TW565447B - Use of compositions containing the combination of acetaminophen, aspirin and caffeine to alleviate the pain and symptoms of migraine - Google Patents

Use of compositions containing the combination of acetaminophen, aspirin and caffeine to alleviate the pain and symptoms of migraine Download PDF

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TW565447B
TW565447B TW087111152A TW87111152A TW565447B TW 565447 B TW565447 B TW 565447B TW 087111152 A TW087111152 A TW 087111152A TW 87111152 A TW87111152 A TW 87111152A TW 565447 B TW565447 B TW 565447B
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Taiwan
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migraine
pain
apap
caf
asa
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TW087111152A
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Chinese (zh)
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Joseph J Armellino
Randy J Koslo
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Bristol Myers Squibb Co
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Abstract

The invention provides a safe and economical nonprescription combination of acetaminophen, aspirin and caffeine (APAP/ASA/CAF) for use in treating migraine pain and the cluster of symptoms characteristic of migraine attack, such as nausea, photophobia, phonophobia and functional disabilities. In accordance with the present invention, the use of the APAP/ASA/CAF combination is also effective in aborting the prodrome phase of a migraine attack, prior to the onset of the migraine-associated symptoms, aborting the symptoms of migraine attack prior to the onset of severe, throbbing migraine pain, and aborting migraine pain after a migraine has fully developed. In accordance with the present invention, the efficacy of the APAP/ASA/CAF combination treatment in reducing and eliminating migraine pain is at a parity with the efficacy of sumatriptan, a known, but dissimilar, anti-migraine agent, used at similar dosing regimens. Use of the APAP/ASA/CAF combination composition treatment at the unit dose also advantageously reduces/obviates the need of the migraine sufferer to re-dose or remedicate at the end of the dosing period in accordance with the present invention.

Description

565447 A7 經濟部智慧財產局員工消费合作社印製 ______B7______五、發明説明（） 本專利之範疇_ 本專利是關於可降低急性偏頭痛症狀的組成物與方法 ，進一步而言，本發明有關於一種非處方籤藥物組合，包 括捕熱息痛、阿司匹靈及咖啡因，以治療個體有偏頭痛前 症狀、偏頭痛相關症狀，與/或輕度至重度偏頭痛。 本發明之背景 估計約有2 3 0 0至2 5 0 0萬美國人，大約是1 8 %的女性與6 %男性，有偏頭痛與偏頭痛相關症狀，發病 是很平常的，5 0 %以上的患者都有每月至少一次或以上 的發症機會。 偏頭痛是一種多種成因的不適症，造成患者各種疼痛 與相關機能失常，約有5 - 1 5%發症只有輕微疼痛且並 無任何機能失常，6 0 - 7 0%發症造成中度到重度疼痛 與機能失常，剩餘的2 5 - 3 5%發症機會中，導致筋疲 力盡的劇痛與完全失能情況。 近期在美國與世界各地以族群爲主的流行病學硏究中 發現，大多數偏頭痛患者並不向醫師諮詢偏頭痛發症問題 ，且約只有三分之一的患者曾受醫師診斷過，在絕大多數 曾使用藥物以降低疼痛的患者（約9 5 %男性與9 7 %女 性）中，大約只有2 8 %男性與4 0 %女性曾使用過處方 籤藥物，9 0%以上偏頭痛者都用非處方籤藥物以對抗偏 頭痛，大多數患者則只使用非處方籤藥物。 許多偏頭痛者使用單方非處方籤藥物以對抗發症，如 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 「心 " (請先閲讀背面之注意事項再填寫本頁) 565447 A7 B7 _______ 五、發明説明（？ (請先閲讀背面之注意事項再填寫本頁) 捕熱息痛、阿斯匹靈、或非固醇類抗發炎藥物，不管這些 到處可得而自行採用的非處方籤藥物’在美國只有處方籤 藥物是經認可的，在一些國家中，有特別通過一些治療偏 頭痛的非處方籤藥物，然而，這些自行治療的非處方籤藥 物並沒有在臨床實驗中得到明確的治療證據，捕熱息痛、 阿斯匹靈、與咖啡因是經認可可以減緩非特異性疼痛與壓 力性頭痛，這些症狀在臨床上有別於偏頭痛。咖啡因已是 一種用途廣泛的止痛劑，也同時在治療偏頭痛的處方籤中 ，已和許多藥物同時合倂使用，如麥角鹼與酒石酸。 雖然偏頭痛患者的症狀互異，但嚴重的頭痛使得大多 數患者都需要進一步治療，傳統治療中，如麥角胺，雖然 對偏頭痛發症前的症狀有效，但也已知如果給藥越慢，效 果越差。麥角胺常與止痛輔助劑咖啡因一倂投予，以加速 麥角鹼的吸收，然而，重覆投予麥角胺將造成長時間與累 積性的血管收縮，因此需要對以口服偏頭痛藥物患者仔細 的解說。 經濟部智慧財產局員工消費合作社印製 有鑑於麥角胺與其衍生物的累積性毒性，較安全的治 療與預防偏頭痛療法以被發現，麥角胺的取代物實施例可 爲麥角新素、心得安（propranolol) 、methysergide，然 而，約有4 0 %服用這些取代藥物者，出現明顯毒性，此 外，許多這類藥劑對急性偏頭痛並無效果，一種麥角胺與 其衍生物的取代物稱爲sumatriptan (或sumatriptan琥ί白 酸鹽），是一種選擇性5-羥基色胺接受器亞型配對體， 可有效控制偏頭痛的發症前症狀。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） _ 5 - 565447 經濟部智慧財產局員工消費合作社印製 A7 ___B7_______五、發明説明（？ 因此，本技藝之明確目標是去發現新穎、安全、無毒 、且有效的抗偏頭痛藥物與治療方式，尤其針對非處方籤 用藥，不需處方籤即可自行服用之治療方式。 截至本發明爲止，捕熱息痛、阿斯匹靈、與咖啡因（ APAP/ASA/CAF)所合倂使用的非處方籤用藥 ，並未被證實對偏頭痛的疼痛與症狀有明確效果，偏頭痛 在臨床與生理判斷上，都是與非偏頭痛的頭痛與壓力性頭 痛不相同的。此外，在本發明之前，捕熱息痛、阿斯匹靈 、與咖啡因（APAP/ASA/CAF)的合倂使用並 未發現可以降低一或數種偏頭痛症狀，如噁心、畏光、怕 吵、與機能失調。進一步而言，在本發明之前，APAP /A S A/C A F的合倂使用也並未知可否降低偏頭痛前 期症狀，即偏頭痛預兆與急性偏頭痛之前期，另外，至本 發明之前，尙未發現合倂使用APAP/ASA/CAF 可以有效降低偏頭痛疼痛、也可以明顯減少偏頭痛噁心、 畏光、怕吵、與機能失調等症狀。本發明在此所提出合倂 使用APAP/ASA/CAF的偏頭痛治療方式，在費 用與效果上都遠優於現今所使用的處方籤藥物。 本發明之總結 本發明之主題是提供非處方籤組成物，以治療偏頭痛 與其症狀，包括疼痛、噁心、畏光、怕吵與機能失調。根 據本發明，偏頭痛與一種或以上上述之偏頭痛相關症狀， 可投予一種非處方籤組成物，包括捕熱息痛、阿斯匹靈、 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 565447 A7 B7 ___ 五、發明説明（今 與咖啡因（APAP/ASA/CAF)，可以降低其發 症症狀。 (請先閲讀背面之注意事項再填寫本頁) 本發明之另一主題，是投予一定劑量的捕熱息痛、阿 斯匹靈、與咖啡因（APAP/ASA/CAF)藥學組 成物’以緩和、降低或消除上述之一種或以上的偏頭痛症 狀。 本發明另一主題，是採用一定劑量的捕熱息痛、阿斯 匹靈、與咖啡因藥學組成物，以降低偏頭痛發症前的症候 ’如此可以減低偏頭痛發症症狀並影響急性偏頭痛的發展 ’根據本發明，這種止痛劑組成物同樣可緩解完全發症的 偏頭症症狀。 本發明之另一主題爲使用上述非處方籤止痛劑，可以 在偏頭疼痛開始後，消除偏頭痛發病。根據本發明，這項 止痛劑組成物不僅可以消除偏頭痛發病之疼痛，且可以消 除發病後一種、宜爲兩種或已上的偏頭痛相關症狀，包括 疼痛、噁心、畏光、怕吵與機能失調。 經濟部智慧財產局員工消费合作社印製 本發明之另一主題爲提供一種非處方籤止痛劑組成物 ，如前所述包括捕熱息痛、阿斯匹靈、與咖啡因，該組成 物可以降低或減輕偏頭痛疼痛與/或其相關症狀，該效用 相似於 sumatriptan，如 sumatriptan 號 ί白酸鹽（Imitrex®， 由Glaxo Wellcome藥廠銷售），可降低或減輕偏頭痛疼 痛與/或期相關症狀。 本發明之另一主題爲提供一種如前所述之非處方籤止 痛劑組成物，以運用在預防與治療偏頭痛疼痛與/或其相 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 565447 A7 B7 五、發明説明（今 關症狀。 (請先閱讀背面之注意事項再填寫本頁) 本發明之另一主題爲降低偏頭痛患者在投予一如前所 述包括捕熱息痛、阿斯匹靈、與咖啡因之組成物後，可降 低重覆投予藥物的情形，因此，根據本發明，將可減少需 要補充藥物的需求。 本發明的其它主題與利益，將於下文中詳細敘述。 圖示說明 附圖所提供之圖示可以進一步說明、幫助瞭解本發明 之各種狀況。 第一 A圖顯示與控制組（空心圓）與投予包括捕熱息 痛、阿斯匹靈、與咖啡因之組成物（實心圓）六小時後， 受測患者的疼痛狀況降低至輕微或無的百分比。第一 B圖 則顯示超過六小時後，控制組（空心圓）與投予包括捕熱 息痛、阿斯匹靈、與咖啡因之組成物（實心圓）之患者疼 痛降至無的百分比。 經濟部智慧財產局員工消費合作社印製 第二圖顯示在投予藥物六小時後，控制組（空心圓） 與投予包括捕熱息痛、阿斯匹靈、與咖啡因之組成物（實 心圓）之患者的中度、重度或嚴重的機能喪失百分比。中 度、重度或嚴重的機能喪失關係到受測者需要部份或很多 額外協助，以進行一般工作與日常生活，或者受測者在投 予包括捕熱息痛、阿斯匹靈、與咖啡因之組成物後，與控 制組相比下可否恢復一般正常活動。 第三A圖顯示與控制組（空心圓）相比下，在投予包 -8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 565447 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明（9 括捕熱息痛、阿斯匹靈、與咖啡因之組成物（實心圓）達 六小時，受測者仍有噁心症狀的百分比。第三B圖顯示與 控制組（空心圓）相比下，在投予包括捕熱息痛、阿斯匹 靈、與咖啡因之組成物（實心圓）達六小時，受測者仍有 畏光症狀的百分比。第三C圖顯示與控制組（空心圓）相 比下，在投予包括捕熱息痛、阿斯匹靈、與咖啡因之組成 物（實心圓）達六小時，受測者仍有怕吵症狀的百分比。 本發明之詳細說明 本發明提供一種組成物與方法，以治療偏頭痛與其症 狀，該組成物是一種非處方鑛組成物，包括捕熱息痛、阿 斯匹靈、與咖啡因（在此簡稱APAP/ASA/CAF )，這種運用在本發明中顯示是具臨床安全並可有效降低 一種或以上的偏頭痛症狀。 本發明提供的捕熱息痛、阿斯匹靈、與咖啡因（ APAP/ASA/CAF)的組成物是一種有功效與利 益的偏頭痛非處方籤治療法，這種非處方籤A P A P / A S A / C A F止痛組成物可以降低與減輕偏頭痛患者的 疼痛，根據本發明所使用的這項APAP/ASA/ C A F組成物，有一特殊實施例是已商業化的產品，即是 非處方籤用藥 Excedrin® Extra-Strength。 一般而言，無論有無預警的偏頭痛都有多種特性，偏 頭痛發病是突然與自行發生的，未經治療或治療不當的偏 頭痛發病可歷經數小時至數天（例如，大約爲四小時至三 本紙張尺度適用中國國家標準（CNS ) A4規格（210X；297公釐） ~ f請先閱讀背面之注意事項再填寫本頁) 565447 A7 經濟部智慧財產局員工消費合作社印製 B7五、發明説明（？ 天），偏頭痛發症並不頻繁，約有75%的患者每月發症 三次或三次以下，偏頭痛的一般特性爲頭部一邊產生抽痛 ，通常爲中度至重度疼痛，且會伴隨常態性生理活動有力口 劇現象，伴隨偏頭痛而來的有一種以上的症狀，如噁心或 想吐，畏光、怕吵、與機能失能，例如無法正常進行常態 性工作相關與非工作相關的勤務。 在本發明之一體系中，APAP/ASA/CAF的 藥學組成物可消除偏頭痛發症前或預警期的相關症狀，預 警期出現時就可引發急性偏頭痛發症與劇烈疼痛。根據本 發明，這種止痛劑組成物可以運用在防止偏頭痛完全發症 〇 開業醫師們將很慶幸在偏頭痛的劇烈疼痛發症前，有 一些前期症狀可供判斷，一般在發症前，患者會有情緖轉 變、無力與倦怠，而在預警期中，約有2 0 %患者開始出 現嚴重偏頭疼痛與抽痛，同時也會在劇烈疼痛開始前出現 聽覺與視覺異常，可能會有眼前發黑、半側盲、與語言障 礙等現象。若不受限於理論分析，偏頭痛的預警期可能與 血小板釋出的血淸素（serotonin )有關，根據本發明所使 用的APAP/ASA/CAF的藥學組成物，可以在患 者感覺出現壓力、嚴重疼痛與相關不適症前，先行除去偏 頭痛的發症機會。 本發明之另一體系則爲這種APAP/ASA/ C A F的藥學組成物，可以在偏頭痛發症前或預警期出現 後，減輕偏頭痛的相關症狀。根據本發明，這項止痛劑組 本紙張尺度適用中.國國家標準（CNS ) A4規格（210X 297公釐) ~ (請先閱讀背面之注意事項再填寫本頁) 565447 經濟部智慈財產局員工消費合作社印製 A7 _____B7五、發明説明（令 成物不僅可以消除偏頭痛發病之疼痛，且可以消除發病後 一種、宜爲兩種或已上的偏頭痛相關症狀，包括疼痛、噁 心、畏光、怕吵與機能失調，這些症狀是在前期症狀出現 後會隨即發生的。 根據本發明，這種APAP/ASA/CAF的藥學 組成物可提供一種非處方籤止痛劑組成物，可以降低或減 輕偏頭痛疼痛與/或其一至多種相關症狀，該效用相似於 sumatriptan，如 sumatriptan 琥 ί白酸鹽（Imitrex®，由 Glaxo Wellcome藥廠銷售）（參看實施例9 )，這兩種藥 學組成物的治療方式，都可降低或減輕偏頭痛疼痛與/或 期相關症狀。這兩種治療方式對減緩偏頭痛的效果都是無 可預期的，因其作用機制互異，當sumatriptan抑制血液 中複合胺（serotonin )接受器之活性時，APAP/ A S A / C A F的藥學組成物則不是產生相似的作用。 使用本發明之APA P/A SA/CA F的藥學組成 物的另一利益，偏頭痛患者在服用一有效劑量的藥物後， 在藥效末期，約4至6小時，有鑑於本藥物組成物的減緩 疼痛效用，患者較不需追加劑量（實施例4和5 )。 爲了方便口服攝取，根據本發明下文所述的A P A P / A S A / C A F藥學組成物的有效劑量如下：補熱息痛 含有300至600毫克，宜爲400至550毫克，更 宜爲5 0 0毫克；阿斯匹靈含有3 0 0至6 0 0毫克，宜 爲400至550毫克，更宜爲500毫克；咖啡因含有 100至250毫克，宜爲125至200毫克，更宜爲 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -n - 565447 經濟部智慧財產局員工消費合作社印製 A7 B7__五、發明説明（9 130毫克。爲方便起見，單位劑量可以採2錠、1錠或 1/2錠的方式投予。 含有APAP/ASA/CAF藥學組成物與傳統藥 學載劑的藥劑製備，可以固態或液態等合適的方式製備， 固態藥物可包括錠、片、膠囊、粉狀、可溶顆粒、豆狀膠 囊、栓劑等，宜爲錠、片或膠囊；液態藥物可包括口服用 之等滲溶液、懸浮液、酊劑、或非經腸道使用的水溶液、 懸浮液與乳劑。單位劑量可採單包裝製備，包裝中可有數 種製備成品，如包裝錠、膠囊、與小玻璃瓶內含粉末等， 單位劑量也可只有膠囊、豆狀膠囊或錠劑本身，可以以任 何合適的方式組合。 錠劑中可能會添加無毒、藥性可相容的賦型劑，以方 便錠劑之製造，這些賦型劑可能爲安定性稀釋劑：如碳酸 鈣、碳酸鈉、乳糖、磷酸鈣、或磷酸鈉，造粒或分解劑： 如玉米澱粉或藻朊酸，結合劑：如澱粉、明膠或阿拉伯膠 ，與潤滑劑：如硬脂酸鎂或硬脂酸。錠劑可不需衣膜，也 可以添加衣膜以延長在消化道崩解與吸收的時間。 此外，錠劑也可以以粉末或顆粒來製備，例如採親水 性的粉末或顆粒與結合劑、潤滑劑、安定性稀釋劑、表面 活性劑或助溶劑來合成，再以壓力成型或成型於安定液態 稀釋劑中，這些錠劑再依選擇作記號或添加衣膜，膠囊與 豆狀膠囊則可以只含有有效成份，或同時寒有其它配方， 膠囊所含的主成份可以存於水或油溶液、懸浮液、或乳劑 中，同時一狀況考量是否有其它配方組成物。 本紙張尺度適用中.國國家標準（CNS ) A4規格（210X297公釐) - (請先閱讀背面之注意事項再填寫本頁) 565447 A7 經濟部智慧財產局員工消費合作社印製 _B7____五、發明説明（）〇 口服配方也可以採用硬膠囊，將APAP/ASA/ C A F活性成份混合安定性固態稀釋劑，如碳酸鈣、磷酸 鈣、白陶土，也可以用軟膠囊，則該有效成份將混合油溶 基質，如花生油、液態石蠘或橄欖油。 其它可用的投予劑型，如栓劑，可包括結合劑與載劑 ，如多烷基二元醇（polyalkylene glycols)或三酸甘油脂 〇 液狀懸浮液則包含了該活性成份，混合適用於製造該 懸浮液的賦型劑，這些賦型劑的實施例包括懸浮劑：如羧 基甲烷木纖維質鈉、甲基纖維質、乙醯丙醇纖維素，藻朊 酸鈉、聚乙醯一氮五圜酮、西黃耆膠、與阿拉伯膠，分散 劑或滲透劑可爲一天然磷脂質，如卵磷脂，含有alkyUne .oxide與脂肪酸的濃稠劑，如聚環氧乙烷硬脂酸，或含有 環氧乙烷與長鏈脂肪醇的濃稠劑，如 heptadecaethyleneoxycetanol，或含有環氧乙院與由脂肪酸 衍生的酯類與hexitol的濃稠劑，如聚環氧乙烷花楸醇單 油酸，或含有環氧乙烷與由脂肪酸衍生的酯類與無水 hexitol的濃稠劑，如聚環氧乙烷花楸醣單油酸。該水溶 性懸浮液可含有一或多種防腐劑，如乙基或正丙基p -羥 基苯甲酸，一或多種調味劑，一或數種甜味劑，如蔗糖、 糖精、或環己基磺醯胺鈣。 根據本發明，有數種投予該APAP/A S A/ C A F藥學組成物的方式，例如在合適的劑型下，運用口 服、舌下、經大腸、靜脈注射、肌肉注射、非腸道、腸栓 1紙張尺度適用中.國國家標準（〇阳）八4規格（210/297公釐） 「13- " " (請先閲讀背面之注意事項再填寫本頁) 565447 A7 ___B7_ 五、發明説明（ 劑或吸入劑等，宜爲口服。 (請先閲讀背面之注意事項再填寫本頁} 單位劑量投予以每天爲宜，每隔4至6小時，宜爲每 6小時投予，最高每日投予8錠，整個服藥期間爲1 〇天 或以內。 根據本發明與下述之實施例中，在三項經設計與控制 的臨床硏究中發現，在投予APAP/ASA/CAF藥 學組成物後1至6小時，與投予安慰劑的控制組相比，受 測偏頭痛患者有明顯減緩偏頭痛的疼痛情況，更甚言之， 在投藥2小時後，投予APAP/ASA/CAF藥學組 成物的患者的偏頭痛疼痛狀況，有5 9 %患者（如3 5 7 / 6 0 2 )可降低至輕微或無，而控制組只有3 3 % (如 203/618)有同樣情況（P<0 · 001 ，95% Cl ，APAP/ASA/CAF組爲55%至63%， 控制組爲2 9 %至3 7 % );在投藥6小時後，投予 APAP/A SA/CAF藥學組成物的患者的偏頭痛疼 痛狀況，有7 9 %患者可降低至輕微或無，而控制組只有 52%有同樣情況（P<0 · 001，CI爲75% — 經濟部智慧財產局員工消費合作社印製 8 2 %對4 8 % — 5 6 % );此外，在投藥6小時後，投 予A P A P /A S A/ C A F藥學組成物的患者的偏頭痛 疼痛狀況，有5 1%患者（如306/60 2)可完全消 除，而控制組只有2 3 % (如1 4 5 / 6 1 8 )有同樣情 況（Ρ<0·001，95% CI，APAP/ASA /CAF組爲4 7%至5 5%，控制組爲2 0%至2 7% )。其它偏頭痛相關症狀，如噁心、畏光、怕吵與機能失 -14 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇><297公釐） 565447 經濟部智慧財產局員工消費合作社印製 A7 B7 _ _五、發明説明（P 調，與控制組相比下，投予A P A P / A S A / C A F藥 學組成物之患者，都可在後2 - 6小時獲得改善（P < 0.01)，因此，這種含也捕熱息痛、阿斯匹靈、與咖 啡因的非處方籤組成物，對偏頭痛疼痛有高效果表現，且 對偏頭痛相關症狀，如噁心、畏光、怕吵與機能失調同樣 可改善，同時，APAP/ASA/CAF藥學組成物是 極爲安全且耐受力佳的藥品。 隨然在下列實驗中採用不同的治療方法，但無論是採 用以族群爲基準的實驗（實驗一），或是採用傳統式徵募 受測者的方式（實驗二與實驗三），都同時顯示以 APAP/A SA/CA F藥學組成物投予的患者，有較 好的治療效果，三項實驗中都發現，再投予A P A P / A S A / C A F藥學組成物後一至六小時，就可出現明顯 的效果差異，在投予APAP/ASA/CAF藥學組成 物與控制組之間的明顯差異，可自投藥後半小時即可發現 ，包括改善頭痛、將疼痛減緩至輕微或無、與其它彙整資 料的分析比較。投予APAP/A S A/CA F藥學組成 物的一組更可感覺在投藥後一小時，即可恢復正常作息， 且之後每個檢測時間點皆同。 雖然已知偏頭痛特殊處方藥可以減緩噁心、畏光、怕 吵等相關症狀，但本發明提供一種有別於處方籤藥物的選 擇，安全、經濟且有效。根據本發明的APAP/ASA / C A F藥學組成物在統計上具有明顯意義’可降低噁心 、畏光、怕吵等相關症狀。在投予藥物3 0分鐘後，匯整 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -15 - (請先閲讀背面之注意事項再填寫本頁) 565447 A7 _______B7 五、發明説明（）3 資料即顯不有明顯的改善效果，更進一步而言，這些投予 APAP/A SA/CAF藥學組成物的利益點，都是來 (請先閱讀背面之注意事項再填寫本頁) 自於有中度至重度的偏頭疼痛與明顯機能缺損之患者所述 〇 本發明對臨床應用、偏頭痛與頭痛照顧政策有重要助 益’許多已核准的偏頭痛處方用藥都很昂貴，且多有治療 限制的副作用，與不適應症。根據本發明，這種非處方籤 的A P A P /A S A/ C A F藥學組成物具有安全的特質 、可有效解除疼痛、機能失常與偏頭痛相關的症狀，這種 組成可提供偏頭痛患者一項安全、經濟的選擇。 實施例 下列所述的實施例乃以各種方式以證明本發明，且並 無意以任何方式限定本發明。 三項獨立、雙盲、隨機、對照與控制組實驗經設計， 以進行評估這種非處方籤AP AP/A S A/CA F藥學 組成物，對於降低急性偏頭痛與其相關症狀的功效，實驗 方法與結果則如下各實施例所述。 經濟部智慧財產局員工消費合作社印製 實施例一 方法 受測者 於1 9 9 5年8月至1 9 9 6年6月間所進行的三項 實驗中，採用雙盲、隨機、對照與控制組的實驗設計，只 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公^16 - 565447 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明（I4 有在受測者的召募方法上互異。實驗一爲一個單一中心實 驗（single-center trial )，採用隨機數値選號，以選出合 適的受測者。實驗二與實驗三則爲多中心實驗（ multicenter trial)，受測者則來自傳統資料（如診所、介 紹者與區域廣告者有7 7%)，與隨機數値選號（2 3% )來召募。 這三項實驗中所應包含與除去的條件皆同，患者皆需 符合國際頭痛協會（International Headache Society, IHS) 的診斷標準，無論有無偏頭痛發症前症狀，至少需年滿 1 8歲，健康大致良好，需有偏頭痛至少每兩個月一次， 但不得多於每月六次，發病之疼痛若未經治療，需有中度 疼痛以上的程度，患者若經常在發病失能者（需臥床休息 )則不在召募之列，患者若在發病期有2 0 %以上的時間 有嘔吐現象也將被排除，因爲這類病患有可能因嘔吐而無 法攝入實驗中所用的藥物，噁心則不被排除，自所有受測 者中取得親筆同意書，整個實驗過程與同意書皆有經過 Institutional Review Board 之認可通過。 爲確定所有受測者都患者偏頭痛，每名需提供一份完 整的病歷，包括有半引導式的頭痛診斷結果、由臨床醫師 完成健康檢查與神經診斷，受測者並需以日記記錄實驗過 程。 實施例二 實驗設計 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -17- 一 (請先閲讀背面之注意事項再填寫本頁) 565447 經濟部智慧財產局員工消費合作社印製 A7 _B7_五、發明説明（）5 步驟 在第一次造訪時，依電腦產生的隨機行程表，將受測 者隨機分成兩組（比例爲1 : 1 )以進行雙盲試驗，其中 一組可得到兩錠未標名的藥品，每錠含有2 5 0 m g捕熱 息痛、2 5 0 m g阿斯匹靈與6 5 m g咖啡因，另一組可 得到外觀相同的安慰劑’兩錠，當自覺偏頭痛發症時即可 服用。當疼痛與症狀符合偏頭痛的定義、發症的疼痛至少 中級以上、或是發症時有其他合適的狀況，受測者則被告 知可以服用實驗藥物。受測者被要求儘可能勿在兩小時內 再度用藥。所有的治療報告以封閉式表格保存，直到封存 所有數據與解決所有問題爲止。 功效測試 首要的功效測試爲從基準點到受測者在服藥後兩小時 之疼痛指數差異（P I D)百分比，在基準點時，受測者 評估§5錄其疼痛指數、功能失調、η惡心、B區吐、畏光與怕 吵的程度，同時也在服藥後〇 · 5、1、2、3、4、與 6小時分別記錄疼痛減緩與其它症狀的情況。受測者以四 個等級來表達疼痛狀況·· 〇分表是不痛，1分表示輕微， 2分表示中度，3分表示嚴重疼痛。同時以〇 — 4表示疼 痛消除狀況：0表示未消除，1表示一點點消除，2表示 部份消除，3表示大部份消除，4表示完全消除。以〇 一 4區分功能失調：〇 =無失調，1 =正常活動需要一點點 額外力氣，2 =正常活動需要部份額外力氣，3 =正常活 本紙張尺度適用中國國家標隼（CNS ) Α4規格（210Χ297公釐） ~~ (請先閱讀背面之注意事項再填寫本頁) 565447 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明（I6 動需要很多額外力氣，4 =完全無法正常活動。噁心、畏 光與怕吵則以0 - 3來分等級：0 =無，1 =輕微，2 = 中度，3 =嚴重。 偏頭痛患者在六小時的療程後，或再度追加藥物時， 需提供完整的止痛功效評估報告。實驗執行者也要提出累 似的評估表，整體的評估分數由1至5分，1 =不良、2 =普通、3=尙可、4=優、5=極優。 其它的功效變數則自受測者的記錄衍生而來，這些功 效變數包括疼痛指數差異（P I D )，受測者的疼痛降至 輕微或無的百分比，受測者覺的完全無痛的百分比，與受 測者在六小時的評估時段內即需治療的百分比。 安全評佔 在第二次造訪時，實驗執行者引導進行相反的實驗’ 並由受測者完全記錄，發病程度、療程與實驗用藥相關的 事項皆被記錄，臨床實驗的數據並無有系統的收集。 統計分析 每項實驗中，每樣品數2 0 0名受測者可提供8 5 % 可信度，供偵測具有臨床意義的差異，該族群中至少有 1 5 %出現疼.痛消除至輕微或無（雙尾分析，a = 0.05)。 實驗組之間的比較，在定量變數上（如年齡）ί采變胃 數分析（A Ν Ο V A )，類別變數上採卡方檢定（chi_ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐) :19 : (請先閱讀背面之注意事項再填寫本頁) 訂 t 565447 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明（V square’ tests )做分析，每項實驗中兩組都依人口統計學與 基準點的特性進行比較。 若受測者因故（如：睡著了）而無法收集所有時間點 的資料，則採用內插法補足數據，例如在〇 · 5小時的數 値未記錄，就採用原點與1小時的平均數値取代。而對需 要追加藥物的受測者，追加藥物後的疼痛指數、機能失常 與噁心狀況，則依原點或最後記錄點何者最嚴重而記錄， 而補加藥物的疼痛減緩記錄需標明：「未減緩」。 主要功效分析則來自有出現藥物功效的族群，此數據 同時也依Intent-to-Ti*eat (ITT)基準作分析，每項實 驗都分別分析，獨立實驗的結果因資料彙整所需而做檢定 〇 兩組受測者在每個時間點的比較，是採用共變方分析 (A N C Ο V A )，以比較自原點到各時間點在疼痛指數 、功能失常、噁心程度、畏光與怕吵的差異。對於受測者 在給藥後六小時的整體記錄，與實驗執行者在第二次造訪 所進行的整體評估，則以A N〇V A進行分析，0〇〇1^11-M a n t e 1 - H a e n s z e 1檢定法，依照原點時將疼痛指數分等級， 用來分析受測者的疼痛指數降到輕微或無的百分比、受測 者的疼痛指數降到全無的百分比、與重覆投要的受測者百 分比，若P値< 0 . 0 5，則表示具有統計學上意義。 實施例三 夸測族群 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) .20 - ' (請先閲讀背面之注意事項再填寫本頁) 565447 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明（P 在隨機分佈於三項實驗中的1 3 5 7名受測者’有 1 250 名人（92%)服用 APAP/ASA/CAF 藥學組成物。其中有兩名實驗組受測者與一名控制組受測 者缺少原點與投藥後的評估記錄’因此這三名受測者的數 據則不受採用，儘存1 2 4 7名受測者可保留在In tent-t〇-Treat ( I T T )組群中，I T T組群與功效測試數據 的檢體差距2 7名（I Τ Τ有1 2 4 7名，功效測試有 1220名），此27名包括了14名並未符合本食驗步 驟之偏頭痛判定標準，9名未在投藥後2小時記錄狀況， 4名未完全服用實驗所需藥物。 在各實驗中的兩組都有類似的人口統計剖析與偏頭痛 病史，第一表顯示所有受測者都真的患有偏頭痛，若未經 治療，偏頭痛發症時有2 8%爲中度疼痛、7 0%爲重度 疼痛、與低於1%爲痛不欲生；分別有3 9%與4 9%有 中度與重度偏頭痛相關失能症；6 3%在偏頭痛發病時， 經常或總是伴隨有噁心情形；藥物治療狀況則爲：曾接受 非處方籤藥物治療者爲6 5%、採用處方籤藥物者爲 1 2 · 5%，兩類藥物都用過者爲2 1%，不曾用過藥物 者爲1 · 5%。第二表則顯示服用APAP/ASA/ C A F藥學組成物的實驗組、與投予安慰劑的控制組在三 項實驗中的原點比較値。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -21 - 565447565447 A7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ______B7______ V. Description of the invention () The scope of this patent _ This patent is about a composition and method that can reduce the symptoms of acute migraine. Further, the present invention relates to An over-the-counter prescription drug combination, including paracetamol, aspirin, and caffeine, to treat individuals with pre-migraine symptoms, migraine-related symptoms, and / or mild to severe migraine. The background of the present invention is estimated to be about 230 to 25 million Americans, about 18% of women and 6% of men, migraine and migraine-related symptoms, the incidence is very common, 50% All of the above patients have at least one or more chances of developing symptoms each month. Migraine is a multi-cause discomfort that causes patients with various pains and related dysfunctions. About 5 to 15% of the onsets have only mild pain and no dysfunction, and 60 to 70% of the onsets cause moderate to Severe pain and dysfunction, the remaining 25-3 5% of the chances of developing symptoms, leading to severe exhaustion and total disability. Recently, in the United States and around the world, ethnic-based epidemiological studies have found that most migraine patients do not consult their physicians about migraine onset, and only about one-third of patients have been diagnosed by a physician. Of the vast majority of patients who have used drugs to reduce pain (about 95% of men and 97% of women), only 28% of men and 40% of women have used prescription drugs and more than 90% have migraines. People use over-the-counter medications to combat migraines, and most patients use only over-the-counter medications. Many people with migraine use unilateral over-the-counter prescription drugs to combat onset of symptoms. For example, this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) "Heart" (Please read the precautions on the back before filling this page) 565447 A7 B7 _______ 5. Description of the invention (? (Please read the notes on the back before filling this page) Paracetamol, aspirin, or non-steroidal anti-inflammatory drugs, regardless of these available everywhere Only over-the-counter prescription drugs are approved in the United States. In some countries, there are some over-the-counter prescription drugs that specifically treat migraine headaches. However, these self-treated over-the-counter prescription drugs have not been tested in clinical trials. There is clear evidence of treatment, and paracetamol, aspirin, and caffeine are recognized to relieve non-specific pain and stress headaches, which are clinically different from migraines. Caffeine is already a type of A wide range of analgesics are also used in prescription prescriptions for migraine headaches. They have been used in combination with many drugs, such as ergot and tartaric acid. Patients' symptoms are different, but severe headaches require most patients to undergo further treatment. Traditional treatments, such as ergotamine, are effective for pre-migraine symptoms, but it is also known that the slower the dose, the better the effect. The worse. Ergotamine is often administered with caffeine, an analgesic adjuvant, to accelerate the absorption of ergotamine. However, repeated administration of ergotamine will cause long-term and cumulative vasoconstriction. Patients with oral migraine medications are carefully explained. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed a safer treatment and prevention of migraine treatment in view of the cumulative toxicity of ergotamine and its derivatives. The replacement of ergotamine The material examples can be ergotoxin, propranolol, and methysergide. However, about 40% of those who take these substitute drugs have obvious toxicity. In addition, many of these agents have no effect on acute migraine. The substitution of ergotamine and its derivatives is called sumatriptan (or sumatriptan succinate), which is a selective 5-hydroxytryptamine receptor subtype counterpart. Effectively control the pre-symptomatic symptoms of migraine. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 5-565447 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 ___B7_______ V. Description of the invention (? Therefore, the clear goal of this technique is to discover novel, safe, non-toxic, and effective anti-migraine drugs and treatment methods, especially for over-the-counter prescription drugs, which can be taken without a prescription. The use of over-the-counter acetaminophen, aspirin, and over-the-counter medication in combination with caffeine (APAP / ASA / CAF) has not been proven to have a clear effect on migraine pain and symptoms. In terms of physical judgment, they are different from non-migraine headaches and stress headaches. In addition, prior to the present invention, the combined use of paracetamol, aspirin, and caffeine (APAP / ASA / CAF) was not found to reduce one or more migraine symptoms, such as nausea, photophobia, Afraid of noise and dysfunction. Furthermore, before the present invention, it was not known whether the combined use of APAP / ASA / CAF could reduce the pre-migraine symptoms, that is, the migraine omen and the pre-migraine period. In addition, before the present invention, no combination was found.倂 The use of APAP / ASA / CAF can effectively reduce migraine pain, and it can also significantly reduce migraine nausea, photophobia, fear of noise, and dysfunction. The migraine treatment method proposed by the present invention in combination with APAP / ASA / CAF is far better in cost and effect than the currently prescribed prescription drugs. SUMMARY OF THE INVENTION The subject matter of the present invention is to provide an over-the-counter prescription composition to treat migraine and its symptoms, including pain, nausea, photophobia, fear of noise, and dysfunction. According to the present invention, migraine and one or more of the aforementioned migraine-related symptoms can be administered to an over-the-counter signature composition, including paracetamol, aspirin, and this paper size applies Chinese National Standard (CNS) A4 specifications (210X297mm) (Please read the precautions on the back before filling out this page) 565447 A7 B7 ___ V. Description of the invention (Jin and Caffeine (APAP / ASA / CAF) can reduce its symptoms. (Please read first (Notes on the back, please fill out this page)) Another subject of the present invention is to administer certain doses of paracetamol, aspirin, and caffeine (APAP / ASA / CAF) pharmaceutical composition to ease and reduce Or eliminate one or more of the symptoms of migraine mentioned above. Another subject of the present invention is to use certain doses of medicinal composition of paracetamol, aspirin, and caffeine to reduce the symptoms of migraine. This can reduce the symptoms of migraine and affect the development of acute migraine. 'According to the present invention, this analgesic composition can also alleviate the symptoms of complete migraine. Another subject of the present invention is the use of the above Prescription of analgesics can eliminate the onset of migraine after the onset of migraine pain. According to the present invention, this analgesic composition can not only eliminate the pain of migraine, but also eliminate one, preferably two, or two Symptoms related to migraine include pain, nausea, photophobia, fear of noise, and dysfunction. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Another subject of the present invention is to provide an over-the-counter painkiller composition, as previously These include therapies for paracetamol, aspirin, and caffeine. The composition can reduce or alleviate migraine pain and / or related symptoms, and its effect is similar to sumatriptan, such as sumatriptan, a white salt (Imitrex® , Sold by Glaxo Wellcome Pharmaceutical Co., Ltd.), can reduce or alleviate migraine pain and / or period-related symptoms. Another subject of the present invention is to provide an over-the-counter painkiller composition as described above for use in prevention and treatment. For the treatment of migraine pain and / or its paper size, the Chinese National Standard (CNS) A4 (210X 297 mm) is applicable. 565447 A7 B7 V. Description of the invention This symptom. (Please read the precautions on the back before filling out this page.) Another subject of the present invention is to reduce migraine in patients who have been administered as previously described including paracetamol, aspirin, and caffeine. The composition can reduce the repeated administration of medicines. Therefore, according to the present invention, the need for replenishing medicines can be reduced. Other subjects and benefits of the present invention will be described in detail below. The diagrams provided can further explain and help understand the various conditions of the present invention. The first panel A shows the control group (open circle) and administration of the composition including paracetamol, aspirin, and caffeine ( (Solid circles) Six hours later, the patient's pain status was reduced to a percentage of mild or none. The first panel B shows the percentage of patients whose pain was reduced to nothing after the control group (open circles) and the administration of the composition (solid circles) including paracetamol, aspirin, and caffeine after more than six hours. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the second picture shows the control group (open circle) and administration of the composition including paracetamol, aspirin, and caffeine (solid %) Of patients with moderate, severe, or severe disability. Moderate, severe, or severe loss of function is related to the subject's need for some or many additional assistance for general work and daily life, or the subject's administration includes paracetamol, aspirin, and coffee Therefore, compared with the control group, can normal activities be resumed after the composition. Figure 3A shows that compared with the control group (open circle), in the investment package -8-This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 565447 A7 B7 employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative. 5. Description of the invention (9 including the composition of trapping paracetamol, aspirin, and caffeine (filled circles) for six hours. The percentage of subjects who still have nausea. The third graph shows Compared to the control group (open circles), the percentage of subjects who still had photophobia symptoms after administration of a composition including solid paracetamol, aspirin, and caffeine (filled circles) for six hours. Figure 3C shows that compared with the control group (open circles), the subjects still feared after administration of a composition including solid paracetamol, aspirin, and caffeine for six hours. Percentage of noisy symptoms. Detailed description of the present invention The present invention provides a composition and method for treating migraine and its symptoms. The composition is an over-the-counter mineral composition, including paracetamol, aspirin, and coffee. Because (herein referred to as APAP / ASA / CAF), this kind of Used in the present invention is clinically safe and can effectively reduce one or more symptoms of migraine. The composition provided by the present invention for capturing paracetamol, aspirin, and caffeine (APAP / ASA / CAF) is An effective and beneficial migraine over-the-counter prescription treatment method. This over-the-counter APAP / ASA / CAF analgesic composition can reduce and alleviate pain in patients with migraine. According to the APAP / ASA / CAF used in the present invention, A special embodiment of the composition is a commercialized product, that is, an over-the-counter prescription drug Excedrin® Extra-Strength. In general, migraine with and without warning has a variety of characteristics, and the onset of migraine is sudden and spontaneous. The onset of untreated or improperly treated migraine can take several hours to several days (for example, approximately four hours to three paper sizes to apply Chinese National Standard (CNS) A4 specifications (210X; 297 mm) ~ f Please read first Note on the back, please fill out this page again) 565447 A7 Printed by B7 of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives V. Invention Description (? Day), migraine attacks are not frequent About 75% of patients develop symptoms three or less times a month. The general characteristic of migraine is that the head side produces throbbing pain, usually moderate to severe pain, and it will be accompanied by normal oral physical activity and powerful oral drama. Migraine comes from more than one symptom, such as nausea or nausea, photophobia, loud noise, and disability, such as the inability to perform normal work-related and non-work-related services. In one system of the present invention The pharmaceutical composition of APAP / ASA / CAF can eliminate the symptoms before or during the early warning period of migraine. When the early warning period appears, it can cause acute migraine attacks and severe pain. According to the present invention, this analgesic composition It can be used to prevent the complete onset of migraine. Practitioners will be very fortunate that before the severe pain of migraine, there are some early symptoms to judge. Generally before the onset, the patient will have emotional changes, weakness and burnout. During the early warning period, about 20% of the patients began to experience severe migraine pain and throbbing. At the same time, hearing and vision abnormalities may occur before severe pain begins, and there may be eyes Black, hemi-blind, with language barriers and so on. If it is not limited to theoretical analysis, the early warning period of migraine may be related to serotonin released by platelets. According to the pharmaceutical composition of APAP / ASA / CAF used in the present invention, patients may feel pressure, Before severe pain and related discomfort, remove the chance of migraine. Another system of the present invention is such a pharmaceutical composition of APAP / ASA / C A F, which can reduce migraine-related symptoms before or after the onset of migraine. According to the present invention, the paper size of this analgesic group is applicable. National National Standard (CNS) A4 (210X 297 mm) ~ (Please read the precautions on the back before filling this page) 565447 Intellectual Property Office of the Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 _____B7 V. Invention Description (Let the finished product not only eliminate the pain of migraine, but also eliminate migraine related symptoms including pain, nausea, and fear after the onset of one, preferably two or more Light, fear of noise, and dysfunction, these symptoms occur immediately after the previous symptoms appear. According to the present invention, the pharmaceutical composition of APAP / ASA / CAF can provide an over-the-counter painkiller composition, which can reduce or Relieves migraine pain and / or one or more related symptoms, the effect is similar to sumatriptan, such as sumatriptan succinate (Imitrex®, sold by Glaxo Wellcome Pharmaceutical Factory) (see Example 9), these two pharmaceutical compositions Treatment can reduce or alleviate migraine pain and / or phase-related symptoms. Both treatments have unpredictable effects on migraine relief. Due to their different mechanisms of action, when Sumatriptan inhibits the activity of the serotonin receptor in the blood, the pharmaceutical composition of APAP / ASA / CAF does not produce similar effects. Using the APA P / A SA / Another benefit of the pharmaceutical composition of CA F is that after taking an effective dose of the drug, migraine patients have about 4 to 6 hours at the end of the effect. In view of the pain-relieving effect of the drug composition, patients need less additional Dosages (Examples 4 and 5). In order to facilitate oral ingestion, the effective dose of the APAP / ASA / CAF pharmaceutical composition according to the present invention described below is as follows: tonicol contains 300 to 600 mg, preferably 400 to 550 mg , More preferably 500 mg; aspirin contains 300 to 600 mg, preferably 400 to 550 mg, more preferably 500 mg; caffeine contains 100 to 250 mg, preferably 125 to 200 mg (Please read the notes on the back before filling out this page) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -n-565447 Printed by A7 B7_ _Fives Description of the invention (9,130 mg. For convenience, the unit dose can be administered in the form of 2 tablets, 1 tablet or 1/2 tablet. Preparations containing APAP / ASA / CAF pharmaceutical composition and traditional pharmaceutical carriers, It can be prepared in a suitable manner, such as solid or liquid. Solid drugs can include tablets, tablets, capsules, powders, soluble granules, bean-shaped capsules, suppositories, etc., preferably tablets, tablets, or capsules; liquid drugs can include oral drugs, etc. Osmotic solutions, suspensions, elixirs, or aqueous solutions, suspensions and emulsions for parenteral use. The unit dose can be prepared in a single package. There can be several kinds of finished products in the package, such as packaging tablets, capsules, and powders in small glass bottles. The unit dose can also be capsules, bean-shaped capsules, or the tablets themselves. Way to combine. Non-toxic, pharmaceutical compatible excipients may be added to the tablets to facilitate the manufacture of the tablets. These excipients may be stable diluents: such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate. Granulating or decomposing agents: such as corn starch or alginic acid, binding agents: such as starch, gelatin or acacia, and lubricants: such as magnesium stearate or stearic acid. The tablets do not need a coating film, and a coating film can be added to extend the time for disintegration and absorption in the digestive tract. In addition, lozenges can also be prepared as powders or granules. For example, hydrophilic powders or granules are used in combination with binding agents, lubricants, stable diluents, surfactants or co-solvents, and then pressure-molded or formed in stable In the liquid diluent, these lozenges can be marked or added with a coating film. Capsules and bean-shaped capsules can contain only active ingredients, or have other formulas at the same time. The main ingredients contained in the capsules can be stored in water or oil solutions. , Suspension, or emulsion, and at the same time consider whether there are other formulations. The size of this paper is applicable. National Standard (CNS) A4 (210X297 mm)-(Please read the precautions on the back before filling this page) 565447 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs_B7____ Description of the invention () 〇 Oral formula can also use hard capsules, APAP / ASA / CAF active ingredients mixed with stable solid diluents, such as calcium carbonate, calcium phosphate, white clay, or soft capsules, the effective ingredients will be mixed Oil-soluble bases such as peanut oil, liquid ballast or olive oil. Other useful dosage forms, such as suppositories, may include binding agents and carriers, such as polyalkylene glycols or triglycerides. Liquid suspensions contain the active ingredient and are suitable for use in manufacturing Excipients of the suspension. Examples of these excipients include suspending agents: such as sodium carboxymethane woody cellulose, methyl cellulose, cellulose acetate propionate, sodium alginate, polyethylene nitrate Testosterone, tragacanth, and gum arabic, the dispersant or penetrant may be a natural phospholipid, such as lecithin, a thickener containing alkyUne.oxide and fatty acids, such as polyethylene oxide stearic acid, or Thickeners containing ethylene oxide and long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or thickeners containing ethylene oxide and fatty acid-derived esters and hexitol, such as polyethylene oxide cedarol monooleic acid , Or thickeners containing ethylene oxide and fatty acid-derived esters and anhydrous hexitol, such as polyethylene oxide anisodose monooleic acid. The water-soluble suspension may contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoic acid, one or more flavoring agents, one or more sweeteners, such as sucrose, saccharin, or cyclohexylsulfonium Amine calcium. According to the present invention, there are several ways of administering the APAP / ASA / CAF pharmaceutical composition, such as oral, sublingual, large intestine, intravenous, intramuscular, parenteral, and intestinal suppositories in appropriate dosage forms. Standards are applicable. National Standard (Oyang) 8 4 specifications (210/297 mm) "13- " " (Please read the precautions on the back before filling out this page) 565447 A7 ___B7_ 5. Description of the Invention (Agent Or inhalants, etc., should be taken orally. (Please read the precautions on the back before filling out this page} Unit doses should be administered daily, preferably every 4 to 6 hours, preferably every 6 hours, up to daily 8 tablets, the entire medication period is 10 days or less. According to the present invention and the following examples, it was found in three designed and controlled clinical studies that after the APAP / ASA / CAF pharmaceutical composition was administered From 1 to 6 hours, compared with the placebo-administered control group, patients with migraine tested had significantly reduced migraine pain, and more specifically, 2 hours after administration, APAP / ASA / CAF pharmaceutical composition was administered. Of migraine pain in 59% of patients (Such as 3 5 7/6 0 2) can be reduced to slight or none, while only 33% of control group (such as 203/618) have the same situation (P < 0 · 001, 95% Cl, APAP / ASA / CAF group 55% to 63% in the control group and 29% to 37% in the control group); Migraine pain in patients who were administered APAP / A SA / CAF pharmaceutical composition 6 hours after administration Reduced to slight or none, and only 52% of the control group had the same situation (P < 0 · 001, CI was 75% — printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 8 2% to 4 8%-5 6%); In addition, after 6 hours of administration, migraine pain in patients administered with APAP / ASA / CAF pharmaceutical composition was completely eliminated in 51% of patients (such as 306/60 2), while only 23% in the control group ( Such as 1 4 5/6 1 8) have the same situation (P < 0.001, 95% CI, APAP / ASA / CAF group is 4 7% to 5 5%, the control group is 20% to 2 7%). Other migraine-related symptoms, such as nausea, photophobia, fear of noise, and dysfunction -14-This paper size applies Chinese National Standard (CNS) A4 specifications (21〇 > < 297 mm) 565447 Employees of the Intellectual Property Office, Ministry of Economic Affairs Printed by Consumer Cooperative A7 B7 _ _V. Explanation of the invention (P tune, compared with the control group, patients administered APAP / ASA / CAF pharmaceutical composition can be improved in the next 2-6 hours (P < 0.01), so, This over-the-counter composition that also captures acetaminophen, aspirin, and caffeine has a high effect on migraine pain and migraine-related symptoms such as nausea, photophobia, fear of noise, and function Imbalance can also be improved. At the same time, APAP / ASA / CAF pharmaceutical composition is extremely safe and well tolerated. Although different treatment methods are used in the following experiments, whether it is the ethnic-based experiment (Experiment 1) or the traditional method of recruiting subjects (Experiment 2 and Experiment 3), it is shown that The APAP / A SA / CA F pharmaceutical composition has a better therapeutic effect in patients. It has been found in all three experiments that one to six hours after the APAP / ASA / CAF pharmaceutical composition is administered, a significant The difference in effect, the obvious difference between the administration of the APAP / ASA / CAF pharmaceutical composition and the control group, can be found half an hour after the administration, including improvement of headache, reduction of pain to slight or no, and analysis of other aggregated data Compare. One group administered with the APAP / A S A / CA F pharmaceutical composition can feel that one hour after the administration, it can resume normal work and rest, and it is the same at every test time point thereafter. Although special prescription medicines for migraine are known to reduce nausea, photophobia, and noisy symptoms, the present invention provides an alternative to prescription drugs, which is safe, economical, and effective. The APAP / ASA / C A F pharmaceutical composition according to the present invention is statistically significant 'and can reduce nausea, photophobia, and noisy related symptoms. 30 minutes after the drug is administered, the paper size of this paper applies the Chinese National Standard (CNS) A4 (210X297 mm) -15-(Please read the precautions on the back before filling this page) 565447 A7 _______B7 V. Invention Note (3) The data shows that there is no obvious improvement effect. Furthermore, these benefits of the APAP / A SA / CAF pharmaceutical composition come from (please read the precautions on the back before filling this page) ) As described in patients with moderate to severe migraine pain and significant functional impairment. The present invention has important benefits for clinical applications, migraine and headache care policies. 'Many approved prescription medications for migraine are expensive, And there are many side effects of treatment limitation and indications. According to the present invention, this over-the-counter APAP / ASA / CAF pharmaceutical composition has safe characteristics, can effectively relieve pain, dysfunction and migraine-related symptoms, and this composition can provide a safe and economical for migraine patients s Choice. Examples The examples described below are intended to demonstrate the invention in various ways and are not intended to limit the invention in any way. Three independent, double-blind, randomized, controlled and control group experiments were designed to evaluate the efficacy of this over-the-counter AP AP / ASA / CA F pharmaceutical composition for reducing acute migraine and its related symptoms. The results are described in the following examples. Example 1: Method printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Three subjects performed double-blind, random, control, and control in three experiments conducted by the subject between August 1995 and June 1996. The experimental design of the group, only this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public ^ 16-565447, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, A7, B7, and V5. Description of the invention (I4 Recruitment methods are different. Experiment 1 is a single-center trial using random numbers and selection numbers to select suitable subjects. Experiments 2 and 3 are multicenter trials. The testers were recruited from traditional data (such as clinics, introducers, and regional advertisers with 7 7%), and random numbers were selected (23%) to recruit. The conditions for inclusion and removal in these three experiments are the same Patients must meet the diagnostic criteria of the International Headache Society (IHS). Regardless of the pre-symptomatic symptoms of migraine, they must be at least 18 years of age, and generally in good health. They must have migraines at least every two years. Once a month, but not more than six times a month, if the onset of pain is untreated, it must have a degree of moderate pain or higher. Patients who are often in the onset of disability (requiring bed rest) are not recruited. Patients Vomiting will be ruled out more than 20% of the time during the onset period, because such patients may not be able to ingest the drugs used in the experiment due to vomiting, and nausea is not ruled out. Obtain written consent, and the entire experimental process and consent have been approved by the Institutional Review Board. To determine that all subjects have migraine, each person must provide a complete medical history, including a semi-guided headache diagnosis Results The health examination and neurodiagnosis were completed by the clinician, and the subjects were required to record the experimental process in a diary. Example 2 Experimental Design This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -17- 1 ( (Please read the notes on the back before filling this page) 565447 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _B7_ V. Description of Invention () 5 steps At the first visit, subjects were randomly divided into two groups (ratio of 1: 1) according to a random schedule generated by the computer for double-blind trials. One group could get two unlabeled medicines, each one Contains 250 mg of paracetamol, 250 mg of aspirin and 65 mg of caffeine. The other group can get the same appearance of two placebos, which can be taken when you feel conscious migraine. When the pain and symptoms meet the definition of migraine, the onset of pain is at least intermediate or higher, or other appropriate conditions are developed, the subject is informed that the test drug can be taken. Subjects are required to refrain from taking medication again within two hours if possible. All treatment reports are saved in a closed form until all data is sealed and all issues resolved. Efficacy test The primary efficacy test is the percentage of pain index difference (PID) from the reference point to the subject's pain within two hours after taking the drug. At the reference point, the subject evaluates § 5 to record his pain index, dysfunction, and η nausea. The degree of vomiting, photophobia, and noisy areas in areas B, B, and pain relief and other symptoms were recorded at 0.5, 1, 2, 3, 4, and 6 hours after taking the drug. Subjects expressed their pain status on four levels ... The score was not painful, with 1 being mild, 2 being moderate, and 3 being severe. At the same time, 0-4 indicates the pain elimination status: 0 means no elimination, 1 means little elimination, 2 means partial elimination, 3 means most elimination, and 4 means complete elimination. Distinguish dysfunction by 〇4: 〇 = no dysfunction, 1 = a little extra effort is needed for normal activities, 2 = a little extra effort is needed for normal activities, 3 = normal living paper size applies Chinese National Standard (CNS) Α4 specifications (210 × 297 mm) ~~ (Please read the precautions on the back before filling out this page) 565447 A7 B7 Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (I6 requires a lot of extra effort, 4 = completely unnormal Activities. Nausea, photophobia and noisy are graded on a scale of 0-3: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Patients with migraine after a six-hour course of treatment, or when taking additional medication. It is necessary to provide a complete evaluation report of analgesic efficacy. The test executor should also submit a tired evaluation form, the overall evaluation score is from 1 to 5 points, 1 = bad, 2 = normal, 3 = acceptable, 4 = excellent, 5 = Excellent. Other efficacy variables are derived from the subject's record. These efficacy variables include the pain index difference (PID), the percentage of the subject's pain reduced to mild or absent, and the subject's perception of complete painlessness. Of the percentage The percentage of test subjects who needed treatment within the six-hour evaluation period. Safety review accounted for the second visit and the test executor conducted the opposite experiment 'and was fully recorded by the test subject. The degree of illness and course of treatment were related to the experimental medication All matters are recorded, and the data of clinical trials are not systematically collected. Statistical analysis In each experiment, 200 subjects per sample can provide 85% confidence for detection of clinically meaningful The difference was that at least 15% of the ethnic groups experienced pain. The pain resolved to slight or none (two-tailed analysis, a = 0.05). Comparison between experimental groups was performed on quantitative variables (such as age). (A Ν Ο VA), Chi-square test on category variables (chi_ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm)): 19: (Please read the precautions on the back before filling this page) Order 565447 Printed by A7 B7, Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. V's' tests for analysis. In each experiment, the two groups are compared according to the characteristics of demographics and benchmarks. Cause (Such as: falling asleep) and unable to collect data at all time points, then use interpolation to supplement the data. For example, if the number of 0.5 hours is not recorded, the original point and the average value of 1 hour are used instead. For those who need additional drugs, the pain index, dysfunction and nausea after the additional drugs are recorded according to which of the origin or the last recorded point is the most serious, and the pain relief records of the additional drugs need to be marked: "Not relieved The main efficacy analysis comes from the ethnic group with drug efficacy. This data is also analyzed according to the Intent-to-Ti * eat (ITT) benchmark. Each experiment is analyzed separately. The results of the independent experiments are required for data aggregation. The test was performed. The comparison between the two groups of subjects at each time point was made by covariation analysis (ANC 〇 VA) to compare the pain index, dysfunction, nausea, photophobia and Afraid of noisy differences. For the overall record of the subject six hours after dosing, and the overall evaluation performed by the experiment performer on the second visit, the analysis was performed by ANOVA, 〇〇001 ^ 11-M ante 1-H aensze 1 Assay method, the pain index is graded according to the origin, which is used to analyze the percentage of the subject's pain index dropped to slight or none, the percentage of the subject's pain index dropped to nothing, and repeated requests The percentage of subjects, if P 値 < 0. 05, is statistically significant. Example 3 Examine the ethnic group The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). 20-'(Please read the precautions on the back before filling out this page) 565447 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Preparation of A7 B7 V. Description of the invention (P Among 1 3 5 7 subjects randomly distributed in three experiments, 1 250 people (92%) took the APAP / ASA / CAF pharmaceutical composition. Two of these experiments Group test subjects and one control group test subject lacked the origin and post-administration evaluation records'. Therefore, the data of these three test subjects are not used, and only 1 2 4 7 test subjects can be kept in In Among the tent-t〇-Treat (ITT) group, there was a gap of 27 between the ITT group and the efficacy test data (1 2 4 7 for ITT and 1220 for the efficacy test). These 27 included 14 did not meet the migraine determination criteria of this test step, 9 did not record the condition 2 hours after administration, and 4 did not fully take the drugs required for the experiment. The two groups in each experiment had similar demographic analysis With a history of migraine, the first table shows that all subjects really had migraine Without treatment, 28% of migraine headaches are moderate pain, 70% are severe pain, and less than 1% are painless; 39% and 49% have moderate and severe migraine, respectively. Related disability; 63% of nausea are often or always accompanied by migraine; 65% of those who have received over-the-counter medications and 1 of 2 have been prescribed medications · 5%, 21% of those who have used both drugs, and 1 · 5% of those who have never used them. The second table shows the experimental group taking APAP / ASA / CAF pharmaceutical composition, and the placebo The original point of the control group in the three experiments is relatively ill. (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) -21-565447

A B 五、發明説明（I9 第1表：功效評估受測者的基本資料與偏頭痛病史 經濟部智慧財產局員工消费合作社印製 實驗1 實驗2 實驗3 匯整資料 APAP/ ASA/CAF (n=187) 控制組 (η 二 191) APAP/ASA /CAF (η=206) 控制組 (η=221) APAP/ASA /CAF (η=209) mm (n=206 APAP/ASA l /CAF )(n=602) 控制組 (n=618) 平均年齡(歲） 35.5 35.8 37.8 35.9 37.8 37.6 37.0 36.4 性別(％) 男性 25 23 24 19 17 17 22 20 女性 75 77 76 81 83 83 78 80 謙(％)， 白種人 78 85 84 88 90 89 84 88 黑人 21 15 11 5 4 7 11 9 其他 1 0 5 6 6 4 4 4 偏頭痛麵(％) 無預兆 86 85 77 75 82 82 81 80 有預兆 14 15 23 25 18 18 19 20 未受治療的疼痛狀況(％)’ 無/輕微 0 0 0 0 0 0 0 0 中度 29 29 21 25 34 28 28 27 重度 71 71 76 71 62 68 70 70 劇痛 0 1 0 <1 <1 <1 <1 一 不明+ 0 0 2 4 3 4 2 3 未受治療的失能狀況 無纖 3 1 1 3 0 0 1 1 無輕微 13 9 7 11 5 4 8 8 中度 47 47 35 30 41 36 41 37 重度 37 41 54 51 r 51 55 48 49 完全失能 0 1 <1 1 0 0 <1 1 个明+ 0 1 2 4 3 4 2 3 發病伴有噁心(％y 每次都有 9 9 15 15 32 29 19 18 經常有 42 46 51 47 39 42 44 45 很少有 27 25 20 23 21 18 22 22 從未出現 22 21 14 15 9 11 15 16 常用治療方式 無 1 2 1 1 1 2 1 2 只用非處方籤藥物 「84 82 59 57 59 52 67 63 只用處方籤藥物 5 4 12 16 19 18 12 13 處方籤藥物與非處 方籤藥物皆用 10 12 28 26 22 28 20 22 百分比總和因四拾五入可能非100。 +統計分析中未含有數據不全的受測者資料 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） -22· (請先閲讀背面之注意事項再填寫本頁) 565447 五、發明説明（卵AB 5. Description of the invention (I9 Table 1: Basic information of the subject of efficacy evaluation and history of migraine. Printed Experiment 1 of Consumer Cooperative of Employees of Intellectual Property Bureau of the Ministry of Economic Affairs. Experiment 1 Experiment 2 Experiment 3. Aggregated data APAP / ASA / CAF (n = 187) Control group (η 191) APAP / ASA / CAF (η = 206) Control group (η = 221) APAP / ASA / CAF (η = 209) mm (n = 206 APAP / ASA l / CAF) (n = 602) Control group (n = 618) Mean age (years) 35.5 35.8 37.8 35.9 37.8 37.6 37.0 36.4 Gender (%) Male 25 23 24 19 17 17 22 20 Female 75 77 76 81 83 83 78 80 80 Modest (%), Caucasian 78 85 84 88 90 89 84 88 Black 21 15 11 5 4 7 11 9 Other 1 0 5 6 6 4 4 4 Migraine face (%) No warning 86 85 77 75 82 82 81 80 With warning 14 15 23 25 18 18 19 20 Untreated pain (%) 'None / Minor 0 0 0 0 0 0 0 0 0 Moderate 29 29 21 25 34 28 28 27 Severe 71 71 76 71 62 68 70 70 Acute pain 0 1 0 < 1 < 1 < 1 < 1 unknown + 0 0 2 4 3 4 2 3 untreated disability condition fiberless 3 1 1 3 0 0 1 1 no slight 13 9 7 11 5 4 8 8 medium Degree 47 47 35 30 41 36 41 37 Severe 37 41 5 4 51 r 51 55 48 49 Total disability 0 1 < 1 1 0 0 < 1 1 Ming + 0 1 2 4 3 4 2 3 Onset with nausea (% y 9 9 15 15 32 29 each time 19 18 Often 42 46 51 47 39 42 44 45 Rarely 27 25 20 23 21 18 22 22 Never appeared 22 21 14 15 9 11 15 16 Common treatments None 1 2 1 1 1 2 1 2 Only over-the-counter Signing a drug `` 84 82 59 57 59 52 67 63 Signing a drug only with a prescription 5 4 12 16 19 18 12 13 Use both a prescription drug and an over-the-counter drug 10 12 28 26 22 28 20 22 Not 100. + The data of the incomplete subject is not included in the statistical analysis. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -22. (Please read the precautions on the back before filling out this page) 565447 V. Description of the invention

經濟部智慧財產局員工消費合作杜印製 第2表：偏頭痛症狀治療之匯整資料 APAP/ASA/CAF 匯整資料 n=602(%) n=618(%) 無預兆之偏頭痛 499(83) 515(83) 一邊頭痛 366(61) 353(57) 頭抽痛 424(70) 456(74) 越動越痛 421(70) 445(72) 有預兆之偏頭痛 103(17) 103(17) 一邊頭痛 71(17) 76(12) 頭抽痛 93(15) 88(14) 越動越痛 86(14) 88(14) 原點疼痛狀況 中度 400(66) 413(67) 重度 202(34) 205(33) 機能狀況 可如常執行例行工作 21⑶ 12(2) 需要一些額外力氣 83(14) 91(15) 需要部份額外力氣 285(47) 292(47) 需要很多額外力氣 184(31) 185(30) 無法正常工作 28(5) 37(6) 不明 1«1) 1«1) 噁心 姐 241(40) 250(40) 輕微 253(42) 259(42) 中度 95(16) 103(17) 重度 13⑵ 6(1) 嘔吐 並 589(98) 613(99) 有 13(2) 5(1) 有下述症狀之受測者數 畏光與怕吵 522(87) 558(90) 只有畏光 51⑻ 25⑷ 只有怕吵 15⑵ 19⑶ 皆無 13⑵ 15⑵ 不明 1(<1) 1«1) (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） -23- 565447 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明（？1 實驗設計的治療方式，在任何時間點檢測功效變數時 ，都沒有統計學上明顯的交互作用出現’但在檢測機能失 常（第2小時）與畏光（第〇 · 5與1小時）時，則出現 明顯的交互作用，然而’這種交互作用實爲量化而非質化 的，因此並不影響實驗結果。有鑑於此，所有數據被匯集 以總結實驗結果。功效與安全試驗結果將分別在這三項實 驗中發表，同時也出現在匯整分析上。 實施例四 疼痛指數與疼痛減緩狀況 在三項實驗中，服用APAP/ASA/CAF藥學 組成物的受測者，在所有的時間點中（從1到6小時）都 比控制組有明顯較高的平均P I D數値（P < 〇 . 〇 〇 1 )。在匯整分析、實驗一與實驗三中，受測者在第0 . 5 小時，實驗組就比控制組有明顯較高的平均P I D數値（ P < 0 . 0 1 7 )。 在三項實驗中，大部份服用APAP/ASA/ C A F藥學組成物的受測者，自服藥後第一小時起至第六 小時止，都有明顯疼痛降低至輕微或無的經驗（P < 0.0 0 2 )，而在匯整分析中，統計上的明顯差異自投 藥後第0 · 5小時起至其後的所有時間點（P < 0.001)(第一圖A)，匯整數據顯示，在投藥後2 小時，59% (357/602)的 APAP/ASA/ C A F藥學組成物的受測者出現疼痛減緩至輕微或無，而 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） _ 24 - (請先閱讀背面之注意事項#填寫本頁) 565447 A7 _B7_五、發明説明（平 控制組只有3 3 % ( 2 0 3 / 6 1 8 )有此狀況（P < 0 · 001，95% Cl，APAP/ASA/CAF 組爲5 5 % - 6 3 %，控制組爲2 9 % — 3 7 % )。六小 時後的對應結果則分別爲7 9 % ( 4 7 3 / 6 0 2 )與 52%(319/618) (P<0.001，APAP /ASA/CAF 組爲 7 5%— 82%，控制組爲 48% — 56%)。 有絕大部份投予A P A P / A S A / C A F藥學組成 物的受測者，在投藥後2小時起至6小時，都比控制組覺 得疼痛消失（P 10.008)，這種明顯差異同時也在 匯整分析（P = 0 · 002)(第一圖B)與實驗三（P =0 · 004)中的投藥後一小時的數據中可見。在投藥 後兩小時，21%(125/602)的APAP/ A S A / C A F藥學組成物的受測者出現完全無偏頭痛， 而控制組只有7%(44/618)(P<0·001 ， 9 5 % Cl ，APAP/ASA/CAF 組爲 18% — 24%，控制組爲5%— 9%)(第三表）。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） -25- 565447DuPont printed by the Intellectual Property Bureau staff of the Ministry of Economic Affairs. Table 2: Aggregated data for migraine symptoms treatment APAP / ASA / CAF Aggregated data n = 602 (%) n = 618 (%) Migraine without warning 499 ( 83) 515 (83) One side headache 366 (61) 353 (57) Head pain 424 (70) 456 (74) The more you move, the more pain 421 (70) 445 (72) Migraine with warning 103 (17) 103 ( 17) Headache 71 (17) 76 (12) Head pain 93 (15) 88 (14) More pain 86 (14) 88 (14) Pain at the origin Moderate 400 (66) 413 (67) Severe 202 (34) 205 (33) Function can perform routine work as usual 21⑶ 12 (2) Need some extra strength 83 (14) 91 (15) Need some extra strength 285 (47) 292 (47) Need a lot of extra strength 184 (31) 185 (30) Not working 28 (5) 37 (6) Unknown 1 «1) 1« 1) Disgusting sister 241 (40) 250 (40) Slight 253 (42) 259 (42) Moderate 95 (16) 103 (17) Severe 13⑵ 6 (1) Vomiting and 589 (98) 613 (99) 13 (2) 5 (1) Subjects who have the following symptoms are photophobia and noisy 522 (87) 558 (90) Only fear of light 51⑻ 25⑷ Only fear of noisy 15⑶ 19⑶ None of 13⑵ 15⑵ Unknown 1 (< 1) 1 «1) (please first Read the notes on the reverse side and fill out this page) This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) -23- 565447 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 1 The experimental design of the treatment method, no statistically significant interaction occurred when the efficacy variable was detected at any point in time, but when the malfunction was detected (2 hours) and photophobia (0.5 and 1 hours) , There is a significant interaction, but 'this interaction is quantitative rather than qualitative, so it does not affect the experimental results. In view of this, all data are compiled to summarize the experimental results. The efficacy and safety test results will be separated Published in these three experiments, but also appeared in the aggregate analysis. Example 4 Pain Index and Pain Relief Status In the three experiments, subjects taking the APAP / ASA / CAF pharmaceutical composition at all times The points (from 1 to 6 hours) had significantly higher average PID numbers (P < 〇〇〇〇1) than the control group. In the aggregate analysis, experiments 1 and 3, the subjects had a significantly higher average PI D number (P < 0.07) than the control group at 0.5 hours. In the three experiments, most of the subjects who took the APAP / ASA / CAF pharmaceutical composition had significant pain reduction experience from the first hour to the sixth hour after taking the drug (P & lt 0.0 0 2), and in the aggregate analysis, the statistically significant difference is from the 0.5 hour after administration to all time points thereafter (P < 0.001) (first graph A), the aggregate data It showed that 2 hours after administration, 59% (357/602) of the APAP / ASA / CAF pharmaceutical composition subjects experienced pain relief to slight or no pain, and this paper size applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) _ 24-(Please read the note on the back #Fill this page first) 565447 A7 _B7_V. Description of the invention (only 3 3% (2 0 3/6 1 8) of the flat control group) < 0 · 001, 95% Cl, 55%-63% for APAP / ASA / CAF group, and 29%-37% for control group). The corresponding results after six hours were 79% ( 4 7 3/6 0 2) and 52% (319/618) (P < 0.001, APAP / ASA / CAF group is 7 5%-82%, control group is 48%-56%). Vote for APAP / ASA / CAF The subjects of the pharmaceutical composition felt that the pain disappeared from the control group from 2 hours to 6 hours after administration (P 10.008). This apparent difference was also analyzed by pooling analysis (P = 0 · 002) (first Figure B) Data from one hour after dosing in experiment three (P = 0.004). Two hours after dosing, 21% (125/602) of APAP / ASA / CAF pharmaceutical composition subjects There was no migraine, and only 7% (44/618) in the control group (P < 0.01, 95% Cl, 18%-24% in the APAP / ASA / CAF group, and 5%-9% in the control group ) (Table 3). (Please read the notes on the back before filling out this page.) Printed on the paper by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm). -25 -565447

AA

7 B 五、發明説明（和 經濟部智慧財產局員工消費合作社印製 账坡^紘較台W盤七 9 鄹盤七CNJ鹚if^wii 职鬆^®_Edvo/vsv/dvdv i^:· ε 派 ia if 0.4 (0.89) 0.9 (1.16) r- On 0.6 (1.17) ?! 1.3 (1.62) S cn cn 11 醒 ^ ^ ^ 5 s 1.0, (0.91) *Ch •ος ^ f—H Λ ν〇 wn cn 诠 1.4· (1.11) *gN 2.4· (1.69) oo m $ ㈡差 cn 盤 控制組 (n=206) 0.4 (0.83) 0.8 (1.10) VO 0.6 (1.17) SR 4 —一· 茺 Μ 0.9* (0.93) i.r (1.45) CO Λ to 1.2· (1.14) VO sS *CN K S 〇〇 π < < S m Μ 控制組 丨（n=221) 0.4 (0.89) r ' Η cn 0.9 (1.20) Os Εη 2 0.6 (1.10) 1.2 (1.57) CN r—* cn 笑 ΤΡ·Ν 0.9· [0.85) 1.6· (1.34) c± t—^ Ε?； ά CN A cn ά 1.3· (1.09) *〇〇 2·2· (1.67) A 卜 $ i| 控制組 (n=191) 0.5 (0.96) 1.0 (1.16) 卜 S 〇〇 S 1.4 (1.69) ?§ s w ^ ^ ^ ^ 〇 /^S P? <N r-£ CO •穿 $ 1.6· (1.07) s 2·7· (1.64) S i oo s *VQ a Iffl vR ¢1 jj Λ a « Φ <k 阳 紲 Hn 赃 a Μ jj a a a m Φ <k Φ 裢 Φ Φ Φ φ m ^KJ Hu Hn Hn 擊 λΜ Hn Hn 囬 Hn * 略 m ig JM11 •Μ 账 m 藜 m ώ| ilte \p « Λ « Λ m lg « 栅 « *$\ e » m t n » ffl 1 Ο f 膨 盤 jM 心} π( s m 遊 ig 雅 含、 pc cs 七 m W 田K s V 遒 職 w fflK ffi 链 K ίΓ © 壊 摧 摧 * « < ST 蚣 ίΓ 壊 * m * p Q Kh # 眛 η # * 邮 # 郫 卿 1 攤 M 辱 蘗 蒺 驛 激 Μ Μ M M Μ Μ & ε p5 ο. 辁迦幽M«^=yvd (請先閲讀背面之注意事項再填寫本頁) -·裝· 訂 ,·, 本紙浪尺度適用中國國家標隼（CNS ) A4規格（210X 297公釐） -26- 565447 Μ ______ Β7 五、發明説明（糾 (請先閲讀背面之注意事項再填寫本頁}7 B V. Description of the invention (printed with the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 纮 Compared with Taiwan W Disk 7 9 鄹 盘 七 CNJ 鹚 if ^ wii 松 ^ ®_Edvo / vsv / dvdv i ^: · ε Paia if 0.4 (0.89) 0.9 (1.16) r- On 0.6 (1.17)?! 1.3 (1.62) S cn cn 11 Wake up ^ ^ ^ 5 s 1.0, (0.91) * Ch • ος ^ f—H Λ ν〇 wn cn Interpretation 1.4 · (1.11) * gN 2.4 · (1.69) oo m $ ㈡ difference cn disk control group (n = 206) 0.4 (0.83) 0.8 (1.10) VO 0.6 (1.17) SR 4 —One · 茺 Μ 0.9 * (0.93) ir (1.45) CO Λ to 1.2 · (1.14) VO sS * CN KS 〇〇π < < S m Μ Control group 丨 (n = 221) 0.4 (0.89) r 'Η cn 0.9 (1.20 ) Os Εη 2 0.6 (1.10) 1.2 (1.57) CN r— * cn 笑 TP · Ν 0.9 · [0.85) 1.6 · (1.34) c ± t— ^ Ε ?; ά CN A cn ά 1.3 · (1.09) * 〇〇2 · 2 · (1.67) A BU $ i | Control group (n = 191) 0.5 (0.96) 1.0 (1.16) BU S 〇〇S 1.4 (1.69)? § sw ^ ^ ^ ^ 〇 / ^ SP? < N r- £ CO • Wear $ 1.6 · (1.07) s 2 · 7 · (1.64) S i oo s * VQ a Iffl vR ¢ 1 jj Λ a «Φ < k 绁 绁 Hn 赃 a Μ jj aaam Φ < k Φ 裢 Φ Φ Φ φ m ^ KJ Hu Hn Hn Hit λΜ Hn Hn back to Hn * slightly mi ig JM11 • Μ account m quinoa m trophy | ilte \ p «Λ« Λ m lg «grid« * $ \ e »mtn» ffl 1 Ο f bulge jM heart} π (sm Youig Yahan, pc cs Seven m W Tian K s V Unemployed w fflK ffi chain K ίΓ © 壊 DESTROY * «< ST 蚣 ίΓ 壊 * m * p Q Kh # 眛 η # * POST # 郫 卿 1 MM 蘖 蒺 激 激 Ｍ Μ MM Μ Μ & ε p5 ο. 辁 加 幽 M ^^ yvd (Please read the precautions on the back before filling out this page) Applicable to China National Standard (CNS) A4 specification (210X 297mm) -26- 565447 Μ ______ Β7 V. Description of the invention (correction (please read the precautions on the back before filling this page)

在投藥後六小時，5 1 % ( 3 0 6 / 6 0 2 )的 A P A P/A SA/CA F藥學組成物的受測者出現完全 無偏頭痛’而控制組只有23% (145/6 18) ( P <0·001，95% Cl，APAP/ASA/ CAF 組爲 47%— 5 5%，控制組爲 20%— 27%) (第四表）。 投予A P A P / A S A / C A F藥學組成物的受測者 的平均疼痛消除分數，在各項實驗中，自投藥後〇 · 5至 6小時’都比控制組明顯偏高，除了實驗二的第〇 . 5小 時以外。以I T T族群分析功效評量數據可產生一致的結 果。 實施例五 補追劑量 在匯整分析中，控制組的受測者顯然比投予A P A p / A S A / C A F藥學組成物的受測者，自投藥後3〜6 小時，更需要追加劑量（P < 0 · 0 0 1 )，例如··在六 經濟部智慧財產局員工消費合作社印災 小時前，只有12 · 5% (7 5/602)投予APAp / A S A / C A F藥學組成物的受測者需要追加藥劑，而 控制組則有 2 7 % ( 1 6 8 / 6 1 8 ) ( P < 〇 . 〇 〇 χ ，95% Cl，APAP/ASA/CAF 組爲 1〇% —1 5 %，控制組爲 2 4 % — 3 1 % )。 實施例六 I紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -27 -~' — 565447 Α7 Β7 五、發明説明（炉 整體評佔 無論是受測者與實驗執行者的整體評估結果，都顯示 投予A P A P/A SA/CA F藥學組成物的受測者的評 價顯然比控制組高（P < 〇 . 〇 〇 1 )，實驗執行者的整 體評估在投予APAP/A SA/CAF藥學組成物的受 測者中有5 1 %爲佳或極優，而控制組只有2 0 % ( P < 〇· 〇〇1，95% CI，APAP/ASA/CAF 組爲4 7 % - 5 5 %，控制組爲1 7 % - 2 3 % )。受測 者有類似的評估結果。 實施例七 對其他偏頭症狀的效用 在對恢復正常機能（只需一點點或完全不需額外力氣 以執行日常活動）的受測者百分比上，投予A P A P / A S A / C A F藥學組成物的受測者顯然高於控制組，這 結果出現在匯整分析（Ρ<0· 001)、其它各實驗自 投藥後1至6小時（Ρ · 0 〇 6 )，與實驗一投藥後 0.5 小時（Ρ = 0·004)(第二圖）。 --:------•裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 t 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -28 - 565447 A7 B7 五、發明説明（妒 經濟部智慧財產局員工消費合作社印製 nlq_^_u Z8I9_^_ειτ—寸 9ε·_^_u 961Q_^^ s 1 III §ιω> (8δ=υ) (309=u)~θηωιΛ~(9〇CNJI=U) (⑦ OCNIHU) ΘΠΙΒ> P^MS~(90CNI=U) ΦΠΙΒΛpl6¥u)(Z8¥sl a.siLL<o/vs<^ i n^<os< d sihll<o/vs<d iliiLL<o/vs< /dVdV /dVdV /dVdV /dvdv?M) _囊 _麵__J3^_響 δο ν 6L 8ε §·> zi, 8ε 300· os εε §·> 3寸 <•001 <001 <•001 <001 CO C0 ¥ CN 1〇 ⑦ IT) 〇 CO Ο) <•001 <001 <•001 <.001 <_001 56 <•001 67 <•001 73 <.001 76 CO <.001 59 <•001 68 <.001 75 <.001 78 CO (D ίο LO 1〇 S LO 卜 〇 〇〇 CM 00 CM C0 寸 CD 1^^ 1Q0V_^_lllo1QQV_^_S 二 00·> licvl_z 寸loolv8ICNJ_5 9 1010> Zl « 50.VIIOI1T·"!6ε§·> 91， 6ICOI5191V 33 S 寸 5〇.> ιιηιειοιον 6 εε §> U 61CNJI50V 9rl9Icol 50.V L ^ 50.Vllnl11CNJ1900· 6 Z15Q> L 91CNII1CNJ1 so. Zllolso. 0|1011101寸3· 々 91 8{Η·Icol9 ~T colu. t ^ ^ δ 6CNIS0·rj<Ο 6Z6. ί ^ ^ --1------•裝----^---訂------^~ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標隼（CNS ) A4規格（210Χ297公釐） -29 - 565447 經濟部智慧財產局員工消費合作社印製 A7 ____B7___五、發明説明（V 雖然在實驗一與實驗三中，若受測者在受測時間中有 2 0 %以上時間會有嘔吐現象者，已被排除在實驗外，但 仍有6 0 %患者在原點時會有噁心情形。投予A P A P / A S A / C A F藥學組成物的受測者出現噁心現象的百分 比顯然比控制組低，如在實驗三中的1至6小時的時間點 (P < 〇 . 〇 4 7 )、實驗一中3到6小時的時間點（p ^ 〇 · 0 2 7 )、與實驗二中4到6小時的時間點（p s 0.0 2 4 )。而在匯整分析中，投藥後2到6小時間， 投予APAP/A SA/CA F藥學組成物的受測者未出 現噁心現象的比例，顯然比控制組高（P S 〇 · 〇 1 〇 ) (第三A圖）。 在匯整分析中同時顯示，投藥後1到6小時間，投予 APAP/A SA/CA F藥學組成物的受測者未出現畏 光與怕吵現象的比例，顯然比控制組高（P > 〇 . 〇 〇工 )(第二B圖與第二C圖）。 實施例八 安全評估結果 在前述的實驗中並未報告有任何嚴重的不良反應（ A E s )，而在三項實驗中的兩個治療組有a e s結果的 比例很低（2 % )且相類似（投予A P A P / A s A / C A F藥學組成物的受測者中佔χ 2 / 6 i 8，安慰劑治 療組爲1 1 / 6 3 2 ) ° —名安慰劑治療組受測者出現喱 吐與畏寒現象’因而自實驗二終止繼續。A e s大於1 % 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -30 - (請先閱讀背面之注意事項再填寫本頁)Six hours after dosing, 51% (306/602) of APAP / A SA / CA F pharmaceutical composition subjects were completely migraine-free, compared with 23% (145/6 18 in the control group). ) (P < 0.001, 95% Cl, 47%-5 5% in the APAP / ASA / CAF group, and 20%-27% in the control group) (Table 4). The average pain elimination score of the subjects administered the APAP / ASA / CAF pharmaceutical composition was significantly higher than that in the control group from 0.5 to 6 hours after each administration, except for the second one in experiment two. . Beyond 5 hours. Analysis of the power measurement data by the IT T population yielded consistent results. Example 5 Replenishment dose In the analysis, the subjects in the control group obviously need more doses than those in the APA p / ASA / CAF pharmaceutical composition 3 to 6 hours after administration (P < 0 · 0 0 1), for example, · Only 12 · 5% (7 5/602) of the APAp / ASA / CAF pharmaceutical composition received The tester needed additional drugs, while the control group had 27% (168/618) (P < 〇. 〇〇χ, 95% Cl, APAP / ASA / CAF group was 10%-1 5 %, The control group is 24%-31%). Example 6 I The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -27-~ '— 565447 Α7 Β7 V. Description of the invention (the overall evaluation of the furnace, whether it is the overall evaluation of the test subject and the experimental performer As a result, it was shown that the subjects who administered the APAP / A SA / CA F pharmaceutical composition had a significantly higher evaluation than the control group (P < 〇. 〇〇1), and the overall evaluation of the experiment performers was administered to APAP / A 51% of the SA / CAF pharmaceutical composition subjects were good or excellent, compared with only 20% in the control group (P < 〇 · 〇〇1, 95% CI, 4 in the APAP / ASA / CAF group 7%-5 5%, the control group is 17%-23%). Subjects have similar evaluation results. The effect of Example 7 on other migraine symptoms is to restore normal function (only a little or completely In the percentage of subjects who did not require extra effort to perform daily activities), the subjects who administered the APAP / ASA / CAF pharmaceutical composition were significantly higher than the control group. This result appeared in the pooling analysis (P < 0 · 001) For other experiments, 1 to 6 hours after administration (P · 0 〇6), and 0.5 hours after administration of Experiment 1 (P = 0 · 004) (second picture).-: ------ • Installation-(Please read the notes on the back before filling this page) Order t Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Standards apply Chinese National Standards (CNS) A4 specifications (210X297 mm) -28-565447 A7 B7 V. Description of invention (printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs nlq _ ^ _ u Z8I9 _ ^ _ ειτ—inch 9ε · _ ^ _ u 961Q _ ^^ s 1 III §ιω > (8δ = υ) (309 = u) ~ θηωιΛ ~ (9〇CNJI = U) (⑦ OCNIHU) ΘΠΙΒ > P ^ MS ~ (90CNI = U) ΦΠΙΒΛpl6 ¥ u) (Z8 ¥ sl a.siLL < o / vs < ^ in ^ < os < d sihll < o / vs < d iliiLL < o / vs < / dVdV / dVdV / dVdV / dvdv? M) _capsula_ 面 __J3 ^ __ Sound δο ν 6L 8ε § · > zi, 8ε 300 · os εε § · > 3-inch < • 001 < 001 < • 001 < 001 CO C0 ¥ CN 1〇⑦ IT) 〇CO Ο) < • 001 < 001 < • 001 < .001 < _001 56 < • 001 67 < • 001 73 < .001 76 CO < .001 59 < • 001 68 < .001 75 < .001 78 CO (D ίο LO 1〇S LO BU〇〇〇CM 00 CM C0 inch CD 1 ^^ 1Q0V _ ^ _ lllo1QQV _ ^ _ S 00 · > licvl_z inch loolv8ICNJ_5 9 1010 > Zl «50.VIIOI1T · "! 6ε§ · > 91, 6ICOI5191V 33 S inch 5〇. ≫ ιιηιειοιον 6 εε § > U 61CNJI50V 9rl9I Vllnl11CNJ1900 · 6 Z15Q > L 91CNII1CNJ1 so. Zllolso. 0 | 1011101 inch 3 · 々91 8 {Η · Icol9 ~ T colu. T ^ ^ δ 6CNIS0 · rj < 〇 6Z6. Ί ^ ^ --1 --------- -• Packing ---- ^ --- Order ------ ^ ~ (Please read the notes on the back before filling in this page) This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) ) -29-565447 Printed by A7 ____B7___ of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (V Although in Experiments 1 and 3, if the test subject has more than 20% of the test time, there will be Vomiting has been excluded from the experiment, but 60% of patients still have nausea at the origin. The percentage of nausea in subjects administered the APAP / ASA / CAF pharmaceutical composition was significantly lower than that in the control group, such as the time point of 1 to 6 hours in experiment three (P < 0.04), the experiment The time point of 3 to 6 hours in the first middle school (p ^ 〇 0 2 7), and the time point of 4 to 6 hours in the second middle school (ps 0.0 2 4). In the pooling analysis, the proportion of subjects who did not experience nausea in the APAP / A SA / CA F pharmaceutical composition 2 to 6 hours after administration was obviously higher than that in the control group (PS 〇 · 〇1 〇 ) (Third A). The pooling analysis also showed that the ratio of photophobia and noisy fear to subjects who were administered APAP / A SA / CA F pharmaceutical composition 1 to 6 hours after administration was obviously higher than that of the control group (P > 〇〇〇〇 工) (second B picture and second C picture). Example 8 The results of the safety assessment did not report any serious adverse reactions (AEs) in the previous experiments, and the proportion of aes results in the two treatment groups in the three experiments was very low (2%) and similar (Χ 2/6 i 8 of APAP / A s A / CAF pharmaceutical composition was administered to the subject, 1 1/6 3 2 in the placebo group) ° — One subject in the placebo group showed a gel The phenomenon of vomiting and chills' has therefore continued since the termination of experiment two. A e s is greater than 1% This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -30-(Please read the precautions on the back before filling this page)

'1T ♦ 565447 經濟部智慧財產局員工消費合作社印製 A7 _B7__五、發明説明（和 的機率是微乎其微且可預期的。會比安慰劑治療組出現較 高機率者有噁心（4 · 9 %對1 · 7 % )、緊張（4 · 4 %對0. 8%)、頭暈（2. 8%對1.1%)。有趣的 是，安慰劑治療組中出現嘔吐現象者比投予A P A P / A S A / C A F藥學組成物的受測者高：1 . 6 % ( 1 Ο /632)對 0.2%(1/618) ( Ρ = Ο . Ο Ο 1 )。在這些實驗中，無發現任何AEs與之前之單一劑量 之阿斯匹靈、補熱息痛、或咖啡因有所不同。 實施例九 在本實施例中，第五表表示投予 sumatriptan(Imitrex®，1 0 0 m g )與 APAP/ASA /CAF藥學組成物（2錠單位劑量中含：500mg APAP、500mg ASA，13〇mg CAF) ，在投藥後2、4、6小時的疼痛消除比較。第五表所顯 示的數據，爲如上所述在第三表顯示的實驗一、二、三所 匯整的投予A P A P/A SA/CA F藥學組成物的數據 ，而 sumatriptan(Imitrex®)的數據貝[J 摘自於 Physician’s Desk Reference ( P DR)，第 5 1 版，醫療顧問爲 R· Arky, MD,由紐澤西洲 Medical Economics Company, Inc. 於1997年出版，摘自第1099 - 1 103頁，與表 1，第1100頁。根據PDR所述，Imitrex®實驗設計 包括了兩項臨床控制實驗（實驗一與二），針對4 4 6名 偏頭痛病患中，有中度到重度頭痛、與一種或以上的噁心 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） _ 31 - (請先閲讀背面之注意事項再填寫本頁) 565447 A7 B7 五、發明説明（莽 、畏光或臨床失能的症狀者，以評估使用單一口服劑量的 Im it rex®之效果（Ibid·，第一表）。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局Μ工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -32 - 565447 經濟部智慧財產局員工消費合作社印製 A 7 B7 五、發明説明（弓〇 第5表:投予Sumatriptan(lmitrex®)錠與77/之APAP/ASA/CAF藥學組成物後，對偏 頭疼痛的消除功效'1T ♦ 565447 Printed by A7 _B7__ of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. The description of the invention (and the probability of the sum is very small and predictable. Those who have a higher probability than the placebo group have nausea (4.9% 1.7%), nervousness (4.4% vs. 0.8%), dizziness (2.8% vs. 1.1%). Interestingly, those who experienced vomiting in the placebo group received APAP / ASA / CAF pharmaceutical composition test subjects were high: 1.6% (10/632) to 0.2% (1/618) (P = Ο. Ο Ο 1). In these experiments, no AEs were found to be the same as before A single dose of aspirin, tonicol, or caffeine is different. Example 9 In this example, the fifth table indicates the administration of sumatriptan (Imitrex®, 100 mg) and APAP / ASA. / CAF pharmaceutical composition (contains 2 tablet unit doses: 500mg APAP, 500mg ASA, and 130mg CAF). Comparison of pain relief at 2, 4, and 6 hours after administration. The data shown in the fifth table are as above. The aggregated data for the APAP / A SA / CA F pharmaceutical composition administered in experiments one, two, and three shown in the third table are described, and sumatriptan (Imi trex®) [J from Physician's Desk Reference (P DR), 51st edition, medical consultant R. Arky, MD, published by Medical Economics Company, Inc., New Jersey, 1997, excerpted from 1099 -Page 1 103, and Table 1, page 1100. According to the PDR, the Imitrex® experimental design includes two clinical control experiments (Experiments 1 and 2), with a moderate severity of 4 46 migraine patients. For severe headaches and one or more types of nausea, the paper size of this paper applies the Chinese National Standard (CNS) A4 (210X297 mm) _ 31-(Please read the precautions on the back before filling this page) 565447 A7 B7 V. Description of the invention (For those with symptoms of recklessness, photophobia, or clinical insufficiency, to evaluate the effect of a single oral dose of Im it rex® (Ibid ·, Table 1). (Please read the precautions on the back before filling out this page) Ministry of Economic Affairs Printed on the paper by the Intellectual Property Bureau, M Industrial Consumer Cooperative, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -32-565447 Printed by the Intellectual Property Bureau Staff Consumer Cooperative of the Ministry of Economic Affairs A 7 B7 V. Description of the invention (bow. number 5 : After administration Sumatriptan (lmitrex®) and the ingot 77 / of the APAP / ASA / CAF pharmaceutical composition, for the partial elimination of head pain efficacy

Imitrex® 實驗1 淀 Imit「ex®i^ 實驗2 APAP/ASA/CAF 藥學組成物 控制組 100mg 控制組 100mg 控制組 100mg 2小時後結果 n=65 n=66 n=47 n=46 n=618 n=602 疼痛消除至〇_1級的 患者佔比0/1 26% 56% 17% 57% 33% 59% 完全無痛的患者佔比 4小時後結果 8% 23% 6% 24% 7% 21% 疼痛消除至〇_1級的 患者佔比0/1 38% 71% 19% 78% — 一 全無痛的患者佔比 6小時後結果 15% 52% 11% 41% — — 疼痛消除至0-1級的 患者佔比 — — — 一 52% 79% 全無痛的患者佔比 — — — — 23% 51% >位劑量:2錠中含有500mg補熱息痛、500mg阿斯匹靈、與I30mg另啡因。 (請先閱讀背面之注意事項再填寫本頁) 33- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇><297公釐） 565447 Μ _ Β7 五、發明説明（今1 (請先閲讀背面之注意事項再填寫本頁) 如第五表所述，在投藥後第二小時，投予sumatriptan (Imitrex®，1 〇 〇 m g )對疼痛消除的百分比類似於本發 明中投予單一劑量A P A P/A SA/CA F藥學組成物 的效果（sumatriptan : APAP/ASA/CAF 爲 5 6 % : 5 7%)，在投藥後二小時，患者覺得完全無痛的比 例在 sumatriptan 爲 2 3% 與 24%，而在 APAP/ A S A / C A F 組則爲 2 1 %，同樣的，在 sumatriptan 投藥後四小時，與A P A P / A S A / C A F投藥後6小 時，患者對疼痛消除的百分比分別爲7 1 % / 7 8 %與 7 9%。而對於疼痛完全消除的效果方面，在 sumatriptan 投藥後四小時爲5 2%與4 1%，而在APAP/ASA / C A F投藥後6小時爲5 1 %。 經濟部智慧財產局員工消費合作社印製 因此，根據本發明投予APAP/ASA/CAF藥 學組成物對減緩偏頭疼痛的效果，是類似於投予 1 0 Omg單一劑量sumatriptan的效果。此外，投予 APAP/A SA/CA F藥學組成物6小時後對偏頭痛 消除疼痛的效果，也類似於sumatriptan在投藥後四小時 的效果，這些證據來自於上述本發明之實驗與P D R所述 Imitrex®的硏究報告。 所有專利內容、專利申請、發表論文、專書、參考資 料等倂入本文爲參考資料者，都在下述文中有完整敘述。 在未偏離本發明的焦點與意義之下，上述主題中許多 變數可有所不同，因此，上述陳列於圖示、定義於所附專 利申請範圍者，將以描述與說明來闡述，而非採用限制性 本紙張尺度適用中國國家標準（CNS ) A4規格(210X 297公釐) :34 - 565447 經濟部智慧財產局W工消費合作社印製 A7B7 五、發明説明（的作法。根據上述技藝，本發明可以有多種修正與變動， 因此可知，在所附專利申請範圍中，本專利可較獨特描述 者，有不同的運用範疇。參考資料 1.Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States; relation to age, income, race, and other sociodemographic factors. JAMA 1992; 267:64-69. 2.Rasmussen BK, Breslau N. Migraine: Epidemiology. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headache. New York, NY: Raven Press; 1993:chptr. 22:169-173. 3 . S te wart Wf, Schecter A, Lipton RB . Migraine heterogeneity: disability, pain intensity, and attack frequence and duration. Neurology. 1994;44(suppl4):S24-S39. 4.Lipton RB, Stewart Wf. Migraine in the United States: A review of epidemiology and health care use. Neurology. 1993:43(suppl3):S6-S10. 5.Edmeds J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact for migraine and tension-type headache on lifestyle, consulting behavior and medication use: a Canadian population survey. Can J. Neurol Sci·1紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐Γ -35- (請先閲讀背面之注意事項再填寫本頁) 565447 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明（ 1993;20:131-137. 6. Lipton R B, Stewart WF. Medical consulation for migraine [abstract], Neurology. 1994;44(suppl2) :199. 7. Rasmussen BK, Jensen R, Olesen J. Impact of migraine on sickness, absence and utilization of medical services: a Danish population study. J Epidemiol Community Health. 1 992;46:443-446. 8. Micieli G. Suffering in silence. In: Edmeads J. Editor. Migraine: a brighter future. Worthing: Cambridge Medical Publication. 1 993:1 -7. 9. Lipton RB, Stewart WF, Celentano DD, Reed M. Undiagnosed migraine: A comparison of symptom-based and physician diagnosis. Arch Int Med. 1992;1 52:1273- 1 278. 10. Celentano DD, Stewart WF, Lipton RB, Reed ML. Medicaiton use and disability among migraineurs: a national probability sample survey. Headache. 1992;32:223-228. 11.Stang PE, Osterhaus JT, Celentano DD. Migraine: patterns of healthcare use. Neurology. 1994;44(suppl 4):S47-S55. 12.Gilkey SJ, Ramadan NM. Use of over-the-counter drugs in migraine. CNS Drugs. 1996;Aug 6(2):83-88. 13.Lipton RB, Newman LC, Solomon S. Over-the-counter medication and the treatment of migraine. Headache. 1994;34:547-548. 本紙張尺度適用中國國家標準（CNS ) a4規格（210X297公釐) -36 _ (請先閲讀背面之注意事項再填寫本頁) 565447 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明（弓4 14.Lipton R B, Solomon S Sheftell FD. Medical sonsultation for migraine: Results of the A AS H Gallup Survey. Headache. 535-563, 1995. 15 .Migliardi JR, Armellino J J, Friedman M, Gillings DB, Beaver WT. Caffeine as an analgesic adjuvant in tension headache. Clin Pharmacol Ther. 1994;56:576-586. 16.Laska EM, Sunshine A, Mueller F, Elvers WB, Siegel C, Rubin A. Caffeine as an analgesic adjuvant. JAMA. 1984;251:1711-1718. 17.Olesen J. A review of current drugs for migraine. J. Neurology. 1 99 1; 23 8(suppl 1):S23-S27. 18.Solomon GD. Therapeutic advances in migraine. J Clin Pharmacol. 1 993;33:200-209. 19.Stewart WF, Lipton RB, Population-based clinical trials in headache. Olesen J, Tfelt-Hansen, P, eds. Headache Treatment: Trials Methodology and New Drugs, New York, NY: Raven Press; 1997:65-70. 20.Headache Classificaiton Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1 988;8(suppl 7):1928. (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -37-Imitrex® Experiment 1 I Imit 「ex®i ^ Experiment 2 APAP / ASA / CAF Pharmaceutical Composition Control Group 100mg Control Group 100mg Control Group 100mg Results after 2 hours n = 65 n = 66 n = 47 n = 46 n = 618 n = 602 Percentage of patients with pain relief to level 0_1 0/1 26% 56% 17% 57% 33% 59% Totally painless patients accounted for 4 hours Results 8% 23% 6% 24% 7% 21% The proportion of patients with pain relief to level 0_1 is 0/1 38% 71% 19% 78% — The proportion of patients with no pain is 6 hours and the result is 15% 52% 11% 41% — — Pain relief to 0-1 The proportion of patients in the first grade — 52% 79% of patients with no pain — — — — 23% 51% > Dose: 2 tablets containing 500mg of acetaminophen, 500mg of aspirin, and I30mg (Please read the notes on the back before filling out this page) 33- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) 565447 Μ Β7. (Today 1 (Please read the precautions on the back before filling out this page) As described in Table 5, the percentage of pain relief after administering sumatriptan (Imitrex®, 1000 mg) two hours after administration Similar to the effect of administering a single dose of the APAP / A SA / CA F pharmaceutical composition in the present invention (sumatriptan: APAP / ASA / CAF is 56%: 57%), two hours after the administration, the patient feels completely painless The ratio was 23% and 24% in sumatriptan, and 21% in APAP / ASA / CAF group. Similarly, the patient's pain was eliminated four hours after the administration of sumatriptan and 6 hours after the administration of APAP / ASA / CAF. The percentages were 71% / 78% and 79%, respectively. For the effect of completely eliminating pain, it was 5 2% and 41% four hours after the administration of sumatriptan, and 6 after APAP / ASA / CAF administration. Hours are 5 1%. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Therefore, the effect of administering the APAP / ASA / CAF pharmaceutical composition according to the present invention on mitigating migraine pain is similar to the administration of a single dose of 10 Omg sumatriptan In addition, the effect of 6 hours after administration of APAP / A SA / CA F pharmaceutical composition on migraine pain relief is also similar to the effect of sumatriptan four hours after administration, these evidences come from the experiments and PDR described by Imitrex® Report on the Study. All patent contents, patent applications, published papers, monographs, reference materials, etc., incorporated herein as reference materials, are fully described in the following text. Many of the variables in the above subject matter may be different without departing from the focus and meaning of the present invention. Therefore, those listed in the diagram and defined in the scope of the attached patent application will be described and described instead of using Restriction This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm): 34-565447 Printed by A7B7, W Industrial Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs 5. Practice of the invention (according to the above techniques, the present invention There can be many amendments and changes, so it can be seen that in the scope of the attached patent application, this patent can be more uniquely described and has different applications. References 1. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States; relation to age, income, race, and other sociodemographic factors. JAMA 1992; 267: 64-69. 2. Rasmussen BK, Breslau N. Migraine: Epidemiology. In: Olesen J, Tfelt-Hansen P , Welch KMA, eds. The Headache. New York, NY: Raven Press; 1993: chptr. 22: 169-173. 3. Stewart Wf, Schecter A, Lipton RB. Migraine heterogeneity: disability, pain intensity, and attack frequence and duration. Neurology. 1994; 44 (suppl4): S24-S39. 4. Lipton RB, Stewart Wf. Migraine in the United States: A review of epidemiology and health care use. Neurology. 1993 : 43 (suppl3): S6-S10. 5.Edmeds J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact for migraine and tension-type headache on lifestyle, consulting behavior and medication use: a Canadian population survey. Can J. Neurol Sci · 1 paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm Γ -35- (Please read the precautions on the back before filling out this page) 565447 Staff of Intellectual Property Bureau, Ministry of Economic Affairs Printed by Consumer Cooperative A7 B7 5. Invention Description (1993; 20: 131-137. 6. Lipton RB, Stewart WF. Medical consulation for migraine [abstract], Neurology. 1994; 44 (suppl2): 199. 7. Rasmussen BK , Jensen R, Olesen J. Impact of migraine on sickness, absence and utilization of medical services: a Danish population study. J Epidemiol Community Health. 1 992; 46: 443-446. 8. Micieli G. Suffering in silence. In: Edmeads J. Editor. Migraine: a brighter future. Worthing: Cambridge Medical Publication. 1 993: 1 -7. 9. Lipton RB, Stewart WF, Celentano DD, Reed M. Undiagnosed migraine: A comparison of symptom-based and physician diagnosis. Arch Int Med. 1992; 1 52: 1273- 1 278. 10. Celentano DD, Stewart WF, Lipton RB, Reed ML. Medicaiton use and disability among migraineurs: a national probability sample survey. Headache. 1992; 32: 223-228. 11.Stang PE, Osterhaus JT, Celentano DD. Migraine: patterns of healthcare use. Neurology. 1994; 44 (suppl 4): S47-S55. 12.Gilkey SJ, Ramadan NM. Use of over-the-counter drugs in migraine. CNS Drugs. 1996; Aug 6 (2): 83-88. 13. Lipton RB, Newman LC, Solomon S. Over-the-counter medication and the treatment of migraine. Headache. 1994 ; 34: 547-548. This paper size applies to Chinese National Standard (CNS) a4 size (210X297mm) -36 _ (Please read the precautions on the back before filling this page) 565447 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs System A7 B7 V. Invention Ming (Bow 4 14. Lipton RB, Solomon S Sheftell FD. Medical sonsultation for migraine: Results of the A AS H Gallup Survey. Headache. 535-563, 1995. 15. Migliardi JR, Armellino JJ, Friedman M, Gillings DB, Beaver WT. Caffeine as an analgesic adjuvant in tension headache. Clin Pharmacol Ther. 1994; 56: 576-586. 16.Laska EM, Sunshine A, Mueller F, Elvers WB, Siegel C, Rubin A. Caffeine as an analgesic adjuvant. JAMA. 1984; 251: 1711-1718. 17.Olesen J. A review of current drugs for migraine. J. Neurology. 1 99 1; 23 8 (suppl 1): S23-S27. 18.Solomon GD. Therapeutic advances in migraine. J Clin Pharmacol. 1 993; 33: 200-209. 19. Stewart WF, Lipton RB, Population-based clinical trials in headache. Olesen J, Tfelt-Hansen, P, eds. Headache Treatment: Trials Methodology and New Drugs , New York, NY: Raven Press; 1997: 65-70. 20.Headache Classificaiton Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalal gia. 1 988; 8 (suppl 7): 1928. (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) -37-

Claims (1)

565447 A8 B8 C8 D8 六、申請專利範圍有效消除偏頭痛疼.痛劑量的捕熱息痛、阿斯匹靈、與咖啡 因的組合。 -- (請先閱讀背面之注意事項再填寫本頁) 、1T ·1 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) Α4規格（2】0Χ 297公釐） -39-565447 A8 B8 C8 D8 6. The scope of the patent application effectively eliminates migraine pain. Pain doses of thermal paracetamol, aspirin, and the combination of caffeine. -(Please read the notes on the back before filling out this page), 1T · 1 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is printed in accordance with the Chinese National Standard (CNS) Α4 specification (2) 0 × 297 mm)- 39-
TW087111152A 1997-07-14 1998-07-09 Use of compositions containing the combination of acetaminophen, aspirin and caffeine to alleviate the pain and symptoms of migraine TW565447B (en)

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