TWI764173B - 含羅替戈汀之貼附劑 - Google Patents
含羅替戈汀之貼附劑Info
- Publication number
- TWI764173B TWI764173B TW109119888A TW109119888A TWI764173B TW I764173 B TWI764173 B TW I764173B TW 109119888 A TW109119888 A TW 109119888A TW 109119888 A TW109119888 A TW 109119888A TW I764173 B TWI764173 B TW I764173B
- Authority
- TW
- Taiwan
- Prior art keywords
- adhesive layer
- rotigotine
- mass
- mentioned
- content
- Prior art date
Links
- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 title claims abstract description 102
- 229960003179 rotigotine Drugs 0.000 title claims abstract description 101
- 239000012790 adhesive layer Substances 0.000 claims abstract description 125
- 125000002723 alicyclic group Chemical group 0.000 claims abstract description 39
- 229930195734 saturated hydrocarbon Natural products 0.000 claims abstract description 39
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- 229920006270 hydrocarbon resin Polymers 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000010410 layer Substances 0.000 claims abstract description 32
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 20
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 claims abstract description 11
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 claims abstract description 9
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940043348 myristyl alcohol Drugs 0.000 claims abstract description 7
- 229940055577 oleyl alcohol Drugs 0.000 claims abstract description 7
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims abstract description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 36
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- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 10
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 10
- 229940057995 liquid paraffin Drugs 0.000 description 10
- 230000035515 penetration Effects 0.000 description 10
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 10
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- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 5
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- 102000005962 receptors Human genes 0.000 description 4
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
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- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
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- 125000001931 aliphatic group Chemical group 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
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- 229940093915 gynecological organic acid Drugs 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
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- GRWFGVWFFZKLTI-IUCAKERBSA-N (-)-α-pinene Chemical compound CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- RXQKKPDQYISKHD-UHFFFAOYSA-N 2-ethylhexyl prop-2-enoate;prop-2-enoic acid Chemical compound OC(=O)C=C.CCCCC(CC)COC(=O)C=C RXQKKPDQYISKHD-UHFFFAOYSA-N 0.000 description 2
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Abstract
本發明之含羅替戈汀之貼附劑係具備支持體層及黏著劑層，且上述黏著劑層含有羅替戈汀及/或其藥學上容許之鹽者，
上述黏著劑層進而含有脂環族飽和烴樹脂、與選自由月桂醇、辛基十二烷醇、油醇、及肉豆蔻醇所組成之群中之至少1種脂肪族醇。
Description
本發明係關於一種含羅替戈汀之貼附劑，更詳細而言係關於一種含有羅替戈汀及/或其藥學上容許之鹽之貼附劑。
羅替戈汀係化合物(-)-5,6,7,8-四氫-6-[丙基-[2-(2-噻吩基)乙基]-胺基]1-萘酚之國際非專有名稱。羅替戈汀係D1/D2/D3多巴胺受體促效劑，主要用於治療帕金森氏症或不寧腿症候群之症狀。
作為用於投予羅替戈汀之製劑，例如，於日本國內外市售有「Neupro(註冊商標)貼片」。又，日本專利特開2010-159302號公報(專利文獻1)中，作為用於治療不寧腿症候群之經外表皮投予形式，記載有一種具有含有羅替戈汀之自接著性基質層之經皮吸收治療系統；日本專利特表2002-509878號公報(專利文獻2)中記載有一種經皮治療系統，其包含相對於基質成分呈惰性之襯底層與含有羅替戈汀之自接著性基質層，且基質以羅替戈汀之溶解度為5%(w/w)以上且非水溶性之丙烯酸酯系或矽酮系之聚合物接著劑作為基材。進而，國際公開第2012/084969號(專利文獻3)中記載有一種經皮吸收系統，其具備由含有苯乙烯系聚合物及/或聚異丁烯、羅替戈汀或其製藥上可容許之鹽、聚乙烯吡咯啶酮或乙烯吡咯啶酮及/或乙酸乙烯酯之黏著劑組合物所形成之黏著劑層。
又，例如，日本專利特開2014-177428號公報(專利文獻4)中記載有經皮吸收型貼附製劑，其包含：支持體、及含藥物層，該含藥物層含有包含松香系樹脂及橡膠系黏著成分之橡膠系黏著劑以及羅替戈汀或其製藥上可容許之鹽；日本專利特開2018-123131號公報(專利文獻5)中記載有一種經皮吸收型貼附劑，其包含支持體、含藥物層及剝離襯墊，該含藥物層含有羅替戈汀、聚異丁烯系黏著劑、液態石蠟及聚乙烯吡咯啶酮。
先前技術文獻
專利文獻
專利文獻1：日本專利特開2010-159302號公報
專利文獻2：日本專利特表2002-509878號公報
專利文獻3：國際公開第2012/084969號
專利文獻4：日本專利特開2014-177428號公報
專利文獻5：日本專利特開2018-123131號公報
[發明所欲解決之問題]
然而，本發明者等人針對含有羅替戈汀及/或其藥學上容許之鹽之含羅替戈汀之貼附劑進行進一步之研究，結果發現以下問題。即，一直以來，作為貼附劑中所含有之黏著賦予劑或藥物之經皮吸收促進劑，已知有眾多劑，但本發明者等人發現即便含有該等劑，先前之含有羅替戈汀及/或其藥學上容許之鹽之含羅替戈汀之貼附劑中，亦存在尚未達成充分之羅替戈汀之皮膚透過性之情形。
本發明係鑒於上述課題而成者，其目的在於提供一種羅替戈汀之皮膚透過性優異之貼附劑。
[解決問題之技術手段]
本發明者等人為了達成上述目的，反覆進行銳意研究，結果發現，於具備支持體層及黏著劑層之貼附劑中，藉由上述黏著劑層中組合含有選自由羅替戈汀及其藥學上容許之鹽所組成之群中之至少1種(以下，視情形稱為「羅替戈汀及/或其藥學上容許之鹽」)、脂環族飽和烴樹脂、及特定之脂肪族醇，從而相較於使用其他黏著賦予劑或經皮吸收促進劑之情形，達成尤高水準之羅替戈汀之皮膚透過性，從而完成本發明。
即，本發明之含羅替戈汀之貼附劑係具備支持體層及黏著劑層，且上述黏著劑層含有羅替戈汀及/或其藥學上容許之鹽者，
上述黏著劑層進而含有脂環族飽和烴樹脂、及選自由月桂醇、辛基十二烷醇、油醇、及肉豆蔻醇所組成之群中之至少1種脂肪族醇。
本發明之含羅替戈汀之貼附劑中，較佳為，上述黏著劑層中之上述脂肪族醇之含量相對於上述黏著劑層之總質量，為1～15質量%。又，亦較佳為，上述黏著劑層中之羅替戈汀及/或其藥學上容許之鹽換算成羅替戈汀游離體之含量相對於上述黏著劑層之總質量，為5～15質量%。
進而，本發明之含羅替戈汀之貼附劑中，較佳為，上述黏著劑層中之上述脂環族飽和烴樹脂之含量相對於上述黏著劑層之總質量，為5～80質量%，又，亦較佳為，上述黏著劑層進而含有苯乙烯系熱塑性彈性體。作為上述黏著劑層中之上述苯乙烯系熱塑性彈性體之含量，更佳為相對於上述黏著劑層之總質量為5～50質量%。
進而，本發明之含羅替戈汀之貼附劑中，較佳為，上述黏著劑層進而含有塑化劑，更佳為，上述黏著劑層中之上述塑化劑之含量相對於上述黏著劑層之總質量為4～50質量%。
[發明之效果]
根據本發明，可提供一種羅替戈汀之皮膚透過性尤其優異之含羅替戈汀之貼附劑。
以下，根據較佳之實施方式詳細地說明本發明。本發明之含羅替戈汀之貼附劑係具備支持體層及黏著劑層，且上述黏著劑層含有羅替戈汀及/或其藥學上容許之鹽者，
上述黏著劑層進而含有脂環族飽和烴樹脂、及選自由月桂醇、辛基十二烷醇、油醇、及肉豆蔻醇所組成之群中之至少1種脂肪族醇。
本發明之含羅替戈汀之貼附劑具備支持體層及黏著劑層。作為上述支持體層，只要為可支持後述之黏著劑層者，則無特別限制，作為貼附劑之支持體層，可適當採用公知者。作為本發明之支持體層之材質，例如可例舉：聚乙烯、聚丙烯等聚烯烴；乙烯-乙酸乙烯酯共聚物、乙酸乙烯酯-氯乙烯共聚物、聚氯乙烯等；尼龍等聚醯胺；聚對苯二甲酸乙二酯(PET)、聚對苯二甲酸丁二酯、聚萘二甲酸乙二酯等聚酯；纖維素衍生物；聚胺酯等合成樹脂、或鋁等金屬。該等之中，就藥物非吸附性或藥物非透過性之觀點而言，較佳為聚酯、聚對苯二甲酸乙二酯。作為上述支持體層之形態，例如可例舉：膜；片材、片狀多孔質體、片狀發泡體等片材類；織布、編織布、不織布等布帛；箔；及該等之積層體。又，上述支持體層之厚度無特別限制，就貼附貼附劑時之作業容易性及製造容易性之觀點而言，較佳為5～1000 μm之範圍內。
本發明之含羅替戈汀之貼附劑亦可為於上述黏著劑層之與上述支持體層相反之面上進而具備剝離襯墊者。作為上述剝離襯墊，可例舉包含聚乙烯、聚丙烯等聚烯烴；乙烯-乙酸乙烯酯共聚物、乙酸乙烯酯-氯乙烯共聚物、聚氯乙烯等；尼龍等聚醯胺；聚對苯二甲酸乙二酯等聚酯；纖維素衍生物；聚胺酯等合成樹脂、或鋁、紙等材質之膜或片材及該等之積層體。作為該等剝離襯墊，較佳為對與該黏著劑層接觸之側之面實施了含矽酮化合物塗佈或含氟化合物塗佈等離型處理以使剝離襯墊可自上述黏著劑層容易地剝離者。
＜羅替戈汀及其藥學上容許之鹽＞
本發明之黏著劑層含有選自由羅替戈汀及其藥學上容許之鹽所組成之群中之至少1種作為藥物。於本發明中，作為上述黏著劑層中所含有之羅替戈汀之形態，可為游離體(自由體)亦可為其藥學上容許之鹽，可為製造過程中及/或製造完成之製劑中，羅替戈汀於藥學上容許之鹽經除鹽而成為自由體者，亦可為該等中之1種或2種以上之混合物。作為羅替戈汀於藥學上容許之鹽，可例舉酸加成鹽，作為上述酸加成鹽之酸，例如可例舉：鹽酸、硫酸、硝酸、磷酸、亞磷酸、氫溴酸、順丁烯二酸、蘋果酸、抗壞血酸、酒石酸、月桂酸、硬脂酸、棕櫚酸、油酸、肉豆蔻酸、月桂基硫酸、次亞麻油酸、反丁烯二酸。該等之中，作為本發明之黏著劑層，較佳為以游離體之形態含有羅替戈汀。
於本發明中，作為上述黏著劑層中所含有之羅替戈汀及/或其藥學上容許之鹽之含量(羅替戈汀之含量或羅替戈汀於藥學上容許之鹽之含量、或者於兩者均含有之情形時為其等之合計含量，以下相同)，以羅替戈汀游離體換算，相對於上述黏著劑層之總質量，較佳為5～15質量%，更佳為7～14質量%，進而較佳為7～12質量%，進而更佳為8～12質量%，特佳為8～10質量%。若羅替戈汀及/或其藥學上容許之鹽之含量未達上述下限，則存在羅替戈汀之皮膚透過性下降之傾向，另一方面，若超過上述上限，則存在羅替戈汀及/或其藥學上容許之鹽之結晶析出，或產生非晶質型，或黏著劑層之黏著力變得容易下降之傾向。
＜脂環族飽和烴樹脂＞
本發明之黏著劑層進而含有脂環族飽和烴樹脂。於本發明中，藉由上述黏著劑層組合含有上述脂環族飽和烴樹脂與下述特定之脂肪族醇，從而達成尤高水準之皮膚透過性。已知有上述脂環族飽和烴樹脂主要作為黏著基劑之黏著賦予劑發揮功能，若本發明之黏著劑層中含有其他黏著賦予劑代替上述脂環族飽和烴樹脂，則存在羅替戈汀之皮膚透過性下降之傾向。
本發明之上述所謂脂環族飽和烴樹脂，係指作為脂環族飽和烴單體之均聚物或共聚物之脂環族系氫化石油樹脂。作為上述脂環族飽和烴樹脂，重量平均分子量較佳為1,000～1,500，更佳為1,200～1,400。作為本發明之脂環族飽和烴樹脂，可單獨使用該等中之1種，亦可組合2種以上使用。作為上述脂環族飽和烴樹脂，更具體而言，可例舉：Arkon P-70、Arkon P-85、Arkon P-90、Arkon P-100、Arkon P-115、Arkon P-125(以上為商品名，荒川化學工業股份有限公司製造)。
於本發明中，作為上述黏著劑層中所含有之上述脂環族飽和烴樹脂之含量(於組合2種以上之上述脂環族飽和烴樹脂之情形時為其等之合計含量，以下相同)，相對於上述黏著劑層之總質量，較佳為5～80質量%，更佳為10～70質量%，進而較佳為10～60質量%，進而更佳為20～60質量%，特佳為20～50質量%。若上述脂環族飽和烴樹脂之含量未達上述下限，則存在黏著劑層之黏著力或對皮膚之附著性下降之傾向，另一方面，若超過上述上限，則存在羅替戈汀之經皮吸收性或黏著劑層之保形性下降之傾向。就羅替戈汀之經皮吸收性之觀點而言，作為上述脂環族飽和烴樹脂之含量，亦較佳為10～50質量%。
＜脂肪族醇＞
本發明之黏著劑層進而含有選自由月桂醇、辛基十二烷醇、油醇、及肉豆蔻醇所組成之群中之至少1種脂肪族醇。再者，於本發明中，所謂脂肪族醇，係指飽和或不飽和之直鏈狀或支鏈狀之1價或2價以上之脂肪族醇。含羅替戈汀之貼附劑中，存在即便使用該等4種以外之脂肪族醇，亦不會發揮充分之羅替戈汀之皮膚透過性之傾向，進而，於使用碳數為6以下之脂肪族醇之情形時，由於沸點變低，故存在難以定量地確保製劑中之含量，經時穩定性下降之傾向。
於本發明中，作為上述黏著劑層中所含有之上述脂肪族醇之含量(於組合2種以上之上述脂肪族醇之情形時為其等之合計含量，以下相同)，相對於上述黏著劑層之總質量，較佳為1～15質量%，更佳為1～10質量%，進而較佳為2～10質量%，進而更佳為2～7質量%，特佳為3～7質量%。若上述脂肪族醇之含量未達上述下限，則存在羅替戈汀之皮膚透過性下降之傾向，另一方面，若超過上述上限，則存在與黏著基劑或其他成分之相容性下降之傾向。
又，於本發明中，作為上述黏著劑層中所含有之上述脂環族飽和烴樹脂之含量與上述脂肪族醇之含量之質量比(脂環族飽和烴樹脂之含量：脂肪族醇之含量)，較佳為17：1～2：1，更佳為12：1～3：1，進而較佳為10：1～5：1。若相對於上述脂肪族醇之含量，上述脂環族飽和烴樹脂之含量未達上述下限，則存在黏著劑層之黏著力或對皮膚之附著性下降之傾向，另一方面，若超過上述上限，則存在羅替戈汀之經皮吸收性下降之傾向。就羅替戈汀之經皮吸收性之觀點而言，上述質量比亦較佳為10：1～2：1。
＜黏著基劑＞
本發明之黏著劑層含有黏著基劑。作為上述黏著基劑，無特別限定，可例舉：橡膠系黏著基劑、丙烯酸系黏著基劑、及矽酮系黏著基劑，可單獨使用該等中之1種，亦可組合2種以上使用，較佳為至少含有橡膠系黏著基劑。
(橡膠系黏著基劑)
作為上述橡膠系黏著基劑，可例舉：苯乙烯系熱塑性彈性體、異戊二烯橡膠、聚異丁烯(PIB)、聚丁烯等，可單獨使用該等中之1種，亦可組合2種以上使用，該等之中，特佳為苯乙烯系熱塑性彈性體。上述所謂苯乙烯系熱塑性彈性體，係指若加熱則軟化而表現出流動性，若冷卻則表現出回復至橡膠狀彈性體之熱塑性的苯乙烯系彈性體。其中，就充分之黏著性賦予及經時穩定性之觀點而言，較佳為苯乙烯系嵌段共聚物。
作為上述苯乙烯系嵌段共聚物，具體而言，可例舉：苯乙烯-丁二烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-異戊二烯嵌段共聚物、苯乙烯-異戊二烯-苯乙烯嵌段共聚物(SIS)、苯乙烯-乙烯/丁烯嵌段共聚物、苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物、苯乙烯-乙烯/丙烯嵌段共聚物、苯乙烯-乙烯/丙烯-苯乙烯嵌段共聚物、苯乙烯-異丁烯嵌段共聚物、苯乙烯-異丁烯-苯乙烯嵌段共聚物等，可單獨使用該等中之1種，亦可組合2種以上使用。再者，上述中，「乙烯/丁烯」表示乙烯及丁烯之共聚物嵌段，「乙烯/丙烯」表示乙烯及丙烯之共聚物嵌段。該等之中，作為本發明之苯乙烯系熱塑性彈性體，更佳為苯乙烯-異戊二烯-苯乙烯嵌段共聚物。
作為上述苯乙烯-異戊二烯-苯乙烯嵌段共聚物，黏度平均分子量較佳為30,000～2,500,000，更佳為100,000～1,700,000。若上述黏度平均分子量未達上述下限值，則存在貼附劑之製劑物性(尤其是黏著劑層之凝集力)下降之傾向，另一方面，若超過上述上限值，則存在與黏著劑層中所含有之其他成分之相容性下降，導致貼附劑之製造變得困難之傾向。
於本發明中，當於上述黏著劑層中含有上述苯乙烯系熱塑性彈性體作為上述黏著基劑時，作為其含量(於組合2種以上之上述苯乙烯系熱塑性彈性體之情形時為其等之合計含量，以下相同)，相對於上述黏著劑層之總質量，較佳為5～50質量%，更佳為10～40質量%，進而較佳為10～30質量%。若上述苯乙烯系熱塑性彈性體之含量未達上述下限，則存在黏著劑層之凝集力或保形性等下降之傾向，另一方面，若超過上述上限，則存在黏著劑層之凝集力過度地增加，導致黏著劑層之黏著力下降或相容性下降之傾向。
又，作為上述橡膠系黏著基劑，就存在進一步提高黏著劑層之黏著性及凝集力之傾向之觀點而言，更佳為苯乙烯系熱塑性彈性體(更佳為苯乙烯-異戊二烯-苯乙烯嵌段共聚物)及聚異丁烯之組合，進而較佳為上述苯乙烯系熱塑性彈性體與聚異丁烯之質量比(苯乙烯系熱塑性彈性體之質量：PIB之質量)為1：2～30：1(進而較佳為1：1～10：1之範圍)。
於本發明中，當於上述黏著劑層中含有橡膠系黏著基劑作為上述黏著基劑時，作為其含量(於2種以上之組合之情形時為其等之合計含量，以下相同)，相對於上述黏著劑層之總質量，較佳為1～60質量%，更佳為5～50質量%，進而較佳為10～40質量%。
(丙烯酸系黏著基劑)
作為上述丙烯酸系黏著基劑，可例舉：「醫藥品添加物事典2016(日本醫藥品添加劑協會編輯)」中作為黏著劑收錄之丙烯酸·丙烯酸辛酯共聚物、丙烯酸2-乙基己酯·乙烯吡咯啶酮共聚物、丙烯酸酯·乙酸乙烯酯共聚物、丙烯酸2-乙基己酯·甲基丙烯酸2-乙基己酯·甲基丙烯酸十二烷基酯共聚物、丙烯酸甲酯·丙烯酸2-乙基己酯共聚樹脂、丙烯酸2-乙基己酯·丙烯酸甲酯·丙烯酸·甲基丙烯酸縮水甘油酯共聚物、丙烯酸2-乙基己酯·乙酸乙烯酯·丙烯酸羥基乙酯·甲基丙烯酸縮水甘油酯共聚物、丙烯酸2-乙基己酯·二丙酮丙烯醯胺·甲基丙烯酸乙醯乙醯氧基乙酯·甲基丙烯酸甲酯共聚物、丙烯酸乙酯·甲基丙烯酸甲酯共聚物、丙烯酸樹脂烷醇胺液中所含有之丙烯酸系高分子等，可單獨使用該等中之1種，亦可組合2種以上使用。
(矽酮系黏著基劑)
作為上述矽酮系黏著基劑，可例舉：聚二甲基矽氧烷(ASTM D-1418之表述中表示為MQ之聚合物等)、聚甲基乙烯基矽氧烷(ASTM D-1418之表述中表示為VMQ之聚合物等)、聚甲基苯基矽氧烷(ASTM D-1418之表述中表示為PVMQ之聚合物等)等，可單獨使用該等中之1種，亦可組合2種以上使用。
於本發明中，當於上述黏著劑層中含有上述丙烯酸系黏著基劑及/或矽酮系黏著基劑作為上述黏著基劑時，作為其含量(於2種以上之組合之情形時為其等之合計含量，以下相同)，相對於上述黏著劑層之總質量，較佳為10質量%以下。
＜其他成分＞
作為本發明之黏著劑層，於不損害本發明之效果之範圍內，亦可進而含有羅替戈汀及其藥學上容許之鹽以外之其他藥物；上述脂環族飽和烴樹脂以外之其他黏著賦予劑；上述脂肪族醇以外之其他吸收促進劑；吸附劑、除鹽劑、塑化劑、溶解劑、填充劑、穩定劑、保存劑等添加劑。
(其他藥物)
作為上述羅替戈汀及其藥學上容許之鹽以外之其他藥物，例如可例舉：非類固醇性消炎鎮痛劑(雙氯芬酸、吲哚美辛、酮洛芬、聯苯乙酸、氯索洛芬、布洛芬、氟比洛芬、噻洛芬、阿西美辛、舒林酸、依託度酸、托美汀、匹洛西卡、美洛昔康、安吡昔康、萘普生、阿紮丙宗、水楊酸甲酯、水楊酸乙二醇酯、伐地昔布、塞來昔布、羅非昔布、氨芬酸等)、退熱鎮痛藥(乙醯胺酚等)、抗組胺劑(苯海拉明、氯芬尼拉明、過敏美奎錠、高氯環嗪等)、降血壓劑(地爾硫卓、尼卡地平、尼伐地平、美托洛爾、比索洛爾、群多普利等)、抗帕金森藥(培高利特、羅匹尼洛、溴麥角環肽、希利治林等)、支氣管擴張劑(妥布特羅、異丙腎上腺素、沙丁胺醇等)、抗過敏藥(可多替芬、氯雷他定、氮卓斯汀、特芬那定、西替利嗪、阿紮司特等)、局部麻醉劑(利多卡因、狄布卡因等)、神經障礙性疼痛治療藥(普瑞巴林等)、非麻藥性鎮痛藥(丁基原啡因、曲馬多、噴他佐辛)、麻醉系鎮痛劑(嗎啡、羥考酮、吩坦尼等)、泌尿器官用劑(奧昔布寧、他蘇洛辛等)、精神神經用劑(丙嗪、氯丙嗪等)、類固醇激素劑(雌二醇、黃體素、炔諾酮、可體松、氫化可體松等)、抗抑鬱藥(舍曲林、氟西汀、帕羅西汀、西酞普蘭等)、抗癡呆藥(多奈哌齊、利凡斯的明、加蘭他敏等)、抗精神病藥(利培酮、奧氮平等)、中樞神經興奮劑(哌醋甲酯等)、骨質疏鬆症治療藥(雷洛昔芬、阿侖膦酸鹽等)、乳癌預防藥(他莫昔芬等)、抗肥胖藥(馬吲哚、西布曲明等)、失眠症改善藥(抑黑素等)、抗風濕藥(阿他利特等)，可單獨使用該等中之1種，亦可組合2種以上使用。
於本發明中，當於上述黏著劑層中進而含有該等其他藥物時，作為其含量，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為10質量%以下。
(其他黏著賦予劑)
作為上述脂環族飽和烴樹脂以外之其他黏著賦予劑，例如可例舉：上述脂環族飽和烴樹脂以外之石油系樹脂、萜烯系樹脂、松香系樹脂、酚系樹脂及二甲苯系樹脂，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述脂環族飽和烴樹脂以外之石油系樹脂，例如可例舉：脂環族系氫化石油樹脂、脂肪族系石油樹脂(脂肪族烴樹脂等)、脂肪族系氫化石油樹脂、芳香族系石油樹脂，更具體而言，可例舉：Escorez 8000(商品名，Esso石油化學股份有限公司製造)等。作為此種石油系樹脂，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述萜烯系樹脂，例如可例舉：蒎烯聚合物(α-蒎烯聚合物、β-蒎烯聚合物等)、萜烯聚合物、雙戊烯聚合物、萜烯-苯酚聚合物、芳香族改性萜烯聚合物、蒎烯-苯酚共聚物，更具體而言，可例舉：YS RESIN(YS RESIN PXN(1150N、300N)、YS RESIN PX1000、YS RESIN TO125、YS RESIN TO105等)、Clearon P105、Clearon M115、Clearon K100(以上為商品名，Yasuhara Chemical股份有限公司製造)、TAMANOL 901(商品名，荒川化學工業股份有限公司製造)，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述松香系樹脂，例如可例舉：氫化松香甘油酯、超淺色松香、超淺色松香酯、酸改性超淺色松香，更具體而言，可例舉：Pine Crystal(KE-311、PE-590、KE-359、KE-100等)(商品名，荒川化學工業股份有限公司製造)等，可單獨使用該等中之1種，亦可組合2種以上使用。
於本發明中，當於上述黏著劑層中進而含有該等其他黏著賦予劑時，作為其含量，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為10質量%以下。
(其他吸收促進劑(經皮吸收促進劑))
作為上述吸收促進劑，可例舉上述特定之脂肪族醇以外之具有藥物經皮吸收促進作用者，例如可例舉：上述特定之脂肪族醇以外之脂肪族醇、碳數6～20之脂肪酸、脂肪酸酯、脂肪醯胺、或脂肪族醇醚；芳香族有機酸；芳香族醇；芳香族有機酸酯或醚；POE(polyoxyethylene，聚氧乙烯)氫化蓖麻油類；卵磷脂類；磷脂質；大豆油衍生物；甘油三乙酸酯，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述特定之脂肪族醇以外之脂肪族醇，例如可例舉：異丙醇、己醇、鯨蠟醇、硬脂醇、異硬脂醇、次亞麻醇、己基癸醇，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述脂肪族醇以外之吸收促進劑，例如可例舉：碳數6～20之脂肪酸、脂肪酸酯、脂肪醯胺、或脂肪族醇醚；芳香族有機酸；芳香族醇；芳香族有機酸酯或醚；POE氫化蓖麻油類；卵磷脂類；磷脂質；大豆油衍生物；甘油三乙酸酯，可單獨使用該等中之1種，亦可組合2種以上使用。
於本發明中，當於上述黏著劑層中進而含有該等其他吸收促進劑時，作為其含量，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為10質量%以下。
(添加劑)
[吸附劑]
作為上述吸附劑，可例舉：具有吸濕性之無機及/或有機物質，更具體而言，可例舉：滑石、高嶺土、膨潤土等礦物；薰製二氧化矽(Aerosil(註冊商標)等)、含水二氧化矽等矽化合物；氧化鋅、乾燥氫氧化鋁凝膠等金屬化合物；乳酸、乙酸等弱酸；糊精等糖；聚乙烯吡咯啶酮(非交聯PVP)、交聯聚乙烯吡咯啶酮(亦稱為「交聯聚維酮」、「交聯PVP」)、甲基丙烯酸胺基烷基酯共聚物、羧乙烯聚合物及甲基丙烯酸丁酯-甲基丙烯酸甲酯共聚物等高分子聚合物，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述交聯聚乙烯吡咯啶酮，可例舉交聯之N-乙烯吡咯啶酮聚合物。作為上述N-乙烯吡咯啶酮聚合物，可為均聚物，亦可為共聚物，例如可例舉：N-乙烯吡咯啶酮之均聚物、N-乙烯吡咯啶酮與多官能單體之共聚物。該等之中，作為本發明之交聯聚乙烯吡咯啶酮，較佳為1-乙烯基-2-吡咯啶酮之交聯均聚物。作為上述交聯聚乙烯吡咯啶酮，亦可使用Kollidon CL、Kollidon CL-M(BASF Japan股份有限公司製造)；Polyplasdone XL、Polyplasdone XL-10、Polyplasdone INF-10(ISP Japan股份有限公司製造)等市售品。
於本發明中，當於上述黏著劑層中進而含有該等吸附劑時，作為其含量，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為10質量%以下。
又，於本發明中，藉由上述黏著劑層中含有上述交聯聚乙烯吡咯啶酮(較佳為以與上述羅替戈汀及/或其藥學上容許之鹽之含量之質量比(羅替戈汀及/或其藥學上容許之鹽之羅替戈汀游離體換算含量：交聯聚乙烯吡咯啶酮含量)計為10：3～1：3)，從而可抑制羅替戈汀及/或其藥學上容許之鹽之結晶之析出，但就羅替戈汀之尤其優異之皮膚透過性之觀點而言，上述黏著劑層中較佳為不含上述交聯聚乙烯吡咯啶酮，作為其含量，相對於上述黏著劑層之總質量，較佳為10質量%以下，更佳為8質量%以下(例如，3～8質量%)。
[除鹽劑]
上述除鹽劑之調配目的主要在於將鹼性藥物之全部或一部分轉化為游離體。作為此種除鹽劑，無特別限定，例如，於調配藥物之酸加成鹽作為上述藥物而獲得含有游離體之藥物之製劑之情形時，較佳為鹼性物質，更佳為含金屬離子之除鹽劑、含鹼性氮原子之除鹽劑。作為上述含金屬離子之除鹽劑，可例舉：乙酸鈉(包括無水乙酸鈉)、氫氧化鈉、氫氧化鉀、氫氧化鎂、碳酸氫鈉、碳酸氫鉀、檸檬酸鈉、乳酸鈉等，可單獨使用該等中之1種，亦可組合2種以上使用。再者，作為本發明之黏著劑層，亦可進而含有源自上述鹼性藥物及上述除鹽劑之化合物(例如，於組合鹽酸羅替戈汀與乙酸鈉之情形時為鹽酸鈉)。於本發明中，當於上述黏著劑層中進而含有該等除鹽劑、以及源自鹼性藥物及除鹽劑之化合物之情形時，作為其含量，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為10質量%以下。
[塑化劑]
上述塑化劑之調配目的主要在於調整上述黏著劑層之黏著物性、上述黏著劑層之製造過程中之流動特性、上述藥物之經皮吸收特性等。作為此種塑化劑，例如可例舉：聚矽氧油；石蠟系加工處理油、環烷系加工處理油及芳香族系加工處理油等石油系油；角鯊烷、角鯊烯；橄欖油、山茶油、蓖麻油、妥爾油及花生油等植物系油；鄰苯二甲酸二丁酯及鄰苯二甲酸二辛酯等二元酸酯；聚丁烯及液狀異戊二烯橡膠等液狀橡膠；二乙二醇、聚乙二醇、丙二醇、二丙二醇等，可單獨使用該等中之1種，亦可組合2種以上使用。該等之中，作為上述塑化劑，較佳為選自由聚矽氧油、液態石蠟、及液狀聚丁烯所組成之群中之至少1種。於本發明中，當於上述黏著劑層中進而含有該等塑化劑時，作為其含量，就提高黏著劑層之黏著力及/或緩和剝離時之局部刺激性之觀點而言，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為4～50質量%，更佳為5～30質量%，進而較佳為10～20質量%，進而更佳為15～20質量%。就羅替戈汀之經皮吸收性之觀點而言，作為上述塑化劑之含量，亦較佳為15～50質量%。
[溶解劑、填充劑]
作為上述溶解劑，例如可例舉：乙酸等有機酸、界面活性劑，可單獨使用該等中之1種，亦可組合2種以上使用。又，上述填充劑之調配目的主要在於調整上述黏著劑層之黏著力，作為該填充劑，例如可例舉：氫氧化鋁、碳酸鈣、碳酸鎂；矽酸鋁或矽酸鎂等矽酸鹽；矽酸、硫酸鋇、硫酸鈣、鋅酸鈣、氧化鋅、氧化鈦，可單獨使用該等中之1種，亦可組合2種以上使用。
[穩定劑]
作為上述穩定劑，例如可例舉：抗壞血酸或其金屬鹽或者酯(較佳為鈉鹽、棕櫚酸酯)、異抗壞血酸或其金屬鹽(較佳為鈉鹽)、乙二胺四乙酸或其金屬鹽(較佳為鈣二鈉鹽、四鈉鹽)、半胱胺酸、乙醯半胱胺酸、2-巰基苯并咪唑、二丁基羥基甲苯、丁基羥基苯甲醚、沒食子酸丙酯、四[3-(3,5-二第三丁基-4-羥基苯基)丙酸]季戊四醇酯、3-巰基-1,2-丙二醇、乙酸維生素E酯、瑞香草酚、大豆卵磷脂、芸香苷、二羥基苯甲酸、二氯異三聚氰酸鉀、槲皮素、對苯二酚、羥基甲亞磺酸金屬鹽(較佳為鈉鹽)、偏重亞硫酸金屬鹽(例如鈉鹽)、亞硫酸金屬鹽(較佳為鈉鹽)、硫代硫酸金屬鹽(較佳為鈉鹽)，可單獨使用該等中之1種，亦可組合2種以上使用。上述中，作為金屬鹽，例如可例舉：鈉鹽、鉀鹽、鈣鹽、鎂鹽。又，作為酯，可例舉：棕櫚酸酯、硬脂酸酯、肉豆蔻酸酯等。
於本發明中，存在藉由使上述黏著劑層中進而含有上述穩定劑，從而進一步提高經時穩定性之傾向，但就羅替戈汀之尤其優異之皮膚透過性之觀點而言，上述黏著劑層中較佳為不含上述穩定劑(例如，2-巰基苯并咪唑)，作為其含量，相對於上述黏著劑層之總質量，較佳為3質量%以下，更佳為2質量%以下，進而較佳為0.25質量%以下(例如，0.005～0.25質量%)。
[保存劑]
作為上述保存劑，例如可例舉：對羥基苯甲酸衍生物、苄醇、苯酚、甲酚等，可單獨使用該等中之1種，亦可組合2種以上使用。
當於上述黏著劑層中進而含有上述添加劑時，作為其含量，於2種以上之情形時以合計來計，相對於上述黏著劑層之總質量，較佳為40質量%以下，更佳為30質量%以下。
本發明之黏著劑層無特別限制，每單位面積(貼附面之面積)之質量較佳為20～200 g/m2
，更佳為30～100 g/m2
，進而較佳為30～70 g/m2
。又，作為本發明之黏著劑層之貼附面之面積，可根據治療之目的或應用對象適當進行調整，無特別限制，通常為0.5～200 cm2
之範圍。
本發明之含羅替戈汀之貼附劑無特別限制，可藉由適當採用公知之貼附劑之製造方法而製造。例如，首先，依據慣常方法，將羅替戈汀及/或其藥學上容許之鹽、上述脂環族飽和烴樹脂、上述特定之脂肪族醇、上述黏著基劑、及視需要之溶劑或上述其他成分進行混練，而獲得均勻之黏著劑層組合物。於使用羅替戈汀游離體作為上述羅替戈汀及/或其藥學上容許之鹽之情形時，可為其I型結晶，可為II型結晶，可為非晶質型，亦可為I型結晶、II型結晶、及非晶質型中之至少2種以上之混合物。又，作為上述羅替戈汀及/或其藥學上容許之鹽，亦可使用溶解於上述溶劑者。作為上述溶劑，可例舉：無水乙醇、甲苯、庚烷、甲醇、乙酸乙酯、己烷、及該等中之至少2種以上之混合液等。
繼而，將該黏著劑層組合物以成為所需之每單位面積之質量之方式，塗佈於上述支持體層之面上(通常為一面上)之後，視需要進行加溫，使上述溶劑乾燥去除，形成黏著劑層，進而視需要切割為所需之形狀，藉此可獲得本發明之貼附劑。
又，作為本發明之含羅替戈汀之貼附劑之製造方法，亦可進而包括於上述黏著劑層之與上述支持體層相反之面上貼合上述剝離襯墊之步驟，首先將上述黏著劑層組合物以成為所需之每單位面積之質量之方式塗佈於上述剝離襯墊之一面上而形成黏著劑層之後，於上述黏著劑層之與上述剝離襯墊相反之面上貼合上述支持體層，視需要切割為所需之形狀，藉此亦可獲得本發明之貼附劑。進而，所獲得之貼附劑亦可視需要封入至保存用包裝容器(例如鋁層壓袋)中，製成包裝體。
實施例
以下，基於實施例及比較例，對本發明更具體地進行說明，但本發明並不受以下實施例限定。再者，各實施例及比較例中，利用以下所示之方法進行皮膚透過試驗。
＜皮膚透過試驗(體外(in vitro)無毛小鼠皮膚透過試驗)＞
首先，剝離無毛小鼠軀體部之皮膚，去除脂肪而獲得脂肪去除皮膚片，於該脂肪去除皮膚片之角質層側切割出1.0 cm2
之正方形，並貼附去除了剝離襯墊之貼附劑，以此製成試驗樣品。以真皮側與受體液接觸之方式，將上述試驗樣品設置於動態式擴散槽中，於上述槽中裝滿受體溶液(磷酸鹽緩衝生理鹽水)。繼而，以受體溶液保溫於32℃之方式，一面使加溫之循環水於外周部循環一面以約5 mL/hr之流速輸送受體溶液，24小時之內每2小時採集受體溶液。利用高效液相層析法測定所採集之受體溶液中之羅替戈汀濃度，分別根據以下式：
羅替戈汀皮膚透過量(μg/cm2
)＝{受體溶液中之羅替戈汀濃度(μg/mL)×流量(mL)}/貼附劑面積(cm2
)
算出黏著劑層之每單位面積中之羅替戈汀皮膚透過量，求出每1小時之皮膚透過量(皮膚透過速度(μg/cm2
/hr))。測定係分別對2個試驗樣品進行，將24小時內各皮膚透過速度之最大值之平均值作為最大皮膚透過速度(Jmax)。
(實施例1)
首先，將羅替戈汀(游離體)9.0質量份、苯乙烯-異戊二烯-苯乙烯嵌段共聚物15.4質量份、聚異丁烯6.6質量份、脂環族飽和烴樹脂(Arkon P-100，荒川化學工業股份有限公司製造)48.4質量份、液態石蠟17.6質量份、及月桂醇3質量份添加至適量之溶劑(無水乙醇及甲苯)中並加以混合，而獲得黏著劑層組合物。繼而，將所獲得之黏著劑層組合物塗佈於剝離襯墊(實施了離型處理之聚對苯二甲酸乙二酯製之膜)上，將溶劑乾燥去除，以每單位面積之質量成為50 g/m2
之方式形成黏著劑層。於所獲得之黏著劑層之與上述剝離襯墊相反之面上積層支持體層(聚對苯二甲酸乙二酯製之膜)，獲得依序積層有支持體層/黏著劑層/剝離襯墊之貼附劑。
(實施例2～4、比較例1～18)
將黏著劑層組合物之組成以成為下述表1或表2所示之組成之方式進行設定，除此以外，以與實施例1相同之方式獲得各貼附劑。
對實施例1～4及比較例1～18中所獲得之貼附劑實施皮膚透過試驗。將結果與各實施例及比較例之黏著劑層組合物之組成(溶劑除外)一併分別示於表1及表2。
[表1]
| 比較例1 | 實施例1 | 實施例2 | 實施例3 | 實施例4 | 比較例2 | 比較例3 | 比較例4 | 比較例5 | 比較例6 | |
| 黏著劑層組合物[質量份] | ||||||||||
| 羅替戈汀 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 |
| 苯乙烯-異戊二烯-苯乙烯嵌段共聚物 | 15.9 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 |
| 聚異丁烯 | 6.8 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 |
| 脂環族飽和烴樹脂 | 50.1 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 |
| 液態石蠟 | 18.2 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 |
| 月桂醇(C12) | - | 3 | - | - | - | - | - | - | - | - |
| 辛基十二烷醇(C20) | - | - | 3 | - | - | - | - | - | - | - |
| 油醇(C18) | - | - | - | 3 | - | - | - | - | - | - |
| 肉豆蔻醇(C14) | - | - | - | - | 3 | - | - | - | - | - |
| 異硬脂醇(C18) | - | - | - | - | - | 3 | - | - | - | - |
| 硬脂醇(C18) | - | - | - | - | - | - | 3 | - | - | - |
| 鯨蠟醇(C16) | - | - | - | - | - | - | - | 3 | - | - |
| 異丙醇(C3) | - | - | - | - | - | - | - | - | 3 | - |
| 己醇(C6) | - | - | - | - | - | - | - | - | - | 3 |
| 合計 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| 評價 | ||||||||||
| 最大皮膚透過速度(Jmax)[μg/cm2 /hr] | 11.7 | 18.6 | 17.6 | 15.1 | 14.2 | 12.9 | 12.7 | 12.3 | 13.6 | 13.2 |
[表2]
| 比較例7 | 比較例8 | 比較例9 | 比較例10 | 比較例11 | 比較例12 | 比較例13 | 比較例14 | 比較例15 | 比較例16 | 比較例17 | 比較例18 | |
| 黏著劑層組合物[質量份] | ||||||||||||
| 羅替戈汀 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 |
| 苯乙烯-異戊二烯-苯乙烯嵌段共聚物 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 | 15.4 |
| 聚異丁烯 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 | 6.6 |
| 脂環族飽和烴樹脂 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 | 48.4 |
| 液態石蠟 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 | 17.6 |
| 單油酸甘油酯 | 3 | - | - | - | - | - | - | - | - | - | - | - |
| 海藻酸 | - | 3 | - | - | - | - | - | - | - | - | - | - |
| 月桂基二甲胺基乙酸甜菜鹼 | - | - | 3 | - | - | - | - | - | - | - | - | - |
| 山梨醇酐月桂酸酯 | - | - | - | 3 | - | - | - | - | - | - | - | - |
| 二甲基亞碸 | - | - | - | - | 3 | - | - | - | - | - | - | - |
| 二乙醇胺 | - | - | - | - | - | 3 | - | - | - | - | - | |
| 棕櫚酸 | - | - | - | - | - | - | 3 | - | - | - | - | |
| 異丙醇胺 | - | - | - | - | - | - | - | 3 | - | - | - | |
| 三異丙醇胺 | - | - | - | - | - | - | - | - | 3 | - | - | |
| 二異丙醇胺 | - | - | - | - | - | - | - | - | - | 3 | - | |
| 己二烯酸 | - | - | - | - | - | - | - | - | - | - | 3 | - |
| 乳酸 | - | - | - | - | - | - | - | - | - | - | - | 3 |
| 合計 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| 評價 | ||||||||||||
| 最大皮膚透過速度(Jmax)[μg/cm2 /hr] | 11.8 | 11.4 | 11.0 | 11.0 | 10.8 | 10.8 | 7.1 | 6.8 | 5.7 | 5.7 | 5.7 | 4.5 |
如表1及表2所示，使用月桂醇、辛基十二烷醇、油醇、或肉豆蔻醇之本發明之貼附劑(實施例1～4)中，確認到達成優異之羅替戈汀之皮膚透過性，尤其是與使用碳數與該等接近或碳數共通之其他脂肪族醇(例如，比較例2～4)之情形相比，亦達成了尤其優異之皮膚透過性。
(實施例5、比較例19～20)
將黏著劑層組合物之組成以成為下述表3所示之組成之方式進行設定，除此以外，以與實施例1相同之方式獲得各貼附劑。表3中，作為萜烯系樹脂，使用「YS RESIN PX1150N(Yasuhara Chemical股份有限公司製造)」，作為氫化松香酯，使用「KE-311(荒川化學工業股份有限公司製造)」。
對實施例5及比較例19～20中所獲得之貼附劑實施皮膚透過試驗。將結果與各實施例及比較例之黏著劑層組合物之組成(溶劑除外)一併分別示於表3。
[表3]
| 實施例5 | 比較例19 | 比較例20 | |
| 黏著劑層組合物[質量份] | |||
| 羅替戈汀 | 9 | 9 | 9 |
| 苯乙烯-異戊二烯-苯乙烯嵌段共聚物 | 13.3 | 13.3 | 13.3 |
| 聚異丁烯 | 5.7 | 5.7 | 5.7 |
| 脂環族飽和烴樹脂 | 41.5 | - | - |
| 萜烯系樹脂 | - | 41.5 | - |
| 氫化松香酯 | - | - | 41.5 |
| 液態石蠟 | 15.2 | 15.2 | 15.2 |
| 辛基十二烷醇 | 5 | 5 | 5 |
| 交聯PVP | 10 | 10 | 10 |
| 穩定劑 (2-巰基苯并咪唑) | 0.3 | 0.3 | 0.3 |
| 合計 | 100 | 100 | 100 |
| 評價 | |||
| 最大皮膚透過速度(Jmax) [μg/cm2 /hr] | 15.8 | 13.6 | 6.7 |
如表3所示，使用辛基十二烷醇及脂環族飽和烴樹脂之本發明之貼附劑(實施例5)中，確認到達成優異之羅替戈汀之皮膚透過性，即便進而含有吸附劑或穩定劑，亦達成充分之皮膚透過性。另一方面，於使用作為其他黏著賦予劑之萜烯系樹脂或氫化松香酯代替脂環族飽和烴樹脂之情形時(比較例19、20)，確認到羅替戈汀之皮膚透過性下降。
(實施例6～7)
將黏著劑層組合物之組成以成為下述表4所示之組成之方式進行設定，除此以外，以與實施例1相同之方式獲得各貼附劑。對實施例6～7中所獲得之貼附劑實施皮膚透過試驗。將結果與各實施例之黏著劑層組合物之組成(溶劑除外)一併分別示於表4。
[表4]
| 實施例6 | 實施例7 | |
| 黏著劑層組合物[質量份] | ||
| 羅替戈汀 | 9 | 9 |
| 苯乙烯-異戊二烯-苯乙烯嵌段共聚物 | 14.2 | 13.3 |
| 聚異丁烯 | 6.0 | 5.7 |
| 脂環族飽和烴樹脂 | 44.6 | 41.8 |
| 液態石蠟 | 16.2 | 15.2 |
| 辛基十二烷醇 | 10 | 15 |
| 合計 | 100 | 100 |
| 評價 | ||
| 最大皮膚透過速度(Jmax)[μg/cm2 /hr] | 17.9 | 17.6 |
如表4所示，確認到即便本發明之脂肪族醇之含量為10質量份或15質量份，本發明之貼附劑(實施例6～7)亦達成優異之羅替戈汀之皮膚透過性。
(實施例8～10)
將黏著劑層組合物之組成以成為下述表5所示之組成之方式進行設定，除此以外，以與實施例1相同之方式獲得各貼附劑。對實施例8～10中所獲得之貼附劑實施皮膚透過試驗。將結果與各實施例之黏著劑層組合物之組成(溶劑除外)一併分別示於表5。
[表5]
| 實施例8 | 實施例9 | 實施例10 | |
| 黏著劑層組合物[質量份] | |||
| 羅替戈汀 | 9 | 11.3 | 13.5 |
| 苯乙烯-異戊二烯-苯乙烯嵌段共聚物 | 14.9 | 14.5 | 14.1 |
| 聚異丁烯 | 6.3 | 6.1 | 6.0 |
| 脂環族飽和烴樹脂 | 46.8 | 45.5 | 44.3 |
| 液態石蠟 | 17.0 | 16.6 | 16.1 |
| 辛基十二烷醇 | 5 | 5 | 5 |
| 交聯PVP | 1 | 1 | 1 |
| 合計 | 100 | 100 | 100 |
| 評價 | |||
| 最大皮膚透過速度(Jmax)[μg/cm2 /hr] | 16.4 | 18.8 | 19.7 |
如表5所示，確認到即便羅替戈汀之含量為11.3質量份或13.5質量份，本發明之貼附劑(實施例8～10)亦達成優異之羅替戈汀之皮膚透過性。
(實施例11～15)
將黏著劑層組合物之組成以成為下述表6所示之組成之方式進行設定，除此以外，以與實施例1相同之方式獲得各貼附劑。對實施例11～15中所獲得之貼附劑實施皮膚透過試驗。將結果與各實施例之黏著劑層組合物之組成(溶劑除外)一併分別示於表6。又，表6中亦一併示出上述實施例8之結果。
[表6]
| 實施例11 | 實施例12 | 實施例13 | 實施例8 | 實施例14 | 實施例15 | |
| 黏著劑層組合物[質量份] | ||||||
| 羅替戈汀 | 9 | 9 | 9 | 9 | 9 | 9 |
| 苯乙烯-異戊二烯-苯乙烯嵌段共聚物 | 16.3 | 12.4 | 13.3 | 14.9 | 10.1 | 21.5 |
| 聚異丁烯 | 8.7 | 5.3 | 5.7 | 6.4 | 4.3 | - |
| 脂環族飽和烴樹脂 | 12.5 | 39.0 | 41.8 | 46.8 | 60.0 | 47.3 |
| 液態石蠟 | 47.5 | 28.3 | 15.2 | 17.0 | 11.6 | 17.2 |
| 辛基十二烷醇 | 5 | 5 | 5 | 5 | 5 | 5 |
| 交聯PVP | 1 | 1 | 10 | 1 | - | - |
| 合計 | 100 | 100 | 100 | 100 | 100 | 100 |
| 評價 | ||||||
| 最大皮膚透過速度(Jmax)[μg/cm2 /hr] | 18.3 | 16.5 | 16.2 | 16.4 | 14.6 | 19.7 |
如表6所示，確認到即便脂環族飽和烴樹脂之含量為12.5質量份或60質量份，又，即便液態石蠟之含量為11.6質量份或47.5質量份，本發明之貼附劑(實施例11～14)亦達成優異之羅替戈汀之皮膚透過性。進而，確認到即便不含有聚異丁烯，本發明之貼附劑(實施例15)亦達成優異之羅替戈汀之皮膚透過性。
[產業上之可利用性]
如上述所說明，根據本發明，可提供一種羅替戈汀之皮膚透過性尤其優異之含羅替戈汀之貼附劑。
Claims (5)
- 一種含羅替戈汀之貼附劑，其係具備支持體層及黏著劑層，且上述黏著劑層含有羅替戈汀及/或其藥學上容許之鹽者，上述黏著劑層進而含有脂環族飽和烴樹脂、與選自由月桂醇、辛基十二烷醇、油醇、及肉豆蔻醇所組成之群中之至少1種脂肪族醇，上述黏著劑層中之羅替戈汀及/或其藥學上容許之鹽換算成羅替戈汀游離體之含量相對於上述黏著劑層之總質量，為5~15質量%，上述黏著劑層中之上述脂環族飽和烴樹脂之含量相對於上述黏著劑層之總質量，為5~80質量%，上述黏著劑層中之上述脂肪族醇之含量相對於上述黏著劑層之總質量，為1~15質量%。
- 如請求項1之含羅替戈汀之貼附劑，其中上述黏著劑層進而含有苯乙烯系熱塑性彈性體。
- 如請求項2之含羅替戈汀之貼附劑，其中上述黏著劑層中之上述苯乙烯系熱塑性彈性體之含量相對於上述黏著劑層之總質量，為5~50質量%。
- 如請求項1或2之含羅替戈汀之貼附劑，其中上述黏著劑層進而含有塑化劑。
- 如請求項4之含羅替戈汀之貼附劑，其中上述黏著劑層中之上述塑化劑之含量相對於上述黏著劑層之總質量，為4~50質量%。
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| WO2012084969A1 (en) * | 2010-12-22 | 2012-06-28 | Hexal Ag | Adhesive composition containing rotigotine and transdermal therapeutic system comprising the adhesive composition |
| TW201431570A (zh) * | 2012-11-22 | 2014-08-16 | Ucb Pharma Gmbh | 用於經皮投服羅替戈汀（Ｒｏｔｉｇｏｔｉｎｅ）之多天式貼片 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2020250840A1 (ja) | 2021-09-13 |
| WO2020250840A1 (ja) | 2020-12-17 |
| CN113950356B (zh) | 2024-12-31 |
| EP3984598A4 (en) | 2023-01-11 |
| KR20210137247A (ko) | 2021-11-17 |
| JP6872675B1 (ja) | 2021-05-19 |
| US20220257528A1 (en) | 2022-08-18 |
| TW202112366A (zh) | 2021-04-01 |
| EP3984598B1 (en) | 2023-10-18 |
| KR102401412B1 (ko) | 2022-05-23 |
| EP3984598A1 (en) | 2022-04-20 |
| ES2962896T3 (es) | 2024-03-21 |
| CN113950356A (zh) | 2022-01-18 |
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