TW200812652A - Adhesive preparation - Google Patents
Adhesive preparation Download PDFInfo
- Publication number
- TW200812652A TW200812652A TW096125256A TW96125256A TW200812652A TW 200812652 A TW200812652 A TW 200812652A TW 096125256 A TW096125256 A TW 096125256A TW 96125256 A TW96125256 A TW 96125256A TW 200812652 A TW200812652 A TW 200812652A
- Authority
- TW
- Taiwan
- Prior art keywords
- patch
- adhesive
- polyisobutylene
- drug
- polymer
- Prior art date
Links
- 239000000853 adhesive Substances 0.000 title claims abstract description 63
- 230000001070 adhesive effect Effects 0.000 title claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 84
- 229920002367 Polyisobutene Polymers 0.000 claims abstract description 42
- 229960002428 fentanyl Drugs 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims abstract 2
- 229940079593 drug Drugs 0.000 claims description 81
- 229920000642 polymer Polymers 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 23
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 17
- 229910052707 ruthenium Inorganic materials 0.000 claims description 17
- 238000010521 absorption reaction Methods 0.000 claims description 14
- 239000003623 enhancer Substances 0.000 claims description 12
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims description 7
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
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- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 claims description 6
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 4
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- 239000001593 sorbitan monooleate Substances 0.000 claims description 4
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- NRZWQKGABZFFKE-UHFFFAOYSA-N trimethylsulfonium Chemical group C[S+](C)C NRZWQKGABZFFKE-UHFFFAOYSA-N 0.000 claims 1
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- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 2
- XMGQYMWWDOXHJM-JTQLQIEISA-N (+)-α-limonene Chemical compound CC(=C)[C@@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-JTQLQIEISA-N 0.000 description 2
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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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
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Description
200812652 九、發明說明 【發明所屬之技術領域】 本發明係關於貼布劑,更詳細而言 尼(fentanyl )及/或該藥學上可容許的 貼布劑。 【先前技術】 芬太尼係選擇性的μ 〇 p i 〇 i d (類嗎 痛藥、麻醉補助藥。尤其,近年來,作 痛之對症療法之嗎啡(Μ 〇 r p h i n e )之類 起堅固的地位。另外,考量癌性疼痛患 質,q u a 1 i t y 〇 f 1 i f e )時,經皮投予可說 予方法之一。 作爲經皮投予之適合形態之一係使 藥物層(含有藥物及黏著劑),此藥物 覆之貼布劑之方法。一般而言,由貼布 ,就藥物之擴散性、皮膚滲透性等之觀 著劑中爲溶解狀態爲宜。進而,爲確保 ,以配合經皮吸收促進劑於黏著劑爲宜 雖然如此地使黏著劑中含有許多液 助溶劑及經皮吸收促進劑等,但因爲使 黏著基劑之凝聚力降低之問題。黏著基 ,藥物之皮膚滲透性亦有降低之趨勢。 之擴散性或皮膚滲透性爲目的’即使增 ,係關於含有芬太 鹽作爲活性成份之 啡類)作用藥之鎭 爲取代對於癌性疼 嗎啡類藥,逐漸築 者之QOL (生活品 是方便性最高的投 用於支持體上具備 層係由離型膜所被 劑經皮投予藥物時 點,此藥物係於黏 所定藥物之吸收量 〇 體成份之溶解劑、 含有此等,而有使 劑之凝聚力降低時 因此,以提昇藥物 加黏著劑中之液體 -4- 200812652 成份,相反地藥物之皮膚滲透性有降低之虞。 一般如芬太尼之鹼性藥物之皮膚滲透性低。因此,於 黏著劑中含有芬太尼時,爲使藥物的擴散性或皮膚滲透性 充份’於黏著劑中必須配合大量的液體成份。然而,配合 許多液體成份時,因上述理由黏著基劑之凝聚力降低,結 果係有不能得到充份的皮膚滲透性之問題。 爲解決如此課題,揭示如專利文獻1〜4之含有芬太 尼之貼布劑。亦即已知藥池型(reservoir )及多層型( multi-laminate )之貼布劑(專利文獻1 )、含有機酸鹽、 苯乙烯一異丁烯一苯乙烯嵌段共聚物及聚異丁烯之貼布劑 (專利文獻2 )、含N —甲基一 2—吡咯烷酮之貼布劑(專 利文獻3 )、懸濁芬太尼粒子於1種以上之溶劑及聚矽氧 烷系黏著劑之貼布劑(專利文獻4)。 專利文獻1 :特開昭6 1 — 3 7 72 5號公報 專利文獻2 :特開平1 〇 — 4 5 5 7 0號公報 專利文獻3:特開2000— 44476號公報 專利文獻4:特表2006— 513160號公報 【發明內容】 發明之揭不 然而,上述傳統之含有芬太尼貼布劑係具有如下述之 問題。 亦即,專利文獻1記載之藥池型之含有芬太尼貼布劑 係具有藥物貯藏層,爲封閉溶液或半固體之藥物於該層, -5- 200812652 要求高精度之製造步驟以不使發生藥物揮發及洩漏。另外 ,因爲於構造上必須爲藥物釋出速度控制膜,所以於構成 貼布劑之零件數量變多等之理由下,而有製造方法不得不 變得複雜之問題。 另外,專利文獻1記載之多層型之含有芬太尼貼布劑 係必須使黏著劑中含有多量(例如10〜30% )的芬太尼, 因爲隨著時間經過,芬太尼有結晶之虞,所以就黏著性或 藥物釋出性之觀點,並不適宜之問題。 專利文獻2及3記載之含有芬太尼貼布劑中,對於製 造步驟(粉碎、混合、成膜、乾燥)之條件限制多,製造 方法複雜而成爲問題。另外,專利文獻3記載之含有芬太 尼貼布劑,因爲藥物釋出性或吸收性高,所以有藥物適用 中之藥物快速枯竭之趨勢之問題。進而,於專利文獻3記 載之含有芬太尼貼布劑,亦有所謂「滲出」之問題。 亦即,通常貼布劑爲防止所含有藥物之揮發或防止對 濕度的影響,藉由對水具有不滲透性之包材,個別包裝。 關於如此個別包裝之貼布劑,有稱爲「滲出」之自貼布劑 周圍滲出黏著劑,附著於包材的內面,或黏著劑繞道滲出 至支持體的背面,使用時而有難以取出貼布劑之問題。尤 其,使於黏著劑中含有可塑劑或增黏劑、溶解劑等時,此 等物質自藥物層周圍滲出,附著(繞道滲出)於支持體或 離型膜之背面,甚至包材的內面。該結果係貼布劑貼附於 包材內面,而有難以取出貼布劑之問題。 專利文獻4記載之含有芬太尼貼布劑,有黏著力降低 -6 - 200812652 、或離型膜之剝離性差之問題。 本發明係有鑑於上述情況而實施者,提供製造方法簡 單,充份防止滲出及結晶析出,而且具有充份的藥物之皮 膚滲透性之含有芬太尼貼布劑爲目的。 用以解決課題之手段 本發明者等重覆努力的結果,發現藉由具備支持體、 及該支持體上所層合之藥物層,藥物層係含有至少1種選 自芬太尼及該藥學上可容許的鹽所成群之化合物、及聚異 丁烯、及含矽聚合物之黏著劑所成,黏著劑中之聚異丁烯 及含矽聚合物之質量比爲20: 1〜7: 3之貼布劑,可達成 上述目的。 如此之含有芬太尼貼布劑係製造方法簡單,充份防止 滲出及結晶析出,而且具有充份的皮膚滲透性。產生如此 效果之理由雖未明朗,但認爲至少起因係使用聚異丁烯及 含矽聚合物之混合物作爲使含有芬太尼之黏著性物質(以 下亦稱爲「黏著基劑」。),並且此等質量比係於一定範 圍內者。 另外’上述構成之貼布劑係因爲製造用所需之零件少 ,而且對於製造步驟之條件限制少,所以與傳統者相比較 ,亦達到可以簡單的製造方法製造之效果。 進一步’於傳統之含有芬太尼貼布劑,自皮膚剝離貼 布劑時,黏著劑多殘留於皮膚(以下稱爲「黏著劑殘留」 。),成爲患者的負擔,但由本發明之含有芬太尼貼布劑 -7- 200812652 ,則可充份地防止黏著劑殘留。 另外,上述聚異丁烯係由平均分子量爲800,000〜 1,600,000之高分子量聚異丁烯,及平均分子量爲30,000 〜8 0,0 00之低分子量聚異丁烯所成爲宜。藉此可提昇貼布 劑之黏著性。 另外,上述之含矽聚合物係以具有有機聚矽氧烷骨架 (以有機聚矽氧烷骨架爲宜)之聚合物或含有此聚合物之 組成物爲宜,作爲具有有機聚矽氧烷骨架之聚合物係該羥 基之至少部份爲三甲基矽烷基所罩住者爲宜。具有羥基之 至少部份爲三甲基矽烷基所罩住之有機聚矽氧烷骨架之聚 合物係因爲自由的矽烷醇基之數量少,所以與藥物之相互 作用(例如化學的、物理的鍵結)弱,藥物釋出性有增大 之趨勢。 如上所述,含矽聚合物係可爲含有具有有機聚矽氧烷 骨架之聚合物之組成物,但以此組成物爲具有黏著性之組 成物爲宜。如此組成物係不使構成藥物層之黏著劑之黏著 性降低,可良好地保持芬太尼或該藥學上可容許的鹽之釋 出性。 另外,黏著以更含有經皮吸收促進劑爲宜。由此藥物 可有效率地爲皮膚吸收。 另外,上述之經皮吸收促進劑係以係至少一種選自肉 豆蔻酸異丙酯、棕櫚酸異丙酯、山梨糖醇酐單油酸酯、油 醇、丙二醇、二丙二醇及辛基十二烷醇所成群之化合物爲 宜。藉此而更提昇藥物之皮膚滲透性。 -8- 200812652 另外,可接觸皮膚之藥劑層面積係以5〜50cm2爲宜 發明之功效 由本發明提供製造方法簡單,充份防止滲出及結晶析 出,而且具有充份的皮膚滲透性、黏著力及對皮膚之附著 性之含有芬太尼貼布劑。另外,由本發明之含有芬太尼貼 布劑,充份地防止黏著劑殘留,另外,與傳統之芬太尼貼 布劑相比較,因藥物經更長時間被吸收,可減輕患者負擔 用以實施發明之最佳型態 以下係詳細地說明關於本發明之貼布劑之適合型態。 另外,本說明書中除非特別例外,「」係指「質量%」。 本發明之貼布劑係具備支持體、及該支持體上所層合 之由特定黏著劑所成之藥物層。 黏著劑係含有至少1種選自芬太尼及該藥學上可容許 的鹽所成群之具有活性(藥效)之藥物、及聚異丁烯及含 矽聚合物之黏著劑所成之黏著基劑。 黏著劑雖可分別單獨含有作爲活性藥物之芬太尼及該 藥學上可容許的鹽,或亦可以混合物含有,但爲使以溶解 狀態含有於黏著劑,以單獨含有芬太尼爲宜。 另外’藥物層中之芬太尼之配合量係基於藥物層整體 的質量,以1〜6%爲宜。藉由芬太尼之配合量爲1%以上 200812652 ,將容易得到作爲貼布劑之充份的藥物皮膚滲透量,藉由 6 %以下,可確實地除去因結晶析出對貼布劑本身物性的不 良影響。芬太尼之配合量若爲1〜6%時,經皮投予藥物時 ,可達成高血中濃度。另外,芬太尼之配合量係就黏著劑 殘留及防止藥物結晶析出之觀點,基於藥物層整體的質量 ,以1〜4%爲宜,以2〜4%尤佳。 聚異丁烯係就黏著性之觀點,由高分子量聚異丁烯及 低分子量聚異丁烯所成爲宜。高分子量聚異丁烯之黏度平 均分子量(Staudinger)係以 800,000 〜1,600,000 爲宜, 進而以 900,000 〜1,500,000 尤佳,以 1,000,000 〜 1,400,000更好。另外,低分子量聚異丁烯之黏度平均分 子量(St an dinger)係以 30,000〜80,000爲宜,進而以 35,000〜70,000尤佳,以35,000〜60,000更好。另外,上 述之平均分子量係由黏度法所測定之黏度平均分子量( S taudinger) ° 另外,高分子量聚異丁烯及低分子量聚異丁烯之質量 係以1 : 9〜2 : 3爲宜,以1 : 7〜1 : 3尤佳。藉由使高分 子量聚異丁烯及低分子量聚異丁烯之質量比於上述範圍, 可確實地防止黏著劑之凝聚及黏著劑殘留。 另外,藥物層中之聚異丁烯之配合量係基於藥物層整 體的質量,以 40〜94%爲宜,以 50〜90%尤佳,以 60〜 85%更好。聚異丁烯之配合量若未滿40%時,有不能得到 充份的黏著性之虞,若超過94%時,將發生黏著劑之凝聚 及黏著劑殘留之虞。 -10- 200812652 藥物層所含之含矽聚合物係指於化學骨架中含矽之聚 合物’以與聚異丁烯混合時,不使藥物之經皮吸收性降低 者,以提高經皮吸收性者爲宜。作爲如此之含矽聚合物, 以具有有機聚矽氧烷骨架之聚合物或含有此聚合物之組成 物爲宜,後者之組成物尤佳。 具有有機聚矽氧烷骨架之聚合物爲具有羥基(例如矽 院醇基)時,該键基之至少部份係由三甲基砂院基所罩住 爲宜。另外,上述組成物係具有黏著性者爲宜。另外,作 爲由三甲基矽烷基罩住係包含將具有有機聚矽氧烷骨架之 聚合物之末端矽烷醇基,由三甲基矽烷基末端罩住之型態 〇 作爲具有有機聚矽氧烷骨架之聚合物,可舉例如聚二 甲基矽氧烷(依據ASTMD— 1418表示,以MQ表示之聚 合物等)、聚甲基乙烯基矽氧烷(依據ASTMD— 1418表 示,以VMQ表示之聚合物等)、聚甲基苯基矽氧烷(依 據ASTMD — 1418表示,以PVMQ表示之聚合物等)等。 作爲含有具有有機聚矽氧烷骨架之聚合物之組成物, 以已知作爲聚矽氧烷黏著劑之組成物爲宜。作爲如此組成 物,可舉例如含有聚二甲基矽氧烷聚合物、聚甲基乙烯基 矽氧烷、聚甲基苯基矽氧烷等之聚矽氧烷生橡膠及MQ樹 脂((CH3)2Si01/2等之「M單位」及Si02等之「Q單位」 所成之3次元構造之聚矽氧烷樹脂)者。 含有聚二甲基矽氧烷聚合物(及/或聚甲基苯基矽氧 烷)及MQ樹脂之組成物係可使用以有機化氧化物所成之 -11 - 200812652 交聯劑,導入如 2SiCH3— Si— CH2— CH2— Si之交聯者。 含有聚甲基乙烯基矽氧烷MQ樹脂之組成物係可使用以具 有SiH基之交聯劑,使發生砂氫化反應(hydrosilylation reaction)者。另外,混合上述聚矽氧烷生橡膠及MQ樹 脂時,例如以鹼性催化劑使聚矽氧烷生橡膠之末端矽烷醇 基與MQ樹脂中之矽烷醇基脫水縮合亦可。 作爲含有具有羥基之至少部份係由三甲基矽烷基罩住 之有機聚矽氧烷骨架之聚合物之組成物,可舉例如該Dow Corning 社製感壓黏著劑之 BIO — PSA 7-4101、BIO — PSA 7-4102、BIO— PSA 7_4103、BIO— PSA 7-420 1、BIO-PSA 7-4202、BIO— PSA 7-4203 ^ BIO - PSA 7-43 0 1、BIO —PSA 7-43 02、BIO— PSA 7-43 03 等。其中,以 Dow Corning社製感壓黏著劑之BIO — PSA 7_4 102尤佳。如此 之含矽聚合物係可使用單獨1種,亦可混合2種以上使用 〇 藥物層中之聚異丁烯及含矽聚合物之質量比爲20: 1 〜7 : 3。另外,聚異丁烯或含矽聚合物係以含有有機溶劑 等之揮發成份之形態供給時,上述質量比係將揮發成份除 外算出。另外,含矽聚合物爲組成物時則使用組成物之總 質量。藉由使聚異丁烯及含矽聚合物之質量比於上述範圍 ’可得到充份地防止滲出及結晶析出,而且具有充份的藥 物皮膚滲透性之貼布劑。進而,就貼布劑中結晶析出及藥 物之皮膚滲透性之觀點,藥物層中之聚異丁烯及含矽聚合 物之質量比係以15: 1〜6: 1爲宜,以1〇: 1〜8: 1尤佳 -12- 200812652 本發明之貼布劑中之黏著基劑係以實質上不含有水爲 宜。在此所謂「實質的」係指於製造步驟中無企圖配合水 於黏著基劑之步驟,並非除去製造原料等所含有的水份等 、或貼布劑應用於皮膚中黏著劑吸收汗等之水份者。 本發明之黏著劑係可含有經皮吸收促進劑。經皮吸收 促進劑係1種或2種以上認爲具有藥劑之經皮吸收促進作 用之化合物即可’例如碳鏈數爲6〜20個之脂肪酸、脂肪 族醇、脂肪酸酯、烷基醚、芳香族系有機酸、芳香族系醇 、芳香族系有機酸酯、芳基醚等。進而,可舉例如乳酸酯 類、醋酸酯類、單萜烯系化合物、倍伴萜烯系化合物、氮 酮(Azone )及其衍生物、脂肪酸甘油酯類、山梨糖醇酐 脂肪酸酯類、聚山梨酸酯類、聚乙二醇脂肪酸酯類、聚環 氧乙烷硬化箆麻油系、蔗糖脂肪酸酯類等。 進一步,作爲適合經皮吸收促進劑之詳細例,可舉例 如辛酸、癸酸、己酸、月桂酸、肉豆蔻酸、棕櫚酸、硬脂 酸、油酸、亞油酸、亞麻酸、月桂醇、肉豆蔻醇、油醇、 十六院醇、辛基十二院醇、月桂酸甲酯、肉豆寇酸異丙酯 、肉豆蔻酸肉豆蔻酯、肉豆蔻酸辛基十二烷基酯、棕櫚酸 十六烷基酯、水楊酸、水楊酸甲酯、水楊酸乙二醇酯、肉 桂酸、肉桂酸甲酯、甲酚、乳酸十六烷基酯、乙酸乙酯、 乙酸丙酯、棕櫚酸異丙酯、山梨糖醇酐單油酸酯' 香葉醇 (geraniol )、百里香酚、丁子香酚、萜品醇、1 —薄荷醇 、龍腦(borneol ) 、d —檸檬烯(Limonene )、異 丁香醇 -13- 200812652 (isoeugenol)、異龍腦(isoborneol)、橙花醇、dl -樟腦 (dl-Camphor )、甘油單月桂酸酯、甘油單油酸酯、山梨 糖醇酐單月桂酸酯、蔗糖單月桂酸酯、聚山梨酸酯20、聚 乙二醇單月桂酸酯、聚乙二醇單硬脂酸酯、HCO — 60 (硬 化篦麻油)、1 一 〔 2 - (癸基硫)乙基〕氮雜環戊烷一 2 一酮,以脂肪酸酯及脂肪族醇爲宜。其中以肉豆蔻酸異丙 酯、棕櫚酸異丙酯、山梨糖醇酐單油酸酯、辛基十二烷醇 及油醇爲宜。 藥物層中之經皮吸收促進劑之配合量係基於藥物層整 體質量之〇·〇1〜20%爲宜,以0.1〜15質量%尤佳,以0.5 〜1 0%更好。藥物層中之經皮吸收促進劑之配合量若超過 2 0%時,有發紅、浮腫等之對皮膚刺激之虞,若未滿 〇·01%時,有不能得到配合經皮吸收促進劑之效果之虞。 另外,於本發明之貼布劑中,爲使吸收自皮膚所發生 的汗等之水性成份,因應需要,亦可配合親水性聚合物。 作爲親水性聚合物,例如以輕質矽酸酐、纖維素衍生物( 羧甲基纖維素(CMC)、羧甲基纖維素鈉(CMCNa)、甲 基纖維素(MC )、羥丙基甲基纖維素(HPMC )、羥丙基 纖維素(HPC )、羥乙基纖維素(HEC ))、澱粉衍生物 (普路蘭)、聚乙烯醇(PVA )、聚乙烯吡咯烷酮(PVP )、聚乙酸乙烯(VA )、羧乙烯聚合物(CVP )、乙基乙 酸乙烯共聚物(EVA ) 、eudragit (丙烯酸樹脂)、明膠 、聚丙烯酸、聚丙烯酸鈉、聚異丁烯馬來酸酐共聚物、褐 藻酸、褐藻酸鈉、鹿角菜膠、阿拉伯膠、西黃蓍膠、刺梧 -14- 200812652 桐膠、聚乙燦甲基丙嫌酸酯爲宜,以輕質砂酸酐、纖維素 衍生物(CMCNa、HPMC、HPC、MC) 、eudragit 爲宜。 另外,基於藥物層整體質量,配合〇 . 1〜2 0 %之親水性聚 合物,以0.5〜10%爲宜。 另外’本發明之貼布劑係因應需要,可使用抗氧化劑 、充塡劑、交聯劑、保存劑、融點降低劑、紫外線吸收劑 及礦物油。作爲抗氧化劑’有生育酚及此等之酯衍生物、 抗壞血酸、抗壞血酸硬脂酸酯、降二氫愈瘡木酸、二丁基 羥基甲苯(BHT) 、丁基羥基苯甲醚(Butylated Hydr〇Xy Anisole )等。 作爲充塡劑,以滑石、陶土、含水二氧化矽、輕質矽 酸、氨執化銘、碳酸銘、碳酸錶、砂酸鹽(例如砂酸銘、 矽酸鎂等)、政酸、硫酸鋇、硫酸鈣、鋅酸鈣、氧化鋅、 氧化鈦等爲宜。 作爲交聯劑’以胺基樹脂、酚醛樹脂、環氧樹脂、醇 酸樹脂、不飽和聚酯等之熱硬化性樹脂、異氰酸酯化合物 、嵌段異氰酸酯化合物、有機系交聯劑、金屬或金屬化合 物等之無機系交聯劑爲宜。 作爲保存劑,以乙二胺四乙酸二鈉、乙二胺四乙酸四 鈉、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯、對羥基苯甲 酸丁酯#爲宜。作爲融點降低劑,以醋酸、丙酸、丁酸、 乳酸、苯甲酸、及水楊酸爲宜。 作爲紫外線吸收劑,以對胺基苯甲酸衍生物、胺茴酸 衍生物、水楊酸衍生物、香豆酸衍生物、胺基酸系化合物 -15- 200812652 、咪唑啉衍生物、吡啶衍生 物油係以流動鏈烷烴爲宜。 如此之抗氧化劑、充塡 低劑、紫外線吸收劑及礦物 配合合計量係以30%以下爲 以下尤佳。 本發明之貼布劑係可由 製造。例如由溶劑法製造時 機溶劑溶液中,添加、攪拌 使乾燥而形成藥物層,可得 可由熱熔法塗布所配合之黏 基劑後,添加、攪拌其他成 物層,可得到本發明之貼布 另外,使用後述之離型 ,藉由貼合支持體,亦可得 另外,本發明之貼付劑 劑所成,具有支持其之支持 之成份並無特別的限制。例 持體及藥物層之外,可包含 作爲支持體,並無特別 織布、聚胺基甲酸乙酯、聚 、聚乙稀、聚對苯二甲酸乙 酯、紙、鋁箔等或此等之複 作爲離型膜係只要具有 物、二噁烷衍生物等爲宜。礦 劑、交聯劑、保存劑、融點降 油係基於藥物層整體質量,可 宜,以20%以下尤佳,以10% 溶劑法、熱熔法等之傳統方法 ,藉由所配合之黏著基劑之有 其他成份後,延展於支持體, 到本發明之貼布劑。另外,爲 著基劑者時,以高溫溶解黏著 份後,延展於支持體,形成藥 膜取代支持體,形成藥物層後 到本發明之貼付劑。 係只要藥物層由如上述之黏著 體者即可,其他層或構成此等 如,本發明之貼布劑係除了支 藥物層上所設置之離型紙。 的限制,但可適合使用布、不 酯、聚乙酸乙烯、聚偏氯乙烯 二醇酯、聚對苯二甲酸丁二醇 合材料。 充份的自藥物層之剝離性即可 -16- 200812652 ,並無特別的限定,可適合使用聚對苯二甲酸乙二醇酯( PET )、聚乙烯薄膜、聚丙烯薄膜、聚四氟乙烯薄膜等。 另外,由本發明之貼布劑,對於活性藥物之適用量, 可由裁切貼布劑等,因應患者的症狀、年齡、體重、性別 #而谷易g周卽。本發明之貼布劑接觸皮膚之藥物層面積雖 無特別的限制,但以5〜50cm2爲宜,以5〜30cm2尤佳, 以5〜10cm2更好。藉由貼布劑接觸皮膚之藥物層面積爲 50cm2以下時,適用時適合操作,5cm2以上時,將容易維 持藥物之充份的皮膚滲透性。 【實施方式】 實施例 以下係表示實施例,更具體地說明本發明,但本發明 之貼布劑並非局限於此等實施例者。 (實施例1 ) 溶解黏度平均分子量爲1,200,000之高分子量聚異丁 烯(Vistanex MM L— 100 Exxon Mobil 社製)及黏度平均 分子量爲 3 5,000之低分子量聚異丁烯(Oppanol B11 BASF社製)於甲苯後,添加含有具有有機聚矽氧烷骨架 之聚合物之組成物BIO — PS A · 7 — 4102 (聚矽氧烷黏著劑 ),作爲黏著基劑溶液。於室溫攪拌由芬太尼所成之活性 藥物、及由肉豆蔻酸異丙酯及油醇所成之其他成份後,添 加、攪拌上述黏著基劑溶液,調製黏著劑溶液。塗布此黏 -17- 200812652 著劑液於經氟碳化合物((fluorocarbon )處理之聚對苯 二甲酸乙二醇酯(PET )製薄膜(離型膜)上後,使乾燥 形成厚度爲90 μπι之藥劑層。於此藥劑層上貼附支持體之 厚度爲76.2μηι之PET薄膜,得到本發明之貼布劑。另外 ,關於各成份之質量比率係如表1所示。 (實施例2〜5 ) 黏著基劑、活性藥物及其他成份係如表1所示之質量 比率,其他則與實施例1同樣地操作,製造實施例2〜5。 〔表1〕 實施例1 實施例2 實施例3 實施例4 實施例5 黏著基劑 高分子量聚異丁烯 (Vistanex MM L-100) 18 17 9.5 11.8 12 低分子量聚異丁烯 (Oppanol B11) 72 68 56.5 70.7 74 聚矽氧烷黏著劑 4.5 9.5 28.4 9.0 4.4 活性藥物 芬太尼 2.5 2.5 2.5 _ 檸檬酚芬太尼 嫌 喊 . 2.5 2.5 其他成分 肉豆蔻酸異丙酯 2.0 3.0 3.0 6.0 棕櫚酸十六烷基酯 • • • 2.0 麵 油醇 1.0 - 雄 流動鏈烷烴 - • 4.0 • CMC-Na 轉 • 1.0 1.0 BHT • • 0.1 0.1 總量 100.0 100.0 100.0 100.0 100.0 聚異丁烯/聚矽氧院黏著劑 20/1 9/1 7/3 9/1 20/1 (比較例1〜8 ) -18- 200812652 黏著基劑、活性藥物及其他成份係如表2所示之質量 比率,其他則與實施例1同樣地操作,製造比較例1〜8。 另外,關於比較例5〜7,因黏著劑溶液分離,難以製造貼 布劑,所以不列入後續之評估對象。 〔表2〕 比較例 1 比較例 2 比較例 3 比較例 4 比較例 5 比較例 6 比較例 7 比較例 8 黏著 基劑 高分子量聚異丁烯 (Vistanex MM L-100) 19 18 18.2 18.3 6.5 3.9 0.95 - 低分子量聚異丁烯 (OppanolBll) 75.5 71.5 72.5 73.2 39.5 23.5 8.45 - 聚矽氧烷黏著劑 1.8 3.0 46.0 65.0 85.1 93.4 活性 藥物 芬太尼 2.5 2.5 2.5 2.5 2.5 - 檸檬酸芬太尼 参 2.5 2.5 _ 2.5 其他 成分 肉豆蔻酸異丙酯 2.0 3.0 3.0 3.0 3.0 3.0 棕櫚酸十六烷基酯 3.0 3.0 • 油醇 1.0 2.0 _ 释 流動鏈烷烴 5.0 2.5 - CMC-Na 2.0 1.0 BHT 0.1 _ 0.1 總量 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 聚異丁烯/聚矽氧烷黏著劑 聚異丁 烯單體 聚異丁 烯單體 50/1 30/1 5/5 3/7 1/9 聚矽氧 烷單體 〔評估貼布劑〕 於上述之實施例1〜3、比較例1〜4及8分別所得之 貼布劑之皮膚滲透性、黏著性、經時安定性及經時之結晶 析出之各種試驗係由下述方法評估。 -19- 200812652 (皮膚滲透性試驗) 首先,剝離裸鼠背部皮膚’以真皮側作爲受體側層, 安裝於外圍循環 33°C溫水之流通槽(flow through cell) 。接著,於皮膚之角質層側,貼附實施例1〜3、比較例1 〜4及8之各貼布劑(藥物層適用面積爲5cm2),作爲受 體層,使用生理食鹽水,每隔1小時採樣受體溶液 lOml/hr,直至12小時,測定該流量,並且使用高效液相 層析儀測定藥物濃度。由所得之測定値算出每1小時之藥 物之皮膚滲透速度,求出於恒定狀態時每單位面積皮膚之 藥物之皮膚滲透速度。試驗開始之每經時之藥物之皮膚滲 透速度係如圖1所示,至1 2小時之間所得之藥物之皮膚 滲透速度之最大値(最大皮膚滲透速度)如表3所示。 (黏著性試驗) 將實施例1〜3、比較例1〜4及8之各貼布劑,裁切 成直徑爲25mm之圓形試驗片後,剝離離型膜,貼附藥劑 層於電木(bakelite )板,官能評估黏著性。該結果如表3 所示。另外,黏著性之評估基準係如下所示。 A :具有適合的黏著力。 B :雖具有黏著力,但容易剝離。 C :不具黏著力。 (長期間保存時之安定性試驗) 放入實施例1〜3、比較例1〜4及8之各貼布劑於硒 -20- 200812652 (Selenium )製之包材中’密封該包材,於25 °C保持1個 月後’對於經時安定性(滲出··支持體與基劑之間部份膏 體(基劑)流出。)進行評估。該結果如表3所示。另外 ,安定性之評估基準係如下所示。 A :未發現滲出,容易自包材取出。 B :略有滲出,難以自包材取出。 C :發現滲出,自包材取出困難。 (長期間保存時之結晶析出試驗) 放入實施例1〜3、比較例1〜4及8之各貼布劑於硒 (Selenium)製之包材中,密封該包材,於25 °C保持1個 月後,目測確認結晶析出。該結果如表3所示。另外,結 晶析出之評估基準如下所示。 A :於2 5 °C保持1個月後,未觀察到結晶。 B ··於2 5 °C保持1個月後,觀察到結晶。 〔表3〕
實施例 1 實施例 2 實施例 3 比較例 1 比較例 2 比較例 3 比較例 4 比較例 5 最大皮膚滲透速度 (gg/cm2/hr) 4.65 5.85 7.91 4.77 5.67 5.48 5.73 8.49 黏著性 A A B B A A A C 安定性 A A A C C C B A 結晶析出 A A A A C A A C 【圖式簡單說明】 -21 - 200812652 〔圖1〕表示貼附本發明之貼布劑於皮膚時之藥物滲 透速度之經時變化圖。 -22-
Claims (1)
- 200812652 十、申請專利範園 1 · 一種貼布劑,其特徵爲,具備支持體及該支持體 上所層合之藥物層, 該樂物層係含有至少1種選自芬太尼(fentanyl)及 該藥學上可容許的鹽所成群之化合物、及聚異丁烯、及含 砂聚合物之黏著劑所成, 該黏著劑中之該聚異丁烯及該含矽聚合物之質量比爲 20 : 1〜7 : 3 。 2 ·如申請專利範圍第1項之貼布劑,其中該聚異丁 燃係黏度平均分子量爲800,000〜1,600,000之高分子量聚 異丁烯,及黏度平均分子量爲30,000〜80,000之低分子量 聚異丁烯所成。 3.如申請專利範圍第1項或第2項之貼布劑,其中 該含砂聚合物係具有有機聚砂氧院骨架之聚合物或含有此 聚合物之組成物。 4 ·如申請專利範圍第3項之貼布劑,其中該具有有 機聚矽氧烷骨架之聚合物係該羥基之至少部份爲三甲基矽 烷基所罩住。 5 ·如申§靑專利範圍第3項或第4項中之貼布劑,其 中該有機聚矽氧烷骨架係聚二甲基矽氧烷骨架。 6·如申師專利範圍第3項至第5項中任一項之貼布 劑’其中該組成物係具有黏性之組成物。 7.如申請專利範圍第1項至第6項中任一項之貼布 劑’其中該黏著劑係更含有經皮吸收促進劑。 -23- 200812652 8 .如申請專利範圍第7項之貼布劑,其中該經皮吸 收促進劑係至少一種選自肉豆蔻酸異丙酯、棕櫚酸異丙酯 、山梨糖醇酐單油酸酯、油醇、丙二醇、二丙二醇及辛基 十二烷醇所成群之化合物。 9.如申請專利範圍第1項至第8項中任一項之貼布 劑,其中與皮膚接觸之該藥物層面積爲5〜50 cm2。 -24-
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EP2295046B1 (de) * | 2009-09-14 | 2012-12-19 | Acino AG | Transdermales therapeutisches System zur Verabreichung von Fentanyl oder einem Analogstoff davon |
JP5875389B2 (ja) * | 2011-02-02 | 2016-03-02 | 日東電工株式会社 | 貼付剤および貼付製剤 |
KR20120107153A (ko) | 2011-03-15 | 2012-10-02 | 아이큐어 주식회사 | 펜타닐 경피 패치제 |
DE102011114411A1 (de) * | 2011-09-26 | 2013-03-28 | Lts Lohmann Therapie-Systeme Ag | Pflaster mit einstellbarer Okklusion |
EP2599478A1 (de) * | 2011-11-30 | 2013-06-05 | Acino AG | Transdermales therapeutisches System zur Verabreichung von Fentanyl oder einem Analogstoff davon |
CN107427472B (zh) * | 2015-03-02 | 2021-04-30 | 久光制药株式会社 | 贴附剂 |
JP6453481B2 (ja) * | 2015-10-26 | 2019-01-16 | 久光製薬株式会社 | 貼付剤 |
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US4588580B2 (en) | 1984-07-23 | 1999-02-16 | Alaz Corp | Transdermal administration of fentanyl and device therefor |
US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
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US20040086551A1 (en) | 2002-10-30 | 2004-05-06 | Miller Kenneth J. | Fentanyl suspension-based silicone adhesive formulations and devices for transdermal delivery of fentanyl |
MY141815A (en) | 2003-04-30 | 2010-06-30 | Purdue Pharma Lp | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer |
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EP1807033B1 (en) * | 2004-10-08 | 2016-07-20 | Noven Pharmaceuticals, Inc. | Transdermal drug delivery device including an occlusive backing |
WO2006041908A2 (en) * | 2004-10-08 | 2006-04-20 | Noven Pharmaceuticals, Inc. | Transdermal delivery of estradiol |
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