TW565457B - Transdermal drug delivery system - Google Patents
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- TW565457B TW565457B TW85108117A TW85108117A TW565457B TW 565457 B TW565457 B TW 565457B TW 85108117 A TW85108117 A TW 85108117A TW 85108117 A TW85108117 A TW 85108117A TW 565457 B TW565457 B TW 565457B
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565457 案號 85108117 A_η 曰 修正 藥物經皮吸收傳輸系統 五、發明說明(1) 發明之名稱: 四、發明摘要 一抗氣喘藥、一接著劑以及一渗透促進劑, 可為院氧基酿胺酯(fatty alkanolamide)、 acid)或脂肪酯(fatty ester);以及一保 膜覆蓋於該藥劑單元之上,且和該離型膜分 的上下兩層,其目的是用來保護該藥劑單 本發明為一種藥物經皮吸收傳輸系統,包括一離型 膜;一藥劑單元,該藥劑單元覆蓋於該離型膜之上,且該 藥劑單元包括 該滲透促進劑 脂肪酸(f a 11 y 護膜’該保護 置於藥劑單元 元。 發明說明 膚傳輸具有生理活性藥劑 加入少量的滲透促進劑來 的貼劑。 劑而言,改良藥劑形態 一直是此領域之研究主 標。在許多的情況下,病 需要並且高於免於副作用 多,例如服用口服藥時, 是藥劑無法成功地被傳輸 放的藥劑以及傳輸方法, 方便。 統之研究相當多,且已經 是***油的處方。這些 有一能持續釋放藥劑的優 有關於一種經由皮 是有關於一種藉由 藥劑經由皮膚傳輸 是新藥或既存的藥 )以及其傳輸方法, 往後研究的主要目 量往往超過實際所 其主要的原因有很 消化系統代謝或者 使用一種能持續釋 又可使病人使用更 物經皮吸收傳輸系 的產品出現,特別 傳輸系統明顯地具 本發明是 的系統,特別 加強生理活性 對於不論 (dosage form 題,並且也是 人所取用的劑 的安全用量, 部份口服藥被 至患部。因此 能夠達成療效 近來,藥 有數種商業化 藥物經皮吸收565457 Case No. 85108117 A_η is a modified drug transdermal absorption and delivery system V. Description of the invention (1) Title of the invention: 4. Summary of the invention An anti-asthma drug, an adhesive and a penetration enhancer, which can be oxyethylated amine (Fatty alkanolamide), acid) or fatty ester; and a protective film covering the drug unit and separating the upper and lower layers of the release film, the purpose of which is to protect the drug It is a drug transdermal absorption and delivery system, which includes a release film; a drug unit covering the release film, and the drug unit includes the penetration enhancer fatty acid (fa 11 y protective film 'the protection Placed in the pharmacy unit. Description of the invention Patches with a physiologically active agent and a small amount of penetration enhancer. In terms of agents, improving the form of the agent has been the main research target in this field. In many cases, the disease requires and It is more than free from side effects. For example, when taking an oral medicine, it is a medicine that cannot be successfully delivered and the method of delivery, which is convenient. There are many and are already prescriptions of nitroglycerin. These have a sustained release of the drug (such as a transdermal or a drug that is transmitted through the skin is a new drug or an existing drug) and its delivery method. The main research in the future The eye volume often exceeds the actual cause. The main reasons are the digestion of the digestive system or the use of a product that can release continuously and allow the patient to use a more transdermal absorption and transmission system. The special transmission system is obviously the system of the present invention. Enhance the physiological activity. Regardless of the dosage form and the safe dosage of the agent, some oral medicines are taken to the affected area. Therefore, the effect can be achieved. Recently, several commercial medicines have been absorbed through the skin.
第5頁 565457 _m , 85118117__ 年 3 a 修正_— 一 五、發明、說明(2) , 點’並且避免了類似口服藥被消化道吸收及代謝的問題。 同時也減少病人藥量的攝取,而達到和高用量口服藥有相 同的效果。雖然如此’但藥物經皮吸收傳輸系統到目前為 止還是受限於藥量減少後藥效的降低及藥劑對水的溶解 度。這些限制來自於動物的皮膚及組織膜,造成不易克服 的障礙’且能使用該方法的身體、系統相當有限。Page 5 565457 _m, 85118117__ year 3 a Correction _ one, five, invention, description (2), point 'and avoid the problem of similar oral drugs being absorbed and metabolized by the digestive tract. At the same time, it reduces the patient's drug intake, and achieves the same effect as high-dose oral drugs. Nonetheless, the drug percutaneous absorption and delivery system has so far been limited by a decrease in drug efficacy and a drug's solubility in water after a decrease in the drug amount. These restrictions come from the skin and tissue membranes of animals, which cause insurmountable obstacles' and the bodies and systems that can use this method are quite limited.
目前一個努力的方向是讓該方法擴大至更多藥劑的使用 上’並且能克服動物皮膚表層組織膜的限制。所以研發的 重點著重於增加樂物從藥物經皮吸收傳輸系統擴散過上述 障礙的能力。另一方面則致力於增進皮膚表層及組織膜本 身的滲透特性。近來努力的成果己證實有部份效果,但藥 劑過度頻繁的使用會造成組織壞死、使用藥劑部位的刺激 以及不受歡迎的副作用。 以氣喘為例,我國罹患氣喘病患近二十年來人數增加 5 - 6倍,其中尤以兒童與老年居多,沙布坦 (albuterol)(或稱為愛卜羅特albuterol)為一種目前使用 量最大的抗氣喘藥,一般常用的劑型為口服錠劑與口腔吸 入劑種’但因其半衰期甚短(<4小時),故每日須服用 ^一4次’氣喘病經常在半夜及凌晨發作,此時藥效已減 紐+無'去達到控制病情的目的。因此開發長效型的氣喘藥 經皮吸收貼為丨 量,a、M ’可在病情最嚴重的時候,提供足夠的劑 里 以適時、查 產生的-ϊ 受到治療效果並減輕因過量服藥(〇 v e r d 〇 s e)所 J副作用。 ~ ^ it ® 足下π τ 用沙布坦的經皮吸收貼劑,其產品規格必須滿 只條件:(1 )每曰給藥劑量可達1 -3毫克,貼劑大A current effort is to extend the method to more agents' and overcome the limitations of the animal's skin surface tissue membrane. Therefore, the focus of research and development is to increase the ability of the animal to spread through the above-mentioned obstacles from the drug transdermal absorption and delivery system. On the other hand, it is committed to improving the permeability of the skin surface layer and the tissue membrane itself. The results of recent efforts have confirmed some effects, but excessive and frequent use of the drug can cause tissue necrosis, irritation at the site where the drug is used, and undesirable side effects. Taking asthma as an example, the number of people suffering from asthma in China has increased 5-6 times in the past two decades. Among them, children and the elderly are the most common. Albuterol (also known as Albuterol) is currently used. The largest anti-asthma drugs, the commonly used dosage forms are oral lozenges and oral inhalants, but because their half-life is very short (< 4 hours), they must be taken ^ 4 times a day. Onset, at this time the drug effect has been reduced + no 'to achieve the purpose of controlling the disease. Therefore, the development of a long-acting asthma drug for transdermal absorption patches, a, M 'can provide sufficient doses in the most serious conditions to timely and check the production-to receive the treatment effect and reduce the overdose ( 〇verd 〇se) side effects. ~ ^ it ® τ τ percutaneous absorption patch with sabutan, the product specifications must be full only conditions: (1) the dosage can be 1-3 mg per day, the patch is large
565457 Λ_η 曰 修正 气、震明1臂5 (3) 劑相容〇 "t (方3公分以下;(2 )長期使用時’人體皮膚可與貼 上· & )’ )可保存在室溫下(低於攝氏3 0度)至少兩年以 、本低廉,容易取得;以及(5 )無毒性,使用在人 體上無安夺令 ώ <顧慮。現有之經皮吸收貼劑僅能滿足上述條 的4刀項目,但均無法同時滿足所有的條件。 因此本發明的主要目的之一 '就是在提供一種藥物經皮 吸收傳輸系統,包括: a· —離型獏; b · —藥劑單元,該藥劑單元覆蓋於該離型膜之上,且 該藥劑單元包括一抗氣喘藥、一接著劑以及一滲透促進 劑’該滲透促進劑可為烧氧基醯胺酯;以及565457 Λ_η said that the correction gas, Zhenming 1 arm 5 (3) agent compatible 0 " t (square 3 cm or less; (2) 'Human skin can be attached to the &)' for long-term use can be stored in the room At least two years at low temperature (less than 30 degrees Celsius), the cost is low, and it is easy to obtain; and (5) non-toxic, no use on the human body < worry. The existing transdermal absorption patches can only meet the 4-knife item mentioned above, but they cannot satisfy all the conditions at the same time. Therefore, one of the main objectives of the present invention is to provide a drug transdermal absorption and delivery system, including: a · —release 貘; b · —a medicament unit covering the release film, and the medicament The unit includes an anti-asthmatic drug, an adhesive, and a penetration enhancer. The penetration enhancer may be a oxyamidine; and
c · 一保護膜,該保護膜覆蓋於該藥劑單元之上,且和 該離型膜分置於藥劑單元的上下兩層,以保護該藥劑單 元0 本發明的主要目的之二就是在提供一種藥物經皮吸收 傳輸系統,該滲透促進劑包括約5 0 %之月桂酸(1 aur i c acid),以及肉豆蔻酸(myristic acid)、標櫚酸 (palmitic acid)和硬脂酸(myristic acid)。 本發明的主要目的之二就疋在^^供一種藥物經皮吸收 傳輸系統,該滲透促進劑包括約5 0 %之月桂酸,以及肉豆 葱酸和標摘酸。 本發明的主要目的之四就是在提供一種藥物經皮吸收 傳輸系統,該滲透促進劑包括約7 0 %之油酸(〇 1 e i c acid),以及亞油酸(1 inoleic acid)、棕櫚酸和硬脂酸。 本發明的主要目的之五就是在提供一種藥物經皮吸收傳輸c. A protective film covering the drug unit and being separated from the release film on the upper and lower layers of the drug unit to protect the drug unit. 0 Another main purpose of the present invention is to provide a Drug transdermal absorption and delivery system. The penetration enhancer includes about 50% of 1 aur ic acid, as well as myristic acid, palmitic acid, and myristic acid. . The second purpose of the present invention is to provide a drug for transdermal absorption and delivery system. The permeation enhancer includes about 50% of lauric acid, and myristic onion and standard acid. The fourth main object of the present invention is to provide a drug transdermal absorption and delivery system. The penetration enhancer includes about 70% oleic acid (〇1 eic acid), and 1 inoleic acid, palmitic acid and Stearic acid. The fifth object of the present invention is to provide a drug for percutaneous absorption and transmission.
565457 案號 85108117 Λ_η 曰 修正 五、發明說明(4) 系統,該滲透促進劑為油酸甘露酯(man n id e monoo1 eate ) 〇 本發明提供一種藥物經皮吸收傳輸系統,將抗氣喘藥 與滲透促進劑混合,組成新的配方,與壓克力膠溶液作成 的感壓接著劑組成藥劑單元,放置在離型膜上,並以保護 膜覆蓋於其上,以形成具有長效牲的經皮吸收貼劑。 為讓本發明之上述和其他目的、特徵、和優點能更明 顯易懂,下文特舉一較佳實施例,並配合所附圖式,作詳 細說明如下: 圖式之簡單說明: 第1圖是依照本發明一較佳實施例的一種藥物經皮吸 收傳輸系統的剖面示意圖。 實施例 請參照第1圖,本發明最具體的表示法是一存在於單 層經皮膚藥劑配方的貼劑,包括一固定厚度的離型膜1 ; 抗氣喘藥2,例如是沙布坦(a 1 b u t e r ο 1 )、滲透促進劑3及 接著劑4,例如是壓克力感壓接著劑,抗氣喘藥2、滲透促 進劑3和接著劑4混合後成為藥劑單元6,均勻塗抹於離型 膜1 ;以及緊接著藥劑單元6,相對於離型膜1之另一側的 保護膜5。 藥劑單元6是由抗氣喘藥2、滲透促進劑3及接著劑4組 合而成。保護膜5的功用是當作藥劑單元6的保護蓋並提供 支撐。保護膜5需能包覆藥劑單元6,故在尺寸上可和藥劑 單元6 —樣大或者比藥劑單元6稍大,以達到能和皮膚更緊 密結合的目的。565457 Case No. 85108117 Λ_η Revision V. Description of the Invention (4) System, the penetration enhancer is man n id e monoo1 eate. The present invention provides a drug transdermal absorption and delivery system that combines anti-asthmatic drugs with The penetration enhancer is mixed to form a new formula, and the pressure-sensitive adhesive made of the acrylic glue solution is used to form a pharmaceutical unit, which is placed on a release film and covered with a protective film to form a long-lasting animal. Dermal absorption patch. In order to make the above and other objects, features, and advantages of the present invention more comprehensible, a preferred embodiment is given below in conjunction with the accompanying drawings for detailed description as follows: Brief description of the drawings: FIG. 1 It is a schematic cross-sectional view of a drug transdermal absorption and delivery system according to a preferred embodiment of the present invention. Example Please refer to FIG. 1. The most specific representation of the present invention is a patch that exists in a single-layer transdermal formulation, including a release film 1 of a fixed thickness; a 1 buter ο 1), penetration enhancer 3 and adhesive 4, for example, acrylic pressure-sensitive adhesive, anti-asthmatic medicine 2, penetration enhancer 3 and adhesive 4 are mixed to form a medicament unit 6, and evenly spread on A mold film 1; and a protective film 5 on the other side of the release film 1 next to the drug unit 6. The medicine unit 6 is a combination of an anti-asthma medicine 2, a penetration enhancer 3, and an adhesive agent 4. The protective film 5 functions as a protective cover for the medicine unit 6 and provides support. The protective film 5 needs to be able to cover the medicine unit 6, so it can be as large as or slightly larger than the medicine unit 6 in size, so as to achieve the purpose of tighter bonding with the skin.
第8頁 565457Page 8 565457
五、發明說¥ (5+) ------- 保羞膜5使用的材質必須能阻止沙布土及藥密丨| 八风的滲透。適合作為保護膜5的枓併π炎一〜 度或低密度的聚乙烯、令㈣心f 5的材質可為局密 酉旨、聚S旨、全屬$ I永丙烯、&虱乙烯、聚胺基甲酸乙 + S曰金屬泊或附著在適當聚合物 膜5可製成任何厚度,口物上的金屬,,自。保濩 I。仅罐臌R沾r ,、要冑b k仏保遠及支撐的功能即 5,,π^ ^ 、、勺攸1至2〇〇ϋ,較適合的厚度約從5 案號 8510S11 了 至50被/取好是約丨0至100微米之間。 喘ί2的含量並不是固定的,只要抗氣喘藥2能提 供該樂物經皮吸收傳輪系統具療效的含量。通常在藥劑單 兀6中胃含有約8%(w/w)的沙布坦,即可提供足夠經皮膚吸收 的劑量。沙布坦的含量也隨著所需要不同的皮膚滲透速率 及藥劑單元6中接著劑4的不同而有所改變。一般而言,其 最具療效也最適合的含量約佔藥劑單元6的〇. 5 %至 20%(w/w)之間。 在藥劑單元6的成份中,所使用的接著劑4必須為生物 體所接受,且和其他成份能相容。特定的接著劑(其組成 為烷基酯(alkylester)、醯胺(amide)、酯肪酸、聚胺基 丙稀酸酯(polyaminoacrylate)或相類似者)能符合上述條 件並且為現今使用較佳者。這種只造成輕微過敏的感壓接 著劑,其用量約佔藥劑單元6的50%彡96%(w/w)之間。 藥劑單元6的另一種成份為滲透促進劑3,其組成可為 烷氧基醯胺酯、脂肪酸或脂肪酯,而烷氧基醯胺酯其化學 式以下列通式來表示:Fifth, the invention said ¥ (5+) ------- The material used in the shroud film 5 must be able to prevent the penetration of sand cloth soil and medicine. Polyethylene suitable for the protective film 5 or low-density or low-density polyethylene, the material of the heart f 5 can be local secret purpose, poly S purpose, all of the $ 1 permanent propylene, & lice vinyl, Polyurethane + S: metal poise or attached to the appropriate polymer film 5 can be made of any thickness, metal on the mouth, since. Paul I. Only the cans R and D, the functions of holding bk, keeping away, and supporting are 5 ,, π ^^, and 1 to 200. The more suitable thickness is from 5 case number 8510S11 to 50%. / Taken is about 0 to 100 microns. The content of asthma 2 is not fixed, as long as the anti-asthma drug 2 can provide the therapeutically effective content of the percutaneous absorption wheel system of the animal. Usually, the stomach contains about 8% (w / w) of sabutan in the pharmaceutical unit 6, which provides a sufficient amount for transdermal absorption. The content of sabutam also varies depending on the required skin penetration rate and the adhesive 4 in the medicament unit 6. Generally speaking, the most effective and most suitable content is about 0.5% to 20% (w / w) of the pharmaceutical unit 6. Among the components of the pharmaceutical unit 6, the adhesive 4 used must be acceptable to the organism and compatible with other components. Specific adhesives (the composition of which is alkylester, amide, fatty acid, polyaminoacrylate, or the like) can meet the above conditions and are better used today By. The pressure-sensitive adhesive, which causes only slight allergies, accounts for about 50% to 96% (w / w) of the pharmaceutical unit 6. Another component of the medicament unit 6 is a penetration enhancer 3, whose composition may be an alkoxyamidate, a fatty acid or a fatty ester, and the chemical formula of the alkoxyamidate is represented by the following general formula:
第9頁 565457 銮號 85108117 曰 修正 R2 五、發明說明(6) 0Page 9 565457 No. 85108117 said Amendment R2 V. Description of the invention (6) 0
Rl - C \ R3 依本發明之一較佳實施例,其中R1可為CH3(CH2) nCH2- ’η值的範圍從6到16,R2車父佳為經基(hydroxy)、甲 氧基(methoxy)、乙氧基(ethoxy)或異丙氧基 (isopropoxy);並且R3較佳為羥基、甲氧基、乙氧基或異 丙氧基;較適合地滲透促進劑3可以為月桂基二乙醇醯胺 (Laurie acid diethanolamide,LAD),或二乙氧基醯胺 揶子酯,其中月桂基二乙醇醯胺的分子式為 C12H25CON(OC2H5)2。 作為滲透促進劑3的脂肪酸可為飽和脂肪酸或不 脂肪酸,其化學式以下列表示,CnH2n+lc〇2H、 或kH2、n_3C〇2H,η值的範圍從1〇到17。較適合的滲透促進劑 可以為月桂酸、肖豆蔻酸、硬脂酸、棕櫚酸、亞油酸或3Rl-C \ R3 According to a preferred embodiment of the present invention, R1 can be CH3 (CH2) nCH2-'η The value ranges from 6 to 16, and R2 is preferably hydroxy, methoxy ( methoxy), ethoxy or isopropoxy; and R3 is preferably hydroxyl, methoxy, ethoxy or isopropoxy; more suitably the penetration enhancer 3 may be lauryl di Laurie acid diethanolamide (LAD), or diethoxybenzidine glutamate, wherein the molecular formula of lauryl diethanolamide is C12H25CON (OC2H5) 2. The fatty acid used as the penetration enhancer 3 may be a saturated fatty acid or a non-fatty acid, and its chemical formula is represented by the following, CnH2n + lcO2H, or kH2, n_3CO2H, and the value of η ranges from 10 to 17. More suitable penetration enhancers can be lauric acid, myristic acid, stearic acid, palmitic acid, linoleic acid or 3
酸。例如Tween 20其包括約5〇%之月桂酸,以及肉豆 酸、棕櫚酸和硬脂辦· T 、士一 — 9酉夂,Tween 21其包括約50%之月桂酸, 以及肉丑%酸和梓撫缺· 以及亞油酸、枰;,Tween 80其包括約70%之油酸, M flu π π ^和硬脂酸。另外,作為滲透促進劑3 的…:為油酸甘露雖,例如ARLACELe 劑3 統。明所製備一個藥物經皮吸收傳輪系 一~;->1^2、苓透促進劑3及接著劑4的混合物 565457 ___案號85108117_年丹- 日 修正 ____ 五、發明說明(7) 均勻攪拌形成一個勻相溶液。接著將混合物靜置數小時, 以將殘留在其中的空氣排除。再利用塗佈刀將該浪合物塗 抹在適當的材質上,例如保護膜5。塗抹的厚度約在1 〇 〇至 6 0 0微米之間,最好約在150至45 0微米之間。再以高溫(50 〜80 °C)來蒸發溶媒,乾燥使之硬化(Curing)後冷卻,最 後將保護膜5覆蓋其上’待黏著後、,即以切片膜子切割成 形。 並且藉由以下的方法來評估依本發明一較佳實施例之 藥物經皮吸收傳輸系統。 (1)活體外皮膚滲透研究 這個實驗是利用冷凍後的人類屍體皮膚來進行。藉由 Kigma和Christophers提出的熱分離法,將屍體皮膚曝露 在攝氏6 0 °C下加熱一分鐘’使表皮能與真皮分開。然後輕 輕地將表皮從皮膚上撕下。將表皮置於二個截面積均為〇 64平方公分的半球形容器間,表皮覆有角質層的那—面朝 向含有一依本發明之較佳實施例之藥物經皮吸收傳輸系統 的上述容裔。表皮原本連接真皮層的那一面則和含有酸驗 值為7 · 4的緩衝溶液接觸,緩衝溶液須維持在攝氏3 2 ^ 續24小時。沙布坦由藥物經皮吸收傳輸系統滲透過角質#層 友表皮層進入緩衝溶液,經過一定的時間間隔,將含有、士 布坦的緩衝溶液取下,並立刻換上新的緩衝溶液。利用^ 效率液相色層分析儀測定已取下緩衝溶液中沙布坦的含问 量,將所有緩衝溶液中沙布坦的含量相加,即可得知經皮 膚滲透的沙布坦總累積量,以時間為沙布坦滲透累積量的 函數,製成圖表可求出在每平方公分每小時沙布坦的經皮acid. For example, Tween 20, which includes about 50% of lauric acid, and myristic acid, palmitic acid, and stearin. T, Shiyi-9, Tween 21, which includes about 50% of lauric acid, and meat ugly acid He Zi Fu Kui, as well as linoleic acid and uric acid; Tween 80 which includes about 70% oleic acid, M flu π π ^ and stearic acid. In addition, as the penetration enhancer 3: is oleic acid manna, such as ARLACELe agent 3 system. A drug transdermal absorption transmission system prepared by the Ming Dynasty ~~-> 1 ^ 2, a mixture of permeation enhancer 3 and adhesive 4 565457 ___Case No. 85108117_year Dan-Japanese amendment ____ V. Description of the invention (7) Stir to form a homogeneous solution. The mixture was then allowed to stand for several hours to remove the air remaining therein. Then, the undulating compound is applied to a suitable material, such as the protective film 5, using a coating knife. The thickness of the application is between about 1000 and 600 microns, and preferably between about 150 and 450 microns. Then, the solvent is evaporated at a high temperature (50 to 80 ° C), dried to be cured, and then cooled, and finally, the protective film 5 is covered thereon. After being adhered, the film is cut into pieces. And the following method is used to evaluate a drug percutaneous absorption and delivery system according to a preferred embodiment of the present invention. (1) In vitro skin penetration study This experiment was performed using frozen human cadaver skin. By the thermal separation method proposed by Kigma and Christophers, the skin of the corpse was exposed to heat at 60 ° C for one minute 'to separate the epidermis from the dermis. Then gently peel the epidermis from the skin. The epidermis is placed between two hemispherical containers each having a cross-section of 64 square centimeters, and the side of the epidermis covered with stratum corneum is facing the above-mentioned container containing a drug percutaneous absorption and delivery system according to a preferred embodiment of the present invention. Descent. The side of the epidermis that was originally connected to the dermal layer was in contact with a buffer solution containing an acid value of 7.4. The buffer solution must be maintained at 3 2 ° C for 24 hours. Sabutan permeates through the stratum corneum layer through the drug transdermal absorption and delivery system. The friendly epidermis layer enters the buffer solution. After a certain time interval, the buffer solution containing the butatan is removed and immediately replaced with a new buffer solution. Use a high-efficiency liquid chromatography to determine the content of sabutan in the buffer solution. Add the content of sabutan in all buffer solutions to get the total accumulation of sabutan through the skin. The amount of time, as a function of the cumulative amount of sabotan permeation, charted to determine the transdermal rate of sabutan per square centimeter per hour
第11頁 565457 案號 85108117 年 月 修正 五、發明說明(8) 膚吸收量。 (2 )對皮膚刺激的評估方法 藥物經皮吸收傳輸系統對皮膚刺激程度的測試是採用 D r a i z e的方法。這種方法慣例使用兔子當作實驗的對象, 因此,在此也選用兔子來作實驗。挑選六隻成熟的白色紐 西蘭兔子當作研究對象,其重量約在1至1. 5公斤。在測試 前須花約四小時用電剪將兔子身上的毛剪掉。對每隻測試 的兔子選擇三個部位做測試,這些測試部位不能有傷口以 免影響測試的結果。 在每一次測試中,對每一隻兔子使用三種不同的貼 劑,一種是依本發明之較佳實施例之藥物經皮吸收傳輸系 統、一種是未含藥效的貼劑、另一種則使用已知的 T r a n s d e r m S c ο p貼劑(當作對照組)。每一種貼劑均使用對 皮膚不會產生刺激的膠布固定住。經過2 4小時後,將固定 用的膠布和貼劑撕去。根據表1檢查每一兔子身上接受測 試部位紅斑及浮腫的程度。將每一受測部位紅斑及浮腫程 度的得分相加,所得之總分除以1 8即可計算出主要刺激指 數(P I I )。依據以往的經驗,當主要刺激指數大於等於5 時,就要慎重考慮此貼劑對皮膚的影響性(見表2)。 表1 :對動物皮膚刺激指數表 指數 0 1 紅斑及褥瘡形成 沒有紅斑......... 非常輕微的紅斑Page 11 565457 Case No. 85108117 Amendment V. Description of the invention (8) Skin absorption. (2) Evaluation method of skin irritation The test of the degree of skin irritation by the drug transdermal absorption and delivery system is the method of D r a i z e. This method routinely uses rabbits as the object of experiments, so rabbits are also selected for experiments here. Five kilograms of mature white New Zealand rabbits were selected as research objects. It will take about four hours before the test to cut off the rabbit's hair. For each rabbit tested, three sites were selected for testing. These sites should not have wounds to prevent the test results from being affected. In each test, three different patches were used for each rabbit. One was a transdermal drug delivery system according to a preferred embodiment of the present invention, one was a non-medicated patch, and the other was used. A known Transderm S c p patch (as a control group). Each patch is fixed with a tape that does not irritate the skin. After 24 hours, remove the adhesive tape and patch. The degree of erythema and edema at the test site was examined on each rabbit according to Table 1. Add the scores of erythema and edema at each site and add the total score divided by 18 to calculate the main stimulus index (P I I). Based on past experience, when the main stimulus index is 5 or more, the effect of the patch on the skin must be carefully considered (see Table 2). Table 1: Index of skin irritation to animals Index 0 1 Erythema and bedsore formation No erythema ......... Very slight erythema
第12頁 565457 _案號85108117_年月曰 修正_ 五、發明說明(9) 一般性的紅斑.......................................... 2 中度至嚴重的紅斑.................................... 3 嚴重的紅斑並有輕微的褥瘡產生..................4 浮腫形成 沒有浮腫................................................ 0 非常輕微的浮腫..................................... 1 一般性的浮腫(四周些微的凸起).................. 2 中度浮腫(凸起大約1公厘)........................ 3 嚴重浮腫(凸起超過1公厘)........................4 表2 :主要刺激指數(P I I )的評估 PI I 0. 00 0.04-0. 99 1.00- 1. 99 2.00- 2.99 3.00- 5.99 6.00- 8.00 評估 無刺激 幾乎不會產生刺激 些許的刺激 輕微的刺激 中度的刺激 嚴重的刺激 利用下述例子更進一步的顯示出本發明當加入了月桂 基二乙醇醯胺後,不但可以使沙布坦更容易經由皮膚吸 收,而且幾乎不會對兔子皮膚產生刺激。 表3列出了第一組編號1至4號的實驗結果,其組成成Page 12 565457 _Case No. 85108117_ Year Month Revision_ V. Description of the invention (9) General erythema ... ..2 Moderate to severe erythema .............. ......... 3 Severe erythema with slight bedsores ... 4 Puffiness formation without edema ... ............... 0 Very slight puffiness ... .................. 1 General swelling (slightly raised around) ... ............. 2 Moderate puffiness (protrusions about 1 mm) .............. 3 Severe edema (protrusions more than 1 mm) ........ 4 Table 2: Evaluation of the main stimulus index (PII) PI I 0. 00 0.04-0. 99 1.00- 1. 99 2.00- 2.99 3.00- 5.99 6.00- 8.00 Evaluate no stimulus hardly produce a little irritation Slight irritation Moderate irritation Severe irritation Use the following example to further show When lauryl diethanolamine is added in the present invention, not only the sabutan can be absorbed through the skin more easily, but it also can hardly cause thorns on rabbit skin. Excited. Table 3 lists the results of the first group of experiments No. 1 to No. 4, which consist of
第13頁 565457 案號 85108117 年月日 修正 五、發明說明(10) 份包括約4%的沙布坦、約8 1〜9 6%的壓克力感壓黏著劑 (Duro Taka2070)及約0.1〜15%的月桂基二乙醇醯胺。 表3 月桂基二乙醇醯胺(LAD)對沙布坦經人類屍體皮膚滲透速 率的影響 ' Q24 § mg/cm2 成份(W/F/o) 編號 次數 Jss § § mg/an2/m 沙布坦 接著劑I * LAD 增強指數 1 4 4 0. 64± 0. 29 1 96 0 12. 64± 5. 56 91 2 4 4 2. 41 土 0· 3 8 3. 5 46. 6 3 ± 6. 88 3 4 4 3 · 3 2 土 0 · 8 5 5 · 86 1 5 64. 5 2 ± 15. 60 81 4 4 4 6· 69 ± 1. 37 12. 5 2 0 1 57·41 ± 42· 11 接著劑I * :壓克力感壓黏著劑(Duro Taka 2 0 7 0 )Page 13 565457 Case No. 85108117 Amended on May 5, V. The description of the invention (10) includes about 4% sabutan, about 8 1-9% 6% acrylic pressure sensitive adhesive (Duro Taka2070) and about 0.1 ~ 15% lauryl diethanolamine. Table 3 Effect of lauryl diethanolamine (LAD) on the penetration rate of sabutan through human cadaver skin 'Q24 § mg / cm2 Ingredient (W / F / o) Number of times Jss § § mg / an2 / m Sabutan Adhesive I * LAD Enhancement Index 1 4 4 0. 64 ± 0. 29 1 96 0 12. 64 ± 5. 56 91 2 4 4 2. 41 Soil 0 · 3 8 3. 5 46. 6 3 ± 6. 88 3 4 4 3 · 3 2 Soil 0 · 8 5 5 · 86 1 5 64. 5 2 ± 15. 60 81 4 4 4 6 · 69 ± 1. 37 12. 5 2 0 1 57 · 41 ± 42 · 11 Then Agent I *: acrylic pressure sensitive adhesive (Duro Taka 2 0 7 0)
mm
II
IS 第14頁 565457 案號 85108Π7 年 月 曰 修正 W".誃來·每..、麵1 五、發明說明(11) Q24 § ·· 24小時内經由皮膚吸收沙布坦的累積量 J s s § § :經皮膚滲透穩定流速 表4列出了第二組編號5至8號的實驗結果,其組成成 份包括約1 0 %的沙布坦、約6 0〜9 0 %的感壓黏著劑(D u r 〇 Taka2154)及約0· 1〜30%的月桂基\二乙醇醯胺。 表4 月桂基二乙醇醯胺(LAD)對沙布坦經人類屍體皮膚滲透速 率的影響 Q24 § mg/cm2 成份(W/W%) 編號 次數 J s s § § mg/an2/m 沙布坦 接著劑Π * LAD 增強指數 5 4 10 2. 75 ± 1. 20 1. 90 6 0. 77 ± 25. 49 6 4 10 8.41± 2. 03 3 80 10 1 82. 84 ± 56. 46 7 4 10 17. 90 ± 2. 70 6 70 20 376.51± 62.42IS Page 14 565457 Case No. 85108Π7 Revised W ". 誃 来 ···, 1st, 5. Description of the invention (11) Q24 § ·· The cumulative amount of sabutan absorbed through the skin within 24 hours J ss § §: Stable permeation flow rate through the skin Table 4 lists the experimental results of the second group No. 5 to No. 8. Its composition includes about 10% sabutan, about 60 ~ 90% pressure-sensitive adhesive ( Dur ur Taka 2154) and about 0.1 to 30% of lauryl \ diethanolamine. Table 4 Effect of lauryl diethanolamine (LAD) on the penetration rate of sabutan through human cadaver skin Q24 § mg / cm2 Composition (W / W%) Number of times J ss § mg / an2 / m Agent Π * LAD enhancement index 5 4 10 2. 75 ± 1. 20 1. 90 6 0. 77 ± 25. 49 6 4 10 8.41 ± 2. 03 3 80 10 1 82. 84 ± 56. 46 7 4 10 17 90 ± 2. 70 6 70 20 376.51 ± 62.42
565457 案號 85108117 年月曰 修正 _霞_ 五、發明說明(12) 8 4 10 23.11± 2. 31 8 60 30 52 2.78 ± 56.77 接著劑Π * :感壓黏著劑(D u r ο T a k a 2 1 5 4 ) Q 2 4 § : 2 4小時内經由皮膚吸收沙布坦的累積量565457 Case No. 85108117 Amendment _ Xia_ V. Description of the invention (12) 8 4 10 23.11 ± 2. 31 8 60 30 52 2.78 ± 56.77 Adhesive Π *: Pressure-sensitive adhesive (D ur ο T aka 2 1 5 4) Q 2 4 §: 2 Cumulative amount of sabutan absorbed through the skin in 4 hours
JSS § § :經皮膚滲透穩定流速N 針對實驗編號4、7、8及T r a n s d e m S c 〇 p a貼劑的主要 刺激指數做測試,並將結果列於表5。 表5 經皮膚吸收沙布坦貼劑的主要刺激指數 實驗編號 實驗次數 主要刺激 4 6 0. 9 7 6 1. 6 8 6 4. 1 Transdem Scopa 12 1,5 由本較佳實施例得知,應用本發明之較佳實施例之藥 物經皮吸收傳輸系統具有下述的優點: 1. 幾乎不會對皮膚產生刺激。 2. 在2 4小時之内經皮膚滲透沙布坦的累積量達到預期 的目標。 3. 此藥物經皮吸收傳輸系統可使皮膚滲透的藥劑量達JSS § §: Transdermal Penetration Stable Flow Rate N Tested for the major irritation indices of Experiment Nos. 4, 7, 8 and Trans d e m S c o p a patch, and the results are listed in Table 5. Table 5 The main irritation index of sabotan patch absorbed through the skin Number of experiments Number of main stimuli 4 6 0. 9 7 6 1. 6 8 6 4. 1 Transdem Scopa 12 1,5 Known from the preferred embodiment, the application The drug transdermal absorption and delivery system of the preferred embodiment of the present invention has the following advantages: 1. It has little irritation to the skin. 2. The cumulative amount of sabotan penetrated through the skin within 24 hours reached the desired target. 3. The drug percutaneous absorption and delivery system can make the skin penetration drug dose up to
ml 第16頁 Μ 565457 - . ' , < ,. .· : r :1· \ - /,- ', - _案號85108117_年月曰 修正_ 五、發明說明(13) 到穩定流速。 雖然本發明已以一較佳實施例揭露如上,然其並非用 以限定本發明,任何熟習此技藝者,在不脫離本發明之精 神和範圍内,當可作些許之更動與潤飾,因此本發明之保 護範圍當視後附之申請專利範圍所界定者為準。ml p. 16 Μ 565457-. ', <,...: r: 1 · \-/,-',-_ Case No. 85108117_ Year, month, and month Amendment _5. Description of the invention (13) To stabilize the flow rate. Although the present invention has been disclosed as above with a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can make some modifications and retouching without departing from the spirit and scope of the present invention. The scope of protection of the invention shall be determined by the scope of the attached patent application.
565457 案號 85108117 Λ___1 修正565457 Case No. 85108117 Λ ___ 1 Amendment
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