JPWO2017006974A1 - Transdermal patch - Google Patents
Transdermal patch Download PDFInfo
- Publication number
- JPWO2017006974A1 JPWO2017006974A1 JP2017527485A JP2017527485A JPWO2017006974A1 JP WO2017006974 A1 JPWO2017006974 A1 JP WO2017006974A1 JP 2017527485 A JP2017527485 A JP 2017527485A JP 2017527485 A JP2017527485 A JP 2017527485A JP WO2017006974 A1 JPWO2017006974 A1 JP WO2017006974A1
- Authority
- JP
- Japan
- Prior art keywords
- drug
- solifenacin
- containing layer
- transdermal
- patch
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
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- 229940079593 drug Drugs 0.000 claims abstract description 89
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- FBOUYBDGKBSUES-KEKNWZKVSA-N 1-azabicyclo[2.2.2]octan-3-yl (1s)-1-phenyl-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(OC2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-KEKNWZKVSA-N 0.000 claims description 38
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Abstract
本発明は、経皮吸収性、保存安定性及び安全性に優れた、ソリフェナシンの薬学的に許容される塩を含有する経皮吸収型貼付剤を提供する。支持体と薬物含有層とを有する経皮吸収型貼付剤であって、該薬物含有層がソリフェナシンの薬学的に許容される塩および無機塩基を含有する、経皮吸収型貼付剤に関する。The present invention provides a transdermally absorbable patch containing a pharmaceutically acceptable salt of solifenacin which is excellent in transdermal absorbability, storage stability and safety. The present invention relates to a transdermal absorption patch having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin and an inorganic base.
Description
本発明は、ソリフェナシンの薬学的に許容される塩を有効成分として含有する経皮吸収型貼付剤に関する。 The present invention relates to a transdermal patch containing a pharmaceutically acceptable salt of solifenacin as an active ingredient.
従来、薬物の投与法としては、錠剤、カプセル剤、シロップ剤等を使用する経口投与法が知られているが、近年、これらの薬物を経皮吸収型貼付剤を用いて皮膚から投与する試みがなされている。経皮吸収型貼付剤は、経口投与法における問題点の解消に加えて、投与回数の減少、コンプライアンスの向上、投与及びその中止の容易さ等の利点を有することから、特に老人や小児の患者の治療における有用な薬物投与法として期待されている。 Conventionally, oral administration methods using tablets, capsules, syrups, etc. are known as drug administration methods, but in recent years, attempts have been made to administer these drugs from the skin using transdermal patches. Has been made. Since transdermal patches have the advantages of reducing the number of administrations, improving compliance, ease of administration and discontinuation, in addition to solving problems in oral administration, especially elderly and pediatric patients It is expected to be a useful drug administration method in the treatment of cancer.
ソリフェナシン((R)−キヌクリジン−3−イル(S)−1−フェニル−1,2,3,4−テトラヒドロイソキノリン−2−カルボキシラート)は、ムスカリンM3受容体に対して高い親和性を有するムスカリン受容体拮抗薬であり(特許文献1)、現在臨床の場において過活動膀胱の治療薬として使用されている。現在実用的に用いられている製剤はソリフェナシンコハク酸塩の錠剤及び口腔内崩壊錠であり、「ベシケア(登録商標)」の商品名で経口剤として過活動膀胱患者に処方されている。 Solifenacin ((R) -quinuclidin-3-yl (S) -1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate) is a muscarin with high affinity for the muscarinic M3 receptor. It is a receptor antagonist (Patent Document 1) and is currently used as a therapeutic agent for overactive bladder in clinical settings. The preparations currently in practical use are solifenacin succinate tablets and orally disintegrating tablets, which are prescribed to patients with overactive bladder as an oral preparation under the trade name “Vesicare®”.
過活動膀胱患者は日常から飲水を控えることが知られており、また、ソリフェナシンは嚥下機能が低下した高齢者が服用する機会の多い薬剤であることから、この場合は、経口投与製剤よりも、むしろ経皮吸収型貼付剤が適している。 Overactive bladder patients are known to refrain from drinking water on a daily basis, and solifenacin is a drug that is often taken by elderly people with reduced swallowing function. Rather, transdermal patches are suitable.
また、過活動膀胱治療薬として、オキシブチニン塩酸塩が「ネオキシ(登録商標)テープ」の商品名で、経皮吸収型貼付剤として現在臨床で使用されているが、副作用として適用部位の皮膚炎や紅斑が高頻度で認められており(非特許文献1)、患者の安全性の観点から、臭気や皮膚刺激の少ない製剤の開発が望まれている。 In addition, as an overactive bladder treatment, oxybutynin hydrochloride is a product name of “Neoxy (registered trademark) tape” and is currently used clinically as a transdermal absorption patch. Erythema is frequently observed (Non-Patent Document 1), and from the viewpoint of patient safety, development of a preparation with less odor and skin irritation is desired.
日米EU医薬品規制調和国際会議(ICH)から発表されている「新有効成分含有医薬品のうち製剤の不純物に関するガイドライン」に、安定性試験において認められる製剤中の分解生成物(不純物)に関する考え方が記されている。これによると、1日に投与される原薬の量が10mg以上、100mg未満の場合には製剤中の分解生成物の安全性確認が必要とされる閾値は、原薬中に含まれる分解生成物の百分率が0.5%あるいは分解生成物の1日摂取量が200μgのいずれか低い方である。そのため、一般的に分解生成物の安全性確認をせずに設定することのできる分解生成物量の規格値としては、10mg製剤の場合には、分解生成物の百分率が0.5%以下であることが好ましい。 The “Guidelines on Impurities in Drugs Among Drugs Containing New Active Ingredients” published by the Japan-US EU Pharmaceutical Regulation Harmonization International Conference (ICH) describes the concept of degradation products (impurities) in pharmaceuticals that are recognized in stability tests. It is written. According to this, when the amount of drug substance administered per day is 10 mg or more and less than 100 mg, the threshold value for the safety confirmation of the degradation product in the drug product is the degradation product contained in the drug substance. The percentage of the product is 0.5%, or the daily intake of decomposition products is 200 μg, whichever is lower. Therefore, as a standard value of the amount of decomposition product that can be generally set without confirming the safety of the decomposition product, in the case of a 10 mg preparation, the percentage of the decomposition product is 0.5% or less. It is preferable.
ソリフェナシンは、一般的な製剤化法では、製剤中の主薬であるソリフェナシンが経時的に分解することが知られており、製剤中の分解物生成を抑制するために、種々の安定化の方法が提案されている(特許文献2、3、4および5)。しかしながら、これらの文献には経皮吸収型貼付剤におけるソリフェナシンの安定性について記載がない。 Solifenacin is known to degrade over time in the general formulation method, solifenacin, the main drug in the formulation, and various stabilization methods are available to suppress the formation of degradation products in the formulation. It has been proposed (Patent Documents 2, 3, 4 and 5). However, these documents do not describe the stability of solifenacin in transdermal patches.
ソリフェナシンを含有する経皮吸収型貼付剤としては、特許文献6にソリフェナシンフリー体と経皮吸収促進剤として脂肪酸エステル類を含有する経皮吸収型貼付剤(テープ剤)が提案されているが、この貼付剤の経時安定性に関する記載はない。
As a transdermal absorption patch containing solifenacin,
また、特許文献7には、熱可塑性エラストマーと熱可塑性エラストマー100重量部に対して300重量部を超える液状成分と、抗コリン作用を有する過活動膀胱治療薬(ソリフェナシン、ダリフェナシン等)を含有する経皮吸収型貼付剤が提案されている。しかし、特許文献7には、この貼付剤の経時安定性に関する記載はない。 Patent Document 7 also includes a thermoplastic elastomer, a liquid component in excess of 300 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, and an overactive bladder therapeutic agent having anticholinergic action (solifenacin, darifenacin, etc.). Skin-absorbing patches have been proposed. However, Patent Document 7 does not describe the temporal stability of this patch.
本発明者は、ソリフェナシンフリー体について苛酷試験により保存安定性を評価したところ、経時的に分解生成物が増加することが確認された(試験例1を参照)。これより、ソリフェナシンフリー体は通常の貯法では経時的に分解することが分かった。そのため、ソリフェナシンフリー体を原薬に用いて経皮吸収型貼付剤を作製した場合、原薬自体に含まれる分解物が貼付剤作製時に混入し、得られた貼付剤の分解物生成物の含有量が0.5%を超える恐れがあった。 When this inventor evaluated the storage stability by the severe test about the solifenacin free body, it was confirmed that a decomposition product increases with time (refer Test example 1). From this, it was found that the solifenacin-free body decomposes with time in the usual storage method. Therefore, when a percutaneous absorption type patch is prepared using solifenacin-free drug substance as a drug substance, the degradation product contained in the drug substance itself is mixed at the time of preparation of the patch, and the content of the resulting patch product is contained. The amount could exceed 0.5%.
一方、ソリフェナシンコハク酸塩のように薬学的に許容される塩の形態では、経時安定性が向上し、通常の貯法では分解がほとんど無いことが確認できた(試験例1を参照)。そのため、経皮吸収型貼付剤の調製にあたり、ソリフェナシンの薬学的に許容される塩を原薬として使用することが好ましい。 On the other hand, in the form of a pharmaceutically acceptable salt such as solifenacin succinate, stability over time was improved, and it was confirmed that there was almost no degradation in a normal storage method (see Test Example 1). Therefore, in preparing a transdermal absorption patch, it is preferable to use a pharmaceutically acceptable salt of solifenacin as a drug substance.
しかし、ソリフェナシンの薬学的に許容される塩を含む一般的な経皮吸収型貼付剤について保存安定性を評価した結果(試験例3、比較例2及び3を参照)、ソリフェナシンが経時的に分解し、その分解生成物の百分率が0.5%を超える場合があることが確認された。そのため、ソリフェナシンの経時的分解を抑制しうる保存安定性に優れた貼付剤が望まれた。 However, as a result of evaluating the storage stability of a general transdermal patch containing a pharmaceutically acceptable salt of solifenacin (see Test Example 3, Comparative Examples 2 and 3), solifenacin was degraded over time. In addition, it was confirmed that the percentage of the decomposition product may exceed 0.5%. Therefore, a patch with excellent storage stability that can suppress the degradation of solifenacin over time has been desired.
勿論、経皮吸収型貼付剤として、望ましいソリフェナシンの皮膚透過性を有し、皮膚に対し低刺激であることも必要である。 Of course, as a transdermal absorption patch, it is necessary to have desirable solifenacin skin permeability and low irritation to the skin.
つまり、本発明は、少なくとも1つの有効成分として、ソリフェナシンの薬学的に許容される塩を含有する経皮吸収型貼付剤において、ソリフェナシンの良好な皮膚透過性を保持し、ソリフェナシンの経時的な分解を抑制し、且つ、皮膚刺激性が低い製剤を提供することを課題とする。 That is, the present invention is a transdermal patch containing a pharmaceutically acceptable salt of solifenacin as at least one active ingredient, maintaining good skin permeability of solifenacin, and degradation of solifenacin over time. An object of the present invention is to provide a preparation that suppresses skin irritation and has low skin irritation.
本発明者らは、前記課題を達成すべく研究を重ねた結果、薬物含有層中にソリフェナシンの薬学的に許容される塩と無機塩基を含む経皮吸収型貼付剤が、経皮吸収性及び保存安定性に優れ、且つ、皮膚刺激が少ないことを見出した。かかる知見に基づいて、さらに検討を加えて本発明を完成するに至った。 As a result of repeated studies to achieve the above problems, the present inventors have found that a transdermal patch containing a pharmaceutically acceptable salt of solifenacin and an inorganic base in a drug-containing layer has a transdermal absorbability and It was found that the storage stability was excellent and the skin irritation was small. Based on this knowledge, further studies have been made and the present invention has been completed.
即ち、本発明は以下の通りである。
[1]支持体と薬物含有層とを有する経皮吸収型貼付剤であって、該薬物含有層が、ソリフェナシンの薬学的に許容される塩および無機塩基を含有する、経皮吸収型貼付剤。
[2]前記薬物含有層がさらに粘着剤を含有し、該粘着剤がゴム系樹脂およびアクリル系樹脂からなる群より選ばれる少なくとも1種を主成分として含有する、[1]に記載の経皮吸収型貼付剤。
[3]前記ゴム系樹脂が、スチレン−イソプレン−スチレンブロック共重合体である、[2]に記載の経皮吸収型貼付剤。
[4]前記薬物含有層がさらに粘着付与剤を含有する、[2]又は[3]に記載の経皮吸収型貼付剤。
[5]前記粘着付与剤が、脂環族飽和炭化水素樹脂である、[4]に記載の経皮吸収型貼付剤。
[6]前記無機塩基が、水酸化カリウムおよび水酸化ナトリウムからなる群より選ばれる少なくとも1種である、[1]〜[5]のいずれかに記載の経皮吸収型貼付剤。
[7]前記薬物含有層がさらに吸収促進剤を含有し、該吸収促進剤がアルコール類およびエステル類からなる群より選ばれる少なくとも1種である、[1]〜[6]のいずれかに記載の経皮吸収型貼付剤。
[8]前記ソリフェナシンの薬学的に許容される塩が、ソリフェナシンコハク酸塩である、[1]〜[7]のいずれかに記載の経皮吸収型貼付剤。
[9]剥離ライナーをさらに有し、支持体、薬物含有層、および剥離ライナーの順に積層されている、[1]〜[8]のいずれかに記載の経皮吸収型貼付剤。
[10]前記[1]に記載の経皮吸収型貼付剤の製造方法であって、ソリフェナシンの薬学的に許容される塩、および無機塩基を含む混合物を剥離ライナー上に塗布(展延)して薬物含有層を形成し、この薬物含有層に支持体を貼り合わせることを特徴とする製造方法。
[11]過活動膀胱の治療剤として使用するための前記[1]〜[9]のいずれかに記載の経皮吸収型貼付剤。
[12]過活動膀胱治療用の経皮投与製剤を製造するための前記[1]〜[9]のいずれかに記載の経皮吸収型貼付剤の使用。
[13]過活動膀胱を治療する方法であって、前記[1]〜[9]のいずれかに記載の経皮吸収型貼付剤を、当該治療を要する患者の皮膚に適用(貼付)することを特徴とする方法。That is, the present invention is as follows.
[1] A transdermal absorption patch having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin and an inorganic base. .
[2] The transdermal system according to [1], wherein the drug-containing layer further contains an adhesive, and the adhesive contains at least one selected from the group consisting of a rubber-based resin and an acrylic resin as a main component. Absorbent patch.
[3] The transdermal patch according to [2], wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer.
[4] The transdermal patch according to [2] or [3], wherein the drug-containing layer further contains a tackifier.
[5] The transdermal patch according to [4], wherein the tackifier is an alicyclic saturated hydrocarbon resin.
[6] The transdermal patch according to any one of [1] to [5], wherein the inorganic base is at least one selected from the group consisting of potassium hydroxide and sodium hydroxide.
[7] The drug-containing layer further contains an absorption accelerator, and the absorption accelerator is at least one selected from the group consisting of alcohols and esters. A transdermal patch.
[8] The transdermal patch according to any one of [1] to [7], wherein the pharmaceutically acceptable salt of solifenacin is solifenacin succinate.
[9] The transdermal absorption patch according to any one of [1] to [8], further comprising a release liner, wherein the support, the drug-containing layer, and the release liner are laminated in this order.
[10] A method for producing a transdermal patch according to [1], wherein a mixture containing a pharmaceutically acceptable salt of solifenacin and an inorganic base is applied (spread) onto a release liner. Forming a drug-containing layer and bonding a support to the drug-containing layer.
[11] The transdermal absorption patch according to any one of [1] to [9] for use as a therapeutic agent for overactive bladder.
[12] Use of the transdermal absorption patch according to any one of [1] to [9] above for producing a transdermal administration preparation for treating overactive bladder.
[13] A method for treating overactive bladder, wherein the transdermal patch of any one of [1] to [9] is applied (pasted) to the skin of a patient in need of the treatment. A method characterized by.
本発明によれば、薬物含有層中にソリフェナシンの薬学的に許容される塩と無機塩基を含有させることによって、高い皮膚透過性を得ることができ、経時的なソリフェナシンの分解が起こらないため保存安定性に優れ、且つ皮膚刺激の少ない経皮吸収型貼付剤を提供することができる。 According to the present invention, by containing a pharmaceutically acceptable salt of solifenacin and an inorganic base in the drug-containing layer, high skin permeability can be obtained, and solifenacin is not decomposed over time, and thus preserved. It is possible to provide a transdermal absorption patch having excellent stability and little skin irritation.
ソリフェナシンの薬学的に許容される塩を経皮吸収貼付剤にすることにより、嚥下障害を有する患者や、飲水を控える過活動膀胱患者に対して、投与の利便性が向上する。また、ソリフェナシンの薬学的に許容される塩の経皮吸収型貼付剤化により目視による投薬確認が可能になるため、服薬アドヒアランスの向上も期待できる。 By using a pharmaceutically acceptable salt of solifenacin as a transdermal absorption patch, the convenience of administration is improved for patients with dysphagia and overactive bladder patients who refrain from drinking. In addition, since it is possible to confirm the dosage visually by making a transdermal absorption patch of a pharmaceutically acceptable salt of solifenacin, an improvement in medication adherence can be expected.
本発明の経皮吸収型貼付剤は、過活動膀胱の治療に有効なソリフェナシンの血中濃度を達成できる。また、ソリフェナシンが持続的に経皮吸収されることにより、長期間にわたり所望の血漿中濃度を維持することができる。 The transdermal absorption patch of the present invention can achieve a blood concentration of solifenacin effective for the treatment of overactive bladder. In addition, since solifenacin is percutaneously absorbed, a desired plasma concentration can be maintained over a long period of time.
本発明において経皮吸収型貼付剤とは、非経口製剤であって、皮膚に貼付して用いられ、有効成分が皮膚を通して吸収され血流に送達されるものをいう。本発明の経皮吸収型貼付剤は、支持体と薬物含有層とを有する貼付剤であり、例えばテープ剤、パップ剤、プラスター剤などが挙げられる。 In the present invention, the transdermal patch is a parenteral preparation which is used by being applied to the skin, and the active ingredient is absorbed through the skin and delivered to the bloodstream. The transdermal patch of the present invention is a patch having a support and a drug-containing layer, and examples thereof include a tape, a poultice, and a plaster.
本発明の経皮吸収型貼付剤は、薬物含有層に粘着剤を含有するマトリックス型貼付製剤でもよく、薬物含有層の皮膚貼付側に、薬剤の経皮吸収を調節するための放出制御膜および皮膚へ貼付するための粘着層をさらに有するリザーバー型貼付製剤であってもよい。このような構造により、ソリフェナシンを効率的に経皮吸収させることが可能となる。 The transdermal patch of the present invention may be a matrix-type patch preparation containing an adhesive in the drug-containing layer, and a release-controlling membrane for adjusting the transdermal absorption of the drug on the skin-pasted side of the drug-containing layer and It may be a reservoir-type patch preparation further having an adhesive layer for sticking to the skin. With such a structure, solifenacin can be efficiently transdermally absorbed.
製剤設計および製造の容易さの観点からは、マトリックス型貼付剤であることが好ましい。以下、マトリックス型貼付剤を例に説明するが本発明はこれに限定されるものではない。 From the viewpoint of ease of formulation design and production, a matrix-type patch is preferable. Hereinafter, the matrix type patch will be described as an example, but the present invention is not limited thereto.
本明細書において、「を含有する」または「を含む」には、「から本質的になる」または「のみからなる」の意味も包含する。
<薬物含有層>
1.有効成分
本発明の経皮吸収型貼付剤において、薬物含有層は、有効成分としてソリフェナシンの薬学的に許容される塩を含有する。薬学的に許容される塩としては、例えば、無機酸塩、例えば、塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩など;および有機酸塩、例えば、ギ酸塩、酢酸塩、トリフルオロ酢酸塩、アスコルビン酸塩、安息香酸塩、桂皮酸塩、クエン酸塩、フマル酸塩、グルタミン酸塩、酒石酸塩、シュウ酸塩、グルタル酸塩、カンファー酸塩、アジピン酸塩、ソルビン酸塩、乳酸塩、マレイン酸塩、リノール酸塩、リノレン酸塩、リンゴ酸塩、マロン酸塩、マンデル酸塩、メタンスルホン酸塩(メシレート)、フタル酸塩、サリチル酸塩、ステアリン酸塩、イソステアリン酸塩、コハク酸塩、プロピオン酸塩、酪酸塩、パモ酸塩、p−トルエンスルホン酸塩(トシレート)、ベンゼンスルホン酸塩(ベシレート)などが挙げられるが、これらに限定されない。In this specification, “comprising” or “including” includes the meaning of “consisting essentially of” or “consisting solely of”.
<Drug-containing layer>
1. Active ingredient In the transdermal patch of the present invention, the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin as an active ingredient. Pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; and organic acid salts such as formate, acetate, Trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate, sorbate , Lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, isostearate Succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate) and the like. Absent.
ソリフェナシンの薬学的に許容される塩は、いずれかを単独で又は2種以上を適宜組み合わせて用いてもよい。本発明では、ムスカリン受容体拮抗薬として、既に経口投与における有用性が確立されているソリフェナシンコハク酸塩を用いることが好ましい。 Any of the pharmaceutically acceptable salts of solifenacin may be used alone or in appropriate combination of two or more. In the present invention, it is preferable to use solifenacin succinate that has already been established to be useful for oral administration as a muscarinic receptor antagonist.
本発明の経皮吸収型貼付剤におけるソリフェナシンの薬学的に許容される塩の含有量は、過活動膀胱の治療に対する有効量である。ここで有効量とは、本発明の経皮吸収型貼付剤を生体の皮膚に適用した場合に、過活動膀胱の治療に有効なソリフェナシンの血中濃度を達成しうる量である。そのような含有量は、経口投与の薬物動態に関する情報に基づいて適宜調整することができ、投与対象、疾患、症状などにより異なりうる。例えば、薬物含有層に対して(即ち、薬物含有層の全質量を基準として;以下同じ)0.2〜50質量%が好ましく、0.5〜35質量%がより好ましく、0.5〜25質量%がさらに好ましい。 The content of the pharmaceutically acceptable salt of solifenacin in the transdermal absorption patch of the present invention is an effective amount for the treatment of overactive bladder. Here, the effective amount is an amount that can achieve the blood concentration of solifenacin effective for treating overactive bladder when the transdermal absorption patch of the present invention is applied to the skin of a living body. Such content can be appropriately adjusted based on information on pharmacokinetics of oral administration, and may vary depending on the administration subject, disease, symptoms, and the like. For example, 0.2-50 mass% is preferable with respect to the drug-containing layer (that is, based on the total mass of the drug-containing layer; the same shall apply hereinafter), more preferably 0.5-35 mass%, and more preferably 0.5-25 More preferred is mass%.
過活動膀胱の治療に有効なソリフェナシンの血中濃度は、ソリフェナシンの薬学的に許容される塩の経口薬の場合と同程度とすることができる。 The blood concentration of solifenacin effective in the treatment of overactive bladder can be comparable to that of an oral drug of a pharmaceutically acceptable salt of solifenacin.
本発明の経皮吸収型貼付剤において、ソリフェナシンの皮膚透過速度を調整することによって、過活動膀胱の治療に有効な血中濃度を達成することができる。皮膚透過速度の調整は、薬物含有層中のソリフェナシンの薬学的に許容される塩の含有量及び投与面積を調整することなど、任意の手段によって行うことができる。なお、本発明においてソリフェナシンの薬学的に許容される塩の皮膚透過速度とは、後述の実施例に記載するインビトロ皮膚透過性試験により測定される値を意味する。 In the transdermal patch of the present invention, a blood concentration effective for treating overactive bladder can be achieved by adjusting the skin permeation rate of solifenacin. The skin permeation rate can be adjusted by any means such as adjusting the content and administration area of a pharmaceutically acceptable salt of solifenacin in the drug-containing layer. In the present invention, the skin permeation rate of a pharmaceutically acceptable salt of solifenacin means a value measured by an in vitro skin permeability test described in Examples described later.
ソリフェナシンの皮膚透過速度は、ソリフェナシンフリー体に換算した値で5〜40μg/cm2/時間が好ましく、5〜35μg/cm2/時間がより好ましい。皮膚透過速度が5μg/cm2/時間以上であれば、十分な血中濃度を得ることができる。皮膚透過速度が40μg/cm2/時間以下であれば、適用皮膚の紅斑などの皮膚刺激が起こり難いため、安全性の観点から好ましい。Skin permeation rate of solifenacin is preferably 5~40μg / cm 2 / time at a value in terms of warpage phenacyl down free form, 5~35μg / cm 2 / time is more preferable. If the skin permeation rate is 5 μg / cm 2 / hour or more, a sufficient blood concentration can be obtained. A skin permeation rate of 40 μg / cm 2 / hour or less is preferable from the viewpoint of safety because skin irritation such as erythema of the applied skin hardly occurs.
2.無機塩基
ソリフェナシンの皮膚透過性を向上し、製剤中のソリフェナシンの分解を抑制するために薬物含有層中には無機塩基を含有する。具体的には、アルカリ金属水酸化物(水酸化カリウム、水酸化ナトリウムなど)、アルカリ金属炭酸塩(炭酸カリウム、炭酸ナトリウムなど)、アルカリ金属炭酸水素塩(炭酸水素カリウム、炭酸水素ナトリウムなど)などが挙げられる。特に、水酸化カリウム、水酸化ナトリウム、炭酸水素ナトリウムなどが好ましく、水酸化ナトリウム、水酸化カリウムがより好ましい。 2. In order to improve the skin permeability of the inorganic base solifenacin and suppress the decomposition of solifenacin in the preparation, the drug-containing layer contains an inorganic base. Specifically, alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.), alkali metal carbonates (potassium carbonate, sodium carbonate, etc.), alkali metal bicarbonates (potassium bicarbonate, sodium bicarbonate, etc.), etc. Is mentioned. In particular, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and the like are preferable, and sodium hydroxide and potassium hydroxide are more preferable.
このような無機塩基は、単独で又は2種以上を混合して用いることができる。無機塩基の含有量は、ソリフェナシンの薬学的に許容される塩(特に、酸付加塩)の当量に対して0.5〜3当量であることが好ましく、0.5〜2当量であることがより好ましい。また、無機塩基の含有量は、薬物含有層に対して0.1〜35質量%であることが好ましく、1〜30質量%であることがより好ましく、1〜20質量%であることがさらに好ましい。このような無機塩基を含有することにより、無機塩基がソリフェナシンの薬学的に許容される塩(特に、酸付加塩)に作用し、ソリフェナシンの皮膚透過性が向上する。特に、無機塩基の含有量を上記範囲内とすることにより、上記範囲外である場合と比較して皮膚透過性の向上効果がより顕著になる。また、無機塩基を用いることにより、薬物含有層中のソリフェナシンの分解を抑制することができる。この効果は、特に有機塩基を用いた場合に比べて顕著に優れている。 Such inorganic bases can be used alone or in admixture of two or more. The content of the inorganic base is preferably 0.5 to 3 equivalents, and preferably 0.5 to 2 equivalents, relative to the equivalent amount of pharmaceutically acceptable salt (especially acid addition salt) of solifenacin. More preferred. Moreover, it is preferable that content of an inorganic base is 0.1-35 mass% with respect to a drug containing layer, It is more preferable that it is 1-30 mass%, It is further that it is 1-20 mass% preferable. By containing such an inorganic base, the inorganic base acts on a pharmaceutically acceptable salt (especially an acid addition salt) of solifenacin, and the skin permeability of solifenacin is improved. In particular, by setting the content of the inorganic base within the above range, the effect of improving skin permeability becomes more remarkable as compared with the case where the content is outside the above range. Moreover, decomposition | disassembly of solifenacin in a drug content layer can be suppressed by using an inorganic base. This effect is remarkably superior especially when an organic base is used.
3.粘着剤
薬物含有層は、さらに粘着剤を含有することができる。薬物含有層に含有される粘着剤としては、ゴム系樹脂、アクリル系樹脂およびシリコーン系樹脂等を含むものが挙げられる。 3. The adhesive drug-containing layer can further contain an adhesive. Examples of the pressure-sensitive adhesive contained in the drug-containing layer include those containing rubber resins, acrylic resins, silicone resins, and the like.
粘着剤としては、アクリル系樹脂、ゴム系樹脂およびシリコーン系樹脂からなる群より選ばれる少なくとも1種を主成分として含有するものが好ましく、さらにアクリル系樹脂およびゴム系樹脂からなる群より選ばれる少なくとも1種を主成分として含有するものがより好ましい。ここで、「主成分」とは、粘着剤の全質量に対し、通常70質量%以上、さらに80質量%以上、よりさらに90質量%以上、特に100質量%を意味する。 The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of acrylic resins, rubber resins and silicone resins as a main component, and at least selected from the group consisting of acrylic resins and rubber resins. What contains 1 type as a main component is more preferable. Here, the “main component” means usually 70% by mass or more, further 80% by mass or more, further 90% by mass or more, and particularly 100% by mass with respect to the total mass of the pressure-sensitive adhesive.
ゴム系樹脂としては、例えば、スチレン−イソプレン−スチレンブロック共重合体(SIS)、スチレン−ブタジエン−スチレンブロック共重合体(SBS)、スチレン−ブタジエンゴム(SBR)、スチレンイソプレンゴム、ポリイソブチレン(PIB)、ポリブテン、ブチルゴム、天然ゴム、生ゴム、アラビアゴム、アラビアゴム末、イソプレンゴムなどが挙げられるが、好ましくはSISである。またクレイトンDポリマーシリーズ(クレイトンポリマージャパン社製)やJSR SIS/TRシリーズ(JSRライフサイエンス社製)やクインタックシリーズ(日本ゼオン社製)などの市販のゴム系樹脂を使用してもよい。 Examples of rubber resins include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, and polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, preferably SIS. Commercially available rubber-based resins such as Kraton D polymer series (manufactured by Kraton Polymer Japan), JSR SIS / TR series (manufactured by JSR Life Sciences) and quintack series (manufactured by Nippon Zeon) may also be used.
アクリル系樹脂としては、例えば、モノマー単位として、アクリル酸2−エチルヘキシル、アクリル酸メチル、アクリル酸ブチル、アクリル酸2−ヒドロキシエチル、メタクリル酸2−エチルヘキシルなどに代表される(メタ)アクリル酸エステルを少なくとも1種含有する重合体または共重合体が挙げられる。具体的には、例えば、アクリル酸・アクリル酸オクチルエステル共重合体、アクリル酸2−エチルヘキシル・ビニルピロリドン共重合体溶液、アクリル酸2−エチルエキシル・N−ビニル−2−ピロリドン・ジメタクリル酸−1,6−ヘキサングリコール共重合体、アクリル酸エステル・酢酸ビニルコポリマー、アクリル酸2−エチルヘキシル・アクリル酸2−ヒドロキシエチル・酢酸ビニル共重合体、アクリル酸2−エチルヘキシル・メタクリル酸2−エチルヘキシル・メタクリル酸ドデシル共重合体溶液、アクリル酸メチル・アクリル酸2−エチルヘキシル共重合樹脂エマルジョン、アクリル樹脂アルカノールアミン液などが挙げられる。また、DURO−TAK(登録商標)アクリル粘着剤シリーズ(DURO-TAK 87-900A、DURO-TAK 87-9301、DURO-TAK 87-4098、DURO-TAK 387-2510、DURO-TAK 87-2510、DURO-TAK 387-2287、DURO-TAK 87-2287、DURO-TAK 87-4287、DURO-TAK 387-2516、DURO-TAK 87-2516、DURO-TAK 87-2074、DURO-TAK 387-235A、DURO-TAK 387-2353、DURO-TAK 87-2353、DURO-TAK 87-2852、DURO-TAK 387-2051、DURO-TAK 87-2051、DURO-TAK 387-2052、DURO-TAK 87-2052、DURO-TAK 387-2054、DURO-TAK 87-2054、DURO-TAK 87-2194、DURO-TAK 87-2196:ヘンケル社製)、GELVAシリーズ(GELVA GMS 3083、GELVA GMS 3253、GELVA GMS 788、GELVA GMS 9073:ヘンケル社製)、MAS−683、MAS−811、MASCOS10、MAS11D1(コスメディ製薬社製)などの市販のアクリル系樹脂を使用してもよい。 As an acrylic resin, for example, (meth) acrylic acid ester represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like is used as a monomer unit. Examples thereof include a polymer or copolymer containing at least one kind. Specifically, for example, acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-hexane glycol copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid Examples thereof include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic resin alkanolamine solution. Also, DURO-TAK (registered trademark) acrylic adhesive series (DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 387-2510, DURO-TAK 87-2510, DURO -TAK 387-2287, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 387-2516, DURO-TAK 87-2516, DURO-TAK 87-2074, DURO-TAK 387-235A, DURO- TAK 387-2353, DURO-TAK 87-2353, DURO-TAK 87-2852, DURO-TAK 387-2051, DURO-TAK 87-2051, DURO-TAK 387-2052, DURO-TAK 87-2052, DURO-TAK 387-2054, DURO-TAK 87-2054, DURO-TAK 87-2194, DURO-TAK 87-2196: made by Henkel, GELVA series (GELVA GMS 3083, GELVA GMS 3253, GELVA GMS 788, GELVA GMS 9073: Henkel Commercially available acrylic resins such as MAS-683, MAS-811, MASCOS10, MAS11D1 (manufactured by Kosmedy Pharmaceutical) may be used.
シリコーン系樹脂としては、例えば、オルガノポリシロキサン骨格を有するポリマーおよびその誘導体が挙げられ、具体的には、例えば、ジメチルポリシロキサン、ポリメチルビニルシロキサン、ポリメチルフェニルシロキサン、ジフェニルシロキサンなどが挙げられる。また、BIO−PSAシリーズ(ダウコーニング社製)などの市販のシリコーン系樹脂を使用してもよい。 Examples of the silicone-based resin include polymers having an organopolysiloxane skeleton and derivatives thereof. Specific examples include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane. Commercially available silicone resins such as BIO-PSA series (Dow Corning) may also be used.
本発明の経皮吸収型貼付剤の薬物含有層に含有される粘着剤として、上述のゴム系樹脂、アクリル系樹脂、およびシリコーン系樹脂のうちの1種を単独で、または2種以上を組み合わせて使用することができる。より好ましくは、アクリル系またはゴム系樹脂の使用であり、さらに好ましくはゴム系樹脂の使用である。 As the pressure-sensitive adhesive contained in the drug-containing layer of the transdermal patch of the present invention, one of the above rubber resins, acrylic resins, and silicone resins may be used alone or in combination of two or more. Can be used. More preferably, acrylic or rubber resin is used, and rubber resin is more preferably used.
本発明の経皮吸収型貼付剤の薬物含有層中に含有される粘着剤の量は、薬物含有層の形成、ソリフェナシンの薬学的に許容される塩の十分な皮膚透過性などを考慮して調整される。粘着剤の含有量は、薬物含有層に対して通常10〜90質量%、好ましくは10〜80質量%である。 The amount of the adhesive contained in the drug-containing layer of the transdermal patch of the present invention is determined in consideration of the formation of the drug-containing layer, sufficient skin permeability of a pharmaceutically acceptable salt of solifenacin, and the like. Adjusted. The content of the pressure-sensitive adhesive is usually 10 to 90% by mass, preferably 10 to 80% by mass with respect to the drug-containing layer.
本発明の経皮吸収型貼付剤の薬物含有層にゴム系樹脂を使用する場合、ゴム系樹脂の含有量は、貼付剤としての十分な凝集力を考慮して、薬物含有層に対して合計で10〜70質量%が好ましく、10〜60質量%がより好ましく、10〜50質量%がさらに好ましい。 When using a rubber-based resin for the drug-containing layer of the transdermal absorption patch of the present invention, the content of the rubber-based resin is a total for the drug-containing layer in consideration of sufficient cohesion as a patch. Is preferably 10 to 70% by mass, more preferably 10 to 60% by mass, and still more preferably 10 to 50% by mass.
本発明の経皮吸収型貼付剤の薬物含有層にアクリル樹脂を使用する場合、アクリル樹脂の含有量は、貼付剤としての十分な凝集力及び粘着力を考慮して、薬物含有層に対して、合計で20〜90重量%が好ましく、20〜80重量%がさらに好ましい。 When an acrylic resin is used for the drug-containing layer of the transdermal absorption patch of the present invention, the acrylic resin content is determined relative to the drug-containing layer in consideration of sufficient cohesive strength and adhesive strength as a patch. The total amount is preferably 20 to 90% by weight, and more preferably 20 to 80% by weight.
本発明の経皮吸収型貼付剤の薬物含有層にシリコーン樹脂を使用する場合、シリコーン樹脂の含有量は、貼付剤としての十分な凝集力及び粘着力を考慮して、薬物含有層に対して、合計で20〜90重量%が好ましく、20〜80重量%がさらに好ましい。 When a silicone resin is used in the drug-containing layer of the transdermal absorption patch of the present invention, the silicone resin content is determined relative to the drug-containing layer in consideration of sufficient cohesion and adhesive strength as a patch. The total amount is preferably 20 to 90% by weight, and more preferably 20 to 80% by weight.
4.粘着付与剤
薬物含有層は、粘着力向上のために粘着付与剤をさらに含有してもよい。粘着付与剤としては、例えば、ロジン、ロジンのグリセリンエステル、水添ロジン、水添ロジンのグリセリンエステルなどのロジン誘導体、脂環族飽和炭化水素樹脂、脂環族炭化水素樹脂、テルペン樹脂、脂肪族飽和炭化水素樹脂、脂肪族炭化水素樹脂、マレイン酸レジン、カルナウバロウ、カルメロースナトリウム、キサンタンガム、キトサン、グリセリン、ケイ酸マグネシウムアルミニウム、軽質無水ケイ酸、酢酸ベンジル、タルク、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒプロメロース、ポリアクリル酸、ポリアクリル酸ナトリウム、ポリアクリル酸部分中和物、ポリビニルアルコールなどが挙げられる。また粘着付与剤として、アルコンシリーズ(荒川化学社製)、パインクリスタルシリーズ(荒川化学社製)、クリアロンシリーズ(ヤスハラケミカル社製)、YSレジンシリーズ(ヤスハラケミカル社製)などの市販されているものを適宜使用してもよい。特に粘着剤として前記ゴム系樹脂を用いる場合には、水添ロジンのグリセリンエステル、脂環族飽和炭化水素樹脂、テルペン樹脂、脂肪族飽和炭化水素樹脂を粘着付与剤として使用することが好ましい。粘着付与剤は、1種を単独で、または2種以上を組み合わせて使用することができる。 4. Tackifier The drug-containing layer may further contain a tackifier to improve the adhesive strength. Examples of the tackifier include rosin derivatives such as rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic Saturated hydrocarbon resin, aliphatic hydrocarbon resin, maleic resin, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose , Polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like. In addition, as the tackifier, commercially available products such as Alcon series (Arakawa Chemical Co., Ltd.), Pine Crystal series (Arakawa Chemical Co., Ltd.), Clearon series (Yasuhara Chemical Co., Ltd.), YS Resin Series (Yasuhara Chemical Co., Ltd.), etc. You may use suitably. In particular, when the rubber-based resin is used as an adhesive, it is preferable to use a glycerin ester of hydrogenated rosin, an alicyclic saturated hydrocarbon resin, a terpene resin, or an aliphatic saturated hydrocarbon resin as a tackifier. A tackifier can be used individually by 1 type or in combination of 2 or more types.
粘着付与剤の含有量は、貼付剤としての十分な粘着力を考慮して、粘着剤としてゴム系樹脂を用いる場合は、薬物含有層に対して合計で5〜70質量%が好ましく、10〜60質量%がより好ましく、20〜50質量%がさらに好ましい。粘着剤としてアクリル系樹脂を用いる場合は、薬物含有層に対して合計で1〜40質量%が好ましく、5〜30質量%がより好ましく、5〜20質量%がさらに好ましい。粘着剤としてシリコーン樹脂を用いる場合は、薬物含有層に対して1〜40質量%が好ましく、5〜30質量%がより好ましく、5〜20質量%がさらに好ましい。 The content of the tackifier is preferably 5 to 70% by mass in total with respect to the drug-containing layer when a rubber-based resin is used as the adhesive in consideration of sufficient adhesive strength as a patch. 60 mass% is more preferable, and 20-50 mass% is further more preferable. When using acrylic resin as an adhesive, 1-40 mass% in total is preferable with respect to a drug containing layer, 5-30 mass% is more preferable, 5-20 mass% is further more preferable. When using a silicone resin as an adhesive, 1-40 mass% is preferable with respect to a drug containing layer, 5-30 mass% is more preferable, 5-20 mass% is further more preferable.
5.可塑剤
薬物含有層は、可塑剤をさらに含有してもよい。可塑剤としては、石油系オイル(例えば、パラフィン系プロセスオイル、ナフテン系プロセスオイル、芳香族系プロセスオイル、流動パラフィンなど)、スクワラン、スクワレン、植物系オイル(例えば、オリーブ油、ツバキ油、ひまし油、トール油、ラッカセイ油など)、シリコーンオイル、二塩基酸エステル(例えば、ジブチルフタレート、ジオクチルフタレートなど)、液状ゴム(例えば、ポリブテン、液状イソプレンゴムなど)、ジエチレングリコール、ポリエチレングリコール、サリチル酸グリコール、トリアセチン、クエン酸トリエチル、クロタミトンなどが挙げられる。また可塑剤として、ハイコールシリーズ(カネダ社製)などの市販されているものを適宜使用してもよい。特に粘着剤として前記ゴム系樹脂を用いる場合には、流動パラフィンを可塑剤として使用することが好ましい。可塑剤は、1種を単独で、または2種以上を組み合わせて使用することができる。 5. Plasticizer The drug-containing layer may further contain a plasticizer. Plasticizers include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, liquid paraffin, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), diethylene glycol, polyethylene glycol, salicylic acid glycol, triacetin, citric acid Examples include triethyl and crotamiton. Moreover, as a plasticizer, you may use suitably what is marketed, such as a high coal series (made by Kaneda Co., Ltd.). In particular, when the rubber-based resin is used as an adhesive, liquid paraffin is preferably used as a plasticizer. A plasticizer can be used individually by 1 type or in combination of 2 or more types.
可塑剤の含有量は、ソリフェナシンの十分な透過性および貼付剤としての十分な凝集力の維持を考慮して調整される。粘着剤としてゴム系樹脂を用いる場合は、薬物含有層に対して合計で1〜70質量%が好ましく、1〜60質量%がより好ましく、1〜50質量%がさらに好ましい。粘着剤としてアクリル系樹脂を用いる場合は、薬物含有層に対して合計で1〜50質量%が好ましく、1〜40質量%がより好ましく、1〜30質量%がさらに好ましい。粘着剤としてシリコーン系樹脂を用いる場合は、薬物含有層に対して合計で1〜50質量%が好ましく、1〜40質量%がより好ましく、1〜30質量%がさらに好ましい。 The content of the plasticizer is adjusted in consideration of sufficient permeability of solifenacin and maintenance of sufficient cohesive strength as a patch. When using rubber-type resin as an adhesive, 1-70 mass% is preferable in total with respect to a drug containing layer, 1-60 mass% is more preferable, 1-50 mass% is further more preferable. When using acrylic resin as an adhesive, 1-50 mass% in total is preferable with respect to a drug containing layer, 1-40 mass% is more preferable, 1-30 mass% is further more preferable. In the case of using a silicone-based resin as the pressure-sensitive adhesive, the total amount is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and further preferably 1 to 30% by mass with respect to the drug-containing layer.
6.吸収促進剤
薬物含有層は、ソリフェナシンの皮膚透過性向上のため、吸収促進剤をさらに含有してもよい。吸収促進剤は、経皮投与において皮膚透過促進作用が認められているいずれの化合物であってもよく、例えばカプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ソルビン酸、オレイン酸、リノール酸、リノレン酸、ミリスチン酸イソプロピル、オレイン酸オレイル、トリ(カプリル・カプリン酸)グリセリン、パルミチン酸イソプロピル、ミリスチン酸オクチルドデシル、グリセリンオレイン酸モノエステル、イソステアリン酸ヘキサデシルなどの脂肪酸またはそのエステル類;乳酸、酢酸、リンゴ酸、クエン酸、酒石酸、シュウ酸、フマル酸、コハク酸、グルタル酸、グリコール酸、アジピン酸、ピメリン酸、セバシン酸、安息香酸、サリチル酸、ニコチン酸、メタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、サッカリンなどの有機酸またはそれらの塩;アジピン酸ジイソプロピル、セバシン酸ジエチル、セバシン酸ジイソプロピルなどの多価カルボン酸エステル類;リン酸などの無機酸またはそれらの塩;ラウリルアルコール、ミリスチルアルコール、オレイルアルコール、イソステアリルアルコール、セチルアルコール、ベンジルアルコール、オレイルアルコール、モノカプリル酸プロピレングリコール、ジカプリル酸プロピレングリコール、モノオレイン酸ポリエチレングリコールなどのアルコール類またはそのエステル類もしくはそのエーテル類;炭素数3〜8の多価アルコール(例えば、プロピレングリコール、1,3−ブタンジオール、1,4−ブタンジオール、グリセリン、ジプロピレングリコール、オクタンジオール等);モノラウリン酸ソルビタン、モノオレイン酸ソルビタンなどのソルビタンエステル類またはエーテル類;モノオレイン酸ポリオキシエチレンソルビタン(ポリソルベート80)、モノパルミチン酸ポリオキシエチレンソルビタンなどのポリオキシエチレンソルビタン脂肪酸エステル類;ポリオキシエチレンノニルフェニルエーテル、ポリオキシエチレンオクチルフェニルエーテルなどのフェノールエーテル類;ヒマシ油または硬化ヒマシ油;オレオイルサルコシン、ラウリルジメチルアミノ酢酸ベタイン、ラウリル硫酸ナトリウムなどのイオン性界面活性剤;炭素数10〜22のポリオキシエチレンアルキルエーテル(例えば、ポリオキシエチレンラウリルエーテル、ポリオキシエチレンオレイルエーテル、ポリオキシエチレンステアリルエーテル、ポリオキシエチレンセチルエーテル、ポリオキシエチレンベヘニルエーテル等);ジメチルラウリルアミンオキサイドなどの非イオン性界面活性剤;ジメチルスルホキサイド、デシルメチルスルホキサイドなどのアルキルメチルスルホキサイド;2−ピロリドン、N−メチル−2−ピロリドン、N−エチル−2−ピロリドンなどのピロリドン類;1−ドデシルアザシクロヘプタン−2−オン、1−ゲラニルアザシクロヘプタン−2−オンなどのアザシクロアルカン類;メントール、カンフル、リモネンなどのテルペン類が挙げられる。 6). The absorption enhancer drug-containing layer may further contain an absorption enhancer for improving the skin permeability of solifenacin. The absorption enhancer may be any compound that has been shown to promote skin permeation through transdermal administration, such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oleic acid, linol. Fatty acids or esters thereof such as acid, linolenic acid, isopropyl myristate, oleyl oleate, glyceryl tri (capryl / caprate), isopropyl palmitate, octyldodecyl myristate, glycerin oleate monoester, hexadecyl isostearate; lactic acid, Acetic acid, malic acid, citric acid, tartaric acid, oxalic acid, fumaric acid, succinic acid, glutaric acid, glycolic acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, salicylic acid, nicotinic acid, methanesulfonic acid, benzenesulfonic acid, Toluene sul Acids, organic acids such as saccharin or salts thereof; polycarboxylic esters such as diisopropyl adipate, diethyl sebacate, diisopropyl sebacate; inorganic acids such as phosphoric acid or salts thereof; lauryl alcohol, myristyl alcohol, Alcohols such as oleyl alcohol, isostearyl alcohol, cetyl alcohol, benzyl alcohol, oleyl alcohol, propylene glycol monocaprylate, propylene glycol dicaprylate and polyethylene glycol monooleate or esters thereof or ethers thereof; 3 to 8 carbon atoms A polyhydric alcohol (for example, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); Sorbitan esters or ethers such as sorbitan nolaurate and sorbitan monooleate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (polysorbate 80) and polyoxyethylene sorbitan monopalmitate; polyoxyethylene nonyl Phenol ethers such as phenyl ether and polyoxyethylene octyl phenyl ether; castor oil or hydrogenated castor oil; ionic surfactants such as oleoyl sarcosine, lauryl dimethylaminoacetic acid betaine, sodium lauryl sulfate; Oxyethylene alkyl ethers (eg, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether) Tellurium, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether, etc.); nonionic surfactants such as dimethyl lauryl amine oxide; alkyl methyl sulfoxides such as dimethyl sulfoxide and decylmethyl sulfoxide; 2-pyrrolidone Pyrrolidones such as N-methyl-2-pyrrolidone and N-ethyl-2-pyrrolidone; azacycloalkanes such as 1-dodecylazacycloheptan-2-one and 1-geranylazacycloheptan-2-one; menthol Terpenes such as camphor and limonene.
なかでも、アルコール類およびエステル類が好ましい。アルコール類としては、例えば、プロピレングリコール、ジプロピレングリコール、1,3−ブタンジオールなどの炭素数3〜8の多価アルコール;オレイルアルコール、イソステアリルアルコールなどの脂肪族アルコールなどが挙げられる。エステル類としては、例えば、多価カルボン酸エステル、脂肪酸エステルなどが好ましい。多価カルボン酸エステルとしては、例えば、アジピン酸ジイソプロピル、セバシン酸ジエチル、セバシン酸ジイソプロピルなどの二価脂肪族カルボン酸エステルが挙げられる。脂肪酸エステルとしては、例えば、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、オレイン酸オレイル、ラウリン酸ヘキシル、モノカプリル酸プロピレングリコール、ジカプリル酸プロピレングリコール、トリ(カプリル・カプリン酸)グリセリンなどが挙げられる。より好ましくは、プロピレングリコール、ジプロピレングリコール、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、ラウリン酸ヘキシル、ジカプリル酸プロピレングリコールである。吸収促進剤は、1種を単独で、または2種以上を組み合わせて使用することができる。 Of these, alcohols and esters are preferred. Examples of the alcohol include polyhydric alcohols having 3 to 8 carbon atoms such as propylene glycol, dipropylene glycol, and 1,3-butanediol; aliphatic alcohols such as oleyl alcohol and isostearyl alcohol. As the esters, for example, polyvalent carboxylic acid esters and fatty acid esters are preferable. Examples of the polyvalent carboxylic acid ester include divalent aliphatic carboxylic acid esters such as diisopropyl adipate, diethyl sebacate, and diisopropyl sebacate. Examples of fatty acid esters include isopropyl myristate, isopropyl palmitate, oleyl oleate, hexyl laurate, propylene glycol monocaprylate, propylene glycol dicaprylate, and tri (caprylic / capric acid) glycerin. More preferred are propylene glycol, dipropylene glycol, isopropyl myristate, isopropyl palmitate, hexyl laurate, and propylene glycol dicaprylate. An absorption accelerator can be used individually by 1 type or in combination of 2 or more types.
吸収促進剤の含有量は、ソリフェナシンの薬学的に許容される塩の種類に応じて適宜調節することができるが、薬物含有層に対して、通常30質量%以下であり、25質量%以下が好ましい。吸収促進剤を含む場合、0.1〜30質量%が好ましく、0.5〜25質量%がより好ましく、1〜25質量%がさらに好ましい。 The content of the absorption promoter can be appropriately adjusted according to the type of pharmaceutically acceptable salt of solifenacin, but is usually 30% by mass or less and 25% by mass or less based on the drug-containing layer. preferable. When an absorption accelerator is included, 0.1 to 30% by mass is preferable, 0.5 to 25% by mass is more preferable, and 1 to 25% by mass is further preferable.
7.その他の任意成分
薬物含有層は、必要に応じて、pH調節剤、架橋剤、抗酸化剤、着色剤、紫外線吸収剤、充填剤、または、防腐剤などの公知の添加剤をさらに含有してもよい。 7. Other optional components The drug-containing layer further contains known additives such as a pH adjuster, a crosslinking agent, an antioxidant, a colorant, an ultraviolet absorber, a filler, or an antiseptic, as necessary. May be.
pH調節剤は、ソリフェナシンの薬学的に許容される塩、またはそれらの溶媒和物の溶解性、安定性、および皮膚透過性の向上、皮膚に対する安全性の向上などの目的で、薬物含有層のpHを調節するために使用することができる。pH調節剤は、医薬品の分野において通常pH調整に用いられる酸もしくは塩基またはそれらの塩であればいずれの化合物であってもよく、例えば、塩酸、硫酸、リン酸、クエン酸、グルコン酸、コハク酸、酢酸、乳酸、メタンスルホン酸、エデト酸、アンモニア水、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミン、メグルミン、トロメタモール、グリシン、水酸化カリウム、水酸化カルシウム、水酸化ナトリウム、水酸化マグネシウム、クエン酸ナトリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウムなどが挙げられる。 The pH adjuster is used in the drug-containing layer for the purpose of improving the solubility, stability and skin permeability of pharmaceutically acceptable salts of solifenacin or solvates thereof, and improving the safety to the skin. Can be used to adjust the pH. The pH adjuster may be any compound as long as it is an acid or base or a salt thereof that is usually used for pH adjustment in the pharmaceutical field. For example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, gluconic acid, succinate Acid, acetic acid, lactic acid, methanesulfonic acid, edetic acid, aqueous ammonia, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, meglumine, trometamol, glycine, potassium hydroxide, calcium hydroxide, hydroxylated Sodium, magnesium hydroxide, sodium citrate, sodium acetate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and the like can be mentioned.
架橋剤としては、例えばアミノ樹脂、フェノール樹脂、エポキシ樹脂、アルキド樹脂、不飽和ポリエステル等の熱硬化性樹脂、イソシアネート化合物、ブロックイソシアネート化合物、有機系架橋剤、金属または金属化合物等の無機系架橋剤が挙げられる。なかでも、イソシアネート化合物またはブロックイソシアネート化合物が好ましい。 Examples of crosslinking agents include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. Is mentioned. Among these, an isocyanate compound or a blocked isocyanate compound is preferable.
抗酸化剤としては、例えばトコフェロール及びこれらのエステル誘導体、アスコルビン酸、アスコルビン酸ステアリン酸エステル、ノルジヒドログアヤレチン酸、ジブチルヒドロキシトルエン(BHT)、ブチルヒドロキシアニソールなどが挙げられる。 Examples of the antioxidant include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.
着色剤としては、例えばインジゴカルミン、黄酸化鉄、黄色三二酸化鉄、カーボンブラック、カラメル、感光素201号、クマザサエキス、黒酸化鉄、ケッケツ、酸化亜鉛、酸化チタン、三二酸化鉄、アマランス、水酸化ナトリウム、タルク、銅クロロフィリンナトリウム、ハダカムギ緑葉エキス末、d−ボルネオール、ミリスチン酸オクチルドデシル、メチレンブルー、リン酸マンガンアンモニウム、ローズ油などが挙げられる。 Examples of colorants include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water Examples include sodium oxide, talc, sodium copper chlorophyllin, green leaf extract powder, d-borneol, octyldodecyl myristate, methylene blue, ammonium manganese phosphate, and rose oil.
紫外線吸収剤としては、例えばアミノ酸系化合物、ベンゾフェノン系化合物、桂皮酸誘導体、シアノアクリレート誘導体、p−アミノ安息香酸誘導体、アントラニル酸誘導体、サリチル酸誘導体、クマリン誘導体、イミダゾリン誘導体、ピリミジン誘導体、ジオキサン誘導体などが挙げられる。 Examples of ultraviolet absorbers include amino acid compounds, benzophenone compounds, cinnamic acid derivatives, cyanoacrylate derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, and the like. Can be mentioned.
充填剤としては、炭酸カルシウム、炭酸マグネシウム、炭酸ナトリウム、炭酸アンモニウム、炭酸カリウム、炭酸水素カリウム、ケイ酸塩(例えば、ケイ酸アルミニウム、ケイ酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウムアルミニウム、ケイ酸マグネシウムナトリウム等)、水酸化マグネシウム、ケイ酸、硫酸バリウム、硫酸カルシウム、亜鉛酸カルシウム、酸化亜鉛、酸化チタンなどが挙げられる。 Fillers include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium bicarbonate, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium), magnesium hydroxide, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.
防腐剤としては、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチルなどが挙げられる。 Examples of the preservative include ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.
その他の任意成分の合計の含有量は、薬物含有層に対して、通常10質量%以下であり、好ましくは5質量%以下である。その他の任意成分を含む場合、0.05〜10質量%が好ましく、0.1〜5質量%がより好ましい。 The total content of other optional components is usually 10% by mass or less, preferably 5% by mass or less, based on the drug-containing layer. When it contains other arbitrary components, 0.05-10 mass% is preferable and 0.1-5 mass% is more preferable.
本発明の経皮吸収型貼付剤における薬物含有層の面積は、ソリフェナシンの薬学的に許容される塩の含有量および/または皮膚透過速度などに応じて適宜調整することができるが、典型的には、2〜140cm2、好ましくは2〜100cm2、さらに好ましくは2〜50cm2の範囲である。またその形状は、特に限定されず、正方形、長方形、円形、楕円形などであってよい。The area of the drug-containing layer in the transdermal patch of the present invention can be appropriately adjusted according to the content of the pharmaceutically acceptable salt of solifenacin and / or the skin permeation rate. Is in the range of 2 to 140 cm 2 , preferably 2 to 100 cm 2 , more preferably 2 to 50 cm 2 . The shape is not particularly limited, and may be a square, a rectangle, a circle, an ellipse, or the like.
本発明の経皮吸収型貼付剤における薬物含有層の厚さは、粘着剤の種類、ソリフェナシンの薬学的に許容される塩の含有量および/または皮膚透過速度などに応じて適宜調整することができ、特に限定されないが、典型的には、20〜300μm、好ましくは25〜150μm、さらに好ましくは25μm〜100μmの範囲である。 The thickness of the drug-containing layer in the transdermal patch of the present invention can be appropriately adjusted according to the type of adhesive, the content of pharmaceutically acceptable salt of solifenacin, and / or the skin permeation rate. Although not particularly limited, it is typically in the range of 20 to 300 μm, preferably 25 to 150 μm, and more preferably 25 μm to 100 μm.
本発明の経皮吸収型貼付剤における薬物含有層には、ソリフェナシンの薬学的に許容される塩及び無機塩基を必須として含有する。 The drug-containing layer in the transdermal absorption patch of the present invention contains a pharmaceutically acceptable salt of solifenacin and an inorganic base as essential components.
ソリフェナシンの薬学的に許容される塩としては、有機酸塩(特に、コハク酸塩)が好ましく、その含有量は、薬物含有層に対して0.5〜25質量%が好ましい。 The pharmaceutically acceptable salt of solifenacin is preferably an organic acid salt (particularly succinate), and the content thereof is preferably 0.5 to 25% by mass with respect to the drug-containing layer.
無機塩基としては、アルカリ金属水酸化物(特に、水酸化カリウム、水酸化ナトリウム)が好ましく、その含有量は、薬物含有層に対して1〜20質量%が好ましい。 As the inorganic base, alkali metal hydroxides (particularly potassium hydroxide and sodium hydroxide) are preferable, and the content thereof is preferably 1 to 20% by mass with respect to the drug-containing layer.
さらに、薬物含有層に粘着剤を含む場合、該粘着剤はゴム系樹脂(特に、SIS)またはアクリル系樹脂であることが好ましい。粘着剤がゴム系樹脂の場合、その含有量は、薬物含有層に対して10〜50質量%が好ましい。粘着剤がアクリル系樹脂の場合、その含有量は、薬物含有層に対して20〜80質量%が好ましい。 Further, when the drug-containing layer contains an adhesive, the adhesive is preferably a rubber-based resin (particularly SIS) or an acrylic resin. When the pressure-sensitive adhesive is a rubber-based resin, the content is preferably 10 to 50% by mass with respect to the drug-containing layer. When the pressure-sensitive adhesive is an acrylic resin, the content is preferably 20 to 80% by mass with respect to the drug-containing layer.
さらに、薬物含有層に粘着付与剤を含む場合、該粘着付与剤は、脂環族飽和炭化水素樹脂が好ましい。粘着剤としてゴム系樹脂を用いる場合、粘着付与剤の含有量は、薬物含有層に対して20〜50質量%が好ましく、粘着剤としてアクリル系樹脂を用いる場合、粘着付与剤の含有量は、薬物含有層に対して5〜20質量%が好ましい。 Furthermore, when the drug-containing layer contains a tackifier, the tackifier is preferably an alicyclic saturated hydrocarbon resin. When a rubber-based resin is used as the adhesive, the content of the tackifier is preferably 20 to 50% by mass with respect to the drug-containing layer. When an acrylic resin is used as the adhesive, the content of the tackifier is 5-20 mass% is preferable with respect to a drug containing layer.
さらに、薬物含有層に吸収促進剤を含む場合、該吸収促進剤は、ミリスチン酸イソプロピルが好ましい。吸収促進剤の含有量は、薬物含有層に対して1〜25質量%が好ましい。 Further, when the drug-containing layer contains an absorption enhancer, the absorption enhancer is preferably isopropyl myristate. The content of the absorption promoter is preferably 1 to 25% by mass with respect to the drug-containing layer.
<支持体>
本発明の経皮吸収型貼付剤における支持体には、薬物不透過性で伸縮性または非伸縮性の支持体を使用することができる。このような支持体としては、医薬品の分野において通常用いられるものであれば特に限定されないが、例えば、ポリエチレン、ポリプロピレン、ポリブタジエン、エチレン酢酸ビニル共重合体、ポリ塩化ビニル、ポリエステル(ポリエチレンテレフタレートなど)、ナイロン、ポリウレタンなどの合成樹脂フィルムもしくはシートまたはこれらの積層体、多孔質体、発泡体、フィルムにアルミニウムを蒸着させたもの、紙、織布、不織布などが挙げられる。<Support>
As the support in the transdermal absorption patch of the present invention, a drug-impermeable, stretchable or non-stretchable support can be used. Such a support is not particularly limited as long as it is usually used in the field of pharmaceuticals. For example, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), Examples thereof include synthetic resin films or sheets such as nylon and polyurethane, laminates thereof, porous bodies, foams, films obtained by vapor-depositing aluminum, paper, woven fabrics, and nonwoven fabrics.
<剥離ライナー>
本発明の経皮吸収型貼付剤は、剥離ライナーをさらに有してもよい。この場合、剥離ライナーは、支持体上に積層された薬物含有層の、支持体に接する面と反対側の面上に積層され、経皮吸収型貼付剤を皮膚に適用するまで薬物含有層を保護することができる。剥離ライナーは、少なくとも薬物含有層中のソリフェナシンについて不透過性であれば特に限定されないが、例えば、ポリエチレン、ポリプロピレン、ポリエステル、ポリエチレンテレフタレートなどの高分子材料で作られたフィルム、フィルムにアルミニウムを蒸着させたもの、紙の上にシリコーンオイルなどを塗付したものなどが挙げられる。<Release liner>
The transdermal absorption patch of the present invention may further have a release liner. In this case, the release liner is laminated on the surface of the drug-containing layer laminated on the support opposite to the surface in contact with the support, and the drug-containing layer is applied until the transdermal absorption patch is applied to the skin. Can be protected. The release liner is not particularly limited as long as it is impervious to at least solifenacin in the drug-containing layer. For example, a film made of a polymer material such as polyethylene, polypropylene, polyester, polyethylene terephthalate, and aluminum is deposited on the film. And those obtained by applying silicone oil or the like on paper.
<経皮吸収型貼付剤の製造>
本発明の経皮吸収型貼付剤は、公知の方法に従って製造することができる。ソリフェナシンの薬学的に許容される塩、無機塩基、ならびに必要に応じて上記任意成分を含む混合物を調製し、この混合物を剥離ライナー上に塗布(展延)して薬物含有層を形成し、この薬物含有層に支持体を貼り合わせることにより製造することができる。<Manufacture of transdermal patches>
The transdermal patch of the present invention can be produced according to a known method. A mixture containing a pharmaceutically acceptable salt of solifenacin, an inorganic base, and, if necessary, the above optional components is prepared, and this mixture is applied (spread) onto a release liner to form a drug-containing layer. It can be produced by attaching a support to the drug-containing layer.
具体的には、例えば、ソリフェナシンの薬学的に許容される塩、無機塩基、ならびに必要に応じて粘着剤、粘着付与剤、可塑剤、吸収促進剤、および/または他の添加剤を、前記含有量となるように有機溶媒に加え、混合撹拌して塗工液を調製する。混合方法としては、例えば撹拌、インラインミキシング、超音波処理等を用いることができる。有機溶媒としては、酢酸エチル、ヘキサン、ペンタン、トルエン、シクロヘキサン、クロロホルム、塩化メチレン、メタノール、エタノール、イソプロピルアルコール、メチルエチルケトン、シクロヘキサノン、アセトン、それらの混合溶媒などを用いることができる。塗工液中の有機溶媒の含有量は、特に限定されず、例えば、塗工液全体に対して30〜90質量%、好ましくは40〜80質量%である。 Specifically, for example, a pharmaceutically acceptable salt of solifenacin, an inorganic base, and, if necessary, a pressure-sensitive adhesive, a tackifier, a plasticizer, an absorption enhancer, and / or other additives, It adds to an organic solvent so that it may become quantity, and mixes and stirs and prepares a coating liquid. As a mixing method, for example, stirring, in-line mixing, ultrasonic treatment, or the like can be used. As the organic solvent, ethyl acetate, hexane, pentane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used. Content of the organic solvent in a coating liquid is not specifically limited, For example, it is 30-90 mass% with respect to the whole coating liquid, Preferably it is 40-80 mass%.
次に、この塗工液を剥離ライナー上に展延し、当該塗工液中の溶媒を蒸発させて薬物含有層を形成した後、支持体を貼り合わせることによって経皮吸収型貼付剤を得ることができる。または、塗工液を支持体上に展延し、当該塗工液中の溶媒を蒸発させて薬物含有層を形成した後、剥離ライナーを貼り合わせることによって経皮吸収型貼付剤を得ることもできる。製造容易かどうかの観点からは、塗工液を剥離ライナー上に展延し、当該塗工液中の溶媒を蒸発させて薬物含有層を形成した後、支持体を貼り合わせる方法が好ましい。塗工液の塗布は、ナイフコーター、コンマコーター、リバースコーター、ダイコーターを用いて行うことができる。製造フローの一例を図1に示すが、これに限定されない。 Next, this coating liquid is spread on a release liner, and after evaporating the solvent in the coating liquid to form a drug-containing layer, a support is attached to obtain a transdermal absorption type patch. be able to. Alternatively, a transdermal absorption patch can be obtained by spreading the coating liquid on a support, evaporating the solvent in the coating liquid to form a drug-containing layer, and then bonding a release liner. it can. From the viewpoint of ease of production, a method of spreading a coating solution on a release liner, evaporating the solvent in the coating solution to form a drug-containing layer, and then laminating the support is preferable. The coating solution can be applied using a knife coater, comma coater, reverse coater, or die coater. Although an example of a manufacturing flow is shown in FIG. 1, it is not limited to this.
また本発明の経皮吸収型貼付剤は、ソリフェナシンの薬学的に許容される塩、無機塩基、ならびに必要に応じその他の任意成分を、加熱溶融させ、この溶融物を剥離ライナー上に塗布(展延)し、薬物含有層を形成した後、支持体を貼り合わせることによって経皮吸収型貼付剤を製造することもできる。溶融物を支持体上に塗布(展延)し、薬物含有層を形成した後、剥離ライナーを貼り合わせることによって経皮吸収型貼付剤を製造してもよい。 In the transdermal patch of the present invention, a pharmaceutically acceptable salt of solifenacin, an inorganic base, and other optional components as necessary are heated and melted, and this melt is applied onto a release liner. And after the drug-containing layer is formed, the transdermal patch can be produced by pasting the support. A transdermal patch may be produced by applying (spreading) a melt on a support to form a drug-containing layer and then bonding a release liner.
<投与方法>
本発明の経皮吸収型貼付剤による過活動膀胱の治療は、本発明の経皮吸収型貼付剤を対象の皮膚に直接貼付して、ソリフェナシンを経皮投与することによって行うことができる。本発明における対象は、ヒトなどの哺乳動物であり、好ましくはヒトである。特に、過活動膀胱の治療は、過活動膀胱の治療を要する患者の皮膚に当該貼付剤を適用(貼付)することにより実施できる。<Administration method>
Treatment of overactive bladder with the transdermal absorption patch of the present invention can be performed by directly applying the transdermal absorption patch of the present invention to the target skin and administering solifenacin transdermally. The subject in the present invention is a mammal such as a human, preferably a human. In particular, treatment of overactive bladder can be performed by applying (applying) the patch to the skin of a patient requiring treatment of overactive bladder.
本発明の経皮吸収型貼付剤によりソリフェナシンを経皮投与する場合、過活動膀胱の治療に有効な血中濃度を達成するように、薬物含有層中のソリフェナシンの含有量および/または皮膚透過速度、ならびに薬物含有層の面積および/または薬物含有層の厚さを適宜調整した上で、本発明の経皮吸収型貼付剤を皮膚に貼付する。 When transdermally administering solifenacin with the transdermal absorption patch of the present invention, the content of solifenacin in the drug-containing layer and / or the skin permeation rate so as to achieve a blood concentration effective for treatment of overactive bladder Then, after appropriately adjusting the area of the drug-containing layer and / or the thickness of the drug-containing layer, the transdermal patch of the present invention is applied to the skin.
本発明の経皮吸収型貼付剤は、貼付可能であれば身体のいずれの部位の皮膚に適用してもよく、例えば、上腕部、腹部、胸部、頸部、腰背部、臀部または脚部などに貼付することができる。 The transdermal absorption patch of the present invention may be applied to the skin of any part of the body as long as it can be applied. For example, the upper arm, abdomen, chest, neck, waist back, buttocks or legs Can be affixed to.
本発明の経皮吸収型貼付剤の対象への経皮投与は、必要に応じて、ソリフェナシンの薬学的に許容される塩以外の医薬成分を含有する医薬組成物の投与と組み合わせてもよい。この場合、投与形態は、同時投与であっても、時間差をおいての投与であってもよく、当該医薬組成物は、静脈内、腹腔内、皮下および筋肉内、経口、局所または経粘膜を含む種々の経路により投与できる。またソリフェナシンの薬学的に許容される塩以外の医薬成分を含有する医薬組成物は、当該医薬成分について通常用いられる投与経路によって対象に投与される。ソリフェナシンの薬学的に許容される塩以外の医薬成分としては、α1アドレナリン受容体拮抗薬、β3アドレナリン受容体作動薬などが挙げられるが、これらに限定されない。 Transdermal administration to the subject of the transdermal patch of the present invention may be combined with administration of a pharmaceutical composition containing a pharmaceutical ingredient other than the pharmaceutically acceptable salt of solifenacin as necessary. In this case, the administration form may be simultaneous administration or administration with a time difference, and the pharmaceutical composition may be intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. It can be administered by various routes including: In addition, a pharmaceutical composition containing a pharmaceutical ingredient other than a pharmaceutically acceptable salt of solifenacin is administered to a subject by an administration route usually used for the pharmaceutical ingredient. Pharmaceutical components other than pharmaceutically acceptable salts of solifenacin include, but are not limited to, α1 adrenergic receptor antagonists, β3 adrenergic receptor agonists, and the like.
以下、実施例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。また各実施例において、%は、特に断りがない限りは全て質量%である。 EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to a following example. Moreover, in each Example,% is mass% unless there is particular notice.
(ソリフェナシンコハク酸塩含有経皮吸収型貼付剤の製造)
実施例1
・ゴム系樹脂組成物(1)の調製
スチレン−イソプレン−スチレンブロック共重合体(クインタック3570C、日本ゼオン社製)、脂環族飽和炭化水素樹脂(アルコンP−100、荒川化学工業社製)、流動パラフィン(ハイコールM−352、カネダ社製)を以下に示す組成;
スチレン−イソプレン−スチレンブロック共重合体 35.0%
脂環族飽和炭化水素樹脂 50.0%
流動パラフィン 15.0%
を固形分濃度が50%となるようにトルエンに溶解し、ゴム系樹脂組成物(1)を得た。(Manufacture of a solifenacin succinate-containing transdermal patch)
Example 1
-Preparation of rubber-based resin composition (1) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries) , Liquid paraffin (Hicoll M-352, manufactured by Kaneda Co.) has the following composition;
Styrene-isoprene-styrene block copolymer 35.0%
Alicyclic saturated hydrocarbon resin 50.0%
Liquid paraffin 15.0%
Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (1).
・経皮吸収型貼付剤の製造
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)を添加し、均一に撹拌した。これに水酸化カリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 75.5%
水酸化カリウム 4.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製した。-Manufacture of transdermal absorption patch The rubber-type resin composition (1) was added to the solifenacin succinate weighed beforehand, and it stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below;
Rubber resin composition (1) 75.5%
Potassium hydroxide 4.5%
Solifenacin succinate 20.0%
A coating solution having
次に、得られた塗工液をポリエチレンテレフタレート製剥離フィルム(フィルムバイナ75E−0010 BD、藤森工業社製)上に、溶媒留去後の厚さが約50μmになるように塗布し、乾燥させた後、支持体として25μmのポリエステルフィルム(ルミラーT−60、東レ社製)を貼り合わせ、経皮吸収型貼付剤を得た。 Next, the obtained coating solution was applied onto a polyethylene terephthalate release film (Film Binner 75E-0010 BD, manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent was about 50 μm and dried. Then, a 25 μm polyester film (Lumirror T-60, manufactured by Toray Industries, Inc.) was bonded as a support to obtain a transdermal absorption patch.
実施例2
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これに水酸化カリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 65.5%
ミリスチン酸イソプロピル 10.0%
水酸化カリウム 4.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Example 2
The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below;
Rubber resin composition (1) 65.5%
Isopropyl myristate 10.0%
Potassium hydroxide 4.5%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例3
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌する。これに水酸化ナトリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 66.8%
ミリスチン酸イソプロピル 10.0%
水酸化ナトリウム 3.2%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Example 3
The rubber-based resin composition (1) and isopropyl myristate are added to the solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of sodium hydroxide and stirred, the composition shown below:
Rubber resin composition (1) 66.8%
Isopropyl myristate 10.0%
Sodium hydroxide 3.2%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
比較例1
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌して以下に示す組成;
ゴム系樹脂組成物(1) 70.0%
ミリスチン酸イソプロピル 10.0%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Comparative Example 1
A rubber-based resin composition (1) and isopropyl myristate are added to solifenacin succinate weighed in advance, and the mixture is stirred uniformly and shown below;
Rubber-based resin composition (1) 70.0%
Isopropyl myristate 10.0%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
試験例1 原薬の安定性試験
ソリフェナシンコハク酸塩、ソリフェナシンフリー体をそれぞれ褐色スクリューバイアルに入れ、60℃にて保存した。経時でサンプリングしたソリフェナシンコハク酸塩、ソリフェナシンフリー体を、それぞれpH3.5リン酸緩衝液/アセトニトリル混液に溶解し、HPLC法により分析を行った。サンプル中のソリフェナシンと分解生成物のピーク面積から、次式により分解生成物量(%)を算出した。得られた結果を表1に示す。Test Example 1 Drug substance stability test Solifenacin succinate and solifenacin free body were each placed in a brown screw vial and stored at 60 ° C. The solifenacin succinate sampled over time and the solifenacin free form were each dissolved in a pH 3.5 phosphate buffer / acetonitrile mixture and analyzed by the HPLC method. From the peak area of solifenacin and the decomposition product in the sample, the amount (%) of the decomposition product was calculated by the following formula. The obtained results are shown in Table 1.
分解生成物量(%)=
(分解生成物のピーク面積)/(ソリフェナシンのピーク面積)×100
<HPLC条件>
HPLCシステム:ACQUITY UPLC H−Classシステム(Waters社製)
カラム:Inertsil ODS−3(2μm、2.1×100mm、GLサイエンス社製)
カラムオーブン:40℃付近の一定温度
移動相:pH3.5リン酸緩衝液/アセトニトリル混液
流量:0.5mL/min
測定波長:210nmDecomposition product amount (%) =
(Peak area of decomposition product) / (Peak area of solifenacin) × 100
<HPLC conditions>
HPLC system: ACQUITY UPLC H-Class system (Waters)
Column: Inertsil ODS-3 (2 μm, 2.1 × 100 mm, manufactured by GL Science)
Column oven: constant temperature around 40 ° C. Mobile phase: pH 3.5 phosphate buffer / acetonitrile mixture Flow rate: 0.5 mL / min
Measurement wavelength: 210 nm
表1から明らかなように、ソリフェナシンコハク酸塩では経時で分解しないのに対して、ソリフェナシンフリー体は経時で分解生成物が増加した。 As is apparent from Table 1, solifenacin succinate did not decompose over time, whereas solifenacin free body increased the degradation products over time.
実施例4
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これに水酸化カリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 77.7%
ミリスチン酸イソプロピル 10.0%
水酸化カリウム 2.3%
ソリフェナシンコハク酸塩 10.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Example 4
The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below;
Rubber resin composition (1) 77.7%
Isopropyl myristate 10.0%
Potassium hydroxide 2.3%
Solifenacin succinate 10.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例5
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これに水酸化ナトリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 78.4%
ミリスチン酸イソプロピル 10.0%
水酸化ナトリウム 1.6%
ソリフェナシンコハク酸塩 10.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Example 5
The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of sodium hydroxide and stirred, the composition shown below:
Rubber-based resin composition (1) 78.4%
Isopropyl myristate 10.0%
Sodium hydroxide 1.6%
Solifenacin succinate 10.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例6
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、プロピレングリコール(SR Propylene Glychol、クローダ社製)を添加し、均一に撹拌した。これに水酸化カリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 65.5%
プロピレングリコール 10.0%
水酸化カリウム 4.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Example 6
The rubber-based resin composition (1) and propylene glycol (SR Propylene Glychol, manufactured by Croda) were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below;
Rubber resin composition (1) 65.5%
Propylene glycol 10.0%
Potassium hydroxide 4.5%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例7
・ゴム系樹脂組成物(2)の調製
スチレン−イソプレン−スチレンブロック共重合体(クインタック3570C、日本ゼオン社製)、水素添加ロジングリセリンエステル(パインクリスタル KE−311、荒川化学工業社製)、流動パラフィン(ハイコールM−352、カネダ社製)を以下に示す組成;
スチレン−イソプレン−スチレンブロック共重合体 35.0%
水素添加ロジングリセリンエステル 50.0%
流動パラフィン 15.0%
を固形分濃度が50%となるようにトルエンに溶解し、ゴム系樹脂組成物(2)を得た。Example 7
-Preparation of rubber-based resin composition (2) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon Co., Ltd.), hydrogenated rosin glycerin ester (Pine Crystal KE-311, manufactured by Arakawa Chemical Industries), Liquid paraffin (Hicoll M-352, manufactured by Kaneda Co.) has the following composition:
Styrene-isoprene-styrene block copolymer 35.0%
Hydrogenated rosin glycerin ester 50.0%
Liquid paraffin 15.0%
Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (2).
・経皮吸収型貼付剤の製造
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(2)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これに水酸化カリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(2) 65.5%
ミリスチン酸イソプロピル 10.0%
水酸化カリウム 4.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。-Production of transdermal patch The rubber-based resin composition (2) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below;
Rubber resin composition (2) 65.5%
Isopropyl myristate 10.0%
Potassium hydroxide 4.5%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例8
あらかじめ秤量したソリフェナシンコハク酸塩にアクリル系樹脂(Duro−Tak 387−2287、ヘンケル社製)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これに水酸化カリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
アクリル樹脂(Duro−Tak 387−2287) 65.5%
ミリスチン酸イソプロピル 10.0%
水酸化カリウム 4.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Example 8
Acrylic resin (Duro-Tak 387-2287, manufactured by Henkel) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added ethanol solution of potassium hydroxide and stirred, the composition shown below;
Acrylic resin (Duro-Tak 387-2287) 65.5%
Isopropyl myristate 10.0%
Potassium hydroxide 4.5%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
比較例2
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)を添加し、均一に撹拌した。これにジイソプロパノールアミンのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 69.5%
ジイソプロパノールアミン 10.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Comparative Example 2
The rubber-based resin composition (1) was added to solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of diisopropanolamine and stirred, the composition shown below:
Rubber-based resin composition (1) 69.5%
Diisopropanolamine 10.5%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
比較例3
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これにジイソプロパノールアミンのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(1) 59.5%
ミリスチン酸イソプロピル 10.0%
ジイソプロパノールアミン 10.5%
ソリフェナシンコハク酸塩 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Comparative Example 3
The rubber-based resin composition (1) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of diisopropanolamine and stirred, the composition shown below;
Rubber resin composition (1) 59.5%
Isopropyl myristate 10.0%
Diisopropanolamine 10.5%
Solifenacin succinate 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
比較例4
あらかじめ秤量したソリフェナシンフリー体にゴム系樹脂組成物(1)、ミリスチン酸イソプロピルを添加し、均一に撹拌して以下に示す組成;
ゴム系樹脂組成物(1) 70.0%
ミリスチン酸イソプロピル 10.0%
ソリフェナシンフリー体 20.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。Comparative Example 4
A rubber-based resin composition (1) and isopropyl myristate are added to a pre-weighed solifenacin-free body, and the mixture is stirred uniformly and shown below:
Rubber-based resin composition (1) 70.0%
Isopropyl myristate 10.0%
Solifenacin free body 20.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
試験例2 インビトロ(in vitro)皮膚透過性試験
得られた経皮吸収型貼付剤を用いて、以下の手順に従ってインビトロ皮膚透過性試験を行った。Test Example 2 In vitro skin permeability test Using the obtained transdermal absorption patch, an in vitro skin permeability test was performed according to the following procedure.
7週齢の雄性ヘアレスマウス摘出皮膚(Hos:HR−1系、星野実験動物飼育所社製)の角層側に各実施例及び比較例の経皮吸収型貼付剤をそれぞれ貼付した後、32℃の温水を外周部に循環させた縦型拡散セル(商品名:パームセル縦型TP−6:ビードレックス社製)に、皮膚基底膜がレシーバー側となるように装着した。レシーバーセルに、リン酸緩衝生理食塩水(PBS(−)、和光純薬工業社製)を満たし、経時的にレシーバー液をサンプリングし、HPLC法によりレシーバー液中のソリフェナシン量を測定した。測定結果より試験開始後24時間でのソリフェナシンの累積透過量を算出し、透過速度を算出した(n=3の平均値)。得られた結果を表2及び表3に示す。
After affixing the transdermal patches of each Example and Comparative Example to the horny layer side of 7-week-old male hairless mouse isolated skin (Hos: HR-1 system, manufactured by Hoshino Laboratory Animal Breeding Co., Ltd.), 32 The skin basement membrane was attached to the receiver side in a vertical diffusion cell (trade name: Palm Cell Vertical TP-6: manufactured by Beadrex Co., Ltd.) in which warm water of 0 ° C. was circulated around the outer periphery. The receiver cell was filled with phosphate buffered saline (PBS (-), manufactured by Wako Pure Chemical Industries, Ltd.), the receiver solution was sampled over time, and the amount of solifenacin in the receiver solution was measured by HPLC. From the measurement results, the cumulative permeation amount of
試験例3 安定性試験
各実施例及び比較例で作製した経皮吸収型貼付剤を、アルミ箔をベースとした複合フィルム(PET 12μm/PE 15μm/Al 9μm/PE 30μm)の袋にヒートシールで密封して60℃に保存した。Test Example 3 Stability test The transdermal patch prepared in each Example and Comparative Example was heat sealed on a bag of composite film (
60℃で4週間保存した後の経皮吸収型貼付剤を、剥離ライナーを剥がして、テトラヒドロフラン2mLで30分間振とう抽出した。この液にpH3.5リン酸緩衝液/アセトニトリル混液8mL加えた後、0.2μmのメンブランフィルターでろ過し、HPLC法により分析を行った。サンプル中のソリフェナシンと分解生成物のピーク面積から、次式により分解生成物量(%)を算出した。得られた結果を表2及び表3に示す。 The transdermal patch after storage at 60 ° C. for 4 weeks was peeled off the release liner and extracted with 2 mL of tetrahydrofuran for 30 minutes. After adding 8 mL of a pH 3.5 phosphate buffer / acetonitrile mixture to this solution, the solution was filtered through a 0.2 μm membrane filter and analyzed by the HPLC method. From the peak area of solifenacin and the decomposition product in the sample, the amount (%) of the decomposition product was calculated by the following formula. The obtained results are shown in Tables 2 and 3.
分解生成物量(%)=
(分解生成物のピーク面積)/(ソリフェナシンのピーク面積)×100Decomposition product amount (%) =
(Peak area of decomposition product) / (Peak area of solifenacin) × 100
試験例2の結果、表2から明らかなように、有効成分としてソリフェナシンコハク酸塩を使用し、無機塩基を添加した場合、十分な皮膚透過性が得られた。一方、表3より、無機塩基を添加しない比較例1では非常に低い透過性となった。有効成分としてソリフェナシンの薬学的に許容される塩を使用する場合、塩基の添加が皮膚透過性向上に効果が高かった。 As is clear from Table 2 as a result of Test Example 2, when solifenacin succinate was used as an active ingredient and an inorganic base was added, sufficient skin permeability was obtained. On the other hand, as shown in Table 3, Comparative Example 1 in which no inorganic base was added exhibited very low permeability. When a pharmaceutically acceptable salt of solifenacin was used as an active ingredient, the addition of a base was highly effective in improving skin permeability.
製剤中の分解生成物量は0.5%以下が好ましいとされるところ、試験例3の結果、表2および3から明らかなように、塩基として無機塩基を使用した実施例1〜8の製剤については、60℃4週間の苛酷条件においても、分解物生成物量が0.5%以下であり、十分な経時安定性と皮膚透過性を有していた。 The amount of decomposition products in the preparation is preferably 0.5% or less. As is apparent from Tables 2 and 3 as a result of Test Example 3, the preparations of Examples 1 to 8 using an inorganic base as the base were used. Even under severe conditions at 60 ° C. for 4 weeks, the amount of decomposed product was 0.5% or less, and it had sufficient aging stability and skin permeability.
一方、表3より、塩基として有機アミンを使用した比較例2および3では、60℃4週間で1%を超える分解生成物が認められ、無機塩基を使用した実施例1〜8に比べ、著しく安定性が低くなった。また、有効成分としてソリフェナシンフリー体を使用した比較例4については、フリー体自体の安定性が低いことに起因して、製剤中の分解生成物量が0.5%を超える結果となった。 On the other hand, from Table 3, in Comparative Examples 2 and 3 using an organic amine as a base, a decomposition product exceeding 1% was observed at 60 ° C. for 4 weeks, which was significantly higher than those in Examples 1 to 8 using an inorganic base. Stability was lowered. Moreover, about the comparative example 4 which uses a solifenacin free body as an active ingredient, it resulted from the decomposition product amount exceeding 0.5% resulting from low stability of free body itself.
実施例9〜15
実施例2のミリスチン酸イソプロピルを表4に示したエステル類に置き換えた以外は、実施例2と同様にして経皮吸収型貼付剤を得た。Examples 9-15
A transdermal patch was obtained in the same manner as in Example 2 except that the isopropyl myristate in Example 2 was replaced with the esters shown in Table 4.
表4において、実施例9〜15の各経皮吸収型貼付剤の皮膚透過速度および分解生成物量は、試験例2及び3と同様にして算出した。また、実施例2および9〜15の各貼付剤の経皮吸収促進効果を、促進比として以下の式より算出した。 In Table 4, the skin permeation rate and the amount of degradation products of each of the transdermal patches of Examples 9 to 15 were calculated in the same manner as in Test Examples 2 and 3. Moreover, the percutaneous absorption promotion effect of each patch of Example 2 and 9-15 was calculated from the following formula as an acceleration ratio.
促進比=
(実施例2及び9〜15のそれぞれの皮膚透過速度)÷(実施例1の皮膚透過速度)
実施例2及び9〜15の各貼付剤はいずれも、分解生成物量が0.07%以下であり充分な経時安定性を有すると共に、実施例1の貼付剤に比べて1.2〜1.7倍の経皮吸収促進効果を示した。Promotion ratio =
(Each skin permeation rate of Examples 2 and 9 to 15) / (Skin permeation rate of Example 1)
Each of the patches of Examples 2 and 9 to 15 has a decomposition product amount of 0.07% or less and has sufficient temporal stability, and is 1.2 to 1 compared to the patch of Example 1. The effect of promoting transdermal absorption 7 times was shown.
実施例16
・ゴム系樹脂組成物(3)の調製
スチレン−イソプレン−スチレンブロック共重合体(クインタック3570C、日本ゼオン社製)、脂環族飽和炭化水素樹脂(アルコンP−100、荒川化学工業社製)、ポリブテン(ポリブテンHV−300、JX日鉱日石エネルギー社製)を以下に示す組成;
スチレン−イソプレン−スチレンブロック共重合体 30.0%
脂環族飽和炭化水素樹脂 50.0%
ポリブテン 20.0%
を固形分濃度が50%となるようにトルエンに溶解し、ゴム系樹脂組成物(3)を得た。Example 16
-Preparation of rubber-based resin composition (3) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries) Polybutene (polybutene HV-300, manufactured by JX Nippon Oil & Energy Corporation) has the following composition;
Styrene-isoprene-styrene block copolymer 30.0%
Alicyclic saturated hydrocarbon resin 50.0%
Polybutene 20.0%
Was dissolved in toluene so that the solid content concentration would be 50% to obtain a rubber-based resin composition (3).
・経皮吸収型貼付剤の製造
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(3)、ミリスチン酸イソプロピルを添加し、均一に撹拌した。これに水酸化ナトリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(3) 78.4%
ミリスチン酸イソプロピル 10.0%
水酸化ナトリウム 1.6%
ソリフェナシンコハク酸塩 10.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。-Manufacture of transdermal patch The rubber-based resin composition (3) and isopropyl myristate were added to solifenacin succinate weighed in advance and stirred uniformly. To this was added an ethanol solution of sodium hydroxide and stirred, the composition shown below:
Rubber resin composition (3) 78.4%
Isopropyl myristate 10.0%
Sodium hydroxide 1.6%
Solifenacin succinate 10.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例16で得られた経皮吸収型貼付剤を用いて、試験例2と同様にしてインビトロ皮膚透過性試験を行った。皮膚透過速度は、25.9μg/cm2/hであった。実施例16で得られた経皮吸収型貼付剤を用いて、試験例3と同様にして安定性試験を行った。分解生成物量は、0.20%(60℃4週)であった。Using the transdermal absorption patch obtained in Example 16, an in vitro skin permeability test was conducted in the same manner as in Test Example 2. The skin permeation rate was 25.9 μg / cm 2 / h. Using the transdermal absorption patch obtained in Example 16, a stability test was conducted in the same manner as in Test Example 3. The amount of decomposition products was 0.20% (60 ° C. for 4 weeks).
参考例1
現在臨床で使用されている、過活動膀胱治療用の「ネオキシ(登録商標)テープ」を使用した。Reference example 1
A “neoxy (registered trademark) tape” for the treatment of overactive bladder, which is currently in clinical use, was used.
試験例4 モルモット皮膚一次刺激性試験
6週齢のHartley雄性モルモットを用いた。投与前日にモルモットの左右側胴部を約4×8cmの大きさに刈毛・剃毛する。刈毛翌日、実施例2、実施例3、実施例5、実施例16、比較例4、および参考例1の貼付剤(15mmφ)を左右側胴部に貼付し、粘着剤付フォームパッドM(3Mヘルスケア社製)で固定し、ポリエチレンフィルムテープ(キープポアA、ニチバン社製)を胴体に巻いた後、シルキーテック(ALCARE、5号)で固定する。投与24時間後、各貼付剤を除去し、アセトンで湿らせた脱脂綿で貼付部位を清拭した。投与より24、48、および72時間後に皮膚反応を観察し、表5に示すDraizeの基準(1959年)を参考に皮膚刺激性指数(Primary irritation index:P.I.I.)を算出し、皮膚刺激性を評価した。但し、投与24時間後は、清拭約1時間後に観察を行った。被験物質ごとに、投与24、48および72時間後における固体別評点を算出し、観察回数(3回)で除して個体別P.I.I.(Individual P.I.I.)を算出した。Individual P.I.I.値を合計し、その平均値を経皮吸収型貼付剤のP.I.I.とした。Test Example 4 Guinea Pig Skin Primary Irritation Test A 6-week-old Hartley male guinea pig was used. On the day before administration, the left and right torso parts of the guinea pig are shaved and shaved to a size of about 4 × 8 cm. On the next day of hair cutting, the patches (15 mmφ) of Example 2, Example 3, Example 5, Example 16, Comparative Example 4, and Reference Example 1 were applied to the left and right body parts, and the foam pad M with adhesive ( 3M Healthcare Co., Ltd.) and a polyethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.) is wound around the body and then fixed with Silky Tech (ALCARE No. 5). 24 hours after administration, each patch was removed, and the applied site was wiped with absorbent cotton moistened with acetone. The skin reaction was observed 24, 48, and 72 hours after the administration, and a skin irritation index (PI) was calculated with reference to the Draize criteria (1959) shown in Table 5. Skin irritation was evaluated. However, 24 hours after administration, observation was performed about 1 hour after wiping. For each test substance, a score by individual at 24, 48 and 72 hours after administration was calculated and divided by the number of observations (three times). I. I. (Individual PI) was calculated. Individual P.M. I. I. Values were summed, and the average value was calculated as P.P. I. I. It was.
結果を表6に示す。なお、刺激性の評価は、P.I.Iが0の場合「無刺激物」、0より大きく2未満の場合「軽度刺激物」、2以上5未満の場合「中等度刺激物」、5以上のときは「強度刺激物」とした。評価に際して統計処理は実施しなかった。 The results are shown in Table 6. The evaluation of irritation is based on P.I. I. When I was 0, it was designated as “non-irritant”, when it was greater than 0 and less than 2, “mildly irritant”, when 2 or more and less than 5, “moderately irritant”, and when 5 or more, “strongly irritant”. Statistical processing was not performed during the evaluation.
表6から明らかなとおり、実施例2、実施例3、実施例5および実施例16の経皮吸収型貼付剤は軽度刺激物であり、比較例4および参考例1の経皮吸収型貼付剤と比べて皮膚刺激性が低い。 As is apparent from Table 6, the transdermal patches of Example 2, Example 3, Example 5 and Example 16 are mildly irritants, and the transdermal patches of Comparative Example 4 and Reference Example 1 were used. Compared with skin irritation.
試験例5 インビボ(in vivo)皮膚透過性試験(ラット)
8週齢の雄性SD系ラット(チャールズリバー社製,n=5)の背部皮膚を電気バリカンで剪毛した。10cm2(3.16cm×3.16cm)の大きさに裁断した実施例16の経皮吸収型製剤(製剤1枚当たりのソリフェナシンコハク酸塩の含有量:約5mg/枚)をラットの背部に貼付し、メンバン(白十字社製)、Tegaderm Roll(スリーエムヘルスケア社製)、不織布粘着包帯(シルキーテック、ALCARE社製)を巻いて24時間投与した。貼付後、0.5、1、3、6、12、20、24、及び30時間(製剤除去後6時間)に、イソフルラン吸入麻酔下で鎖骨下静脈より採血(約0.3mL)し、遠心分離(4℃、2000G、15分)して血漿を得た。Test Example 5 In vivo skin permeability test (rat)
The back skin of 8-week-old male SD rats (Charles River, n = 5) was shaved with an electric clipper. The percutaneously absorbable preparation of Example 16 (content of solifenacin succinate per preparation: about 5 mg / sheet) cut into a size of 10 cm 2 (3.16 cm × 3.16 cm) on the back of the rat Affixed, wrapped in member (white cross), Tegaderm Roll (manufactured by 3M Healthcare), and non-woven adhesive bandage (silky tech, manufactured by ALCARE) and administered for 24 hours. After application, blood was collected from the subclavian vein under isoflurane inhalation anesthesia (approximately 0.3 mL) at 0.5, 1, 3, 6, 12, 20, 24, and 30 hours (6 hours after removal of the preparation) and centrifuged. Plasma was obtained after separation (4 ° C., 2000 G, 15 minutes).
また、比較としてソリフェナシンコハク酸塩を生理食塩水に溶解したものを静脈内投与した(n=4)。投与量はラット体重に対して、0.3及び1mg/kgとなるように投与液を調整し、投与液量は1mL/kgになるように投与した。投与後、1、3、5、10、15及び30分、1、2、3及び6時間に、イソフルラン吸入麻酔下で鎖骨下静脈より採血(約0.3mL)し、遠心分離(4℃、2000G、15分)して血漿を得た。 For comparison, solifenacin succinate dissolved in physiological saline was intravenously administered (n = 4). The administration solution was adjusted so that the dosage was 0.3 and 1 mg / kg relative to the body weight of the rat, and the administration solution was administered so that the dosage was 1 mL / kg. At 1, 3, 5, 10, 15 and 30 minutes, 1, 2, 3 and 6 hours after administration, blood was collected from the subclavian vein under isoflurane inhalation anesthesia (about 0.3 mL), and centrifuged (4 ° C., 2000 G, 15 minutes) to obtain plasma.
得られた血漿50μLにアセトニトリル150μLを加えて混和し、遠心分離(4℃、20000G、5分)して除タンパクを行い、孔径0.2μmのメンブランフィルター(メルクミリポア社製)でろ過し、LC/MS/MSを用いて各時間におけるソリフェナシンの血漿中濃度(ng/mL)を測定した。得られた結果を図2に示す。
<LC/MS/MS測定条件>
装置:ACQUITY UPLC H-Classシステム(Waters社製)
カラム:Acquity UPLC BEH C18 1.7μm 2.1×50mm(Waters社製)
カラム温度:40℃
流速:0.4mL/分
検出器:Xevo G2-S Q-Tof(Waters社製)
検出条件:Resolution・Positive、m/z=363.21
移動相:0.1%ギ酸水溶液と0.1%ギ酸-アセトニトリル溶液の混合液
サンプル注入量:1μL150 μL of acetonitrile is added to and mixed with 50 μL of the resulting plasma, centrifuged (4 ° C., 20000 G, 5 minutes) for protein removal, filtered through a 0.2 μm membrane filter (manufactured by Merck Millipore), LC The plasma concentration of solifenacin at each time (ng / mL) was measured using / MS / MS. The obtained results are shown in FIG.
<LC / MS / MS measurement conditions>
Equipment: ACQUITY UPLC H-Class system (Waters)
Column: Acquity UPLC BEH C18 1.7μm 2.1 x 50mm (Waters)
Column temperature: 40 ° C
Flow rate: 0.4mL / min Detector: Xevo G2-S Q-Tof (manufactured by Waters)
Detection condition: Resolution / Positive, m / z = 363.21
Mobile phase: 0.1% formic acid aqueous solution and 0.1% formic acid-acetonitrile solution mixture Sample injection volume: 1μL
図2より明らかなように、ソリフェナシンを静脈内投与した場合は、速やかに血漿中から消失しているのに対して、実施例16の経皮吸収型製剤をラットに貼付した場合、ソリフェナシンが持続的に経皮吸収されることで,貼付している24時間の間、一定以上の血漿中濃度が維持されることが確認された。 As is clear from FIG. 2, when solifenacin was administered intravenously, it disappeared rapidly from plasma, whereas when the percutaneous absorption preparation of Example 16 was applied to rats, solifenacin persisted. It was confirmed that the plasma concentration was maintained above a certain level for 24 hours after being applied.
実施例17
・ゴム系樹脂組成物(4)の調製
スチレン−イソプレン−スチレンブロック共重合体(クインタック3570C、日本ゼオン社製)、脂環族飽和炭化水素樹脂(アルコンP−100、荒川化学工業社製)、流動パラフィン(ハイコールM−352、カネダ社製)を以下に示す組成;
スチレン−イソプレン−スチレンブロック共重合体 30.0%
脂環族飽和炭化水素樹脂 50.0%
流動パラフィン 20.0%
を固形分濃度が50%となるようにトルエンに溶解し、ゴム系樹脂組成物(4)を得た。Example 17
-Preparation of rubber-based resin composition (4) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Nippon Zeon), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industries) , Liquid paraffin (Hicoll M-352, manufactured by Kaneda Co.) has the following composition;
Styrene-isoprene-styrene block copolymer 30.0%
Alicyclic saturated hydrocarbon resin 50.0%
Liquid paraffin 20.0%
Was dissolved in toluene so that the solid content concentration would be 50% to obtain a rubber-based resin composition (4).
・経皮吸収型貼付剤の製造
あらかじめ秤量したソリフェナシンコハク酸塩にゴム系樹脂組成物(4)、ミリスチン酸イソプロピル、ジブチルヒドロキシトルエン(東京化成工業社製)を添加し、均一に撹拌した。これに水酸化ナトリウムのエタノール溶液を加えて撹拌し、以下に示す組成;
ゴム系樹脂組成物(4) 77.4%
ミリスチン酸イソプロピル 10.0%
水酸化ナトリウム 1.6%
ソリフェナシンコハク酸塩 10.0%
ジブチルヒドロキシトルエン 1.0%
を有する塗工液を調製し、実施例1と同様に塗工して経皮吸収型貼付剤を得た。-Manufacture of a transdermal absorption type patch The rubber-type resin composition (4), isopropyl myristate, and dibutylhydroxytoluene (made by Tokyo Chemical Industry Co., Ltd.) were added to the solifenacin succinate weighed beforehand, and it stirred uniformly. To this was added an ethanol solution of sodium hydroxide and stirred, the composition shown below:
Rubber resin composition (4) 77.4%
Isopropyl myristate 10.0%
Sodium hydroxide 1.6%
Solifenacin succinate 10.0%
Dibutylhydroxytoluene 1.0%
A coating solution having the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal absorption patch.
実施例17で得られた経皮吸収型貼付剤を用いて、試験例2と同様にしてインビトロ皮膚透過性試験を行った。皮膚透過速度は、18.7μg/cm2/hであった。また、試験例3と同様にして安定性試験を行った結果、分解生成物量は、0.15%(60℃4週)であった。Using the transdermal absorption patch obtained in Example 17, an in vitro skin permeability test was conducted in the same manner as in Test Example 2. The skin permeation rate was 18.7 μg / cm 2 / h. Moreover, as a result of conducting a stability test in the same manner as in Test Example 3, the amount of the decomposition product was 0.15% (60 ° C., 4 weeks).
本発明によれば、経皮吸収性、保存安定性および安全性に優れたソリフェナシンの薬学的に許容される塩を含有する経皮吸収型貼付剤が提供される。本発明の経皮吸収型貼付剤は、過活動膀胱の治療をより効果的に行うことが可能である。 According to the present invention, a transdermal patch containing a pharmaceutically acceptable salt of solifenacin excellent in transdermal absorbability, storage stability and safety is provided. The transdermal patch of the present invention can more effectively treat overactive bladder.
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JPH02174716A (en) * | 1988-09-05 | 1990-07-06 | Takeda Chem Ind Ltd | Percutaneous preparation |
WO2005077364A1 (en) * | 2004-02-18 | 2005-08-25 | Yamanouchi Pharmaceutical Co., Ltd. | Transdermal solifenacin preparation and method of improving transdermal permeability thereof |
JP2009013171A (en) * | 2007-06-07 | 2009-01-22 | Hisamitsu Pharmaceut Co Inc | Memantine-containing transdermally absorbable preparation |
WO2009145177A1 (en) * | 2008-05-30 | 2009-12-03 | 日東電工株式会社 | Donepezil-containing patch preparation and packaging thereof |
WO2013081014A1 (en) * | 2011-11-28 | 2013-06-06 | 株式会社 ケイ・エム トランスダーム | Adhesive skin patch |
JP2015010066A (en) * | 2013-06-28 | 2015-01-19 | 久光製薬株式会社 | Method for producing patch, patch and package |
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JPH02174716A (en) * | 1988-09-05 | 1990-07-06 | Takeda Chem Ind Ltd | Percutaneous preparation |
WO2005077364A1 (en) * | 2004-02-18 | 2005-08-25 | Yamanouchi Pharmaceutical Co., Ltd. | Transdermal solifenacin preparation and method of improving transdermal permeability thereof |
JP2009013171A (en) * | 2007-06-07 | 2009-01-22 | Hisamitsu Pharmaceut Co Inc | Memantine-containing transdermally absorbable preparation |
WO2009145177A1 (en) * | 2008-05-30 | 2009-12-03 | 日東電工株式会社 | Donepezil-containing patch preparation and packaging thereof |
WO2013081014A1 (en) * | 2011-11-28 | 2013-06-06 | 株式会社 ケイ・エム トランスダーム | Adhesive skin patch |
JP2015010066A (en) * | 2013-06-28 | 2015-01-19 | 久光製薬株式会社 | Method for producing patch, patch and package |
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