TWI775149B - 含羅匹尼羅之貼附劑及羅匹尼羅之皮膚透過性之提升方法 - Google Patents
含羅匹尼羅之貼附劑及羅匹尼羅之皮膚透過性之提升方法 Download PDFInfo
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- TWI775149B TWI775149B TW109132052A TW109132052A TWI775149B TW I775149 B TWI775149 B TW I775149B TW 109132052 A TW109132052 A TW 109132052A TW 109132052 A TW109132052 A TW 109132052A TW I775149 B TWI775149 B TW I775149B
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- Prior art keywords
- ropinirole
- adhesive layer
- mentioned
- adhesive
- fatty acid
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- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 title claims abstract description 145
- 229960001879 ropinirole Drugs 0.000 title claims abstract description 129
- 231100000245 skin permeability Toxicity 0.000 title description 38
- 238000000034 method Methods 0.000 title description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 130
- 239000012790 adhesive layer Substances 0.000 claims abstract description 104
- 239000000853 adhesive Substances 0.000 claims abstract description 80
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 72
- 239000000194 fatty acid Substances 0.000 claims abstract description 72
- 229930195729 fatty acid Natural products 0.000 claims abstract description 72
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 69
- 229910052751 metal Inorganic materials 0.000 claims abstract description 69
- 239000002184 metal Substances 0.000 claims abstract description 69
- 230000001070 adhesive effect Effects 0.000 claims abstract description 64
- 239000010410 layer Substances 0.000 claims abstract description 35
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 21
- -1 alkali metal fatty acid salt Chemical class 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 229920001971 elastomer Polymers 0.000 claims description 16
- 239000005060 rubber Substances 0.000 claims description 16
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- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 10
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 7
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 6
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 6
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- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 6
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 5
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 5
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- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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Abstract
本發明之含羅匹尼羅之貼附劑具備黏著劑層及支持體層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種、碳數為7以上之脂肪酸金屬鹽、以及黏著劑。
Description
本發明係關於一種貼附劑及藥物之皮膚透過性之提升方法，更詳細而言，係關於一種含有羅匹尼羅及/或其藥學上容許之鹽之貼附劑、及羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性之提升方法。
羅匹尼羅係作為對治療帕金森氏症或不寧腿綜合征等有用之藥物而為人所知，近年來，就投予次數減少、依從性提升、投予及其中止容易等觀點而言，進行與含有羅匹尼羅及/或其藥學上容許之鹽之製劑之經皮投予相關的研究。
例如，於國際公開第2010/134433號(專利文獻1)中，記載有一種經皮吸收製劑，其具備支持體及含有羅匹尼羅或其藥學上容許之酸加成鹽之黏著劑層，於國際公開第2012/165253號(專利文獻2)及國際公開第2012/165254號(專利文獻3)中，記載有一種含羅匹尼羅之貼附劑，其具備支持體層及含有羅匹尼羅及/或其藥學上容許之鹽之黏著劑層。
又，於國際公開第2009/107478號(專利文獻4)及國際公開第2009/107479號(專利文獻5)中，記載有於具備支持體及黏著劑層之貼附劑中，上述黏著劑層含有藉由羅匹尼羅之酸加成鹽與脫鹽劑之反應所產生之羅匹尼羅及金屬鹽。
對於含有羅匹尼羅及/或其藥學上容許之鹽之製劑之經皮投予，要求其皮膚透過性優異，於專利文獻1～5中，記載有可使用以促進羅匹尼羅及/或其藥學上容許之鹽之經皮吸收為目的之吸收促進劑，作為上述吸收促進劑，例如可列舉：脂肪族醇或脂肪酸等。又，如專利文獻4～5所記載，亦已知於製造中或製造出之製劑中，藉由利用脫鹽劑使羅匹尼羅之酸加成鹽脫鹽而經皮吸收羅匹尼羅游離體(free cartilage bodies)，例如，於專利文獻1～5中，列舉氫氧化鈉等作為上述脫鹽劑。然而，除了該等使用了吸收促進劑之構成、或使用了氫氧化鈉等脫鹽劑之構成以外，關於提升羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性之方法，尚未進行充分研究。
先前技術文獻
專利文獻
專利文獻1：國際公開第2010/134433號
專利文獻2：國際公開第2012/165253號
專利文獻3：國際公開第2012/165254號
專利文獻4：國際公開第2009/107478號
專利文獻5：國際公開第2009/107479號
[發明所欲解決之問題]
本發明係鑒於上述先前技術所具有之課題而完成者，目的在於從與先前之含羅匹尼羅之貼附劑之構成不同之觀點，提供一種羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性優異之含羅匹尼羅之貼附劑、及羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性之提升方法。
[解決問題之技術手段]
本發明人等為了達成上述目的而反覆銳意研究，結果發現：藉由於具備支持體層及黏著劑層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種及黏著劑的貼附劑中，使上述黏著劑層中進而含有碳數為7以上之脂肪酸金屬鹽，能夠製成羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性優異之貼附劑。又，發現：與羅匹尼羅之酸加成鹽組合之情形時，該優異之皮膚透過性也不是由單純之脫鹽所預料到之效果，即，不是上述脂肪酸金屬鹽作為羅匹尼羅之酸加成鹽之脫鹽劑發生反應而生成脂肪酸，其發揮作為吸收促進劑之功能這一效果；其理由不確定，令人驚訝的是，其係藉由使用特定之上述脂肪酸金屬鹽而不同地產生之效果；從而完成本發明。
即，本發明之含羅匹尼羅之貼附劑之特徵在於：其具備支持體層及黏著劑層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種、碳數為7以上之脂肪酸金屬鹽、以及黏著劑。
於本發明之含羅匹尼羅之貼附劑中，上述脂肪酸金屬鹽較佳為脂肪酸鹼金屬鹽，又，上述脂肪酸金屬鹽亦較佳為選自由辛酸、油酸、月桂酸、硬脂酸、癸酸、肉豆蔻酸、及棕櫚酸所組成之群中之至少1種脂肪酸之金屬鹽。
進而，於本發明之含羅匹尼羅之貼附劑中，上述黏著劑較佳為選自由橡膠系黏著劑、不具有羧基之丙烯酸系黏著劑、及矽酮系黏著劑所組成之群中之至少1種。
又，於本發明之含羅匹尼羅之貼附劑中，上述脂肪酸金屬鹽之含量較佳為相對於上述黏著劑層之總質量為0.1～45質量%，於上述黏著劑層中，上述脂肪酸金屬鹽之含量亦較佳為相對於上述選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種的以羅匹尼羅游離體換算之含量1.0莫耳，為0.1～5.0莫耳。
進而，於本發明之含羅匹尼羅之貼附劑中，相對於上述黏著劑層之總質量，上述選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種的以羅匹尼羅游離體換算之含量較佳為5～30質量%。
本發明之羅匹尼羅之皮膚透過性之提升方法係一種選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種之皮膚透過性之提升方法，其包括如下步驟：
於具備支持體層及黏著劑層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種、以及黏著劑的含羅匹尼羅之貼附劑中，
使上述黏著劑層含有碳數為7以上之脂肪酸金屬鹽。
[發明之效果]
根據本發明，可提供一種羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性優異的含羅匹尼羅之貼附劑、及羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性之提升方法。
以下，對本發明結合其較佳之實施方式詳細地進行說明。
本發明之含羅匹尼羅之貼附劑(以下，視情形簡稱為「本發明之貼附劑」)具備支持體層及黏著劑層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種、碳數為7以上之脂肪酸金屬鹽、以及黏著劑。
本發明之貼附劑具備支持體層及黏著劑層，較佳為於上述支持體層之一個面上配置有上述黏著劑層。
作為本發明之支持體層，只要為可支持下述黏著劑層者則無特別限制，可適當採用公知者作為貼附劑之支持體層。作為本發明之支持體層之材質，例如可列舉：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；聚胺基甲酸酯等合成樹脂、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。作為上述支持體層之形態，例如可列舉：膜；片、片狀多孔質體、片狀發泡體等片類；織布、編織布、不織布等布帛；箔；及其等之積層體。又，作為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。
本發明之貼附劑亦可於上述黏著劑層之與上述支持體層相反之面上進而具備離型襯墊。作為該離型襯墊，可列舉：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；聚胺基甲酸酯等合成樹脂、或鋁、紙等材質之膜或片及其等之積層體。作為該等離型襯墊，為了能夠容易地自上述黏著劑層剝離，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、含氟化合物塗佈等離型處理。
本發明之黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種(本說明書中，視情形稱為「羅匹尼羅及/或其藥學上容許之鹽」)作為藥物。
作為本發明之黏著劑層中所含有之羅匹尼羅，可為游離體(本說明書中，視情形稱為「羅匹尼羅游離體」)，亦可為其藥學上容許之鹽，亦可於製造中及/或製造後之製劑中，羅匹尼羅之藥學上容許之鹽脫鹽而成為羅匹尼羅游離體，可為該等中之單獨1種，亦可為2種以上之混合物。
作為上述羅匹尼羅之藥學上容許之鹽，較佳為羅匹尼羅之藥學上容許之酸加成鹽(本說明書中，視情形稱為「羅匹尼羅酸加成鹽」)。作為上述羅匹尼羅酸加成鹽之酸，例如可列舉：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、及反丁烯二酸。
於使黏著劑層中含有上述羅匹尼羅酸加成鹽作為本發明之貼附劑之原材料之情形時，由於下述脂肪酸金屬鹽亦為弱鹼，故而藉由該羅匹尼羅酸加成鹽於製造時與其混合，而於製造過程及/或製造後之製劑之黏著劑層中，上述羅匹尼羅酸加成鹽之全部或一部分脫鹽(中和)而獲得自由鹼狀態之羅匹尼羅游離體，結果，於貼附製劑時，可使組織吸收性更高之羅匹尼羅游離體存在於黏著劑層中。
作為本發明之羅匹尼羅及/或其藥學上容許之鹽之含量(羅匹尼羅游離體之含量或羅匹尼羅之藥學上容許之鹽之含量、或於含有羅匹尼羅游離體及羅匹尼羅之藥學上容許之鹽兩者之情形時為其等之合計含量，以下相同)，以羅匹尼羅游離體換算計，相對於上述黏著劑層之總質量，較佳為5～30質量%，更佳為5～25質量%，進而較佳為5～20質量%，進而更佳為5～13.2質量%。於上述羅匹尼羅及/或其藥學上容許之鹽之含量未達上述下限之情形時，有羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性(以下，視情形稱為「羅匹尼羅之皮膚透過性」)降低之傾向，另一方面，於超過上述上限之情形時，由於黏著劑層中之絕對量變多，故而有於上述黏著劑層之形成時不易塗佈黏著劑層組合物，難以獲得均勻之製劑之傾向。
本發明之黏著劑層含有碳數為7以上之脂肪酸金屬鹽(本說明書中，只要無特別說明，則以相同含義使用「脂肪酸金屬鹽」)。本發明之脂肪酸金屬鹽係碳數為7以上之長鏈烴之一元羧酸(脂肪酸)與金屬離子進行離子鍵結而成者。
作為本發明之脂肪酸金屬鹽，需要其碳數為7以上。作為上述脂肪酸金屬鹽之碳數，較佳為8以上，更佳為8～22，進而較佳為10以上，進而更佳為10～22，尤佳為10～20，特佳為10～18。若上述碳數未達上述下限，則存在羅匹尼羅之皮膚透過性變低之情形。又，若上述碳數超過上述上限，亦有羅匹尼羅之皮膚透過性變低之傾向。
作為構成本發明之脂肪酸金屬鹽之脂肪酸，可飽和亦可不飽和，可為直鏈狀，亦可具有支鏈，較佳為選自由油酸、月桂酸、硬脂酸、癸酸、肉豆蔻酸、棕櫚酸、辛酸、亞麻油酸、及山萮酸所組成之群中之至少1種，更佳為選自由辛酸、油酸、月桂酸、硬脂酸、癸酸、肉豆蔻酸、及棕櫚酸所組成之群中之至少1種，進而較佳為選自由辛酸、油酸、月桂酸、硬脂酸、及癸酸所組成之群中之至少1種。又，作為構成本發明之脂肪酸金屬鹽之金屬，較佳為選自由鹼金屬、及鹼土金屬所組成之群中之至少1種，更佳為選自由鹼金屬所組成之群中之至少1種，進而較佳為選自由鈉及鉀所組成之群中之至少1種，進而更佳為鈉。
作為本發明之脂肪酸金屬鹽，更具體而言，可列舉：辛酸鈉、辛酸鉀、油酸鈉、油酸鉀、油酸鋰、肉豆蔻酸鈉、肉豆蔻酸鉀、肉豆蔻酸鋰、月桂酸鈉、月桂酸鉀、硬脂酸鈉、硬脂酸鉀、硬脂酸鋰、癸酸鈉、癸酸鉀、癸酸鋰、棕櫚酸鈉、棕櫚酸鉀等，可為該等中之單獨1種，亦可為2種以上之組合。該等之中，作為本發明之脂肪酸金屬鹽，較佳為選自由辛酸鈉、油酸鈉、癸酸鈉、月桂酸鈉、硬脂酸鈉、及硬脂酸鉀所組成之群中之至少1種，更佳為選自由辛酸鈉、油酸鈉、癸酸鈉、月桂酸鈉、及硬脂酸鉀所組成之群中之至少1種，進而更佳為選自由油酸鈉、癸酸鈉、及月桂酸鈉所組成之群中之至少1種。
作為本發明之脂肪酸金屬鹽之含量(於2種以上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0.1～45質量%，更佳為0.1～40質量%，進而較佳為1～30質量%，進而更佳為5～20質量%。於上述脂肪酸金屬鹽之含量未達上述下限之情形時，有羅匹尼羅之皮膚透過性下降之傾向，另一方面，於超過上述上限之情形時，有黏著劑層之凝集力下降之傾向。再者，於本發明之脂肪酸金屬鹽之含量中，除了包含該脂肪酸金屬鹽之含量以外，於含有下述源自脂肪酸金屬鹽之成分之情形時，包含以該脂肪酸金屬鹽換算之含量。
又，於本發明之黏著劑層中，作為上述脂肪酸金屬鹽之含量，以脂肪酸換算(羧基殘基(COO)數換算)計，相對於上述羅匹尼羅及/或其藥學上容許之鹽的以羅匹尼羅游離體換算之含量1.0莫耳，較佳為0.1～5.0莫耳，更佳為0.2～4.0莫耳，進而較佳為0.5～3.0莫耳，進而更佳為0.6～3.0莫耳。於上述脂肪酸金屬鹽之含量未達上述下限之情形時，有羅匹尼羅之皮膚透過性下降之傾向，另一方面，於超過上述上限之情形時，有黏著劑層之凝集力下降之傾向。
於使黏著劑層中含有上述羅匹尼羅酸加成鹽作為本發明之貼附劑之原材料之情形時，如上所述，該羅匹尼羅酸加成鹽藉由亦為弱鹼之脂肪酸金屬鹽而於製造過程及/或製造後之製劑之黏著劑層中全部或一部分脫鹽。因此，於該情形時，作為本發明之黏著劑層，除了含有下述黏著劑以外，只要至少含有上述羅匹尼羅酸加成鹽與上述脂肪酸金屬鹽之混合物即可，作為上述混合物，亦可含有羅匹尼羅游離體及源自上述脂肪酸金屬鹽之成分(脂肪酸金屬鹽來源成分)作為上述羅匹尼羅酸加成鹽與上述脂肪酸金屬鹽之脫鹽反應生成物。
作為上述源自脂肪酸金屬鹽之成分，可列舉：脂肪酸、脂肪酸根離子、金屬離子、金屬鹽，可為該等中之單獨1種，亦可為2種以上之組合。作為上述金屬鹽，取決於上述羅匹尼羅酸加成鹽之酸、或視需要可於黏著劑層中含有之酸之種類而有多種，例如可列舉：與鹽酸、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、反丁烯二酸之金屬鹽。
本發明之黏著劑層含有黏著劑。作為本發明之黏著劑，可列舉：橡膠系黏著劑、丙烯酸系黏著劑、矽酮系黏著劑等，可為該等中之單獨1種，亦可為2種以上之組合。該等之中，作為本發明之黏著劑，較佳為選自由橡膠系黏著劑、不具有羧基之丙烯酸系黏著劑、及矽酮系黏著劑所組成之群中之至少1種，更佳為選自由橡膠系黏著劑、及不具有羧基之丙烯酸系黏著劑所組成之群中之至少1種，進而較佳為至少含有橡膠系黏著劑。
於本發明之黏著劑層中，作為上述黏著劑之含量(於2種以上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10～90質量%，更佳為20～70質量%。
作為本發明之橡膠系黏著劑，可列舉：天然橡膠、合成橡膠，就有黏著劑層之凝集力及羅匹尼羅之皮膚透過性更加優異之傾向之觀點而言，更佳為選自由苯乙烯-異戊二烯-苯乙烯嵌段共聚物(SIS)、異戊二烯橡膠、聚異丁烯(PIB)、苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-丁二烯橡膠(SBR)、聚丁烯等不具有羥基及羧基之合成橡膠所組成之群中之至少任1種。於本發明中，「不具有羥基及羧基之合成橡膠」表示實質上不具有羥基及羧基、較佳為分子中之羥基及羧基之含量均未達3質量%之合成橡膠。
於本發明之黏著劑層含有上述橡膠系黏著劑之情形時，作為其含量(於2種以上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10～80質量%，更佳為10～70質量%，進而較佳為10～55質量%，進而更佳為15～35質量%。於上述橡膠系黏著劑之含量未達上述下限之情形時，有上述黏著劑層之凝集力下降之傾向，另一方面，於超過上述上限之情形時，有上述黏著劑層變得過硬而使貼附劑之黏著性下降之傾向。
作為本發明之丙烯酸系黏著劑，可列舉於「醫藥品添加物事典2016(日本醫藥品添加劑協會編輯)」中收載為黏著劑者，可為該等中之單獨1種，亦可為2種以上之組合，較佳為不具有羧基之丙烯酸系黏著劑，更佳為不具有官能基之丙烯酸系黏著劑。於本發明中，「不具有羧基之丙烯酸系黏著劑」及「不具有官能基之丙烯酸系黏著劑」分別表示實質上不具有羧基及官能基、較佳為高分子中之羧基及官能基之含量分別未達3質量%之丙烯酸系高分子。
作為上述不具有羧基之丙烯酸系黏著劑，例如可列舉：丙烯酸-2-乙基己酯·乙烯基吡咯啶酮共聚物、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-2-乙基己酯·乙酸乙烯酯共聚物、丙烯酸-2-乙基己酯·甲基丙烯酸甲酯·丙烯酸丁酯共聚物、丙烯酸-2-乙基己酯·甲基丙烯酸共聚物、丙烯酸乙酯·甲基丙烯酸甲酯共聚物等實質上不具有官能基之丙烯酸系黏著劑；(甲基)丙烯酸-2-乙基己酯·乙酸乙烯酯·丙烯酸2-羥基乙酯共聚物、(甲基)丙烯酸2-羥基乙酯共聚物、(甲基)丙烯酸2-羥基丙酯共聚物、(甲基)丙烯酸3-羥基丙酯共聚物、(甲基)丙烯酸4-羥基丁酯共聚物、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等具有羥基之丙烯酸系黏著劑；可為該等中之單獨1種，亦可為2種以上之組合。
作為上述不具有羧基之丙烯酸系黏著劑，亦可適當使用市售者，例如可適當使用：MAS 811、MAS 683(Cosmed公司製造)；Duro-Tak(註冊商標)丙烯酸系黏著劑系列(Henkel公司製造)之87-900A、87-901A、87-9301、87-4098、87-9088、87-9085；GELVA(註冊商標)丙烯酸系黏著劑系列(Henkel公司製造)之GMS 3083、GMS 3253、GMS 3235等所含有之丙烯酸系高分子、或Duro-Tak(註冊商標)丙烯酸系黏著劑系列(Henkel公司製造)之87-202A、87-2287、87-2516、87-2510、87-4287、87-2525、87-201A、87-202A、87-208A、87-502A、87-503A、87-504A；GELVA(註冊商標)丙烯酸系黏著劑系列(Henkel公司製造)之GMS 788、GMS 737等所含有之丙烯酸系高分子等。
於本發明之黏著劑層含有上述丙烯酸系黏著劑之情形時，作為其含量(於2種以上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10～90質量%，更佳為10～80質量%，進而較佳為20～70質量%。於上述丙烯酸系黏著劑之含量未達上述下限之情形時，有黏著劑層之凝集力下降之傾向，另一方面，於超過上述上限之情形時，有羅匹尼羅之皮膚透過性下降之傾向。
作為本發明之矽酮系黏著劑，可列舉：於ASTM標準(ASTM D 1418)中表示為MQ(聚二甲基矽氧烷)、VMQ(聚甲基乙烯基矽氧烷)、PMQ(聚甲基苯基矽氧烷)、PVMQ(聚苯基乙烯基甲基矽氧烷)之矽酮橡膠、或該等中之至少1種與聚二-三甲基矽烷基矽氧烷等除了矽酮橡膠以外之矽酮樹脂之混合物等，可為該等中之單獨1種，亦可為2種以上之組合。再者，於混合上述除了矽酮橡膠以外之矽酮樹脂之情形時，相對於矽酮系黏著劑之總質量，較佳為0.1～20質量%。
又，作為該等矽酮系黏著劑，亦可適當使用市售者，例如可適當使用由道康寧公司以如下型號所提供之矽酮系黏著劑等：BIO-PSA-7-410X、BIO-PSA-7-420X、BIO-PSA-7-430X、BIO-PSA-7-440X、BIO-PSA-7-450X、BIO-PSA-7-460X(上述各X分別獨立地為1或2)、BIO-PSA AC7-4201、BIO-PSA AC7-4301、BIO-PSA AC7-4302、MD7-4502、MD7-4602、7-9700、MG7-9800、MG7-9850；作為熱熔矽酮黏著劑之BIO-PSA-7-4560等。
進而，作為本發明之矽酮系黏著劑，例如，於具有甲基之情形時，可為藉由調配過氧化物而使該甲基之氫原子脫氫從而使該甲基間交聯而成者；於具有乙烯基之情形時，可為使含有含SiH基之矽氧烷化合物之交聯劑鍵結而使該乙烯基間交聯而成者；於具有羥基之情形時(即，具有矽烷醇基之情形)，可為藉由脫水縮合而使該矽烷醇基間交聯而成者等。
於本發明之黏著劑層含有上述矽酮系黏著劑之情形時，作為其含量(於2種以上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10～90質量%，更佳為10～80質量%，進而較佳為20～70質量%。於上述矽酮系黏著劑之含量未達上述下限之情形時，有黏著劑層之凝集力下降之傾向，另一方面，於超過上述上限之情形時，有羅匹尼羅之皮膚透過性下降之傾向。
作為本發明之黏著劑層，亦可於不妨礙本發明之效果之範圍內，進而含有：除了羅匹尼羅及其藥學上容許之鹽以外之其他藥物；吸收促進劑(經皮吸收促進劑)；吸附劑、黏著賦予劑、塑化劑、用於藥物之溶解劑、填充劑、穩定劑、保存劑等添加劑等。
作為上述除了羅匹尼羅及其藥學上容許之鹽以外之其他藥物，例如可列舉：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、匹洛昔康、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(Amfenac)等)、抗組織胺劑(苯海拉明、氯菲安明、過敏美奎錠、高氯環𠯤(Homochlorcyclizine)等)、降壓劑(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)、抗帕金森劑(培高利特、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(Isoproterenol)、沙丁胺醇等)、抗過敏劑(可多替芬、氯雷他定、氮卓斯汀、特非那定、西替利𠯤、阿紮司特等)、局部麻醉劑(利多卡因、狄布卡因(Dibucaine)等)、麻醉系鎮痛劑(嗎啡等)、泌尿器官用劑(奧昔布寧、他蘇洛辛等)、精神神經用劑(普馬𠯤(Promazine)、氯丙𠯤等)、類固醇激素劑(雌二醇(Estradiol)、黃體酮、炔諾酮、可體松、氫化可體松等)、抗抑鬱劑(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)、乳腺癌預防藥(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。
作為上述吸收促進劑，例如可列舉：肉豆蔻酸異丙酯、棕櫚酸異丙酯、月桂醇、月桂酸己酯、肉豆蔻醇、油醇、異硬脂醇、辛基十二烷醇、苄醇、甘油單油酸酯(GMO)、丙二醇單月桂酸酯(PGML)、聚氧乙烯山梨醇酐單油酸酯(Tween80)、聚氧乙烯山梨醇酐三硬脂酸酯(Tween65)、聚氧乙烯山梨醇酐單硬脂酸酯(Tween60)、聚氧乙烯山梨醇酐單月桂酸酯(Tween20)、二乙醇胺月桂酸(LADA)等，可單獨使用該等中之1種，亦可組合2種以上使用。
作為上述吸附劑，可列舉：具有吸濕性之無機及/或有機物質，更具體而言，可列舉：滑石、高嶺土、膨潤土等礦物；薰製二氧化矽(艾羅技(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；聚乙烯基吡咯啶酮、甲基丙烯酸胺基烷基酯共聚物、交聯聚維酮、羧基乙烯基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。
上述黏著賦予劑主要係以提高上述黏著劑之黏著性為目的進行調配。作為此種黏著賦予劑，例如可列舉：松香系樹脂、萜烯系樹脂、石油系樹脂(脂環族飽和烴樹脂等)、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。於在上述黏著劑層中進而含有此種黏著賦予劑之情形時，作為其含量(於2種以上之情形時為其等之合計含量)，就提升上述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，相對於上述黏著劑層之總質量，更佳為10～80質量%，進而較佳為20～60質量%。
上述塑化劑主要係以對上述黏著劑層之黏著物性、上述黏著劑層之製造中之流動特性、上述藥物之經皮吸收特性等進行調整為目的進行調配。作為此種塑化劑，例如可列舉：矽酮油；石蠟系加工處理油(液態石蠟等)、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；液態聚丁烯及液態異戊二烯橡膠等液態橡膠；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，較佳為選自由矽酮油、液態石蠟、及液態聚丁烯所組成之群中之至少1種。於在上述黏著劑層中進而含有此種塑化劑之情形時，作為其含量(於2種以上之情形時為其等之合計含量)，就使作為貼附劑之黏著力變得更加良好之觀點而言，相對於上述黏著劑層之總質量，更佳為5～60質量%，進而較佳為7～40質量%。
上述溶解劑主要係以促進上述藥物之溶解為目的進行調配。作為此種溶解劑，例如可列舉：乙酸等有機酸、脂肪族醇、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。該等之中，作為上述溶解劑，較佳為選自由有機酸、及脂肪族醇所組成之群中之至少1種。
上述填充劑主要係以調整上述黏著劑層之黏著力為目的進行調配。作為此種填充劑，例如可列舉：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。
作為本發明之黏著劑層，亦可於不妨礙本發明之效果之範圍內，進而使用除了本發明之脂肪酸金屬鹽以外的作為羅匹尼羅之藥學上容許之酸加成鹽之脫鹽劑發揮功能之成分。作為該成分，例如可列舉：含金屬離子之脫鹽劑、及含鹼性氮原子之脫鹽劑，作為上述含金屬離子之脫鹽劑，可列舉：乙酸鈉(包含無水乙酸鈉)、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，可為該等中之單獨1種，亦可為2種以上之組合。於本發明中，由於即便不調配該等成分，羅匹尼羅之皮膚透過性亦優異，故而較佳為實質上不調配，更具體而言，上述成分之調配量(於2種以上之情形時為其等之合計調配量)相對於上述黏著劑層之總質量，較佳為1質量%以下，更佳為0.1質量%以下。
作為本發明之黏著劑層之厚度，無特別限制，例如，較佳為上述黏著劑層之每單位面積之質量為25～250 g/m2
之厚度，更佳為50～200 g/m2
之厚度，進而較佳為50～150 g/m2
之厚度，進而更佳為50～120 g/m2
之厚度。
作為本發明之貼附劑，自製造後至使用時之間，亦可包裝(較佳為封入)於包裝容器內。作為上述包裝容器，無特別限制，可適當使用通常能夠作為貼附劑之包裝容器使用者，例如，較佳為使用塑膠製包裝袋、形成有金屬層(例如鋁層)之塑膠製包裝袋、金屬製包裝袋(例如鋁性包裝袋)等。
又，作為在上述包裝容器內包裝有本發明之貼附劑之包裝體，亦可進而具有脫氧機構。作為上述脫氧機構，可列舉：封入至上述包裝容器內之使用鐵粉之脫氧劑或以維生素C為主成分之脫氧劑(更具體而言，AGELESS系列(三菱瓦斯化學公司製造)、PharmaKeep系列(三菱瓦斯化學公司製造)等)；具備具有脫氧功能之層(更具體而言，混合有鋁、鋅、錳、銅、鐵、亞硫酸氫鹽、活性碳等粉末之層等)之上述包裝容器。
本發明之貼附劑例如可藉由如下之製造方法製造。首先，按照慣例將上述羅匹尼羅及/或其藥學上容許之鹽、上述脂肪酸金屬鹽、及上述黏著劑、以及視需要之其他藥物、上述吸收促進劑、上述添加劑、及溶劑等加以混合而獲得均勻之黏著劑層組合物。作為上述溶劑，例如可列舉：水、無水乙醇、甲苯、己烷、乙酸乙酯、環己烷、庚烷、乙酸丁酯、乙醇、甲醇、二甲苯、異丙醇、及該等中之2種以上之混合液等。其次，將該黏著劑層組合物塗佈於上述支持體層之面上(通常為一個面上)後，視需要乾燥去除上述溶劑而形成黏著劑層，進而視需要裁成所需之形狀，藉此可獲得本發明之貼附劑。
又，作為本發明之貼附劑之製造方法，可進而包括使上述離型襯墊貼合於上述黏著劑層之與上述支持體層相反之面上之步驟，亦可將上述黏著劑層組合物首先塗佈於上述離型襯墊之一個面上而形成上述黏著劑層後，使上述支持體層貼合於上述黏著劑層之與上述離型襯墊相反之面上，視需要裁成特定之形狀，藉此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上述包裝容器內而製成包裝體。
本發明之羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性之提升方法包括如下步驟：
於具備支持體層及黏著劑層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種、以及黏著劑的含羅匹尼羅之貼附劑中，
使上述黏著劑層進而含有碳數為7以上之脂肪酸金屬鹽。
作為上述支持體層、上述黏著劑層、上述羅匹尼羅及其藥學上容許之鹽、上述黏著劑、以及上述碳數為7以上之脂肪酸金屬鹽，包括其較佳之態樣在內分別如上所述。
作為使上述黏著劑層進而含有本發明之脂肪酸金屬鹽之方法，如上述本發明之貼附劑之製造方法中所述，例如可列舉如下方法，即，將上述羅匹尼羅及/或其藥學上容許之鹽、上述脂肪酸金屬鹽、及上述黏著劑、以及視需要之其他藥物、上述吸收促進劑、上述添加劑、及溶劑等加以混合，使所獲得之黏著劑層組合物成型而獲得上述黏著劑層。藉此，於所獲得之含羅匹尼羅之貼附劑中，可提升羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性。
實施例
以下，基於實施例、比較例、及參考例，更加具體地說明本發明，但本發明並不限定於以下之實施例。再者，各實施例、比較例、及參考例所獲得之貼附劑之皮膚透過試驗係藉由以下所示之方法進行。
＜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，將切成3.14 cm2
之大小且去除了離型襯墊之貼附劑貼附於表皮側。將其以真皮側與接受液相接之方式設置於流通型之Franz型透過試驗池，使接受溶液(PBS)填滿上述池。其次，一面以接受溶液保溫為32℃之方式，使加溫之循環水於外周部循環，一面以約2.5 mL/hr之流速輸送接受溶液，每4小時採取接受溶液直至24小時。藉由高效液相層析法測定所採取之接受溶液中之羅匹尼羅(羅匹尼羅鹽酸鹽)之濃度，藉由下式：
羅匹尼羅皮膚透過量(μg/cm2
)＝{接受溶液中之羅匹尼羅濃度(μg/mL)×流量(mL)}/貼附劑面積(cm2
)
計算黏著劑層之每單位面積之羅匹尼羅皮膚透過量，求出每1小時之皮膚透過量(皮膚透過速度(μg/cm2
/hr))。將自貼附開始至24小時中之上述皮膚透過速度之最大值設為最大皮膚透過速度(Jmax、μg/cm2
/hr)。又，將自貼附開始至24小時之累積皮膚透過量設為24 hr累積皮膚透過量(μg/cm2
)。於24 hr累積皮膚透過量為200 μg/cm2
以上時，可評價羅匹尼羅之皮膚透過性尤其優異。
進而，根據各貼附劑中調配之羅匹尼羅鹽酸鹽之質量與24 hr累積皮膚透過量(μg/cm2
)，藉由下式：
利用率(%)＝｛24 hr累積皮膚透過量(μg/cm2
)×貼附劑面積(cm2
)×100｝/貼附劑中調配之羅匹尼羅鹽酸鹽之質量
求出貼附劑中調配之藥物(羅匹尼羅)之利用率(%)。利用率為14%以上時，可評價羅匹尼羅之皮膚透過性尤其優異。
(實施例1)
首先，將羅匹尼羅鹽酸鹽15.0質量份、油酸鈉15.4質量份(相對於羅匹尼羅鹽酸鹽之莫耳數1.0莫耳，相當於1.0莫耳)、苯乙烯-異戊二烯-苯乙烯嵌段共聚物(SIS)11.6質量份、聚異丁烯(PIB)7.7質量份、脂環族飽和烴樹脂34.8質量份、及液態石蠟15.5質量份加入至適量之溶劑(水、甲醇、及甲苯)中加以混合，從而獲得黏著劑層組合物。其次，以厚度成為100 g/m2
之方式將所獲得之黏著劑層組合物塗佈於離型襯墊(實施了離型處理之聚酯製膜)上，乾燥去除溶劑而形成黏著劑層。於所獲得之黏著劑層之與上述離型襯墊相反之面上積層支持體層(聚酯製膜)，從而獲得以支持體層/黏著劑層/離型襯墊之順序積層之貼附劑。
(實施例2～4、比較例1～3)
將黏著劑層組合物之組成設為下述表1～2所示之組成，除此以外，以與實施例1相同之方式獲得各貼附劑。
對於實施例1～4及比較例1～3所獲得之貼附劑，分別進行上述皮膚透過試驗。將結果與各黏著劑層組合物之組成(溶劑除外)一起分別示於下述表1～2。再者，於以下之表中，羅匹尼羅鹽酸鹽之欄之括弧內之數值表示以羅匹尼羅游離體換算之質量份。
[表1]
| 實施例1 | 實施例2 | 實施例3 | 實施例4 | |
| 黏著劑層組合物[質量份] | ||||
| 羅匹尼羅鹽酸鹽 (游離體換算) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) |
| 油酸鈉(碳數18) | 15.4 | - | - | - |
| 癸酸鈉(碳數10) | - | 9.8 | - | - |
| 月桂酸鈉(碳數12) | - | - | 11.2 | - |
| 硬脂酸鉀(碳數18) | - | - | - | 16.3 |
| SIS | 11.6 | 12.5 | 12.3 | 11.4 |
| PIB | 7.7 | 8.4 | 8.2 | 7.6 |
| 脂環族飽和烴樹脂 | 34.8 | 37.6 | 36.9 | 34.4 |
| 液態石蠟 | 15.5 | 16.7 | 16.4 | 15.3 |
| 合計 | 100 | 100 | 100 | 100 |
| 最大皮膚透過速度[μg/cm2 /hr] | 36.9 | 43.0 | 49.4 | 23.9 |
| 24 hr累積皮膚透過量[μg/cm2 ] | 526.3 | 524.7 | 812.2 | 444.7 |
| 利用率[%] | 35.1 | 35.0 | 54.1 | 29.6 |
[表2]
| 比較例1 | 比較例2 | 比較例3 | |
| 黏著劑層組合物[質量份] | |||
| 羅匹尼羅鹽酸鹽 (游離體換算) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) |
| 苯甲酸鈉 | 7.3 | - | - |
| 山梨酸鉀(碳數6) | - | 7.6 | - |
| 乳酸鈉 | - | - | 5.7 |
| SIS | 12.9 | 12.9 | 13.2 |
| PIB | 8.6 | 8.6 | 8.8 |
| 脂環族飽和烴樹脂 | 38.9 | 38.7 | 39.7 |
| 液態石蠟 | 17.3 | 17.2 | 17.6 |
| 合計 | 100 | 100 | 100 |
| 最大皮膚透過速度[μg/cm2 /hr] | 4.1 | 5.5 | 1.1 |
| 24 hr累積皮膚透過量[μg/cm2 ] | 67.3 | 98.8 | 18.7 |
| 利用率[%] | 4.5 | 6.6 | 1.2 |
由表1所示之結果確認，於使用碳數7以上之脂肪酸金屬鹽所獲得之本發明之貼附劑(例如實施例1～4)中，羅匹尼羅之皮膚透過性尤其優異。另一方面，由表2所示之結果確認，於使用芳香族酸之金屬鹽(例如比較例1)或碳數未達7之脂肪酸之金屬鹽(例如比較例2)、或其他弱酸之金屬鹽(例如比較例3)代替碳數7以上之脂肪酸金屬鹽之情形時，24 hr累積皮膚透過量及利用率均較低，與本發明之貼附劑相比，羅匹尼羅之皮膚透過性較差。
(參考例1～3)
為了確認上述實施例1～4所獲得之貼附劑之優異之皮膚透過性產生之原因並不僅單純地在於羅匹尼羅鹽酸鹽與脂肪酸金屬鹽脫鹽，結果生成羅匹尼羅游離體與脂肪酸，研究將脂肪酸與羅匹尼羅鹽酸鹽及脫鹽劑組合之情形時之皮膚透過性之提升效果。即，將黏著劑層組合物之組成設為下述表3所示之組成，除此以外，以與實施例1相同之方式獲得各貼附劑。
對於參考例1～3所獲得之貼附劑，分別進行上述皮膚透過試驗。將結果與各黏著劑層組合物之組成(溶劑除外)一起示於下述表3。
[表3]
| 參考例1 | 參考例2 | 參考例3 | |
| 黏著劑層組合物[質量份] | |||
| 羅匹尼羅鹽酸鹽 (游離體換算) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) |
| 氫氧化鈉 | 1.62 | 1.62 | 1.62 |
| 油酸 | - | 5 | - |
| 異硬脂酸 | - | - | 5 |
| SIS | 16.68 | 15.68 | 15.68 |
| PIB | 7.15 | 6.72 | 6.72 |
| 脂環族飽和烴樹脂 | 40.5 | 38.07 | 38.07 |
| 液態石蠟 | 19.05 | 17.91 | 17.91 |
| 合計 | 100 | 100 | 100 |
| 最大皮膚透過速度[μg/cm2 /hr] | 20.8 | 15.7 | 13.2 |
| 24 hr累積皮膚透過量[μg/cm2 ] | 400.5 | 226.6 | 222.8 |
| 利用率[%] | 26.7 | 15.1 | 14.9 |
由表3所示之結果確認，於使用先前作為羅匹尼羅之鹽之脫鹽劑使用之氫氧化鈉之情形時(參考例1)，亦達成作為製劑而言充分之皮膚透過性，即便於其中添加碳數7以上之脂肪酸，皮膚透過性亦不會特別提升，甚至有下降之傾向(參考例2～3)。因此，確認，本發明之貼附劑之優異之皮膚透過性產生之原因並不僅單純地在於：藉由羅匹尼羅鹽酸鹽與碳數7以上之脂肪酸金屬鹽之脫鹽反應而生成羅匹尼羅游離體與脂肪酸。
(實施例5～7)
將黏著劑層組合物之組成設為下述表4所示之組成，除此以外，以與實施例1相同之方式獲得各貼附劑。表4中，各黏著劑分別如下所示：
MAS-811B：實質上不具有官能基之丙烯酸系黏著劑(Cosmed公司製造)、
Duro-Tak-87-4287：實質上不具有羧基之含OH基之丙烯酸系黏著劑(Henkel公司製造)、
Bio-PSA-7-4202：Bio-PSA-7-4202、矽酮系黏著劑(道康寧公司製造)、
(以下，於表6中相同)。
對於實施例5～7所獲得之貼附劑，分別進行上述皮膚透過試驗。將結果與各黏著劑層組合物之組成(溶劑除外)一起示於下述表4。
[表4]
| 實施例5 | 實施例6 | 實施例7 | |
| 黏著劑層組合物[質量份] | |||
| 羅匹尼羅鹽酸鹽 (游離體換算) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) |
| 硬脂酸鉀(碳數18) | 16.3 | 16.3 | 16.3 |
| MAS-811B | 68.7 | - | - |
| Duro-Tak-87-4287 | - | 68.7 | - |
| BiO-PSA-7-4202 | - | - | 68.7 |
| 合計 | 100 | 100 | 100 |
| 最大皮膚透過速度[μg/cm2 /hr] | 24.1 | 19.4 | 10.4 |
| 24 hr累積皮膚透過量[μg/cm2 ] | 458.9 | 370.9 | 211.1 |
| 利用率[%] | 30.6 | 24.7 | 14.1 |
由表4所示之結果確認，於使用丙烯酸系黏著劑或矽酮系黏著劑代替橡膠系黏著劑(例如SIS及PIB)作為黏著劑之情形時，亦與使用橡膠系黏著劑之情形(例如實施例4)同樣地，於使用碳數7以上之脂肪酸金屬鹽所獲得之本發明之貼附劑(例如實施例5～7)中，羅匹尼羅之皮膚透過性優異。
(實施例8、比較例4～5)
將黏著劑層組合物之組成設為下述表5所示之組成，除此以外，以與實施例1相同之方式獲得各貼附劑。
對於實施例8、比較例4～5所獲得之貼附劑，分別進行上述皮膚透過試驗。將結果與各黏著劑層組合物之組成(溶劑除外)一起示於下述表5。
[表5]
| 實施例8 | 比較例4 | 比較例5 | |
| 黏著劑層組合物[質量份] | |||
| 羅匹尼羅鹽酸鹽 (游離體換算) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) |
| 辛酸鈉(碳數8) | 8.4 | - | - |
| 己二酸鈉(碳數6) | - | 9.6 | - |
| 葡萄糖酸鈉(碳數6) | - | - | 11 |
| SIS | 12.77 | 12.57 | 12.33 |
| PIB | 8.51 | 8.38 | 8.22 |
| 脂環族飽和烴樹脂 | 38.3 | 37.7 | 37 |
| 液態石蠟 | 17.02 | 16.75 | 16.45 |
| 合計 | 100 | 100 | 100 |
| 最大皮膚透過速度[μg/cm2 /hr] | 26.2 | 3.6 | 0.8 |
| 24 hr累積皮膚透過量[μg/cm2 ] | 438 | 53 | 12 |
| 利用率[%] | 29.2 | 3.5 | 0.8 |
由表5所示之結果確認，於使用碳數7以上之脂肪酸金屬鹽所獲得之本發明之貼附劑(例如實施例8)中，羅匹尼羅之皮膚透過性尤其優異。另一方面，於使用碳數未達7之脂肪酸之金屬鹽(例如比較例4～5)代替碳數7以上之脂肪酸金屬鹽之情形時，24 hr累積皮膚透過量及利用率均較低，與本發明之貼附劑相比，羅匹尼羅之皮膚透過性較差。
(實施例9～14)
將黏著劑層組合物之組成設為下述表6所示之組成，除此以外，以與實施例1相同之方式獲得各貼附劑。
對於實施例9～14所獲得之貼附劑，分別進行上述皮膚透過試驗。將結果與各黏著劑層組合物之組成(溶劑除外)一起示於下述表6。
[表6]
| 實施例9 | 實施例10 | 實施例11 | 實施例12 | 實施例13 | 實施例14 | |
| 黏著劑層組合物[質量份] | ||||||
| 羅匹尼羅鹽酸鹽 (游離體換算) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) | 15.0 (13.2) |
| 辛酸鈉(碳數8) | 8.4 | 8.4 | 8.4 | 8.4 | 8.4 | 42 |
| SIS | 21.28 | - | - | - | - | 7.17 |
| PIB | - | 76.6 | - | - | - | 4.78 |
| 脂環族飽和烴樹脂 | 38.3 | - | - | - | - | 21.5 |
| 液態石蠟 | 17.02 | - | - | - | - | 9.55 |
| MAS-811B | - | - | 76.6 | - | - | - |
| Duro-Tak-87-4287 | - | - | - | 76.6 | - | - |
| BiO-PSA-7-4202 | - | - | - | - | 76.6 | - |
| 合計 | 100 | 100 | 100 | 100 | 100 | 100 |
| 最大皮膚透過速度[μg/cm2 /hr] | 24.8 | 46.9 | 52.8 | 19.7 | 52.3 | 58.4 |
| 24 hr累積皮膚透過量[μg/cm2 ] | 314 | 452 | 586 | 355 | 830 | 820 |
| 利用率[%] | 20.9 | 30.1 | 39.1 | 23.7 | 55.3 | 54.7 |
由表6所示之結果確認，於僅使用SIS或PIB作為橡膠系黏著劑之情形(例如實施例9～10)、或使用丙烯酸系黏著劑或矽酮系黏著劑代替橡膠系黏著劑之情形時(例如實施例11～13)，亦與使用橡膠系黏著劑之情形(例如實施例8)同樣地，於使用碳數7以上之脂肪酸金屬鹽所獲得之本發明之貼附劑中，羅匹尼羅之皮膚透過性優異。又，確認，即便碳數7以上之脂肪酸金屬鹽之含量相對於以羅匹尼羅游離體換算之含量1.0莫耳為5.0莫耳，於本發明之貼附劑(例如實施例14)中，羅匹尼羅之皮膚透過性亦優異。
[產業上之可利用性]
如以上說明，根據本發明，可提供一種羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性優異之含羅匹尼羅之貼附劑、及羅匹尼羅及/或其藥學上容許之鹽之皮膚透過性之提升方法。
Claims (6)
- 一種含羅匹尼羅之貼附劑，其具備支持體層及黏著劑層，且上述黏著劑層含有選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種、碳數為7以上之脂肪酸金屬鹽、以及黏著劑，且相對於上述黏著劑層之總質量，上述脂肪酸金屬鹽之含量為8.4~42質量%。
- 如請求項1之含羅匹尼羅之貼附劑，其中上述脂肪酸金屬鹽為脂肪酸鹼金屬鹽。
- 如請求項1或2之含羅匹尼羅之貼附劑，其中上述脂肪酸金屬鹽係選自由辛酸、油酸、月桂酸、硬脂酸、癸酸、肉豆蔻酸、及棕櫚酸所組成之群中之至少1種脂肪酸之金屬鹽。
- 如請求項1或2之含羅匹尼羅之貼附劑，其中上述黏著劑係選自由橡膠系黏著劑、不具有羧基之丙烯酸系黏著劑、及矽酮系黏著劑所組成之群中之至少1種。
- 如請求項1或2之含羅匹尼羅之貼附劑，其中於上述黏著劑層中，相對於上述選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種的以羅匹尼羅游離體換算之含量1.0莫耳，上述脂肪酸金屬鹽之含量為0.1~5.0莫耳。
- 如請求項1或2之含羅匹尼羅之貼附劑，其中相對於上述黏著劑層之總質量，上述選自由羅匹尼羅及其藥學上容許之鹽所組成之群中之至少1種的以羅匹尼羅游離體換算之含量為5~30質量%。
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