JP2001508069A - Acetylsalicylic acid-containing transdermal therapeutic system with enhanced absorbability - Google Patents
Acetylsalicylic acid-containing transdermal therapeutic system with enhanced absorbabilityInfo
- Publication number
- JP2001508069A JP2001508069A JP53137698A JP53137698A JP2001508069A JP 2001508069 A JP2001508069 A JP 2001508069A JP 53137698 A JP53137698 A JP 53137698A JP 53137698 A JP53137698 A JP 53137698A JP 2001508069 A JP2001508069 A JP 2001508069A
- Authority
- JP
- Japan
- Prior art keywords
- limonene
- acetylsalicylic acid
- dimethyl isosorbide
- transdermal therapeutic
- layer
- 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.)
- Pending
Links
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960001138 acetylsalicylic acid Drugs 0.000 title claims abstract description 24
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 14
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims abstract description 38
- 229940087305 limonene Drugs 0.000 claims abstract description 19
- 235000001510 limonene Nutrition 0.000 claims abstract description 19
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims abstract description 18
- 239000010410 layer Substances 0.000 claims abstract description 18
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000011241 protective layer Substances 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 8
- 239000011159 matrix material Substances 0.000 claims description 7
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 5
- 229940124597 therapeutic agent Drugs 0.000 claims 5
- 238000010521 absorption reaction Methods 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- 241000566113 Branta sandvicensis Species 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 239000002356 single layer Substances 0.000 claims 1
- 239000004744 fabric Substances 0.000 description 16
- 230000035699 permeability Effects 0.000 description 8
- 229920000728 polyester Polymers 0.000 description 8
- 239000000853 adhesive Substances 0.000 description 6
- 230000001070 adhesive effect Effects 0.000 description 6
- 229920000742 Cotton Polymers 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229920005601 base polymer Polymers 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- GNYWBJRDQHPSJL-UHFFFAOYSA-N 6-acetyl-6-hydroxycyclohexa-2,4-diene-1-carboxylic acid Chemical compound CC(=O)C1(O)C=CC=CC1C(O)=O GNYWBJRDQHPSJL-UHFFFAOYSA-N 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 229920002367 Polyisobutene Polymers 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005573 silicon-containing polymer Polymers 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】 本発明のアセチルサリチル酸含有経皮吸収治療システムは、本質的に活性成分および水分に対して不透過性の裏当て層、活性成分貯蔵部および、必要に応じて、取り外し可能な保護層を備える。この経皮吸収治療システムは、リモネンおよびジメチルイソソルビドを、ジメチルイソソルビド５０ｇに対してリモネン５０ｇ以上の混合比で活性成分の領域に含有することを特徴とする。 (57) [Summary] The acetylsalicylic acid-containing transdermal therapeutic system of the present invention comprises a backing layer that is essentially impermeable to active ingredients and moisture, an active ingredient reservoir, and, if desired, a removable protective layer. This transdermal therapeutic system is characterized in that limonene and dimethyl isosorbide are contained in the active ingredient region in a mixing ratio of 50 g of limonene to 50 g of dimethyl isosorbide.
Description
【発明の詳細な説明】 吸収性を高めたアセチルサリチル酸含有経皮吸収治療システム 本発明は、本質的に活性成分および水分に対して不透過性の裏当て層、活性成 分貯蔵部、および必要に応じて、再び取り外すことが可能な保護層を備えたアセ チルサリチル酸含有経皮吸収治療システムに関する。 経皮吸収治療システム（ＴＴＳ）は、多くの疾患の医学的治療のために既に市 販されている。 理論上、活性成分アセチルサリチル酸は、ヒトの皮膚を透過することができ、 したがって好適な活性成分となり得ることも公知である。これまで、ロジャー（ Rougier et al.）らは、アセチルサリチル酸が生体吸収される速度の皮膚の選択 された部位に対する依存性（かなり低い）を報告している（ジャーナル オブ ファーマスーティカル サイエンス（J．Pharm．Sci．176，451-454，1987）） 。 アセチルサリチル酸は、高い治療指数を有する比較的安全な医薬物質である。 それは、非常に高用量(１ｇ／１日を超える)では、抗不整脈薬として、中用量（ ２５０〜５００ｍｇ）では、解熱剤／鎮痛剤として、また、低用量（３０〜１５ ０ｍｇ／１日）では、血小板凝集阻害薬として使用される。アセチルサリチル酸 は、低温（約１３９℃）で溶解し、その温度で顕著な揮発性を示す物質である。 不安定なエステル基のために、アセチルサリチル酸は、加水分解やエステル交 換反応の影響を受けやすい。そのため、例えば、エステル交換反応または加水分 解反応において、水、アルコールおよびエステル類を可能な対(partner)で除去 すること、酢酸もしくは無水酢酸を添加すること、またはｐＨを２〜３に調整す ること等、多くの安定化の方法がこれまで考えられてきた。米国特許第4,228,16 2号明細書も安定化用の溶媒としてジメチルイソソルビドを開示している。 アセチルサリチル酸を含有する薬学的効果のある経皮吸収治療システムの開発 における大きな障害は、治療のために必要な１日用量の高さに比べて活性成分の 皮膚からの透過性が低いことである。そのため、アゾン、カルボン酸エステル、 表面活性物質等の多くの透過促進剤が添加物としてこれまで提案されている。 米国特許第5,164,416号明細書も、アセチルサリチル酸のための透過促進剤と して、リモネンを示しているが、その使用は、刺激可能性のあるアルカリ添加物 を同時に添加する場合に限定されている。さらに、この教示によれば、アセチル サリチル酸が透過される速度は、まだ十分高いとは言えない。 驚くべきことに、今般、リモネン(limonene)とジメチルイソソルビド(dimethy lisosorbide)を特定の比率の量で組み合わせて添加すれば、アセチルサリチル酸 の皮膚からの透過性が大きく改善されることがわかった。これは予測されていな かったことである。 したがって、最初に述べた本発明の経皮吸収治療システムは、本質的に、その 活性成分活性領域(activeingredient-activeregion)にリモネンとジメチルイソ ソルビドを５０：５０（ｇ／ｇ）以上の混合比で含有することを特徴とする。 前記問題に対するこの解決法は驚くべきものである。なぜなら、当業者は、良 好な溶媒である基剤によって、より良好な生物学的利用能をもつ薬用形態を達成 できるからである。尚、リモネンは、ジメチルイソソルビドを添加しても、アセ チルサリチル酸に対する溶解性は非常に低い。 本発明の特別な特徴を請求の範囲および以下の明細書で明らかにする。 本発明の原理は、マトリックスシステムならびに貯蔵部／薄膜システムにおい て利用できる。また、基剤であるアセチルサリチル酸、リモネンおよびジメチル イソソルビドを皮膚に供給するのに好適な剤型である限り、ポリマー類、樹脂類 およびその他の可能な添加物を添加してもかまわない。 最も簡単には、特徴となる３つの開始物質のすべてを基剤のポリマー溶液に溶 解または分散させることが可能である。また、その混合物を、通常はシリコン処 理した治療用シートである好適な基板上に塗布し、その後、必要に応じて加熱し て、溶媒含有物を蒸発させ、後に経皮吸収治療システムの裏側部分となる他のシ ートで被覆することが可能である。そのような積層体を求める形状（円形、楕円 等）の平らな構造に切断することによって、経皮吸収治療システムを得る。 しかしながら、さらに別の態様によれば、活性成分を分散もしくは溶解させた 形態で含有する皮膚側の層と、リモネンおよびジメチルイソソルビドを望ましい 混合比で含有する皮膚と反対側の第２の層からなる２層マトリックスを形成する ことができる。しかしながら、これらのデザインの変形は、当業者にとって公知 のシステムの多くの可能な概念中の最も単純なものにすぎない。したがって、２ 層より多くの層を備えたマトリックスシステムも当然可能である。また、必要に 応じて、さらに活性成分を備えることもできる。 本発明によるシステムとして好適な基剤であるポリマー類としては、特に、ア クリレートポリマー、スチレン／ジエンコポリマー類、シリコンポリマー類、ポ リイソブチレンと好適な熱可塑性樹脂との混合物が挙げられる。ここには、すべ てを挙げてはいないが、本発明の原理の適用可能性を広く示している。 リモネンとジメチルイソソルビドの混合比は、特に、５０：５０〜９９：１、 好ましくは８５：１５〜９５：５、特に９０：１０であることが好ましい。さら に、アセチルサリチル酸の濃度とほぼ同じリモネン含有物を含むことが可能であ り、また有用である。実施例１ 微粒化したアセチルサリチル酸２０ｇ、リモネン３０ｇおよびジメチルイソソ ルビド１ｇを、６００ｇのアクリレートコポリマー溶液（固体含有量：５０％ｇ ／ｇ）中に溶解または分散させる。 前記組成物を、シリコン処理したポリエステルシート（厚さ１００μｍ）上に 塗布し、単位面積当たりの重量が１５０ｇ／ｍ2の層にする。１０時間空気中で 室温で保存することによって、穏やかな条件のもとで乾燥させる。このようにし て得られたマトリックスに別のシート（厚さ１５μｍのポリエステルシート）を 重ねて積層体にし、パンチを用いて２０cm2の円形に切り抜く。 こうして、望ましい治療効果を生み出すために、シリコン処理したポリエステ ルシートから取り外して直ぐ皮膚に直接貼付することができる経皮吸収治療シス テムが得られる。実施例２ １）微粒化したアセチルサリチル酸２０ｇを、１６０ｇのアクリレートコポリ マー溶液（固体含有量：５０％（ｇ／ｇ））中に分散させる。前記組成物を、シ リコン処理したポリエステルシート（厚さ１００μｍ）上に塗布し、単位面積当 たりの重量が５２ｇ／ｍ2の層にする。１０時間空気中で室温で保存することに よって乾燥させる。このようにして得られたマトリックスに別のシート（厚さ１ ５μｍのポリエステルシート）を重ねて積層体にする。 ２）微粒化したアセチルサリチル酸２０ｇを、１６０ｇのアクリレートコポリ マー溶液（固体含有量：５０％（ｇ／ｇ））中に分散させる。前記組成物を、シ リコン処理したポリエステルシート（厚さ１００μｍ）上に塗布し、単位面積当 たりの重量が９３ｇ／ｍ2の層にする。１０時間空気中で室温で保存することに よって乾燥させる。 ２．５４cm2の円盤形の布（綿）を（２）の積層体の接着剤部分に塗布する。 室温で５時間攪拌し、続いて濾過することによって、アセチルサリチル酸で飽和 された、１０％（ｇ／ｇ）のジメチルイソソルビドと９０％（ｇ／ｇ）のリモネ ンとの混合物８．５ｍｇを前記円盤形の布に滴下する。（１）の積層体と円盤形 の布の接着剤側を層（２）で被覆し、その結果、ポリエステルシート（１５μｍ ）、５２ｇ／m2アセチルサリチル酸含有ポリアクリレート、ドープ処理された円 盤形の布２．５４cm2および９３ｇ／m2のアセチルサリチル酸含有ポリアクリレ ートからなるサンドイッチ構造を形成し、次にその接着剤側を、滑らかな作用(a bhesive action)を有する、シリコン処理されたポリエステル保護シートで被覆 する。 円盤形の布が中央に位置するように、この積層体を７．１０cm2の円形に切断 する。切除したラットの皮膚に塗布して、生体外での透過性を測定する。 ４８時間後のアセチルサリチル酸の平均透過量は、６３２．６μｇ／cm2であ った。実施例３（実施例２との比較例） 層１および２は、実施例２と同様にして製造する。 ２．５４cm2の円盤形の布（綿）を（２）の積層体の接着剤部分に塗布する。 室温で５時間攪拌し、続いて濾過することによってアセチルサリチル酸で飽和さ れた８．５ｇの純粋なジメチルイソソルビドを前記円盤形の布に滴下する。（１ ）の積層体と円盤形の布を実施例２と同様にして切断し、７．１０cm2の試験布 を作成する。切除したラットの皮膚での透過性の測定も同様に行った。 ４８時間後のアセチルサリチル酸の平均透過量は、１３０．４μｇ／cm2であ った。実施例４（実施例２との比較例） 層１および２は、実施例２と同様にして製造する。 ２．５４cm2の円盤形の布（綿）を（２）の積層体の接着剤部分に塗布する。 常温で５時間攪拌し、続いて濾過することによってアセチルサリチル酸で飽和さ れた８．５ｇの純粋なリモネンを前記円盤形の布に滴下する。（１）の積層体と 円盤形の布を実施例２と同様にして切断し、７．１０cm2の試験布を作成する。 、切除されたラットの皮膚での透過性の測定も同様に行った。 ４８時間後のアセチルサリチル酸の平均透過性は、２５３．３μｇ／cm2であ った。実施例５（実施例２との比較） 層１および２は、実施例２と同様にして製造する。 ２．５４cm2の円盤形の布（綿）を（２）の積層体の接着剤部分に塗布する。 媒体の滴下は行わない。（１）の積層体と円盤形の布を実施例２と同様に切断し 、７．１０cm2の試験布を作成する。切除されたラットの皮膚での透過性の測定 も同様に行った。 ４８時間後のアセチルサリチル酸の平均透過量は、５２．９μｇ／cm2であっ た。 実施例２〜５の透過性の比較から、本発明のシステムがすぐれていることが明 らかである。The present invention relates to a transdermal therapeutic system containing acetylsalicylic acid with enhanced absorbability. The present invention provides a backing layer, an active ingredient reservoir, and a storage medium that are essentially impermeable to active ingredients and moisture. Accordingly, the present invention relates to an acetylsalicylic acid-containing transdermal therapeutic system having a protective layer that can be removed again. Transdermal therapeutic systems (TTS) are already commercially available for medical treatment of many diseases. It is also known that, in theory, the active ingredient acetylsalicylic acid can penetrate human skin and thus be a suitable active ingredient. So far, Rougier et al. Have reported (substantially low) dependence of the rate at which acetylsalicylic acid is bioabsorbed on selected sites of the skin (Journal of Pharmaceutical Sciences (J. Pharm. Sci. 176, 451-454, 1987)). Acetylsalicylic acid is a relatively safe drug substance with a high therapeutic index. It is very anti-arrhythmic at high doses (> 1 g / day), antipyretic / analgesic at medium doses (250-500 mg) and at low doses (30-150 mg / day). , Used as a platelet aggregation inhibitor. Acetylsalicylic acid is a substance that dissolves at low temperatures (about 139 ° C.) and exhibits significant volatility at that temperature. Because of the unstable ester groups, acetylsalicylic acid is susceptible to hydrolysis and transesterification. Thus, for example, in a transesterification or hydrolysis reaction, removal of water, alcohols and esters in possible partners, addition of acetic acid or acetic anhydride, or adjustment of the pH to 2-3. Many stabilization methods have been considered. U.S. Pat. No. 4,228,162 also discloses dimethylisosorbide as a stabilizing solvent. A major obstacle in the development of pharmaceutically effective transdermal therapeutic systems containing acetylsalicylic acid is the low permeability of the active ingredient from the skin compared to the high daily dose required for treatment. . For this reason, many permeation enhancers such as azone, carboxylic acid esters, and surface active substances have been proposed as additives. U.S. Pat. No. 5,164,416 also shows limonene as a permeation enhancer for acetylsalicylic acid, but its use is limited to the simultaneous addition of potentially irritating alkali additives. Furthermore, according to this teaching, the rate at which acetylsalicylic acid permeates is not yet sufficiently high. Surprisingly, it has now been found that the combined addition of limonene and dimethy lisosorbide in specific proportions greatly improves the permeability of acetylsalicylic acid from the skin. This was unexpected. Therefore, the first-mentioned transdermal therapeutic system of the present invention essentially contains limonene and dimethyl isosorbide in a mixing ratio of 50:50 (g / g) or more in its active ingredient-active region. It is characterized by doing. This solution to the above problem is surprising. Because a person skilled in the art can achieve a medicinal form with better bioavailability by using a base that is a good solvent. Note that limonene has a very low solubility in acetylsalicylic acid even when dimethyl isosorbide is added. Particular features of the invention are set forth in the claims and the following description. The principles of the present invention can be used in matrix systems as well as reservoir / thin film systems. In addition, polymers, resins and other possible additives may be added as long as the dosage form is suitable for supplying the bases acetylsalicylic acid, limonene and dimethylisosorbide to the skin. Most simply, it is possible to dissolve or disperse all three characteristic starting materials in the base polymer solution. Also, the mixture is applied to a suitable substrate, usually a siliconized therapeutic sheet, and then, if necessary, heated to evaporate the solvent content and later to the backside of the transdermal therapeutic system. It is possible to cover with other sheets that By cutting such a laminate into a flat structure of the desired shape (circular, oval, etc.), a transdermal therapeutic system is obtained. However, according to yet another aspect, it comprises a skin-side layer containing the active ingredient in dispersed or dissolved form and a second layer opposite the skin containing limonene and dimethylisosorbide in the desired mixing ratio. A two-layer matrix can be formed. However, these design variants are but the simplest of many possible concepts of systems known to those skilled in the art. Thus, matrix systems with more than two layers are of course also possible. Further, if necessary, an active ingredient can be further provided. Suitable base polymers for the system according to the invention include, in particular, acrylate polymers, styrene / diene copolymers, silicone polymers, mixtures of polyisobutylene with suitable thermoplastics. This is not an exhaustive list, but broadly illustrates the applicability of the principles of the present invention. The mixing ratio of limonene and dimethyl isosorbide is preferably from 50:50 to 99: 1, more preferably from 85:15 to 95: 5, especially preferably 90:10. In addition, it is possible and useful to include limonene-containing material at about the same concentration as acetylsalicylic acid. Example 1 20 g of micronized acetylsalicylic acid, 30 g of limonene and 1 g of dimethyl isosorbide are dissolved or dispersed in 600 g of an acrylate copolymer solution (solids content: 50% g / g). The composition is applied on a siliconized polyester sheet (100 μm thick) to form a layer having a weight per unit area of 150 g / m 2 . Dry under mild conditions by storing at room temperature in air for 10 hours. Another sheet (a polyester sheet having a thickness of 15 μm) is overlaid on the matrix thus obtained to form a laminate, which is cut into a circular shape of 20 cm 2 using a punch. Thus, a transdermal therapeutic system is provided that can be removed from the siliconized polyester sheet and applied directly to the skin to produce the desired therapeutic effect. Example 2 1) 20 g of micronized acetylsalicylic acid are dispersed in 160 g of an acrylate copolymer solution (solid content: 50% (g / g)). The composition is applied on a siliconized polyester sheet (100 μm thick) to form a layer having a weight per unit area of 52 g / m 2 . Dry by storing at room temperature in air for 10 hours. Another sheet (a 15 μm-thick polyester sheet) is stacked on the matrix thus obtained to form a laminate. 2) Disperse 20 g of micronized acetylsalicylic acid in 160 g of acrylate copolymer solution (solids content: 50% (g / g)). The composition is applied on a siliconized polyester sheet (100 μm thick) to form a layer having a weight per unit area of 93 g / m 2 . Dry by storing at room temperature in air for 10 hours. A 2.54 cm 2 disk-shaped cloth (cotton) is applied to the adhesive portion of the laminate of (2). By stirring at room temperature for 5 hours, followed by filtration, 8.5 mg of a mixture of 10% (g / g) dimethylisosorbide and 90% (g / g) limonene, saturated with acetylsalicylic acid, was added to the disc. Drip on a shaped cloth. The adhesive side of the laminate of (1) and the disc-shaped cloth is coated with a layer (2), resulting in a polyester sheet (15 μm), a polyacrylate containing 52 g / m 2 acetylsalicylic acid, a doped disc-shaped Cloth 2.54 cm 2 and 93 g / m 2 of acetylsalicylic acid-containing polyacrylate sandwich structure, the adhesive side of which is treated with a bhesive action, siliconized polyester protective sheet Cover with. The laminate is cut into circles of 7.10 cm 2 such that the disc-shaped cloth is located in the center. It is applied to the excised rat skin and the permeability in vitro is measured. The average permeation amount of acetylsalicylic acid after 48 hours was 632.6 μg / cm 2 . Example 3 (Comparative Example with Example 2) Layers 1 and 2 are manufactured in the same manner as in Example 2. A 2.54 cm 2 disk-shaped cloth (cotton) is applied to the adhesive portion of the laminate of (2). Stir at room temperature for 5 hours, then add 8.5 g of pure dimethylisosorbide saturated with acetylsalicylic acid by filtration to the disc-shaped cloth. The laminate (1) and the disk-shaped cloth are cut in the same manner as in Example 2 to prepare a test cloth of 7.10 cm 2 . Permeability measurements on excised rat skin were similarly performed. The average permeation amount of acetylsalicylic acid after 48 hours was 130.4 μg / cm 2 . Example 4 (Comparative Example with Example 2) Layers 1 and 2 are manufactured in the same manner as in Example 2. A 2.54 cm 2 disk-shaped cloth (cotton) is applied to the adhesive portion of the laminate of (2). Stir at room temperature for 5 hours, then add 8.5 g of pure limonene saturated with acetylsalicylic acid by filtration to the disc-shaped cloth. The laminate of (1) and the disc-shaped cloth are cut in the same manner as in Example 2 to prepare a test cloth of 7.10 cm 2 . The measurement of the permeability of the excised rat skin was performed in the same manner. The average permeability of acetylsalicylic acid after 48 hours was 253.3 μg / cm 2 . Example 5 (Comparison with Example 2) Layers 1 and 2 are manufactured in the same manner as in Example 2. A 2.54 cm 2 disk-shaped cloth (cotton) is applied to the adhesive portion of the laminate of (2). No medium is dropped. The laminate of (1) and the disc-shaped cloth are cut in the same manner as in Example 2 to prepare a test cloth of 7.10 cm 2 . Permeability measurements on excised rat skin were performed similarly. The average permeation amount of acetylsalicylic acid after 48 hours was 52.9 μg / cm 2 . From the comparison of the permeability of Examples 2 to 5, it is clear that the system of the present invention is superior.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 キンデル、ハインリッヒ ドイツ、デー 56581 エールシャイド フリーデアヴェーグ ５ (72)発明者 マーフィー、テレサ、マリア イギリス、エヌピー44 ３ピーエックス グェント、クムブラン、サウスヴィル、ホ ワイト ブルーク ウェイ ３────────────────────────────────────────────────── ─── Continuation of front page (72) Kinder and Heinrich, inventors Germany, Day 56581 Alescheid Frieda Aweg 5 (72) Inventors Murphy, Teresa, Maria UK, NP44 3PEX Ghent, Cumbrant, Southville, E Wight Brooke Way 3
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19701059.8 | 1997-01-15 | ||
| DE19701059A DE19701059C2 (en) | 1997-01-15 | 1997-01-15 | Transdermal therapeutic system with absorption enhancement containing acetylsalicylic acid |
| PCT/EP1998/000013 WO1998031348A1 (en) | 1997-01-15 | 1998-01-03 | Transdermal, acetylsalicylic acid-containing therapeutic system with reinforced resorption |
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| JP2001508069A true JP2001508069A (en) | 2001-06-19 |
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| JP53137698A Pending JP2001508069A (en) | 1997-01-15 | 1998-01-03 | Acetylsalicylic acid-containing transdermal therapeutic system with enhanced absorbability |
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| Country | Link |
|---|---|
| EP (1) | EP1023053A1 (en) |
| JP (1) | JP2001508069A (en) |
| KR (1) | KR20000070228A (en) |
| AU (1) | AU726094B2 (en) |
| CA (1) | CA2277366A1 (en) |
| DE (1) | DE19701059C2 (en) |
| NO (1) | NO993435L (en) |
| WO (1) | WO1998031348A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009512645A (en) * | 2005-10-21 | 2009-03-26 | エルテーエス ローマン テラピー−ジステーメ アーゲー | Transdermal therapeutic system for administering lipophilic and / or low skin-penetrating active substances |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19949202A1 (en) * | 1999-10-13 | 2001-05-03 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for the delivery of acetylsalicylic acid and / or salicylic acid |
| DE19949252B4 (en) * | 1999-10-13 | 2004-02-12 | Lts Lohmann Therapie-Systeme Ag | Use of a superficial therapeutic system for the topical application of acetylsalicylic acid for the treatment of acne disorders and process for its preparation |
| DE19959913A1 (en) * | 1999-12-11 | 2001-06-28 | Lohmann Therapie Syst Lts | Transdermal system for the treatment of migraines containing acetylsalicylic acid |
| KR100448469B1 (en) * | 2001-10-26 | 2004-09-13 | 신풍제약주식회사 | Transdermal composition and device of anti-inflammatory agents |
| DE60227691D1 (en) | 2001-11-01 | 2008-08-28 | Nektar Therapeutics | SPRAY DRYING PROCESS |
| DE10338162B3 (en) † | 2003-08-20 | 2005-06-02 | Haldex Brake Products Gmbh | Method for operating a compressed air procurement system of a motor vehicle and compressed air treatment device |
| DE102005033543A1 (en) * | 2005-07-14 | 2007-01-18 | Grünenthal GmbH | A fragrance-containing transdermal therapeutic system |
| IT202000014578A1 (en) * | 2020-06-18 | 2021-12-18 | Poli Md S R L | MEDICAL DEVICE INCLUDING ACETYL SALICYLIC ACID |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4228162A (en) * | 1979-07-09 | 1980-10-14 | Research Corporation | Dimethyl isosorbide in liquid formulation of aspirin |
| US5164416A (en) * | 1989-02-03 | 1992-11-17 | Lintec Corporation | Transdermal therapeutic formulation containing a limonene |
| DE4332093C2 (en) * | 1993-09-22 | 1995-07-13 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with the active ingredient acetylsalicylic acid and process for its preparation |
| DE4332094C2 (en) * | 1993-09-22 | 1995-09-07 | Lohmann Therapie Syst Lts | Active substance plaster which can be produced without solvent and process for its preparation |
-
1997
- 1997-01-15 DE DE19701059A patent/DE19701059C2/en not_active Expired - Fee Related
-
1998
- 1998-01-03 EP EP98902976A patent/EP1023053A1/en not_active Withdrawn
- 1998-01-03 WO PCT/EP1998/000013 patent/WO1998031348A1/en not_active Application Discontinuation
- 1998-01-03 CA CA002277366A patent/CA2277366A1/en not_active Abandoned
- 1998-01-03 JP JP53137698A patent/JP2001508069A/en active Pending
- 1998-01-03 AU AU59862/98A patent/AU726094B2/en not_active Ceased
- 1998-01-03 KR KR1019997006454A patent/KR20000070228A/en not_active Application Discontinuation
-
1999
- 1999-07-12 NO NO993435A patent/NO993435L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009512645A (en) * | 2005-10-21 | 2009-03-26 | エルテーエス ローマン テラピー−ジステーメ アーゲー | Transdermal therapeutic system for administering lipophilic and / or low skin-penetrating active substances |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5986298A (en) | 1998-08-07 |
| KR20000070228A (en) | 2000-11-25 |
| DE19701059C2 (en) | 2000-12-21 |
| CA2277366A1 (en) | 1998-07-23 |
| EP1023053A1 (en) | 2000-08-02 |
| NO993435D0 (en) | 1999-07-12 |
| NO993435L (en) | 1999-07-12 |
| DE19701059A1 (en) | 1998-07-16 |
| AU726094B2 (en) | 2000-11-02 |
| WO1998031348A1 (en) | 1998-07-23 |
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