生主藥釋放性的降低。According to the research conducted by the inventors, it was found that the preferred weight ratio of hydrogenated rosin glycerol ester to donepezil free body in the transdermal absorption preparation containing donepezil of the present invention is hydrogenated rosin glycerol ester/donepezil free body = 1.5 to 8, more preferably 4 to 7, and even more preferably 6 to 7. That is, when the hydrogenated rosin glycerol ester/donepezil free body is less than 1.5, the solubility of donepezil free body in the preparation is low, so there is a concern that the main drug in the preparation during storage may crystallize, and when it is greater than 8, the release of the main drug may decrease.
進一步地，在SIS製劑中，判明SIS調配量與多奈哌齊自由體的結晶化具有關聯性。亦即，藉由調配SIS，抑制製劑中多奈哌齊自由體的移動性，其結果，可以抑制主藥的結晶化。但是，當調配大量SIS時，具有引起製劑的黏著性降低的可能性。 相反地，調配液態石蠟將促進多奈哌齊自由體的結晶化。亦即，藉由調配液態石蠟，不僅將促進製劑中多奈哌齊自由體的移動性，由於液態石蠟自身對多奈哌齊自由體的溶解性較低，將降低作為製劑全體之多奈哌齊自由體的溶解性，但是，抑制、降低液態石蠟的調配量將導致黏著物性的降低。 Furthermore, in SIS preparations, it was found that the amount of SIS added is correlated with the crystallization of donepezil free bodies. That is, by adding SIS, the mobility of donepezil free bodies in the preparation is suppressed, and as a result, the crystallization of the main drug can be suppressed. However, when a large amount of SIS is added, there is a possibility that the adhesion of the preparation is reduced. On the contrary, adding liquid wax will promote the crystallization of donepezil free bodies. That is, by adding liquid wax, not only will the mobility of donepezil free bodies in the preparation be promoted, but since the solubility of liquid wax itself in donepezil free bodies is low, the solubility of donepezil free bodies as the whole preparation will be reduced. However, suppressing and reducing the amount of liquid wax added will lead to a reduction in adhesion properties.
鑑於該些狀況，在本發明中，藉由使液態石蠟及SIS的重量比進行最適化，可以在不損害黏著物性的情況下，可以抑制多奈哌齊自由體的結晶化。 亦即，本發明中SIS與液態石蠟的重量比，SIS/液態石蠟=0.7~1.8，較佳為0.8~1.6，更佳為1~1.5。當SIS/液態石蠟小於0.7時，液態石蠟的調配量過剩，擔憂在長期保存製劑中多奈哌齊自由體的結晶化。另一方面，當大於1.8時，由於SIS含量過高，導致黏著力的降低。 In view of these conditions, in the present invention, by optimizing the weight ratio of liquid wax and SIS, the crystallization of donepezil free body can be suppressed without damaging the adhesive properties. That is, the weight ratio of SIS to liquid wax in the present invention is SIS/liquid wax = 0.7~1.8, preferably 0.8~1.6, and more preferably 1~1.5. When SIS/liquid wax is less than 0.7, the amount of liquid wax is excessive, and there is a concern about the crystallization of donepezil free body in the long-term storage preparation. On the other hand, when it is greater than 1.8, the SIS content is too high, resulting in a decrease in adhesion.
在本發明提供的經皮吸收製劑中，可視需求使用抗氧化劑、充填劑、交聯劑、防腐劑、紫外線吸收劑。 作為抗氧化劑，期望為生育酚及該些的酯衍生物、抗壞血酸、抗壞血酸硬脂酸酯、降二氫癒瘡木酸、二丁基羥基甲苯(BHT)、丁基羥基茴香醚等。 作為充填劑，期望為碳酸鈣、碳酸鎂、矽酸鹽(例如，矽酸鋁、矽酸鎂等)、矽酸、硫酸鋇、硫酸鈣、鋅酸鈣、氧化鋅、氧化鈦、二氧化矽等。 In the percutaneous absorption preparation provided by the present invention, antioxidants, fillers, crosslinking agents, preservatives, and ultraviolet absorbers can be used as needed. As antioxidants, tocopherol and its ester derivatives, ascorbic acid, ascorbic acid stearate, nordihydrohealing acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole, etc. are expected. As fillers, calcium carbonate, magnesium carbonate, silicates (e.g., aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide, silicon dioxide, etc. are expected.
作為交聯劑，期望為胺基樹脂、酚樹脂、環氧樹脂、醇酸樹脂、不飽和聚酯等熱硬化性樹脂、異氰酸酯化合物、嵌段異氰酸酯化合物、有機系交聯劑、金屬或金屬化合物等之無機系交聯劑。 作為防腐劑，期望為對羥基苯甲酸乙酯、對羥基苯甲酸丙酯、對羥基苯甲酸丁酯等。 作為紫外線吸收劑，期望為對胺基苯甲酸衍生物、鄰胺苯甲酸衍生物、水楊酸衍生物、胺基酸系化合物、二噁烷衍生物、香豆素衍生物、咪唑啉衍生物、嘧啶衍生物等。 As crosslinking agents, thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, metals or metal compounds, etc. are expected. As preservatives, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, etc. are expected. As ultraviolet absorbers, p-aminobenzoic acid derivatives, amine benzoic acid derivatives, salicylic acid derivatives, amino acid compounds, dioxane derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, etc. are expected.
基於製劑的黏著劑層的組成全體的重量，此類抗氧化劑、充填劑、交聯劑、防腐劑、紫外線吸收劑等可以較佳為10重量%以下，進一步較佳為5重量%以下，特別較佳為2重量%以下進行調配。Based on the weight of the entire composition of the adhesive layer of the preparation, such antioxidants, fillers, crosslinking agents, preservatives, ultraviolet absorbers, etc. can be preferably formulated in an amount of 10 weight % or less, more preferably 5 weight % or less, and particularly preferably 2 weight % or less.
本發明的經皮吸收製劑，可以用於治療失智症(例如阿茲海默型失智症及路易氏體失智症等)。The percutaneous absorption preparation of the present invention can be used to treat dementia (such as Alzheimer's dementia and Lewy body dementia).
在本發明中，「治療」是指將本發明的經皮吸收製劑向已經出現疾病或症狀的個體進行給藥的行為。因此，對已經出現疾病或症狀的個體進行給藥以防止症狀等的惡化、發作或復發的行為是「治療」的一態樣。In the present invention, "treatment" refers to the act of administering the percutaneous absorption preparation of the present invention to an individual who has developed a disease or symptom. Therefore, administering a drug to an individual who has developed a disease or symptom to prevent the deterioration, onset or recurrence of the symptom is an aspect of "treatment".
本發明的經皮吸收製劑通常向患有失智症或具有失智症風險的患者，例如人或動物，較佳為人進行給藥。給藥次數可依疾病或症狀的嚴重程度、患者的年齡、體重、性別及經皮吸收製劑中的多奈哌齊自由體的調配量等的條件而適當變化。當在向人給藥的情況下，本發明的經皮吸收製劑通常給藥1日1次。The percutaneous absorption preparation of the present invention is usually administered to patients suffering from dementia or at risk of dementia, such as humans or animals, preferably humans. The frequency of administration can be appropriately changed depending on the severity of the disease or symptoms, the age, weight, gender of the patient, and the amount of free donepezil in the percutaneous absorption preparation. When administered to humans, the percutaneous absorption preparation of the present invention is usually administered once a day.
具有上述組成之本發明的經皮吸收製劑，可以藉由任何方法製造。例如，一般被稱為熱熔法的方法，其是將包含藥物的基劑組成進行熱熔解，塗敷在剝離薄膜或支撐體上後，與支撐體或剝離薄膜進行貼合以獲得目標本劑的方法；或是一般被稱為溶劑法的方法，其是將包含藥物的基劑成分溶解在甲苯、己烷、乙酸乙酯等之溶劑中，在剝離薄膜或支撐體上伸展並將溶劑乾燥除去後，與支撐體或剝離薄膜進行貼合以獲得目標本劑的方法。The percutaneous absorption preparation of the present invention having the above-mentioned composition can be produced by any method. For example, a method generally known as a hot melt method is a method in which a base composition containing a drug is heat-melted, applied to a peeling film or a support, and then bonded to the support or peeling film to obtain the target agent; or a method generally known as a solvent method is a method in which a base component containing a drug is dissolved in a solvent such as toluene, hexane, ethyl acetate, etc., spread on a peeling film or a support, and after drying and removing the solvent, bonded to the support or peeling film to obtain the target agent.
作為本發明的經皮吸收製劑的支撐體，可以使用伸縮性或非伸縮性的支撐體。例如選自：布、不織布、聚胺基甲酸酯、聚酯、聚乙酸乙烯酯、聚偏二氯乙烯、聚乙烯、聚對苯二甲酸乙二酯(以下，簡稱為「PET」)、鋁片等，或該些的複合素材。As the support for the percutaneous absorption preparation of the present invention, a stretchable or non-stretchable support can be used, for example, selected from: cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate (hereinafter referred to as "PET"), aluminum sheet, etc., or a composite material thereof.
此外，剝離薄膜只要是在將經皮吸收製劑適用於皮膚之前，保護黏著劑層，使含有的作為抗失智症劑之多奈哌齊自由體不產生變質，且以可以容易剝離的方式塗覆有矽塗層者，即沒有特別限定。 作為其具體例，可列舉：塗覆有矽塗層之聚乙烯膜、聚對苯二甲酸乙二酯膜或聚丙烯膜者。 In addition, the peeling film is not particularly limited as long as it protects the adhesive layer before applying the percutaneous absorption preparation to the skin so that the free form of donepezil contained therein, which is an anti-dementia agent, does not deteriorate, and is coated with a silicon coating in an easily peelable manner. Specific examples thereof include polyethylene films, polyethylene terephthalate films, or polypropylene films coated with a silicon coating.
本發明的經皮吸收製劑的黏著劑層具有黏著力，但是當適用於皮膚時，為了補強與皮膚的黏著，可以使用固定用片材。本發明的經皮吸收製劑的製劑面積為10~100cm 2，較佳為20~90cm 2，製劑的形狀並不限制，但固定用片材的黏著面的面積並不被包含在本發明所定義的製劑面積內。 The adhesive layer of the percutaneous absorption preparation of the present invention has adhesive force, but when applied to the skin, a fixing sheet can be used to enhance the adhesion to the skin. The preparation area of the percutaneous absorption preparation of the present invention is 10-100 cm 2 , preferably 20-90 cm 2 , and the shape of the preparation is not limited, but the area of the adhesive surface of the fixing sheet is not included in the preparation area defined in the present invention.
如上述般調製之本發明的經皮吸收製劑，將作為有效成分之多奈哌齊自由體，溶解於調配有疏水性高分子及吸收促進劑，進一步調配有上述各種添加劑之貼附劑基劑中，藉此，能發揮給藥後多奈哌齊自由體在血中濃度快速上升，長時間維持有效血中濃度之優異的效果。 [實施例] The percutaneous absorption preparation of the present invention prepared as described above dissolves the free body of donepezil as the active ingredient in a patch base prepared with a hydrophobic polymer and an absorption enhancer, and further prepared with the above-mentioned various additives, thereby achieving the excellent effect of rapidly increasing the concentration of the free body of donepezil in the blood after administration and maintaining the effective blood concentration for a long time. [Example]
以下，顯示本發明的實施例，進一步具體說明本發明，但本發明不限於該些實施例，並且可以在不脫離本發明的技術思想的範圍內進行各種變更。The following shows embodiments of the present invention and further describes the present invention in detail, but the present invention is not limited to these embodiments and various modifications can be made without departing from the technical concept of the present invention.
實施例： 將多奈哌齊自由體預先溶解在脂肪族醇及甲苯的混合溶液後，與溶解在甲苯中的剩餘成分進行混合。將混合物塗敷在剝離薄膜上後，將甲苯乾燥除去，並與PET膜支撐體進行貼合，以使製劑面積為22cm 2(13.75mg製劑)、44cm 2(27.5mg製劑)、88cm 2(55mg製劑)的方式進行裁切，獲得本發明的經皮吸收製劑。 Example: Donepezil free body was dissolved in a mixed solution of aliphatic alcohol and toluene, and then mixed with the remaining components dissolved in toluene. The mixture was applied on a peeling film, the toluene was dried and removed, and the film was laminated to a PET film support, and the preparation area was cut into 22 cm2 (13.75 mg preparation), 44 cm2 (27.5 mg preparation), and 88 cm2 (55 mg preparation) to obtain the percutaneous absorption preparation of the present invention.
接著，以試驗例顯示本發明的經皮吸收製劑的效果。在以下的試驗例中，所謂的本發明貼布劑是指具有實施例的構成之本發明的經皮吸收製劑的意思。Next, the effects of the percutaneous absorption preparation of the present invention are shown in the test examples. In the following test examples, the so-called patch of the present invention means the percutaneous absorption preparation of the present invention having the constitution of the embodiment.
試驗例1 試驗方法： 將健康高齡男性48例作為對象進行的4群、2期的交叉試驗中，I期：將27.5mg之本發明貼布劑給藥於背部，1日1次持續17日；II期：將5mg多奈哌齊鹽酸鹽口服製劑1日1次，持續21日重複給藥，在各時間點測定多奈哌齊之血中濃度。基於所得之血中濃度的數值，進行I期及II期的參數比較。 採血時間如下。 本發明貼布劑：貼附於健康高齡男性48名的背部，於貼附後立刻、初次貼附後2、4、6、8、12、24、48、96、144、146、148、150、152、156、168、216、264、312、336、384、386、388、390、392、396、408、420、432、456、504、552、624、696小時後。 多奈哌齊鹽酸鹽口服製劑：向健康高齡男性46名進行口服給藥，於服用後立刻、初次服用後：0.5、1、2、3、4、6、8、12、24、48、72、96、120、144、168、192、216、240、264、288、312、336、360、384、408、432、456、480、480.5、481、482、483、484、486、488、492、504、528、552、576、600、648、744小時後。 Test Example 1 Test method: In a 4-group, 2-phase crossover test with 48 healthy elderly male subjects, Phase I: 27.5 mg of the patch of the present invention was applied to the back once a day for 17 days; Phase II: 5 mg of donepezil hydrochloride oral preparation was administered once a day for 21 days, and the blood concentration of donepezil was measured at each time point. Based on the blood concentration values obtained, the parameters of Phase I and Phase II were compared. The blood collection time is as follows. The patch of the present invention was applied to the backs of 48 healthy elderly men immediately after application and 2, 4, 6, 8, 12, 24, 48, 96, 144, 146, 148, 150, 152, 156, 168, 216, 264, 312, 336, 384, 386, 388, 390, 392, 396, 408, 420, 432, 456, 504, 552, 624, and 696 hours after the first application. Donepezil hydrochloride oral preparation: 46 healthy elderly men were given the drug orally immediately after taking it and after the first dose: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 480.5, 481, 482, 483, 484, 486, 488, 492, 504, 528, 552, 576, 600, 648, 744 hours later.
結果： 結果如表2所示。 關於27.5mg之本發明貼布劑的藥物動態，I期相對於II期之最終給藥日的AUC 0-24h的幾何平均值之比為0.956，由於90%信賴區間包含1，顯示藉由重複貼附本發明貼布劑持續17日，可獲得與重複口服給藥多奈哌齊鹽酸鹽口服製劑持續21日相同程度的曝露量。同樣地，關於波谷濃度(C trough)，由於幾何平均值之比的90%信賴區間包含1，顯示本發明貼布劑可獲得與多奈哌齊鹽酸鹽口服製劑相同程度的曝露量。 一般情況下，血中濃度峰值越高，副作用的表現率趨於較高，但在最終給藥日之C max的幾何平均值中，I期較II期更低。另一方面，在最終給藥日之C trough的幾何平均值中，I期較II期更高。從以上可知，本發明貼布劑藉由在抑制、降低副作用表現風險的同時，維持較高血中濃度而獲得穩定的效果。 Results: The results are shown in Table 2. Regarding the drug dynamics of the 27.5 mg patch of the present invention, the ratio of the geometric mean values of AUC 0-24h on the final dosing day of Phase I to Phase II was 0.956. Since the 90% confidence interval included 1, it was shown that repeated application of the patch of the present invention for 17 days could achieve the same level of exposure as repeated oral administration of donepezil hydrochloride oral formulation for 21 days. Similarly, regarding the trough concentration (C trough ), since the 90% confidence interval of the ratio of the geometric means included 1, it was shown that the patch of the present invention could achieve the same level of exposure as donepezil hydrochloride oral formulation. Generally, the higher the peak blood concentration, the higher the incidence of side effects, but the geometric mean of Cmax on the final dosing day was lower in Phase I than in Phase II. On the other hand, the geometric mean of Ctrough on the final dosing day was higher in Phase I than in Phase II. From the above, it can be seen that the patch of the present invention achieves a stable effect by suppressing and reducing the risk of side effects while maintaining a relatively high blood concentration.
試驗例2 試驗方法 本試驗使用13.75mg之本發明貼布劑、27.5mg之本發明貼布劑及55mg之本發明貼布劑進行。 將健康高齡男性36例(3群，各群12例)作為對象進行的3群、3期的交叉試驗中，各期在1日1次持續17日，於背部重複進行給藥。在各時間點測定多奈哌齊之血中濃度。基於所得之血中濃度的數值，在各用量的穩定狀態下比較藥物動態及C max與AUC 0-24。 各期的採血時間如下。 貼附後立刻、初次貼附後2、4、6、8、12、24、72、120、168、216、264、312、336、360、384、386、388、390、392、396、408、420、432、456、504、552、624、696小時 Test Example 2 Test method This test was conducted using 13.75 mg of the patch of the present invention, 27.5 mg of the patch of the present invention, and 55 mg of the patch of the present invention. In a 3-group, 3-period crossover trial involving 36 healthy elderly males (3 groups, 12 cases in each group) as subjects, the drug was administered repeatedly on the back once a day for 17 days in each period. The blood concentration of donepezil was measured at each time point. Based on the blood concentration values obtained, the drug dynamics and C max and AUC 0-24 were compared under stable conditions at each dosage. The blood sampling time for each period is as follows. Immediately after application, 2, 4, 6, 8, 12, 24, 72, 120, 168, 216, 264, 312, 336, 360, 384, 386, 388, 390, 392, 396, 408, 420, 432, 456, 504, 552, 624, 696 hours after initial application
結果 結果如表3及表4所示。 在第17天，C max之幾何平均值，在13.75mg之本發明貼布劑為12.317ng/mL，在27.5mg之本發明貼布劑為23.354ng/mL，及在55mg之本發明貼布劑為49.452ng/mL。AUC 0-24h之幾何平均值各自為268.10ng·h/mL(57.17%)、508.11ng·h/mL及1077.02ng·h/mL，認為C max及AUC 0-24h具有隨用量增加而增大的傾向。 第17天中，將藥物動態參數的線形性以功率模型進行評價，C max及AUC 0-24h的迴歸線斜率的點推定值(95%信賴區間)均為1.00(0.96~1.04)，由於95%信賴區間包含1，顯示C max及AUC 0-24h與劑量成比例地線性增加。 Results The results are shown in Tables 3 and 4. On day 17, the geometric mean values of Cmax were 12.317 ng/mL for 13.75 mg of the patch of the present invention, 23.354 ng/mL for 27.5 mg of the patch of the present invention, and 49.452 ng/mL for 55 mg of the patch of the present invention. The geometric mean values of AUC0-24h were 268.10 ng·h/mL (57.17%), 508.11 ng·h/mL, and 1077.02 ng·h/mL, respectively, indicating that Cmax and AUC0-24h tended to increase with increasing dosage. On day 17, the linearity of the pharmacodynamic parameters was evaluated using a power model, and the point estimates (95% confidence intervals) of the slopes of the regression lines for C max and AUC 0-24h were both 1.00 (0.96-1.04). Since the 95% confidence interval included 1, it showed that C max and AUC 0-24h increased linearly in proportion to the dose.
試驗例3 (1)非劣性：雙盲期 試驗方法 將輕度/中等度阿茲海默型失智症患者339例(27.5mg之本發明貼布劑：173例，多奈哌齊口服製劑(含有5mg多奈哌齊鹽酸鹽)：166例)作為對象，進行1日1次，持續24週的試驗。本發明貼布劑將貼附於背部。從ADAS-Jcog的基線到24週時的變化量，進行相對於口服製劑之非劣性的研究。此外，對於失智症功能障礙評估量表(Disability Assessment for Dementia, DAD)及ABC失智症量表(ABC Dementia Scale)，也從基線到24週時的變化量進行評價。 Trial Example 3 (1) Non-inferiority: Double-blind period Trial method A total of 339 patients with mild/moderate Alzheimer's dementia (27.5 mg of the patch of the present invention: 173 patients, and donepezil oral preparation (containing 5 mg donepezil hydrochloride): 166 patients) were selected as subjects for a trial once a day for 24 weeks. The patch of the present invention was attached to the back. The change from baseline to 24 weeks of ADAS-Jcog was studied for non-inferiority relative to the oral preparation. In addition, the change from baseline to 24 weeks of the Disability Assessment for Dementia (DAD) and the ABC Dementia Scale was also evaluated.
結果 其結果如表5及表6所示。 從基線到24週時之ADAS-Jcog的變化量的最小二乘平均值±標準誤差，在本發明貼布劑群為-0.7±0.4，在多奈哌齊鹽酸鹽口服製劑群為0.2±0.4。本發明貼布劑群及多奈哌齊鹽酸鹽口服製劑群之間的最小二乘平均值的差(95%信賴區間)為-0.9(-2.01~0.14)，由於群間差的95%信賴區間的上限低於事前設定的非劣性限界值2.15，因此驗證相對於多奈哌齊鹽酸鹽口服製劑群，本發明貼布製劑群的非劣性。 此外，DAD及ABC失智症量表之各域的從基線到24週時的變化量，在本發明貼布劑群及多奈哌齊鹽酸鹽口服製劑群各自的DAD為-2.2±12.3及-3.5±10.9、日常生活活動能力(activities of daily living, ADL)為-0.5±4.5及-0.5±3.8、失智伴發精神行為障礙(behavioral and psychological symptoms of dementia, BPSD)為-0.4±2.6及-0.3±2.5，認知功能為-0.6±3.7及-0.8±3.5，三維距離(three-dimensional distance, TDD)為-0.8±4.7及-0.8±4.1。 Results The results are shown in Tables 5 and 6. The least square mean ± standard error of the change in ADAS-Jcog from baseline to 24 weeks was -0.7±0.4 in the patch group of the present invention and 0.2±0.4 in the donepezil hydrochloride oral preparation group. The difference (95% confidence interval) in the least square mean between the patch group of the present invention and the donepezil hydrochloride oral preparation group was -0.9 (-2.01~0.14). Since the upper limit of the 95% confidence interval of the inter-group difference was lower than the pre-set non-inferiority limit of 2.15, the non-inferiority of the patch group of the present invention relative to the donepezil hydrochloride oral preparation group was verified. In addition, the changes in each domain of the DAD and ABC dementia scale from baseline to 24 weeks in the patch group of the present invention and the donepezil hydrochloride oral preparation group were -2.2±12.3 and -3.5±10.9 for DAD, -0.5±4.5 and -0.5±3.8 for activities of daily living (ADL), -0.4±2.6 and -0.3±2.5 for behavioral and psychological symptoms of dementia (BPSD), -0.6±3.7 and -0.8±3.5 for cognitive function, and -0.8±4.7 and -0.8±4.1 for three-dimensional distance (TDD).
(2)繼續：非盲檢期 試驗方法 將結束非劣性試驗(雙盲期)之持續24週重複給藥的輕度/中等度阿茲海默型失智症患者301例作為對象，將27.5mg之本發明貼布劑貼附在背部、上臂或胸部，1日1次持續28週(從雙盲期算起共52週)，評價從基線及24週至52週時的ADAS-Jcog及ABC失智症量表的合計分數的變化量。 (2) Continuation: Open-label testing period Trial method 301 patients with mild/moderate Alzheimer's dementia who completed the non-inferiority trial (double-blind period) and repeated dosing for 24 weeks were selected as subjects. 27.5 mg of the patch of the present invention was applied to the back, upper arm or chest once a day for 28 weeks (52 weeks in total from the double-blind period). The changes in the total scores of the ADAS-Jcog and ABC dementia rating scales from baseline and from 24 weeks to 52 weeks were evaluated.
結果 結果如表7及表8所示。 從24週時之ADAS-Jcog的變化量的平均值±標準差，本發明貼布劑群在28週時為0.5±4.3，在36週時為0.8±5.1及在52週時為1.2±5.2。多奈哌齊鹽酸鹽口服製劑群(28週後切換為本發明貼布劑群)在28週時為1.5±4.5，在36週時為1.4±4.5及在52週時為1.9±5.4。 此外，從24週時之ABC失智症量表(合計分數)的變化量的平均值±標準差，本發明貼布劑群在28週時為-1.0 ±4.3，在36週時為-1.1±5.1及在52週時為-2.6±6.8，切換群在28週時為-0.1±4.4，在36週時為-1.0±4.9及在52週時為-2.8 ±6.6。 Results The results are shown in Tables 7 and 8. From the mean ± standard deviation of the change in ADAS-Jcog at 24 weeks, the patch group of the present invention was 0.5±4.3 at 28 weeks, 0.8±5.1 at 36 weeks, and 1.2±5.2 at 52 weeks. The donepezil hydrochloride oral preparation group (switched to the patch group of the present invention after 28 weeks) was 1.5±4.5 at 28 weeks, 1.4±4.5 at 36 weeks, and 1.9±5.4 at 52 weeks. In addition, the mean ± standard deviation of the change in the ABC Dementia Rating Scale (total score) at 24 weeks was -1.0 ± 4.3 at 28 weeks, -1.1 ± 5.1 at 36 weeks, and -2.6 ± 6.8 at 52 weeks in the patch group of the present invention, and -0.1 ± 4.4 at 28 weeks, -1.0 ± 4.9 at 36 weeks, and -2.8 ± 6.6 at 52 weeks in the switch group.
試驗例4 試驗方法 本試驗使用55mg之本發明貼布劑來進行。 將高度阿茲海默型失智症患者64例作為對象，於非盲檢及非對照試驗1日1次持續52週，貼附於背部、上臂或胸部，對MMSE及ABC失智症量表之從基線到52週時的變化量進行評價。 Test Example 4 Test Method This test was conducted using 55 mg of the patch of the present invention. 64 patients with severe Alzheimer's dementia were selected as subjects. The patch was applied to the back, upper arm or chest once a day for 52 weeks in an open-label and uncontrolled trial. The changes in the MMSE and ABC dementia scales from baseline to 52 weeks were evaluated.
結果 結果如表9及表10所示。 從基線之MMSE的變化量的平均值±標準差，在12週時為0.0±2.7，在24週時為-0.2±3.0，在52週時為-1.1±3.4，並直到24週為止維持基線的分數。 此外，從基線之ABC失智症量表(TDD)的變化量的平均值±標準差，在篩選時為1.0±5.3，在12週時為-0.2 ±5.3，在24週時為-2.2±6.2，及在52週時為-4.3±6.9。ABC失智症量表的合計分數及各域別(ADL、BPSD、認知功能)也顯示出與TDD同樣的分數。 Results The results are shown in Tables 9 and 10. The mean ± standard deviation of the change in MMSE from baseline was 0.0 ± 2.7 at 12 weeks, -0.2 ± 3.0 at 24 weeks, and -1.1 ± 3.4 at 52 weeks, and the baseline score was maintained until 24 weeks. In addition, the mean ± standard deviation of the change in the ABC Dementia Rating Scale (TDD) from baseline was 1.0 ± 5.3 at screening, -0.2 ± 5.3 at 12 weeks, -2.2 ± 6.2 at 24 weeks, and -4.3 ± 6.9 at 52 weeks. The total score and each domain (ADL, BPSD, cognitive function) of the ABC Dementia Rating Scale also showed the same scores as TDD.
尚且，藉由將27.5mg之本發明貼布劑重複貼附於人的背部、上臂或胸部，使穩定狀態的AUC 0-24h變得與5mg之多奈哌齊鹽酸鹽口服製劑同等。 Furthermore, by repeatedly applying 27.5 mg of the patch of the present invention to the back, upper arm or chest of a person, the AUC 0-24h in the steady state became equivalent to that of a 5 mg oral preparation of donepezil hydrochloride.
試驗例5 試驗方法 本試驗使用13.75mg之本發明貼布劑來進行。 在將健康高齡男性64例(A~D群：各16例)作為對象，進行4群、2期的交叉試驗中，各期1日1次持續17日，重複進行給藥至背部、上臂或胸部，測定各時點之多奈哌齊的血中濃度。基於所得的血中濃度，對貼附部位間的藥物動態的等效性進行研究。 各期的採血時間如下。 貼附後立刻、初次貼附後2、4、6、8、12、24、72、120、168、216、264、312、336、360、384、386、388、390、392、396、408、420、432、456、504、552、624、696小時 Test Example 5 Test Method This test was conducted using 13.75 mg of the patch of the present invention. In a 4-group, 2-period crossover trial, 64 healthy elderly men (A-D groups: 16 cases each) were used as subjects. In each period, the drug was administered once a day for 17 days to the back, upper arm or chest, and the blood concentration of donepezil at each time point was measured. Based on the obtained blood concentration, the equivalence of drug dynamics between the application sites was studied. The blood collection time for each period is as follows. Immediately after application, 2, 4, 6, 8, 12, 24, 72, 120, 168, 216, 264, 312, 336, 360, 384, 386, 388, 390, 392, 396, 408, 420, 432, 456, 504, 552, 624, 696 hours after initial application
結果 結果如表11所示。 第17天中，貼附背部時與貼附上臂時的C max及AUC 0-24h的幾何平均值的差(90%信賴區間)各自為1.03(0.96~1.11)及1.08(1.03~1.14)。 第17天中，貼附背部時與貼附胸部時的C max及AUC 0-24h的幾何平均值的差(90%信賴區間)各自為1.03(0.96~1.11)及1.04(0.97~1.12)。 由於貼附背部時與貼附上臂時，以及貼附背部時與貼附胸部時的幾何平均值之比均接近1，且對數值之平均值的差之90%信賴區間，包含於作為生物學等效性的判定基準之log(0.80)~log(1.25)的範圍內，確認貼附背部時與貼附上臂以及貼附胸部時的藥物動態為同等。 Results The results are shown in Table 11. On the 17th day, the difference (90% confidence interval) of the geometric mean of Cmax and AUC0-24h when attached to the back and the upper arm was 1.03 (0.96-1.11) and 1.08 (1.03-1.14), respectively. On the 17th day, the difference (90% confidence interval) of the geometric mean of Cmax and AUC0-24h when attached to the back and the chest was 1.03 (0.96-1.11) and 1.04 (0.97-1.12), respectively. Since the ratios of the geometric means when attached to the back and the upper arm, and when attached to the back and the chest were close to 1, and the 90% confidence interval of the difference in the mean values of the logarithmic values was included in the range of log(0.80) to log(1.25) which is the criterion for determining bioequivalence, it was confirmed that the drug dynamics when attached to the back, the upper arm, and the chest were equivalent.
試驗例6 釋放試驗 試驗方法 藉由日局釋放試驗法中所記載的旋轉圓筒法，對試驗製劑(27.5mg及55mg之本發明貼布劑)所致之藥物釋放性進行試驗。試驗條件如表12所示。 Test Example 6 Release Test Test Method The drug release of the test preparations (27.5 mg and 55 mg of the patch of the present invention) was tested by the rotating cylinder method described in the Japanese release test method. The test conditions are shown in Table 12.
結果 結果如表13-1及表13-2所示。27.5mg製劑的釋放率在3小時後為27.9±0.9%、在6小時後為45.6±0.5%、在9小時後為59.5±1.0%。55mg製劑的釋放率在3小時後為21.6 ±0.1%、在6小時後為33.0±0.2%、在9小時後為42.5± 0.8%。 Results The results are shown in Tables 13-1 and 13-2. The release rate of the 27.5 mg preparation was 27.9 ± 0.9% after 3 hours, 45.6 ± 0.5% after 6 hours, and 59.5 ± 1.0% after 9 hours. The release rate of the 55 mg preparation was 21.6 ± 0.1% after 3 hours, 33.0 ± 0.2% after 6 hours, and 42.5 ± 0.8% after 9 hours.
配方例 按照表14的調配量，以與實施例相同的方式獲得配方例1~4的經皮吸收製劑。 Formulation Example According to the formulation amount in Table 14, the percutaneous absorption preparations of Formulation Examples 1 to 4 are obtained in the same manner as in the embodiment.
試驗例7 體外( in vitro)皮膚透過性試驗 對實施例及配方例1~4的經皮吸收製劑，進行體外( in vitro)無毛大鼠皮膚透過性試驗。摘出雄性無毛大鼠(HWY系，7週齡)的腹部皮膚，設置於佛蘭茲靜態擴散槽中，以真皮側作為受體側，使其內側充滿磷酸緩衝生理食鹽水，水套以37℃的溫水進行回流。將各貼附劑作成圓形(1.54cm 2)，並貼附於摘出皮膚，在試驗開始後24小時時取樣受體液，藉由高速液體層析法測定藥物之皮膚穿透量。相對於實施例的累積穿透量，配方例1~4的累積穿透量如表14所示。 Test Example 7 In vitro skin permeability test The percutaneous absorption preparations of Examples and Formulation Examples 1 to 4 were subjected to an in vitro hairless rat skin permeability test. The abdominal skin of male hairless rats (HWY strain, 7 weeks old) was removed and placed in a Franz static diffusion chamber, with the dermis side as the receptor side. The inner side was filled with phosphate-buffered saline, and the water jacket was refluxed with warm water at 37°C. Each patch was made into a circular shape (1.54 cm 2 ) and attached to the removed skin. The receptor fluid was sampled 24 hours after the start of the test, and the skin penetration of the drug was determined by high-speed liquid chromatography. Compared with the cumulative penetration of the embodiment, the cumulative penetration of formulation examples 1 to 4 is shown in Table 14.
配方例1~4的製劑顯示與實施例相同程度的透過性，與實施例同樣地，說明可以提供表現出與多奈哌齊鹽酸鹽口服製劑相同程度的藥物動態的經皮吸收製劑。 [產業利用性] The preparations of formulation examples 1 to 4 showed the same degree of permeability as the examples, and similarly to the examples, it was demonstrated that a percutaneous absorption preparation showing the same degree of drug dynamics as the oral preparation of donepezil hydrochloride can be provided. [Industrial Applicability]
根據本發明所提供的含多奈哌齊之經皮吸收製劑，可以將作為有效成分的多奈哌齊自由體，透過皮膚有效率地吸收到循環血中，可以得到與口服製劑同等的治療效果。 因此，本發明為進行症狀之患者提供新的治療選擇的同時，假定使吞嚥功能下降之患者服藥容易，及從其可見性而提升服藥順從性，期待將減輕介護者的負擔。此外，作為以多奈哌齊自由體的長時間給藥為目標之經皮吸收製劑特別有效，為失智症疾病的治療提供光明。 According to the transdermal absorption preparation containing donepezil provided by the present invention, the free form of donepezil as an active ingredient can be efficiently absorbed into the circulating blood through the skin, and the same therapeutic effect as the oral preparation can be obtained. Therefore, the present invention provides a new treatment option for patients with symptoms, and at the same time, it is assumed that patients with decreased swallowing function can take medicine more easily, and the compliance of medication can be improved due to its visibility, which is expected to reduce the burden of caregivers. In addition, as a transdermal absorption preparation aimed at long-term administration of free form of donepezil, it is particularly effective, providing hope for the treatment of dementia.
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