JP2006169238A - Medicament-containing patch - Google Patents
Medicament-containing patch Download PDFInfo
- Publication number
- JP2006169238A JP2006169238A JP2005334012A JP2005334012A JP2006169238A JP 2006169238 A JP2006169238 A JP 2006169238A JP 2005334012 A JP2005334012 A JP 2005334012A JP 2005334012 A JP2005334012 A JP 2005334012A JP 2006169238 A JP2006169238 A JP 2006169238A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- melting point
- acid
- patch
- risperidone
- 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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- 230000008018 melting Effects 0.000 claims abstract description 78
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- 229960001534 risperidone Drugs 0.000 claims description 58
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- 229920001577 copolymer Polymers 0.000 claims description 15
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Abstract
Description
本発明は、薬物を含有する外用貼付剤に関する。 The present invention relates to an external patch containing a drug.
リスペリドンは、ヤンセン・ファーマ社（ベルギー）によって開発されたベンゾイソキサゾール誘導体化合物である（特許文献１参照）。その薬理作用としては、抗ドパミン作用、抗セロトニン作用、カタレプシー惹起作用が確認されており、現在では統合失調症治療薬として広く臨床の場において用いられているほか、過食症の治療や敏感肌の処理のための化粧品組成物への使用などが提案されてきた（特許文献２および３参照）。
リスペリドンの統合失調症に対する効果は、主としてドパミンＤ２受容体拮抗作用及びセロトニン５−ＨＴ２受容体拮抗作用に基づく中枢神経系の調節によるものと考えられている。また、リスペリドンは、幻覚、妄想などの陽性症状に対する優れた効果とともに、感情的引きこもり、情動鈍麻などの陰性症状に対しても強い効果を示す一方で、従来の定型抗精神病薬に比べて錐体外路系の副作用（ふるえ、こわばり等）が比較的少ないという特徴を有することから、患者のＱＯＬ（生活の質）を著しく改善し得る極めて有用な統合失調症治療薬であると考えられている。
Risperidone is a benzisoxazole derivative compound developed by Janssen Pharma (Belgium) (see Patent Document 1). As its pharmacological action, it has been confirmed to have anti-dopamine action, anti-serotonin action, and catalepsy-inducing action, and is now widely used in clinical settings as a schizophrenia treatment, as well as treating bulimia and sensitive skin. Use in cosmetic compositions for treatment has been proposed (see Patent Documents 2 and 3).
The effect of risperidone on schizophrenia is thought to be mainly due to the regulation of the central nervous system based on dopamine D 2 receptor antagonism and serotonin 5-HT 2 receptor antagonism. Risperidone has a positive effect on positive symptoms such as hallucinations and delusions, as well as a strong effect on negative symptoms such as emotional withdrawal and emotional dullness. It is considered to be an extremely useful schizophrenia drug that can significantly improve the quality of life (QOL) of patients because it has the characteristic of relatively few side effects (trembling, stiffness, etc.) of the extracorporeal system. .
リスペリドンの投与法としては、従来から、錠剤や細粒剤、内服液剤等を使用する経口投与法が用いられているものの、経口投与の場合、薬物が吸収された後、肝臓で初回通過効果を受けたり、投与後一時的に必要以上の血中濃度が認められたりする等の欠点があった。また経口投与においては、胃腸障害、嘔吐感、食欲不振等の副作用も多く報告されている。さらに、統合失調症患者においては、実際に、その約７５％は経口剤を規則的に服用することが困難であると言われている。したがって、このような経口投与の問題点を解消し、安全かつ持続的に患者が服用し易い製剤とすることを目的として、近年、貼付剤を用いて投与する方法が検討されてきた。貼付剤を用いる投与方法は、経口投与法による上記のような種々の問題を解消でき、また、投与回数の低減、コンプライアンスの向上、投与及び中止の容易さ等の利点を有することから、有用な投与法として期待されている。 Although risperidone has traditionally been administered orally using tablets, fine granules, internal liquids, etc., in the case of oral administration, the first-pass effect in the liver is obtained after the drug has been absorbed. There are drawbacks such as receiving blood pressure and temporarily observing blood concentration more than necessary after administration. In oral administration, many side effects such as gastrointestinal disorders, vomiting, and loss of appetite have been reported. Furthermore, in schizophrenic patients, it is actually said that about 75% of them are difficult to take oral preparations regularly. Therefore, in recent years, methods of administration using a patch have been studied for the purpose of eliminating such problems of oral administration and making the preparation safe and sustainable for patients to easily take. The administration method using the patch is useful because it can solve the above-mentioned various problems caused by the oral administration method, and has advantages such as reduction in the number of administrations, improvement in compliance, and ease of administration and discontinuation. Expected to be an administration method.
しかしながら、角質層はケラチン質を多く含む細胞と細胞間脂質とが層状に積層しているため、一般的に薬物の透過性が著しく低い上に、正常皮膚の角質層は異物の体内への侵入を防ぐバリアー機能を有しているため、従来の貼付剤の粘着剤層組成物中に単にリスペリドンを配合しただけでは、充分な経皮吸収性を有するリスペリドン含有貼付剤を得ることはできなかった。 However, since the stratum corneum is composed of cells containing a large amount of keratin and intercellular lipids, the drug permeability is generally extremely low, and the stratum corneum of normal skin penetrates foreign matter into the body. Because it has a barrier function to prevent risperidone, it has not been possible to obtain a risperidone-containing patch having sufficient transdermal absorbability simply by blending risperidone into the adhesive layer composition of a conventional patch. .
そこで、貼付剤を用いた経皮投与法におけるリスペリドンの経皮吸収性を高めるべく、脂肪酸類等の皮膚浸透促進剤やプロピレングリコールなどの溶媒をリスペリドンと共に含有させたパッチが提案されてきた（特許文献４参照）。しかし、これらの試みによってもなお、貼付剤中に配合されたリスペリドンの経皮吸収性は十分なものとはいえず、現実には、リスペリドンを含有する貼付剤は未だに市販されるには至っていない。したがって、治療に供することが可能な程度の優れた経皮吸収性ならびに持続性を備えた製剤の開発が望まれていた。 Therefore, in order to enhance the transdermal absorbability of risperidone in the transdermal administration method using a patch, a patch containing a skin penetration enhancer such as fatty acids and a solvent such as propylene glycol together with risperidone has been proposed (patent) Reference 4). However, even with these attempts, the transdermal absorbability of risperidone incorporated in the patch is not sufficient, and in reality, patches containing risperidone have not yet been marketed. . Therefore, it has been desired to develop a preparation having excellent transdermal absorbability and sustainability enough to be used for treatment.
一方、塩基性薬物を含有する経皮吸収型製剤において、塩基性薬物と共に有機酸塩や有機酸を配合することにより、塩基性薬物の皮膚透過性が向上することは既に提案され（特許文献５〜７参照）、これらの文献には、塩基性薬物として、催眠・鎮静剤、精神神経用剤等が例示されているが、実際に、患者の治療に供することができる程度の十分な経皮吸収性を持たせた有効な製剤として、薬物を含有する貼付剤を作製することができるかどうかを示唆するものではなかった。また、イオン性薬物と対イオンとなる物質とがイオン性液体を形成することにより、経皮吸収性を高めた外用剤についても既に提案されているものの（特許文献８参照）、イオン性薬物としてはインドメタシン、ジクロフェナクナトリウム、クロモグリク酸ナトリウム、塩酸トラマドール、ピロキシカムが例示されるに止まり、また、イオン性薬物としてインドメタシンまたはジクロフェナクナトリウムを使用し、対イオンとなる物質としてリドカインや塩酸リドカインを使用して調製したイオン性液体の融点が低下したことが開示されているものの、インドメタシンやジクロフェナクは酸性薬物であり、塩基性薬物の融点降下については具体的に開示されていない。また、イオン性薬物としてインドメタシンまたはジクロフェナクナトリウムを含有し、対イオンとなる物質としてリドカインや塩酸リドカインを配合した軟膏剤が開示されているが、かかる薬物のイオン性液体を含有する貼付剤が、十分な経皮吸収性と持続性とを備えたものとして実現可能かどうかについて何ら示唆するものではなかった。 On the other hand, in a percutaneous absorption preparation containing a basic drug, it has already been proposed that the skin permeability of the basic drug is improved by blending an organic acid salt or an organic acid with the basic drug (Patent Document 5). These references exemplify hypnotics / sedatives, psychiatric nerve agents, and the like as basic drugs, but sufficient transcutaneous enough to actually be used for treatment of patients. It did not suggest whether a patch containing a drug could be prepared as an effective preparation with absorbability. Moreover, although the external preparation which improved transdermal absorbability by forming the ionic liquid with the ionic drug and the substance serving as a counter ion has already been proposed (see Patent Document 8), Examples include indomethacin, diclofenac sodium, cromoglycate sodium, tramadol hydrochloride, and piroxicam. In addition, indomethacin or diclofenac sodium is used as an ionic drug, and lidocaine or lidocaine hydrochloride is used as a counter ion. However, indomethacin and diclofenac are acidic drugs, and the melting point lowering of basic drugs is not specifically disclosed. Further, an ointment containing indomethacin or diclofenac sodium as an ionic drug and lidocaine or lidocaine hydrochloride as a counter ion substance is disclosed, but a patch containing an ionic liquid of such a drug is sufficient. There was no suggestion as to whether it would be feasible as having good transdermal absorbability and sustainability.
したがって、本発明の課題は、製剤中の薬物の経皮吸収性が極めて良好であって、かつ、薬効の持続性に優れた薬物含有貼付剤、すなわち、患者の治療に実際に供することができる程度の十分な経皮吸収性および効果持続性を有する薬物含有貼付剤を提供することにある。 Therefore, the subject of the present invention is a drug-containing patch that has a very good transdermal absorbability of the drug in the preparation and is excellent in sustained drug efficacy, that is, can be actually used for treatment of patients. It is an object of the present invention to provide a drug-containing patch having sufficient transdermal absorbability and sustained effect.
本発明者らは、上記課題を解決すべく、リスペリドンを中心に薬物の経皮吸収性等の向上を目的に鋭意検討を行う中で、薬物と該薬物に対する融点降下剤とを粘着基剤に配合することにより、薬物の経皮吸収性および薬効持続性が飛躍的に向上することを初めて見出し、さらに研究を進めた結果、本発明を完成させるに至った。 In order to solve the above-mentioned problems, the present inventors have conducted intensive studies for the purpose of improving the transdermal absorbability of drugs centering on risperidone, and have used a drug and a melting point lowering agent for the drug as an adhesive base. For the first time, it has been found that the combination of the percutaneous absorbability and the sustained efficacy of the drug is drastically improved, and as a result of further research, the present invention has been completed.
すなわち、本発明は、薬物、融点降下剤、および粘着基剤を含有する貼付剤に関する。
また、本発明は、融点降下剤が薬物の融点を６０℃以上低下させることを特徴とする、前記貼付剤に関する。
さらに、本発明は、融点降下剤が、酢酸、プロピオン酸、酪酸、乳酸、安息香酸、およびサリチル酸、ならびにこれらの塩からなる群から選択される１種または２種以上である、前記貼付剤に関する。
またさらに、本発明は、融点降下剤が、酢酸および／または酢酸ナトリウムである、前記の貼付剤に関する。
また、本発明は、薬物が塩基性薬物である、前記貼付剤に関する。
本発明はまた、塩基性薬物が、オキシブチニン、フェンタニル、ペルゴリド、タンドスピロン、ドネペジル、タムスロシン、リスペリドン、フルラゼパム、ブトルファノール、ペリソキサール、プリジノール、トリヘキシフェニジル、アマンタジン、ツロブテロール、イソプレナリン、プロプラノロール、ケトチフェン、ジフェニドール、モルヒネ、メロキシカム、バルデコキシブおよびセレコキシブからなる群から選択される、前記の貼付剤に関する。
さらに、本発明は、塩基性薬物がリスペリドンである、前記貼付剤に関する。 またさらに、本発明は、粘着基剤が、スチレン−イソプレン−スチレンブロック共重合体および／またはアクリル酸エステル共重合体を含有する、前記の貼付剤に関する。
また、本発明は、吸収促進剤として、ラウリン酸ジエタノールアミド、カプリン酸、ミリスチン酸イソプロピル、およびモノラウリン酸プロピレングリコールからなる群から選択される１種以上をさらに含有する、前記の貼付剤に関する。
That is, the present invention relates to a patch containing a drug, a melting point lowering agent, and an adhesive base.
The present invention also relates to the above patch, wherein the melting point depressant lowers the melting point of the drug by 60 ° C. or more.
Furthermore, the present invention relates to the patch, wherein the melting point depressant is one or more selected from the group consisting of acetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, salicylic acid, and salts thereof. .
Furthermore, the present invention relates to the above-mentioned patch, wherein the melting point depressant is acetic acid and / or sodium acetate.
The present invention also relates to the patch, wherein the drug is a basic drug.
The present invention also provides that the basic drug is oxybutynin, fentanyl, pergolide, tandospirone, donepezil, tamsulosin, risperidone, flurazepam, butorphanol, perisoxal, pridinol, trihexyphenidyl, amantadine, tulobuterol, isoprenaline, propranolol, ketotidolol, diketoridol, , Said patch selected from the group consisting of meloxicam, valdecoxib and celecoxib.
Furthermore, the present invention relates to the patch, wherein the basic drug is risperidone. Furthermore, the present invention relates to the patch, wherein the adhesive base contains a styrene-isoprene-styrene block copolymer and / or an acrylate copolymer.
The present invention also relates to the above-mentioned patch, which further contains at least one selected from the group consisting of lauric acid diethanolamide, capric acid, isopropyl myristate, and propylene glycol monolaurate as an absorption accelerator.
すなわち、薬物と融点降下剤とを含有する上記構成の貼付剤とすることにより、粘着剤層中において、イオン対の形成を介して薬物が融点降下剤付加塩の形態で存在するようにし、薬物の安定性の向上ならびに融点の著しい降下を可能にすることよって、薬物の経皮吸収性および薬効持続性に極めて優れた本発明の貼付剤が実現し、上記課題が解決された。 That is, by forming a patch having the above-described constitution containing a drug and a melting point depressant, the drug is present in the form of a melting point depressant addition salt through the formation of an ion pair in the adhesive layer. By enabling the improvement of the stability and the remarkable lowering of the melting point, the patch of the present invention having excellent drug percutaneous absorption and sustained drug efficacy was realized, and the above problems were solved.
本発明の貼付剤は、貼付剤の粘着剤層に、特定の薬物と共にその薬物の融点を降下させる融点降下剤を配合することにより、充分な経皮吸収性が実現されなかった従来の貼付剤に比べて、貼付剤中に配合された薬物の皮膚への透過性が飛躍的に向上し、極めて優れた経皮吸収性を有する製剤とすることができる。また、本発明の貼付剤にさらに特定の吸収促進剤を配合することによって、薬物の経皮吸収性をより一層優れたものとすることができる。 The patch of the present invention is a conventional patch whose sufficient transdermal absorbability has not been realized by blending a melting point lowering agent that lowers the melting point of the drug with a specific drug in the adhesive layer of the patch. In comparison with the above, the permeability of the drug blended in the patch to the skin is remarkably improved, and a preparation having extremely excellent transdermal absorbability can be obtained. Further, by incorporating a specific absorption accelerator in the patch of the present invention, the transdermal absorbability of the drug can be further improved.
また、リスペリドン等の従来の経口製剤として投与されていた薬物を、本発明の外用貼付剤として投与することにより、消化器中での分解や肝臓等での代謝を受けることなく、薬効の持続性に優れた製剤として投与することができる。したがって、本発明の貼付剤は、従来の服用方法の簡便化およびコンプライアンスの改善を可能とし、統合失調症等の患者における極めて低い服用率をも大きく改善することができるものである。 In addition, by administering a drug that has been administered as a conventional oral preparation such as risperidone as an external patch of the present invention, it is possible to maintain the efficacy without undergoing degradation in the digestive organs or metabolism in the liver. Can be administered as an excellent preparation. Therefore, the patch of the present invention enables simplification of conventional administration methods and improvement of compliance, and can greatly improve the extremely low administration rate in patients with schizophrenia and the like.
すなわち、本発明の貼付剤は、貼付剤中に配合された薬物が十分に経皮吸収されて、その効果の持続性に優れたものであることから、薬物の効果を充分に発揮させることができるものである。なお、薬物とその薬物の融点を降下させる融点降下剤とを粘着剤層に含有させるという構成を有する薬物含有貼付剤は、本発明において初めて実現されたものであり、したがって、上記の効果を奏する薬物含有貼付剤も、本発明において初めて実現されたものである。 That is, the patch of the present invention is capable of sufficiently exerting the effect of the drug because the drug blended in the patch is sufficiently transdermally absorbed and has excellent durability. It can be done. Note that a drug-containing patch having a constitution in which a drug and a melting point depressant that lowers the melting point of the drug are contained in the pressure-sensitive adhesive layer is realized for the first time in the present invention, and thus exhibits the above-described effect. The drug-containing patch is also realized for the first time in the present invention.
以下、本発明の実施形態について詳しく説明する。
本発明に用いられる薬物は、常温において固体であるものであれば特に限定されず、消炎鎮痛薬、鎮痛薬、抗アレルギー薬、強心薬、気管支拡張薬、筋弛緩薬、鎮暈薬、抗不整脈薬、抗パーキンソン病薬、抗精神薬、抗うつ薬、抗不安薬、制吐薬、去痰薬、頻尿治療薬、麻酔薬、抗痴呆薬、血圧降下薬、催眠・鎮静薬、偏頭痛薬、興奮・覚醒薬、自律神経用薬等が挙げられ、遊離酸あるいは遊離塩基および／またはその薬学的に許容される塩の形で用いることができる。また、本発明に用いられる薬物としては、塩基性薬物が好ましい。さらに、常温において固体である塩基性薬物としては、オキシブチニン、フェンタニル、ペルゴリド、タンドスピロン、ドネペジル、タムスロシン、リスペリドン、フルラゼパム、ブトルファノール、ペリソキサール、プリジノール、トリヘキシフェニジル、アマンタジン、ツロブテロール、イソプレナリン、プロプラノロール、ケトチフェン、ジフェニドール、モルヒネ、メロキシカム、バルデコキシブ、セレコキシブ等がより好ましく、これらのうち特にリスペリドンが好ましい。リスペリドンとしては、遊離塩基のリスペリドンおよび／またはその薬学的に許容される塩を用いることができる。なお、薬学的に許容される塩とは、特に限定されることなく無機塩であっても有機塩であってもよい。また、リスペリドンは遊離塩基の形態で融点降下剤とともに粘着基剤等と配合されて貼付剤として製造され、貼付剤中ではリスペリドンは融点降下剤の酸付加塩の形態で存在することが好ましい。
薬物および／またはその薬学的に許容される塩は、製剤物性および経皮吸収性という観点から、粘着剤層の組成全体の重量を基準として３〜３０重量％で配合されることが好ましく、さらに好ましくは５〜２０重量％、特に好ましくは１０〜２０重量％で配合される。
Hereinafter, embodiments of the present invention will be described in detail.
The drug used in the present invention is not particularly limited as long as it is solid at room temperature, and is an anti-inflammatory analgesic, analgesic, antiallergic drug, cardiotonic drug, bronchodilator, muscle relaxant, antipruritic drug, antiarrhythmic drug Antiparkinsonian, antipsychotic, antidepressant, anxiolytic, antiemetic, expectorant, pollakiuria, anesthetic, anti-dementia, antihypertensive, hypnotic / sedative, migraine, agitation -Stimulants, drugs for autonomic nerves and the like can be mentioned, and they can be used in the form of free acid or free base and / or pharmaceutically acceptable salt thereof. The drug used in the present invention is preferably a basic drug. Further, basic drugs that are solid at room temperature include oxybutynin, fentanyl, pergolide, tandospirone, donepezil, tamsulosin, risperidone, flurazepam, butorphanol, perisoxal, pridinol, trihexyphenidyl, amantadine, tulobuterol, isoprenaline, propranolol, ketoprolol, Diphenidol, morphine, meloxicam, valdecoxib, celecoxib and the like are more preferable, and among these, risperidone is particularly preferable. As risperidone, free base risperidone and / or a pharmaceutically acceptable salt thereof can be used. The pharmaceutically acceptable salt is not particularly limited and may be an inorganic salt or an organic salt. Also, risperidone is prepared in the form of a free base by mixing with a melting point depressant and an adhesive base or the like to produce a patch. In the patch, risperidone is preferably present in the form of an acid addition salt of the melting point depressant.
The drug and / or a pharmaceutically acceptable salt thereof is preferably blended in an amount of 3 to 30% by weight based on the weight of the entire composition of the pressure-sensitive adhesive layer, from the viewpoint of pharmaceutical properties and transdermal absorbability. Preferably it is 5 to 20% by weight, particularly preferably 10 to 20% by weight.
また、必要に応じて１種以上の、他の薬効成分を含有させてもよい。かかる薬効成分は、特に限定されないが、例えば、消炎鎮痛薬、鎮痛薬、抗アレルギー薬、強心薬、気管支拡張薬、筋弛緩薬、鎮暈薬、抗不整脈薬、抗パーキンソン病薬、抗精神薬、抗うつ薬、抗不安薬、制吐薬、去痰薬、頻尿治療薬、麻酔薬、抗痴呆薬、血圧降下薬、催眠・鎮静薬、偏頭痛薬、興奮・覚醒薬、自律神経用薬等が挙げられる。 Moreover, you may contain 1 or more types of other medicinal ingredients as needed. Such medicinal ingredients are not particularly limited, for example, anti-inflammatory analgesics, analgesics, antiallergic drugs, cardiotonic drugs, bronchodilators, muscle relaxants, antipruritics, antiarrhythmic drugs, antiparkinsonian drugs, antipsychotic drugs, Antidepressants, anti-anxiety drugs, antiemetics, expectorants, frequent urination drugs, anesthetics, anti-dementia drugs, antihypertensive drugs, hypnotics / sedatives, migraine drugs, excitement / stimulants, autonomic drugs, etc. Can be mentioned.
本発明の貼付剤に用いられる融点降下剤は、粘着剤層組成物中に薬物と共に配合することにより、薬物の融点を降下させることができるものであれば、特に限定されないが、薬物の融点が大幅に低下することによって粘着剤層中での薬物の分子運動はより自由となり、薬物の経皮吸収性を高めることができる。具体的には、融点降下剤としては、薬物の融点を６０℃以上低下させるものが好ましく、９０℃以上低下させるものがより好ましく、１２０℃以上降下させるものが特に好ましい。
例えば、塩基性薬物の場合、有機酸および／またはその塩が好適に用いられ、特に、炭素数２〜７のカルボン酸および／またはその塩が好ましい。炭素数２〜７のカルボン酸としては、脂肪族（モノ、ジ、トリ）カルボン酸（例えば、酢酸、プロピオン酸、酪酸、乳酸、マレイン酸、フマル酸、ピルビン酸、シュウ酸、コハク酸、酒石酸等）、芳香族カルボン酸（例えば、サリチル酸、安息香酸等）等が挙げられる。さらに、これらの中でも、酢酸、プロピオン酸、酪酸、乳酸、安息香酸、サリチル酸が好ましく、酢酸が特に好ましい。有機酸の塩としては、このような酸の無機塩であっても有機塩であってもよいが、酢酸の塩、プロピオン酸の塩、酪酸の塩、乳酸の塩、安息香酸の塩、サリチル酸の塩が好ましく、酢酸ナトリウムが特に好ましい。
The melting point lowering agent used in the patch of the present invention is not particularly limited as long as it can lower the melting point of the drug by being mixed with the drug in the adhesive layer composition, but the melting point of the drug is not limited. By drastically decreasing, the molecular motion of the drug in the pressure-sensitive adhesive layer becomes more free, and the transdermal absorbability of the drug can be enhanced. Specifically, the melting point depressant is preferably one that lowers the melting point of the drug by 60 ° C. or more, more preferably 90 ° C. or more, and particularly preferably 120 ° C. or more.
For example, in the case of a basic drug, an organic acid and / or a salt thereof is preferably used, and a carboxylic acid having 2 to 7 carbon atoms and / or a salt thereof is particularly preferable. Examples of the carboxylic acid having 2 to 7 carbon atoms include aliphatic (mono, di, tri) carboxylic acids (for example, acetic acid, propionic acid, butyric acid, lactic acid, maleic acid, fumaric acid, pyruvic acid, oxalic acid, succinic acid, and tartaric acid. Etc.), aromatic carboxylic acids (for example, salicylic acid, benzoic acid, etc.) and the like. Further, among these, acetic acid, propionic acid, butyric acid, lactic acid, benzoic acid, and salicylic acid are preferable, and acetic acid is particularly preferable. The organic acid salt may be an inorganic salt or an organic salt of such an acid, but an acetic acid salt, a propionic acid salt, a butyric acid salt, a lactic acid salt, a benzoic acid salt, or a salicylic acid salt. Of which sodium acetate is particularly preferred.
これらのうち、酸である好ましい融点降下剤は、遊離塩基の薬物を溶解する作用があり、塩基性薬物の融点を極めて顕著に降下させる。融点が低下するということは、結晶状態における塩基性薬物の分子間相互作用エネルギーが減少することを意味する。分子の結晶化と溶解とは、平衡的に起こる現象であるから、融点の降下は分子運動の制限を緩和するように働くと考えられる。したがって、塩基性薬物が粘着剤層中で融点降下剤の酸付加塩の形態で存在する場合には、遊離塩基の形態で存在する場合と比較して、粘着剤層中における分子運動の制限が緩和されているために、高い経皮吸収性が実現されると考えられる。 Among these, a preferable melting point depressant which is an acid has an action of dissolving a free base drug, and extremely lowers the melting point of a basic drug. Lowering the melting point means that the intermolecular interaction energy of the basic drug in the crystalline state is decreased. Since crystallization and dissolution of molecules are phenomena that occur in equilibrium, it is thought that a drop in melting point acts to relax the restriction of molecular motion. Therefore, when the basic drug is present in the form of the acid addition salt of the melting point depressant in the pressure-sensitive adhesive layer, the molecular motion in the pressure-sensitive adhesive layer is limited compared to the case where it is present in the form of the free base. Since it is relaxed, it is considered that high transdermal absorbability is realized.
また、上記の酸である好ましい融点降下剤は、遊離塩基の薬物の粘着基剤への溶解性を高める。これは、遊離塩基の薬物は極性を有するため、非極性の粘着基剤等に対する溶解性が小さいが、塩基性薬物と共に融点降下剤を加えることにより、酸である融点降下剤がＨ＋を放出して−イオンになるのに伴って、放出されたＨ＋が塩基性薬物と共に（薬物・Ｈ＋）を形成し、融点降下剤の−イオンと安定にイオン対を形成するために、見かけ上、遊離塩基の薬物よりも極性が小さくなることによる。さらに、酸であるこれらの好ましい融点降下剤は、粘着剤層を可塑化する働きがある。したがって、これらの好ましい融点降下剤を用いることにより、皮膚側への拡散速度を高めることができるだけでなく、遊離塩基の薬物の粘着基剤への溶解度を高めることもできる。 Moreover, the preferable melting point depressant which is the above-mentioned acid enhances the solubility of the free base drug in the adhesive base. This is because the free base drug is polar and therefore has low solubility in non-polar adhesive bases, etc., but by adding a melting point depressant together with the basic drug, the melting point depressant that is an acid releases H + . to - with to become ions, the released H + is a basic drug to form a (drug · H +), melting point depressant - in order to form an ion and stable ion pair, apparently This is due to the fact that it is less polar than the free base drug. Furthermore, these preferred melting point depressants that are acids serve to plasticize the pressure-sensitive adhesive layer. Therefore, by using these preferable melting point depressants, not only can the diffusion rate to the skin side be increased, but also the solubility of the free base in the adhesive base of the drug can be increased.
一方、塩基性薬物が、遊離塩基でなく何らかの酸の付加塩である場合には、上記の好ましい融点降下剤である有機酸の塩を融点降下剤として粘着基剤と共に配合することができる。これにより、塩基性薬物は粘着剤層中で融点降下剤である酸の付加塩となり、上記の場合と同様、薬物の融点が低下して、薬物の皮膚への透過性が大きく上昇する。例えば、リスペリドンの酸（融点降下剤でない酸）付加塩と酢酸ナトリウムとを粘着基剤と共に配合すると、粘着剤層においてリスペリドンは酢酸リスペリドンとして存在することになり、その融点降下により優れた皮膚透過性を有する貼付剤を作製することができる。 On the other hand, when the basic drug is not a free base but an addition salt of any acid, an organic acid salt, which is the preferred melting point depressant, can be blended with the adhesive base as a melting point depressant. As a result, the basic drug becomes an acid addition salt which is a melting point depressant in the pressure-sensitive adhesive layer, and the melting point of the drug is lowered and the permeability of the drug to the skin is greatly increased as in the above case. For example, when risperidone acid (an acid that is not a melting point depressant) addition salt and sodium acetate are blended together with an adhesive base, risperidone exists as risperidone acetate in the adhesive layer, and the skin permeability is excellent due to its melting point depression. Can be prepared.
これらの融点降下剤は、１種を単独で用いても２種以上を組み合わせて用いてもよい。また、これらの融点降下剤の配合量は、外用貼付剤としての安定性および皮膚透過性、製剤の粘着物性を考慮すると、薬物１モルに対して好ましくは０．５〜５モルであり、より好ましくは１〜４モル、特に好ましくは１〜３モルである。これは、融点降下剤の薬物に対するモル比が０．５未満であると経皮吸収性が低下する傾向にあり、モル比が５を超えると、粘着剤層の凝集性や粘着性が低下する傾向にあるためである。 These melting point depressants may be used alone or in combination of two or more. In addition, the blending amount of these melting point depressants is preferably 0.5 to 5 moles per mole of drug, considering the stability and skin permeability as an external patch and the adhesive physical properties of the preparation. Preferably it is 1-4 mol, Most preferably, it is 1-3 mol. When the molar ratio of the melting point depressant to the drug is less than 0.5, the percutaneous absorbability tends to decrease. When the molar ratio exceeds 5, the cohesiveness and adhesiveness of the adhesive layer decrease. It is because it is in a tendency.
また、本発明の貼付剤に用いられる融点降下剤が酸である場合には（すなわち、塩基性薬物として遊離塩基の形態のものを用いる場合には）、その酸に対応する塩である融点降下剤をさらに本発明の貼付剤に含有させることが好ましく、かかる塩は対応する酸の無機塩であっても有機塩であってもよい。したがって、融点降下剤として、例えば酢酸を用いる場合には、酢酸の塩（例えば酢酸ナトリウム）をさらに含有させることが好ましい。貼付剤の調製中または保存中あるいは適用期間中、上記の酸である融点降下剤は揮発してしまう場合があるが、これは、融点降下剤が上記の通り皮膚への吸収性において重要な役割を果たしていることから考えれば極めて重大な問題である。しかしながら、このように酸である融点降下剤の塩をさらに含有させることにより、粘着剤層組成物または粘着剤層における融点降下剤の含有量の減少を効果的に抑制することが可能となり、優れた経皮吸収性と薬効持続性を安定に発揮し得る貼付剤を提供することができる。 In addition, when the melting point depressant used in the patch of the present invention is an acid (that is, when the basic drug is in the form of a free base), the melting point depressant is a salt corresponding to the acid. It is preferable to further include an agent in the patch of the present invention, and such a salt may be an inorganic salt or an organic salt of the corresponding acid. Therefore, for example, when acetic acid is used as the melting point depressant, it is preferable to further contain a salt of acetic acid (for example, sodium acetate). During preparation, storage, or application period of the patch, the above-mentioned acid melting point depressant may volatilize, and this is an important role in the absorption of the melting point depressant to the skin as described above. This is a very serious problem considering that However, it is possible to effectively suppress the decrease in the content of the melting point depressant in the pressure-sensitive adhesive layer composition or the pressure-sensitive adhesive layer by further containing the salt of the melting point depressant that is an acid as described above. In addition, it is possible to provide a patch capable of stably exhibiting transdermal absorbability and sustained drug efficacy.
このような場合には、塩である融点降下剤の塩の配合量は、塩基性薬物に対するモル比として０．５〜５であることが好ましく、さらに好ましくは１〜４であり、特に好ましくは２〜３である。 In such a case, the compounding amount of the salt of the melting point depressant, which is a salt, is preferably 0.5 to 5, more preferably 1 to 4, and particularly preferably as a molar ratio to the basic drug. 2-3.
本発明の貼付剤に用いられる粘着基剤は、粘着剤層の基剤となり得るものであれば特に限定されないが、例えば、スチレン−イソプレン−スチレンブロック共重合体（以下、「ＳＩＳ」と略記する。）、イソプレンゴム、ポリイソブチレン（以下、「ＰＩＢ」と略記する。）、スチレン−ブタジエン−スチレンブロック共重合体（以下、「ＳＢＳ」と略記する。）、スチレン−ブタジエンゴム（以下、「ＳＢＲ」と略記する。）、アクリル酸エステル共重合体（２−エチルヘキシルアクリレート、酢酸ビニル、メタクリレート、メトキシエチルアクリレート、ヒドロキシエチルアクリレートおよびアクリル酸からなる群から選ばれる少なくとも２種の共重合体）、ポリジメチルシロキサン等の疎水性高分子を挙げることができる。これらの中でも、ＳＩＳおよびアクリル酸エステル共重合体が特に好ましい。 The adhesive base used in the patch of the present invention is not particularly limited as long as it can be a base of the adhesive layer. For example, a styrene-isoprene-styrene block copolymer (hereinafter abbreviated as “SIS”). ), Isoprene rubber, polyisobutylene (hereinafter abbreviated as “PIB”), styrene-butadiene-styrene block copolymer (hereinafter abbreviated as “SBS”), styrene-butadiene rubber (hereinafter referred to as “SBR”). ), Acrylic acid ester copolymers (at least two copolymers selected from the group consisting of 2-ethylhexyl acrylate, vinyl acetate, methacrylate, methoxyethyl acrylate, hydroxyethyl acrylate and acrylic acid), poly Mention may be made of hydrophobic polymers such as dimethylsiloxane. Among these, SIS and acrylate copolymer are particularly preferable.
これらの粘着基剤は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。また、粘着基剤の配合量は、粘着剤層の形成および有効成分の皮膚への透過性を考慮して、粘着剤層の組成全体の重量を基準として５〜５０重量％であることが好ましく、さらに好ましくは１０〜４０重量％であり、特に好ましくは１０〜３０重量％である。 These adhesive bases may be used individually by 1 type, and may be used in combination of 2 or more type. Further, the amount of the adhesive base is preferably 5 to 50% by weight based on the weight of the entire composition of the adhesive layer in consideration of the formation of the adhesive layer and the permeability of the active ingredient to the skin. More preferably, it is 10 to 40% by weight, and particularly preferably 10 to 30% by weight.
本発明による貼付剤には、上記必須成分（薬物、融点降下剤および粘着基剤）の他、薬効成分の経皮吸収性をさらに高めるために吸収促進剤を配合してもよい。本発明に用いられる吸収促進剤としては、例えば、炭素鎖数６〜２０の脂肪酸、脂肪族アルコール、脂肪酸エステルまたはエーテルまたはアミド類、芳香族系有機酸、芳香族系アルコール、芳香族系有機酸エステルまたはエーテル類（以上は飽和、不飽和のいずれでもよく、環状、直鎖状分枝状のいずれでもよい）、さらに、乳酸エステル類、酢酸エステル類、モノテルペン系化合物、セスキテルペン系化合物、エイゾン（Ａｚｏｎｅ）、エイゾン（Ａｚｏｎｅ）誘導体、グリセリン脂肪酸エステル類、ソルビタン脂肪酸エステル類（Ｓｐａｎ系）、ポリソルベート系（Ｔｗｅｅｎ系）、ポリエチレングリコール脂肪酸エステル類、ポリオキシエチレン硬化ヒマシ油系（ＨＣＯ系）、ショ糖脂肪酸エステル類等が挙げられる。これらのうち、ラウリン酸ジエタノールアミド、カプリン酸、ミリスチン酸イソプロピル、モノラウリン酸プロピレングリコールは、本発明の粘着剤層組成物に配合することにより、本発明による貼付剤の経皮吸収性を大きく向上させるので特に好ましい。 In addition to the above essential components (drug, melting point depressant and adhesive base), the patch according to the present invention may contain an absorption enhancer in order to further enhance the transdermal absorbability of the medicinal component. Examples of the absorption accelerator used in the present invention include fatty acids having 6 to 20 carbon chains, aliphatic alcohols, fatty acid esters or ethers or amides, aromatic organic acids, aromatic alcohols, and aromatic organic acids. Esters or ethers (they may be either saturated or unsaturated, and may be cyclic or linear branched), lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone derivatives, glycerin fatty acid esters, sorbitan fatty acid esters (Span system), polysorbate (Tween system), polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil system (HCO system), Examples thereof include sucrose fatty acid esters. Of these, lauric acid diethanolamide, capric acid, isopropyl myristate, and propylene glycol monolaurate greatly improve the transdermal absorbability of the patch of the present invention by blending with the adhesive layer composition of the present invention. Therefore, it is particularly preferable.
これらの吸収促進剤は１種を単独で用いても、２種以上を組み合わせて用いてもよい。また、吸収促進剤の配合量は、貼付剤としての皮膚への有効成分の充分な透過性および皮膚への刺激性等を考慮して、粘着剤層の組成全体の重量を基準として１〜１０重量％であることが好ましく、さらに好ましくは２〜８重量％であり、特に好ましくは３〜６重量％である。 These absorption promoters may be used alone or in combination of two or more. In addition, the amount of the absorption enhancer is 1 to 10 based on the weight of the entire composition of the pressure-sensitive adhesive layer in consideration of sufficient permeability of the active ingredient to the skin as a patch, irritation to the skin, and the like. It is preferable that it is weight%, More preferably, it is 2-8 weight%, Especially preferably, it is 3-6 weight%.
また、本発明の貼付剤の粘着剤層において、粘着力が不足している場合には、さらに粘着付与樹脂を配合することが望ましい。使用され得る粘着付与樹脂としては、ロジン誘導体（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、ロジンのペンタエリストールエステル等）、脂環族飽和炭化水素樹脂（例えばアルコンＰ-１００、荒川化学工業）、脂肪族系炭化水素樹脂（例えばクイントンＢ１７０、日本ゼオン）、テルペン樹脂（例えばクリアロンＰ-１２５、ヤスハラケミカル）、マレイン酸レジン等が挙げられる。中でも特に好ましい粘着付与樹脂は、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、脂肪族系炭化水素樹脂、テルペン樹脂である。 Moreover, in the adhesive layer of the patch of the present invention, when the adhesive strength is insufficient, it is desirable to further add a tackifier resin. Examples of tackifying resins that can be used include rosin derivatives (for example, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythritol ester of rosin), alicyclic saturated hydrocarbon resins (for example, Alcon P-100, Arakawa Chemical Industries), aliphatic hydrocarbon resins (for example, Quinton B170, Nippon Zeon), terpene resins (for example, Clearon P-125, Yasuhara Chemical), maleic resin, and the like. Among them, particularly preferred tackifying resins are hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin.
これらの粘着付与樹脂は、１種を単独で用いても２種以上を組み合わせて用いてもよい。また、粘着付与樹脂の粘着層の組成全体に基づく配合量は、貼付剤としての充分な粘着力および剥離時の皮膚への刺激性を考慮して、粘着剤層の組成全体の重量を基準として２０〜６０重量％であることが好ましく、さらに好ましくは３０〜６０重量％であり、特に好ましくは４０〜６０重量％である。 These tackifier resins may be used alone or in combination of two or more. The amount of the tackifying resin based on the entire composition of the adhesive layer is based on the weight of the entire composition of the adhesive layer in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. It is preferably 20 to 60% by weight, more preferably 30 to 60% by weight, and particularly preferably 40 to 60% by weight.
さらに、本発明の貼付剤には可塑剤を配合してもよい。本発明に用いられる可塑剤としては、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等）、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）、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等）、液状ゴム（例えば、ポリブテン、液状イソプレンゴム）、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、プロピレングリコール、ジプロピレングリコール、クロタミトン等が挙げられる。これらのうち、特に、流動パラフィン、液状ポリブテン、サリチル酸グリコール、クロタミトンが好ましい。 Furthermore, you may mix | blend a plasticizer with the patch of this invention. Examples of the plasticizer used in the present invention include petroleum oils (for example, paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (for example, olive oil, camellia oil, castor oil, Tall oil, peanut oil), dibasic acid esters (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber), diethylene glycol, polyethylene glycol, salicylate glycol, propylene glycol, dipropylene glycol, crotamiton Etc. Of these, liquid paraffin, liquid polybutene, glycol salicylate, and crotamiton are particularly preferable.
これらの可塑剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。このような可塑剤の配合量は、皮膚への充分な有効成分の透過性及び貼付剤としての充分な凝集力の維持を考慮して、粘着剤層の組成全体の重量を基準として５〜３０重量％であることが好ましく、さらに好ましくは１０〜３０重量％であり、特に好ましくは１０〜２０重量％である。 These plasticizers may be used alone or in combination of two or more. The blending amount of such a plasticizer is 5 to 30 on the basis of the weight of the whole composition of the pressure-sensitive adhesive layer in consideration of sufficient permeability of the active ingredient to the skin and maintenance of sufficient cohesive force as a patch. It is preferable that it is weight%, More preferably, it is 10-30 weight%, Especially preferably, it is 10-20 weight%.
また、本発明の貼付剤には、必要に応じて、抗酸化剤、充填剤、架橋剤、防腐剤および紫外線吸収剤等を配合することができる。抗酸化剤としては、トコフェロールおよ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等が好ましく、充填剤としては、炭酸カルシウム、炭酸マグネシウム、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等）、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、酸化チタン等が好ましく、架橋剤としては、アミノ化合物、フェノール化合物、エポキシ化合物、イソシアネート化合物、有機過酸化物、金属アルコラート、金属キレート等が好ましく、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等が好ましく、紫外線吸収剤としては、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、アミノ酸系化合物、イミダゾリン誘導体、ピリミジン誘導体、ジオキサン誘導体等が好ましい。 Moreover, an antioxidant, a filler, a crosslinking agent, an antiseptic, an ultraviolet absorber, and the like can be blended in the patch of the present invention as necessary. As the antioxidant, tocopherol and their ester derivatives, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole, etc. are preferable, and as the filler, calcium carbonate , Magnesium carbonate, silicate (for example, aluminum silicate, magnesium silicate, etc.), silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like are preferable. Phenol compounds, epoxy compounds, isocyanate compounds, organic peroxides, metal alcoholates, metal chelates, etc. are preferred, and as preservatives, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc. are preferred. Properly, as the ultraviolet absorber, p- aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid-based compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like are preferable.
このような抗酸化剤、充填剤、架橋剤、防腐剤および紫外線吸収剤は、貼付剤の粘着剤層の組成全体を基準として、合計で、好ましくは１０重量％以下、さらに好ましくは５重量％以下、特に好ましくは２重量％以下の量で配合することができる。 Such antioxidants, fillers, crosslinking agents, preservatives and ultraviolet absorbers are preferably 10% by weight or less, more preferably 5% by weight, based on the total composition of the adhesive layer of the patch. In the following, it can be blended particularly preferably in an amount of 2% by weight or less.
薬物を含有する上記組成の粘着剤層を含む本発明の貼付剤は、既知のいずれの方法によっても製造することができるが、例えば、薬物および融点降下剤を、粘着基剤成分と共にジクロロメタン、トルエン、ヘキサン、酢酸エチル等の溶媒に溶解させ、剥離ライナー又は支持体上に伸展して溶剤を乾燥除去後、支持体あるいは剥離ライナーと張り合わることにより得ることができる。 The patch of the present invention containing the adhesive layer having the above-mentioned composition containing a drug can be produced by any known method. For example, a drug and a melting point lowering agent together with an adhesive base component together with dichloromethane, toluene It can be obtained by dissolving in a solvent such as hexane, ethyl acetate and the like, extending on a release liner or support, drying and removing the solvent, and then bonding to the support or release liner.
本発明の貼付剤における支持体は、粘着剤層を支持するのに適したものであれば特に限定はされないが、伸縮性または非伸縮性のものを用いることができる。例えば布、不織布、ポリウレタン、ポリエステル、ポリ酢酸ビニル、ポリ塩化ビニリデン、ポリエチレン、ポリエチレンテレフタレート、アルミニウムシート等、又はそれらの複合素材等を用いることができる。 The support in the patch of the present invention is not particularly limited as long as it is suitable for supporting the pressure-sensitive adhesive layer, but a stretchable or non-stretchable support can be used. For example, cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, aluminum sheet, or a composite material thereof can be used.
また、本発明の貼付剤に用いられる剥離ライナーとしては、具体的にはポリエチレンテレフタラートなどのポリエステル、ポリ塩化ビニル、ポリ塩化ビニリデン等のフィルム、上質紙とポリオレフィンとのラミネートフィルム等を用いることができる。これらの剥離ライナーは、貼付側から剥離ライナーを剥離する際の作業容易性を高めるために、剥離ライナーの粘着剤層と接触する側の面にフッ素処理やシリコン処理を施すことが好ましい。 In addition, as the release liner used in the patch of the present invention, specifically, a polyester such as polyethylene terephthalate, a film such as polyvinyl chloride or polyvinylidene chloride, a laminate film of fine paper and polyolefin, or the like may be used. it can. These release liners are preferably subjected to fluorine treatment or silicon treatment on the surface of the release liner that comes into contact with the pressure-sensitive adhesive layer in order to enhance the workability when the release liner is peeled from the application side.
以下、試験例および本発明の実施例を示して、本発明をさらに具体的に説明するが、本発明はこれら実施例に限定されることなく、各成分の配合順序も特に限定されない。
また、本発明の技術的思想を逸脱しない範囲での種々の変更が可能である。
EXAMPLES Hereinafter, although a test example and the Example of this invention are shown and this invention is demonstrated further more concretely, this invention is not limited to these Examples, The compounding order of each component is not specifically limited.
Various modifications can be made without departing from the technical idea of the present invention.
試験例１．融点測定
リスペリドン約１ｇと融点降下剤としてそれぞれペアイオンとなる酸（酢酸、乳酸、安息香酸およびメタンスルホン酸）の等モル量を秤取し、溶媒としてジクロロメタン約５ｍｌを加えて溶解させる。室温で静置してジクロロメタンを揮発させ、リスペリドンの各酸付加塩の析出を待ち、ろ過して結晶を得る。得られた結晶の融点測定は、日本薬局方に準じて行った。
Test Example 1 Melting point measurement About 1 g of risperidone and equimolar amounts of acids (acetic acid, lactic acid, benzoic acid and methanesulfonic acid) which are each a pair ion as a melting point depressant are weighed and dissolved by adding about 5 ml of dichloromethane as a solvent. Let stand at room temperature to volatilize dichloromethane, wait for precipitation of each acid addition salt of risperidone, and filter to obtain crystals. The melting point of the obtained crystal was measured according to the Japanese Pharmacopoeia.
表１の結果が示すように、リスペリドンの酢酸塩（酢酸リスペリドン）、乳酸塩（乳酸リスペリドン）、安息香酸塩（安息香酸リスペリドン）は、遊離塩基のリスペリドン（リスペリドン）に比べて融点が著しく低下している。一方、本発明の融点降下剤でないメタンスルホン酸の付加塩（メタンスルホン酸リスペリドン）は、遊離塩基のリスペリドン（リスペリドン）に比べて、融点が上昇していることが理解される。 As shown in the results of Table 1, the melting point of risperidone acetate (risperidone acetate), lactate (risperidone lactate), and benzoate (risperidone benzoate) is significantly lower than the free base risperidone (risperidone). ing. On the other hand, it is understood that the addition salt of methanesulfonic acid (risperidone methanesulfonate), which is not the melting point depressant of the present invention, has an increased melting point compared to the free base risperidone (risperidone).
表２の下記成分を溶剤トルエンに溶解後（固形分４０重量％）、ポリエチレンテレフタラートフィルム（剥離ライナー、７５μｍ）のシリコン処理面上に塗工し、７０℃で１０分間乾燥した。その後、支持体のポリエチレンテレフタラートフィルム（サンドマット処理、２５μｍ）を積層して、本発明のリスペリドン含有貼付剤（実施例１〜１３）および融点降下剤を含有しないリスペリドン含有貼付剤（比較例１〜４）を得た。粘着剤層の厚みはいずれにおいても７０μｍであった。 The following components in Table 2 were dissolved in a solvent toluene (solid content: 40% by weight), coated on a silicon-treated surface of a polyethylene terephthalate film (release liner, 75 μm), and dried at 70 ° C. for 10 minutes. Thereafter, a polyethylene terephthalate film (sand mat treatment, 25 μm) as a support was laminated, and the risperidone-containing patch of the present invention (Examples 1 to 13) and the risperidone-containing patch containing no melting point depressant (Comparative Example 1) To 4). The thickness of the pressure-sensitive adhesive layer was 70 μm in all cases.
表２中の％は全て重量％を表す。
表２中のモル比は全てリスペリドンに対するモル比を表す。
a) Duro-Tak 87-4098（ナショナルスターチ）アクリル酸エステル共重合体（分子内に極性官能基を有さない）
b) Duro-Tak 87-2516（ナショナルスターチ）アクリル酸エステル共重合体（分子内に水酸基を有する）
SIS：（クレイトンポリマー）スチレン-イソプレン−スチレンブロック共重合体
アルコンP-100：（荒川化学工業）粘着付与樹脂
IPM：ミリスチン酸イソプロピル
PGML：モノラウリン酸プロピレングリコール
All percentages in Table 2 represent weight percent.
All molar ratios in Table 2 represent molar ratios to risperidone.
a) Duro-Tak 87-4098 (National Starch) acrylate copolymer (no polar functional group in the molecule)
b) Duro-Tak 87-2516 (National Starch) acrylate copolymer (having hydroxyl groups in the molecule)
SIS: (Clayton polymer) Styrene-isoprene-styrene block copolymer Alcon P-100: (Arakawa Chemical Industries) Tackifying resin
IPM: Isopropyl myristate
PGML: Propylene glycol monolaurate
試験例２．in vitro皮膚透過試験
ヘアレスマウス胴体部皮膚を剥離し、真皮側をレセプター層側に向け、３２℃の温水を外周部に循環させたフロースルーフランツ型セル（３．１４ｃｍ2）に装着した。角質層側に、上記のようにして作製した本発明の貼付剤（実施例２、４および６〜１３）または融点降下剤を含有しない貼付剤（比較例１〜４）をそれぞれ貼付し、５．５ｍｌ／時間（ｈｒ）の速さで２時間毎に２４時間までサンプリングを行った。レセプター層には、生理食塩水を使用した。各時間毎に得られたレセプター液中のリスペリドン含有量を高速液体クロマトグラフ法により測定し、１時間当たりの各貼付剤からのリスペリドンの皮膚最高透過速度を算出した結果を以下の表３に示す。
Test Example 2 In Vitro Skin Permeation Test Hairless mouse body skin was peeled off and attached to a flow-through Franz-type cell (3.14 cm 2 ) in which warm water at 32 ° C. was circulated to the outer periphery with the dermis side facing the receptor layer side. A patch (Examples 2, 4 and 6 to 13) of the present invention prepared as described above or a patch not containing a melting point lowering agent (Comparative Examples 1 to 4) was pasted on the stratum corneum side, respectively. Sampling was performed every 2 hours for up to 24 hours at a rate of 5 ml / hour (hr). Saline was used for the receptor layer. Table 3 below shows the results obtained by measuring the risperidone content in the receptor solution obtained every hour by high performance liquid chromatography and calculating the maximum skin permeation rate of risperidone from each patch per hour. .
表３の結果が示すように、融点降下剤を含有しない比較例の貼付剤では、皮膚への透過が検出されないか（比較例１）もしくはわずかに検出されたに過ぎない（比較例２〜４）のに対し、酢酸、乳酸、または安息香酸といった融点降下剤を含有する本発明の貼付剤（実施例２、４および６〜１３）は、いずれもリスペリドンの極めて良好な皮膚への透過が観察された。したがって、既知の粘着基剤や吸収促進剤を含有する粘着剤層にリスペリドンなどの薬物を含有させただけでは、充分な経皮吸収性および持続性を有する貼付剤を得ることはできないが、融点降下剤を薬物とともに粘着剤層に含有させて貼付剤として製造し、薬物を融点降下剤付加塩の状態で粘着剤層中に存在させることにより、薬物の経皮吸収性が飛躍的に向上し、持続性に優れた薬効を十分に発揮できる貼付剤とすることができることが明らかになった。 As shown in the results of Table 3, in the patch of the comparative example containing no melting point depressant, permeation through the skin was not detected (Comparative Example 1) or only slightly detected (Comparative Examples 2 to 4). In contrast, the patches (Examples 2, 4 and 6 to 13) of the present invention containing a melting point depressant such as acetic acid, lactic acid, or benzoic acid all observed very good permeation of risperidone to the skin. It was done. Therefore, it is not possible to obtain a patch having sufficient transdermal absorbability and persistence by simply adding a drug such as risperidone to a pressure-sensitive adhesive layer containing a known pressure-sensitive adhesive base or absorption promoter. Produced as a patch by containing a depressant together with the drug in the adhesive layer, and by allowing the drug to be present in the adhesive layer in the form of a melting point depressant addition salt, the transdermal absorbability of the drug is dramatically improved. Thus, it was revealed that the patch can exhibit a long-lasting medicinal effect sufficiently.
また、表３の結果を表１の結果と合わせて考察すると、リスペリドンの酢酸塩（酢酸リスペリドン）、乳酸塩（乳酸リスペリドン）、安息香酸塩（安息香酸リスペリドン）は、遊離塩基のリスペリドン（リスペリドン）に比べて、融点が大きく低下しており、リスペリドンをこれらの融点降下剤付加塩として含有する本発明の貼付剤（実施例１〜１３）は、リスペリドンを遊離塩基として含有する貼付剤（比較例１〜３）と比べて、皮膚透過速度が数倍〜数十倍以上も高くなっていることから、リスペリドンの融点降下剤付加塩は遊離塩基に比べて極めて優れた経皮吸収性を有することが示唆されたといえる。一方、本発明の融点降下剤でないメタンスルホン酸の付加塩（メタンスルホン酸リスペリドン）は、遊離塩基のリスペリドン（リスペリドン）に比べて融点が上昇し、リスペリドンをメタンスルホン酸付加塩として含有する貼付剤（比較例４）は、皮膚透過速度も大きく低下していることから、メタンスルホン酸はリスペリドンの皮膚透過性を改善しないことが理解される。 When the results in Table 3 are considered together with the results in Table 1, risperidone acetate (risperidone acetate), lactate (risperidone lactate), and benzoate (risperidone benzoate) are free base risperidone (risperidone). The patches of the present invention (Examples 1 to 13) containing risperidone as a melting point depressant addition salt (Examples 1 to 13) having a greatly reduced melting point compared to 1-3), the permeation rate of the skin is several times to several tens of times higher, so that the melting point depressant addition salt of risperidone has extremely superior transdermal absorbability compared to the free base. Can be said to have been suggested. On the other hand, the addition salt of methanesulfonic acid (risperidone methanesulfonate) which is not a melting point depressant of the present invention has a melting point higher than that of the free base risperidone (risperidone), and contains a risperidone as a methanesulfonic acid addition salt. In (Comparative Example 4), since the skin permeation rate is also greatly reduced, it is understood that methanesulfonic acid does not improve the skin permeability of risperidone.
さらに、吸収促進剤としてミリスチン酸イソプロピル（ＩＰＭ）またはモノラウリン酸プロピレングリコール（ＰＧＭＬ）を含有させた場合には（実施例４および７）、これらを含有しない場合（実施例２）と比べて、本発明の貼付剤の皮膚透過性をさらに大きく（約４倍程度）向上させることが示された。 Furthermore, when isopropyl myristate (IPM) or propylene glycol monolaurate (PGML) is included as an absorption enhancer (Examples 4 and 7), compared with the case where these are not included (Example 2), It was shown that the skin permeability of the patch of the invention was further increased (about 4 times).
また、粘着基剤としてＳＩＳを用いた場合、アクリル酸エステル共重合体を用いた場合、ならびにＳＩＳおよびアクリル酸エステル共重合体の両者を用いた場合には、いずれも良好なリスペリドンの皮膚透過性が得られた（実施例１〜１３）。また、アクリル酸エステル共重合体を用いた場合には、分子内に極性官能基（水酸基）を有するアクリル酸エステル共重合体（実施例９）のほうが、分子内に極性官能基を有さないアクリル酸エステル共重合体（実施例１０）よりも、経皮吸収性に優れていることが示された。さらに、アクリル酸エステル共重合体のみを粘着基剤に用いた場合よりも、ＳＩＳのみを用いた場合、あるいはＳＩＳおよびアクリル酸エステル共重合体の両者を用いた場合のほうがより一層優れた経皮吸収性を示すことが明らかになった。 In addition, when SIS is used as the adhesive base, when acrylic acid ester copolymer is used, and when both SIS and acrylic acid ester copolymer are used, risperidone has good skin permeability. Were obtained (Examples 1 to 13). When an acrylate copolymer is used, the acrylate copolymer (Example 9) having a polar functional group (hydroxyl group) in the molecule does not have a polar functional group in the molecule. It was shown that the transdermal absorbability is superior to the acrylic ester copolymer (Example 10). Furthermore, the transcutaneous case where only SIS is used, or when both SIS and acrylate copolymer are used, is superior to the case where only acrylic ester copolymer is used as the adhesive base. It became clear that it showed absorbency.
以上の結果より、本発明に用いられる融点降下剤によって、特定の薬物の経皮吸収性が飛躍的に改善されることが示されると共に、融点降下剤を特定の薬物とともに粘着剤層に含有させた本発明の貼付剤は、皮膚透過性に優れ、製剤中の薬効成分の安定性にも問題がなく、持続して薬効を発揮できるものであることが明らかになった。また、薬物とその融点降下剤を含有する貼付剤において、ミリスチン酸イソプロピル（ＩＰＭ）、モノラウリン酸プロピレングリコール（ＰＧＭＬ）、ラウリン酸ジエタノールアミド、カプリン酸などの吸収促進剤を配合することにより、より一層優れた皮膚透過性を有する貼付剤を提供できることが明らかになった。さらに、かかる貼付剤において、粘着剤としてＳＩＳおよび／またはアクリル酸エステル共重合体を用いることにより、極めて優れた経皮吸収性および薬効持続性を備えた貼付剤を提供できることが明らかになった。 From the above results, it is shown that the transdermal absorbability of a specific drug is dramatically improved by the melting point depressant used in the present invention, and the melting point depressant is included in the adhesive layer together with the specific drug. It was also found that the patch of the present invention is excellent in skin permeability, has no problem with the stability of medicinal ingredients in the preparation, and can exert its medicinal effects continuously. Further, in a patch containing a drug and its melting point depressant, by adding an absorption promoter such as isopropyl myristate (IPM), propylene glycol monolaurate (PGML), diethanolamide laurate, capric acid, etc. It was revealed that a patch having excellent skin permeability can be provided. Furthermore, in such patches, it has become clear that by using SIS and / or an acrylate copolymer as an adhesive, it is possible to provide a patch having extremely excellent transdermal absorbability and sustained drug efficacy.
以上説明したとおり、本発明によれば、製剤中の薬物の経皮吸収性が極めて良好であって、かつ薬効の持続性に優れた貼付剤を提供することが可能になることから、本発明の貼付剤は、服用方法の簡便化およびコンプライアンスの向上を達成することができる、患者の治療に使用可能な医薬品としての応用が期待される。 As described above, according to the present invention, it is possible to provide a patch with extremely good transdermal absorbability of the drug in the preparation and excellent durability of the drug. This patch is expected to be applied as a medicine that can be used for treatment of patients, which can achieve the simplification of taking method and the improvement of compliance.
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| WO2007119656A1 (en) * | 2006-04-11 | 2007-10-25 | Nichiban Co., Ltd. | Tamsulosin-containing percutaneous absorption type preparation |
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| WO2010098261A1 (en) * | 2009-02-24 | 2010-09-02 | 久光製薬株式会社 | Risperidone-containing transdermal preparation and adhesive patch using same |
| WO2010109913A1 (en) * | 2009-03-27 | 2010-09-30 | トーアエイヨー株式会社 | Transdermal preparation |
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