TWI313598B - Compositions of non-steroidal anti-inflammatory drugs, decongestants and anti-histamines - Google Patents
Compositions of non-steroidal anti-inflammatory drugs, decongestants and anti-histamines Download PDFInfo
- Publication number
- TWI313598B TWI313598B TW092135802A TW92135802A TWI313598B TW I313598 B TWI313598 B TW I313598B TW 092135802 A TW092135802 A TW 092135802A TW 92135802 A TW92135802 A TW 92135802A TW I313598 B TWI313598 B TW I313598B
- Authority
- TW
- Taiwan
- Prior art keywords
- ibuprofen
- pharmaceutical composition
- amount
- antihistamine
- decongestant
- Prior art date
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- 239000000739 antihistaminic agent Substances 0.000 title claims description 47
- 239000000850 decongestant Substances 0.000 title claims description 41
- 230000001387 anti-histamine Effects 0.000 title claims description 37
- 239000000203 mixture Substances 0.000 title claims description 12
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- 229940124581 decongestants Drugs 0.000 title description 10
- 229940125715 antihistaminic agent Drugs 0.000 title description 8
- 208000024891 symptom Diseases 0.000 claims description 50
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 39
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 37
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 22
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical group CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 17
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- Medicinal Preparation (AREA)
Description
1313598 玟、發明說明: 本申請案係請求在2002年12月18曰所槎由,g 疋甲之美國臨時 申請案第60/434,342號的利益,其全部内容係 令诉以引用的方式 併入本文中。 C發明所屬之技術領域】 鳘兒領域 本發明係關於治療過敏及感冒相關鼻炎夕越 樂學上改良 的劑量型式。 C先前技術3 10 IJlti 鼓除充血劑及坑组鐵胺 鼻炎係指鼻道的一種發炎性疾患。典型 士丄士 土W异炎症狀含 有打噴涕、鼻溢、鼻充血,以及鼻分泌物拇 a加。不治療鼻 15 2〇 k可能導至其它的疾患,包括f、眼睛及下㈣道的感染。
兩種口服藥品通常被用於治療鼻炎:解除充血劑及抗 組織胺。解除充血劑及抗組織胺於作用機制、.A «ο* » 及副作用上有所不同。通常習慣將這兩種、 未ασ結合使用甚 於可能單獨使用其中一種,以得到鼻炎更完 Α 罡的症狀減輕。 解除充也劑通常用於治療鼻炎,包括侗 ^ * … 麻育驗及脫經 貧上腺素的擬交感神經劑。這些藥劑的作 « F用马收縮鼻黏膜 内之血管並因此降低組織膨脹及鼻充血。 '、 啤除充血劑被發 現對恢復充★鼻道的開放度比抗組織胺為佳。鼻解除充灰 劑具刺激性。然而’解除充血劑可能產生神經質、不安及 失眠’特別若是在晚上服用。 5 1313598 組織胺為沿著鼻黏膜排列之細胞(肥大細胞)所釋放的 一中介物。當被釋放時,已知組織胺會與局部受體結合並 因此造成打噴洋、鼻癢、鼻黏膜膨脹及鼻分泌物增加。抗 組織胺可減輕這些影響,雖然相較於解除充血劑為不同的 5 機制。抗組織胺阻斷組織胺與鼻黏膜内組織胺受體的結 合。抗組織胺的副作用包括精神敏銳度的損傷及鎮靜作用。 結合解除充血劑及抗組織胺利用了兩種機制方法,且 已减不比單獨使用其中之一成份的治療對鼻炎症狀提供更 心整的減輕。近來’許多減輕感冒及過敏的產品皆含有兩 1〇者。合併解除充金劑及鎮靜性抗組織胺成一單一劑量單位 可平衡該成份的刺激性及鎮靜作用。然而,某些個體對該 解除充血劑或者該抗組織胺的敏感性不同。因此,某些個 體使用這些結合物會經歷興奮及/或鎮靜作用。 含有解除充血劑及鎮靜性抗組織胺之市售配方的範例 15 包括: 1. CHLOR-TRIMET〇ntm。含有4毫克之氯苯吼胺(鎧靜 性抗組織胺)及6〇毫克之假麻黃驗鹽類(刺激性解除充血劑) 的4小時過敏/解除充血劑,且其被建議每隔4至6小時服用(6 至I2歲以下孩童為該劑量的1/2)。 20 2. CHLOR-TRIMET〇NTm 〇 人士 e 主士 ^ iUJN 。含有8¾克之氯苯吼胺(鎮靜 性抗組織胺)及120毫克之假麻黃鹼鹽類(刺激性解除充血劑) 的12小時過敏/解除充灰劑,且其被建議每隔12小時服用⑽ 成人及12歲以上孩童); 3. BROMFED™。含右4念 ± 、6 # 毫克之溴本比胺(鎮靜性抗組織 6 1313598 胺)及60毫克之假麻黃驗鹽類(刺激性解除充血劑)的旋劑, 且其被建議每隔4至6小時服用(6至12歲以下孩童 的 1/2); ^置 4. BR〇MFED™。含有战克之鮮比胺(鎮靜性抗組 5織胺)及120毫克之假麻黃驗鹽類(刺激性解除充血劑)的勝 囊,且其猶議每隔12小時㈣(限成人及12歲以上孩童); 5. BENADRYL™。含有25毫克之鹽酸二苯胺明(鎮靜性 柷組織胺)及60毫{之假麻黃驗鹽類(刺激性解除充金劑)的 過敏解除充血劑錠劑,且其被建議在成人及12歲以上孩童 10每隔4至6小時服用,24小時内不超過4錠;及 6. TAVIST-D™。含有1J4毫克之富馬酸克雷滿汀 (clemastine fumarate)(鎮靜性抗組織胺)及75毫克之鹽酸苯 丙醇胺(刺激性解除充血劑)的錠劑,且其被建議每隔12小時 服用(限成人及12歲以上孩童)。 15 合併一種解除充血劑及一種非鎮靜性抗組織胺二者至 一單一劑量單位的配方已被商品化。該配方提供非鎮靜性 之優點時’其效力不及鎮靜性抗組織胺所提供的效力,特 別對於感冒所造成之鼻炎。 非類固醢抗發炎藥 20 非類固醇抗發炎藥(NSAIDS)因其止痛、抗發炎,及抗 發熱作用與不良副作用的低發生率,理想上適合使用於感 冒配方。含有非類固醇抗發炎劑之感冒配方的示範包括 Advil Cold and Sinus™、Motrin Cold and Flu™及Dristan Sinus™,分別含有200毫克布洛芬(ibuprofen)及30毫克假麻 7 1313598 對相同病患組別的核准劑量(例如, 孩),及核准的相同劑量型式(例如, 圓藥錠、控制釋放劑,等等)。 本發明的實施中,一通常熟習此 項技%者可使用任何 不用處方箋(OTC)或處方之一核准劑晷 里裂式的解除充血劑 及/或抗組織胺,減少其,例如,250/ 。-或更多,並和 一核准量(劑量)的一 NSAID共同投+ /達到減少副作用之 鼻炎的有效減輕。在一具體例中,太 女 本發明預期使用一或更 多的解除充血劑、止咳藥或抗纽織胺,其 10 、叱存在在'核准 劑$中之一量少於或等於約75%及 ,與該NSAID的 一量而定’該相應之NSAID以一樟進故也 θ . ^ 、強度劑量型式約100% 的里存在。一供選擇的範圍從約1〇 I約65°/。。其它的範圍 從約30%至約55%。範圍也有可能從約至約 15 當本發明預期組成物含有所有= m , ~檀成份(例如,解除充 血劑 '抗組織胺及NSAID),與該解险古丄 ^ 唧于、充血劑或抗組織胺, 或兩者’相對於市面上常見的〇Tc解除 螂丨示充血劑及/或抗組織 20 成人對成人或小孩對小 、錠劑、膠囊、糖 ㈣品以較低量存在時,便可藉由減少市面上常見之抗組 織胺及/或解除充血劑的產品劑量來容易的達到本發明,在 它們與含有-標準的—NSAm產品—起投予時。此等 減少可藉由將-成人劑量切分—半來達成,例如,投予一 半量的糖渡或將-錠劑切成—半,或藉由使用_減少的劑 ,型式,諸如為孩童配製的一解除充血劑及/或抗組織胺產 品’其為結合一核准劑量之NSAID的成人配方。 抗組織胺 11 1313598 該名詞“抗組織胺”,其與用來治療過敏或感冒相關之 鼻部症狀有關,通常意指組織胺印受體拮抗劑。已知許多 化學物質具有組織胺Hi受體括抗劑活性。許多有用的化合 物可被分類為乙醇胺、乙二胺、烷基胺、硫二苯胺或呱啶。 5 典型的受體拮抗劑,包括,不限制為:阿司σ米峻 (astemizole)、阿札他定(azatadine)、阿斯拉汀(azelastine)、 阿伐斯汀(acrivastine)、溴苯比胺、氯苯吡胺、克雷滿汀 (clemastine)、苯甲、卡瑞斯汀(carebastine)、賽庚啶 (cyproheptadine)、卡比諾沙明(carbinoxamine)、迪卡波伊辛 10 諾那他定(descarboethoxyloratadine)(也已知為 SCH-34117)、地洛他定多西拉敏(desloratadine doxylamine)、二曱茚定(dimethindene)、伊巴斯汀 (ebastine)、依匹斯汀(epinastine)、乙氟利嗪(efletirizine)、 非索非那丁(fexofenadine)、經嗪(hydroxyzine)、酮替芬 15 (ketotifen)、氣雷他定(loratadine)、左卡巴斯汀 (levocabastine)、咪唑斯汀(miz〇iastine)、美喹他嗪 (mequitazine)、米安色林(mianserin)、諾貝斯汀 (noberastine)、虱苯甲〇秦(meciiz{ne)、去甲阿司味哇 (norastemizole)、皮可斯特(picurnast)、π比拉明(pyrilamine)、 2〇 異丙喚(Pr〇methazine)、特非那定(terfenadine)、曲。比那敏 (tripelennamine)、替美斯汀(ternelastine)、三甲丙咪嗪 (trimeprazine)及曲普利σ定(tripr〇iidine)。其它化合物可容易 的藉由已知的方法評估以決定其在Hl受體的作用,包括對 分離的天竺鼠迴腸中之組織胺收縮反應的特定阻斷。 12 1313598 NSAIDs 本發明之藥學組成物及使用方法所使用的非類固醇抗 發炎藥(NSAID’s)可選自以下任何類型: (1)該丙酸衍生物; 5 (2)該醋酸衍生物; (3) 該芬那酸衍生物; (4) 該鄰苯基苯甲酸衍生物; (5) 該昔康類(oxicams),及 (6) Cox-2抑制物 10 因此,於此所使用之該名詞“NSAID”任何非類固醇抗 發炎化合物,由此所包括藥學上可接受的無毒性鹽類,屬 於上述六種結構類型其中之一。 本發明所使用之屬於前述非類固醇抗發炎藥定義的該 特定化合物,已被熟習此項技藝者所熟知,並且其有關的 15 化學結構、藥學作用、副作用、標準劑量範圍等等之參考 可在數種文獻參考來源中找到。例如,醫生桌上參考手冊 (Physician’s Desk Reference)及默克索引。 在此所使用之丙酸衍生物中,布洛芬、奈普生、氟比 洛芬(flurbiprofen)、菲諾洛芬(fen〇profen)、酮布洛芬 20 (ketoprofen)、舒洛芬(suprofen)、芬布芬(fenbufen)和氟洛芬 (fluprofen)可作為示範化合物。在該醋酸衍生物中,示範的 化合物包括托美汀鈉(tolmetin sodium)、佐美酸 (zomepirac)、舒林酸(sulindac)及弓I朵美酒辛 (indomethacin)。在該芬那酸衍物中,示範的化合物包括美 14 1313598 芬那酸(mefenamic acid)及曱氯芬那酸鈉(mecl〇fenainate sodium)。本發明中使用之示範的鄰苯基苯甲酸衍生物包括 二氟尼柳(diflunisal)及氟芬尼柳(flufenisai)。示範的昔康類 (oxicams)包括匹洛西卡(piroxicam)、舒多昔康(Sud〇xicam) 5及伊索昔康(isoxicam)。示範的Cox-2抑制物包括希樂葆 (celecoxib)、羅非昔布(rofecoxib)、美洛昔康(meloxicam), 及尼美舒利(nimesulide)。前述之非類固醇抗發炎藥,在本 發明實施中示範的具體例,以布洛芬來示範。 有關本發明組成物内該非類固醇抗發炎藥的劑量的 10量,雖然特定劑量會依病患的年齡及體重、症狀的嚴重性、 副作用及其相似作用的發生而有所不同,對人類,NSAID 的典型有效止痛量為約100_500毫克之二氟尼柳 (difUmisal)、約25-100毫克之佐美酸鈉(z〇mepirac s〇dium)、 約50-400毫克之布洛芬,更佳的為1〇〇_2〇〇毫克之佐美酸 15鈉、約10-20毫克之奈普生(naproxen)、約125-250毫克之美 非那fit、約100-400毫克之芬布芬(fenbufen)或約25_5〇毫克 之酮布洛芬(ketoprofen);然而,若想要或有需要,可使用 較多或較少的量。 抗咳嗷劊 20 抗咳嗷劑作用於頭腦以抑制咳嗽反射。此咳嗽抑制物 被使用來減輕持續性的乾咳。最常用的藥物為右美沙芬 (dextromethorphan)(—種NMDA受體拮抗劑),可待因 (codeine)和福可汀(pholcodine)(其為鴉片類藥物)。然而,熟 習此項技藝者會瞭解可使用許多其它已被熟知及常見的抗 15 1313598 咳嗽劑。本發明選擇性的針對使用抗咳嗽劑。該抗咳嗷劑 可以較核准劑量少於或等於75%的使用量。 藥學組成物 本發明組成物以單一劑量型式配製,且其可能為固體 5 (諸如錠劑、膠囊、小袋、片劑及其相似物)、液體(諸如溶 液或懸浮液)或吸入性煙霧劑或貼片。當該固體化合物典型 地以口服投予,該液體可被口服或注射投予。其它劑量型 式,諸如栓劑,也是有用的。 本發明作為示範的組成物係針對固體型式,諸如散裝 10 粉末、錠劑、橢圓藥錠、藥丸、膠囊、小袋、顆粒,及任 何適合口服投予的劑量型式。為了此規格及伴隨申請專利 的用途,該名詞“錠劑”同樣意指一錠劑、一橢圓藥錠或任 何其它適合口服投予的固體劑量型式。 黏結劑為用來給予粉末原料凝聚特性的物質。黏結劑 15 給予錠劑配方凝聚性以確保該錠劑在壓縮後仍保持完整, 且藉由形成所欲之硬度及大小的顆粒來增進其自由流動的 特性。合適的黏結劑原料包括,但不限制於,澱粉(包括玉 米澱粉及前明膠澱粉)、明膠、糖類(包括蔗糖、葡萄糖、右 旋糖、乳糖及山梨醇)、聚乙二醇、臘、自然及合成的樹脂, 20 例如,阿拉伯樹膠、特拉加康斯樹膠、褐藻酸鈉、纖維素, 及矽酸鋁鎂,及諸如丙稀酸酯與聚乙烯吡咯烷酮的合成聚 合物。 潤滑劑在錠劑製造上有許多功能。它們預防錠劑原料 黏著至鋼模及穿孔機,減少顆粒間的摩擦,增進錠劑從鋼 16 泠病患、複合劑量、安慰劑控制的、雙盲的、雙類比的、 平行小組、隨機的試驗。 病患選擇。該研究納入1070位適當選擇的病患,其至 少為12歲並同時包括男性及女性。研究參與者被要求具 5有:(1)至少二年病史之季節性過敏性鼻炎(其包含—或更多 以下症狀,流鼻水、眼睛發癢/流淚/發紅、鼻充血、打喷涕、 鼻/喉觉/顎發4、過敏相關之頭痛及臉部疼痛/壓迫/不舒服) 及(2)經歷至少中度的頭痛,及/或臉部疼痛/壓迫/不舒服的 一病史,其在過敏季節期間惡化且對不用處方箋(〇tc)的止 ίο痛藥有反應(基於自我報告)。合格的個案被要求接受 天的一預備期以確定該病患有足夠嚴重的過敏症狀在此 期間於早晨(醒來時)和晚上(就寢前)評估他們以下反應症 狀的嚴重程度:鼻充企、打噴洋、鼻溢、鼻/喉嚷/韻發疼、 眼睛發癢/流淚/發紅和頭痛/臉部疼痛/壓迫/不舒服。每個症 15狀的嚴重性利用一種4點絶對級別來評估,其中0=無(無症 狀呈現)、1=輕微(最小察覺到症狀,症狀容易忍受卜2=中 等(症狀呈現且擾人,但可忍受)及3=嚴重(症狀難以忍受; 可能造成日常活動/_的干擾)。他們也被要求若該疼痛為 一頭痛或臉部疼痛/壓迫/不舒服時,需將該疼痛從〇=無(無 20症狀呈現)、1=輕微(最小察覺到症狀,症狀容易忍受)、2= 中等狀呈現且擾人,但可忍受)和3=嚴重(症狀難以忍 文,玎肊迨成日常活動/睡眠的干擾)分級。當病患經歷至少 中等強度之過敏相關疼痛’並在前六個早晨及晚上的症狀 嚴重度5平估為總和反應過敏症狀評分的至少48分,病患被 19 1313598 投予第-劑量之研究藥物(第!天)。如果他們正在疼痛中, 也對病患的過敏相關之疼痛進行評估及詢問。 本研究所納入及包括在安全性分析的1〇7〇位個案中, 有1044位個案有資格進行傾向治療分析,且在這1〇44位病 5患中,256位接受第1治療法;265位接受第2治療法;266位 接受第3治療法,及257位接受第4治療法。以下為該治療法 的說明。此外1032位病患被包括在修改的傾向治療分析。 劑量組成物。本研究之病患被隨機分配至四個治療 組。第1治療法包含1安慰劑錠劑加上2橢圓藥錠之布洛芬/ 10假麻黃鹼/氯苯°比胺(每橢圓藥錠分別為200/30/2毫克)至一 每6小時總劑量為400/60/4毫克的布洛芬/假麻黃鹼/氯苯。比 胺。第2治療法包含每6小時1安慰劑錠劑、1安慰劑橢圓藥 錠加上1橢圓藥錠之布洛芬/假麻黃鹼/氣笨吡胺(每橢圓藥 錠分別為200/30/2毫克)。第3治療法包含每6小時1錠劑之假 15 麻黃鹼/氯苯吡胺(每錠劑分別為30/2毫克)加上2安慰劑橢 圓藥錠。第4治療法包含每6小時1安慰劑錠劑和2安慰劑橢 圓藥疑。 劑量時間和症狀監測。該病患大約每天3次每6小時投 藥(早晨、中午及晚上)超過7天直到總共19-21劑。在服用第 2〇 一劑後第二和第三小時,以一種4點級別來評估該病患之過 敏相關疼痛的嚴重性,〇=無(無症狀呈現)、1=輕微(最小察 覺到症狀,症狀容易忍受)、2=中等(症狀呈現且擾人,但可 忍受)和3=嚴重(症狀難以忍受;可能造成日常活動/睡眠的 干擾)。在每一次接下來投藥之前,病患指出他們是否正經 20 1313598 歷任何過敏相關的頭痛及/或臉部疼痛/壓返/不舒服(要求回 答是或不是)。在第1天晚上(就寢前)及每個早晨(醒來時)和 第2-7天的晚上,該病患自我評估以下過敏症狀的嚴重性: 鼻充血、打噴涕、鼻溢、鼻/喉嚨/顎發癢、眼睛發癢/流淚/ 5發紅及與過敏相關的頭痛及/或臉部疼痛/壓迫/不舒服。每 一症狀的嚴重性利用一種4點絶對級別來評估,其中〇==無 (無症狀壬現)、1=輕微(最小察覺到症狀,症狀容易忍受)、 2-中專(症狀呈現且擾人,但可忍受)和3=嚴重(症狀難以忍 受;可能造成曰常活動/睡眠的干擾)。在第7天晚上,完成 10過敏症狀評估後,個案們提供該研究藥物的一全面性評 估’以〇(差)至4(很好)的級別對該過敏症狀的治療作分級。 此外,該病患評估在這7天研究藥物期間任何他們曾經歷過 的負面經驗。該病患以輕微、中等或嚴重來評估該負面經 驗。負面經驗的範例包括,但不限制於,困倦、口乾、頭 15昏眼花,及失眠症。 評估標準。該主要效力參數為在這7天内從基礎線變化 的量,全部平均反應總症狀的評分。第二效力參數包含關 鍵變項:(1)該研究第一次投藥後在第二和第三小時之疼痛 強度差異評分的時間加權總合;(2)從&礎線變化的全部平 20均反應總抗組織胺症狀評分(打噴涕、眼睛發癢/流淚/發 紅、鼻/喉嚨/顎發癢)減去該全部平均反應總症狀評分;(3) 前投藥過敏相關疼痛的發生(基礎線測量除外)(4)從基礎線 變化的每-治療天之平均總反應症狀評分(5)該研究藥物的 全部評估。 4 21 1313598 統計分析。所有分析係使用SAS第6·12版執行。症狀減 輕的開始係被定義為一個案經歷在總症狀評分中從基礎線 減少215%的該第一時間點。如果一個案在整個研究過程中 沒有經歷從基礎線減少215%,開始的時間會被審查且被指 5 派至—7天的評分。如果在治療組別間的隨機發生機率為 S0.05則宣告在統計學上有顯著的治療差異。如果在治療組 別間隨機發生機率為0·05<ρ^0.15或觀察到在治療組別間的 差異至少為10%,則宣告有統計學上的趨勢。其它合適的 統計學方法被熟習此項技藝者適當的應用來証實該研究。 10 所有自基礎線改變的變項經由一ANOVA模式分析,包 括對治療的效果、對應的基礎線和中心。此外,評估以基 礎線治療與以中心治療的相互影響效果。前投藥過敏相關 疼痛(基礎線除外)之發生經由一重覆測量邏輯模式分析。該 模式經由廣義估計方程式與可變的相關結構來配合。該研 15 究藥物評分的全部評估是藉由Cochran-Mantel-Haenszel檢 驗、中心控制來分析,使用修改的ridit評分。此外,使用擬 同質性檢驗計算該中心治療的相互影響。使用Kaplan-Meier 估計法來估計症狀減輕開始時時間的分佈;以Simon and Lee方法導出中間時間及它們95〇/0的信賴極限。 2〇 對每個經由ANOVA模式分析的參數,該治療差異的 95%信賴區間係基於最小平方法及對應標準誤差之差異所 導出。對於每配對聰明治療差異的過敏相關疼痛及症狀減 輕開始時間之發生的95%信賴區間,係基於對數勝算比率 及對數危害比率,及它們分別對應的標準誤差(基於Wald檢 22 1313598 驗)。對該研究藥物全部評估之該治療差異的信賴區間是基 於Goodman-Kruskal Gamma統計量及其標準誤差。 效力結果。全部1044位病患被納入且服用至少一劑量 的研究藥物。全部957位病患完成該研究。全部1〇44位病患 5被包括在所有效力變項的分析,保留該疼痛強度差異的時 間加權總和,其中1032位病患被評估。 在效力變項的分析中,以基礎線治療及以中心治療的 相互影響效果被發現在變項間一般為不顯著(p>〇 1}。個體 反應症狀的該基礎線平均值分別為鼻充血2_3、打噴涕丨.7、 1〇流鼻水2_〇、鼻/喉嚨/顎發癢2.0、眼睛發癢/流淚/發紅2 〇及 頭痛/臉部疼痛/壓迫/不舒服2.3。該平均反應症狀評分及該 平均總反應抗組織胺評分在基礎線分別為1221及571。當 給予病患該研究藥劑的第一劑量時,在1〇32位病患中之個 案,是s平估其疼痛強度差異的時間加權總和,該過敏相關 15疼痛有49%被列為中等及51%被列為嚴重。幾乎所有個案 (9 9.6 %)在服用該研究藥物的第一劑量時都曾經歷過敏相 關的疼痛。有關上述基礎線變項,該治療組別可如同該基 礎線個體反應症狀一樣比較。 該主要效力參數及關鍵第二參數的結果強調第i治療 20法和第2治療法(較低劑量)可得到比第3治療法(無布洛芬) 和第4治療法(完全安慰劑)顯著較好的結果。 第1治療法及第2治療法組別之病患疼痛強度差異超過 3小時的時間加權總合為2.8。第3治療法及第个冶療法的評 分分別為2.1及2.0。第1-4治療法從基礎線平均改變之全部 23 1313598 平均反應總症狀評分分別為5·6、5_4、4_6 ’及3.8。治療級 別從基礎線的平均改變之舊有全部總反應抗組織胺症狀評 分分別為2.9、2.8、2.4及L9。 因此第2治療法組別之該病患在經歷疼痛強度差異超 5 過3小時的時間加權總和增進33%,且在從基礎線平均改變 之全部平均反應總症狀評分比第3治療法組別(無布洛芬)增 進17%。第2治療法組別的該病患也經歷比第4治療法組別 從基礎線的平均改變之舊有全部總反應抗組織胺症狀評分 增進47%。當第1治療法組別在對於所有過敏症狀及組織胺 10引致症狀之數據上有較佳的共同評分顯示,一統計學趨勢 無法被確立。此外第1治療法及第2治療法組別在疼痛強度 差異的時間加權總合擁有幾乎同樣的評分。 該結果顯示2毫克劑量的氯苯吡胺作為一抗組織胺是 足夠的,因它在減輕組織胺引致症狀比安慰劑有效报多。 15同樣也證實第1治療法組別較第2治療法組別病患的困倦増 加。 結論。本研究的結果顯示所給予之布洛芬/假麻黃鹼/ 氯笨吼胺劑量比單獨相關的解除充血劑及抗組織胺治療之 測試症狀有顯著的止痛/解除充血劑/類抗組織胺的效力。意 2〇外的發現布洛芬在該結合物中所貢獻的全部效果不但減輕 過敏相關疼痛且降低其它季節性過敏性鼻炎症狀的嚴重 性。此由第2治療法(其含有布洛芬)較第3治療法(其不含布 洛芬)有全純㈣料—。也料的魏_布洛芬/ 假麻黃鹼/氣苯吼胺(總量分別為侧_及2〇_2毫克)的 24 1313598 劑量在減輕季節性過敏性鼻炎的組織胺引致症狀同 樣有 效。此外,在第1治療法及 的劑量反應。 第2治療法組別間沒有見到明顯 所有治療法皆可忍受且與含有同樣劑量之假麻黃驗及 5 氯苯吡胺類似藥物所報告的負面經驗發生一致。該提議之 布洛芬/假麻黃驗/氣苯°比胺劑量為每4至6小時1橢圓藥錠^ 24小時期間内不超過6橢圓藥錠-因為兩種i/p/c劑量都同樣 有效且證明2-橢圓藥錠I/P/C劑量相對於1_橢圓藥錢劑量發 生較多的困倦、口乾及無力感。此種劑量將允許該產品在 10就寢前及/或在夜間服用(除了白天的劑量),並與核准之布 洛芬OTC的每日劑量(1200毫克)一致,且仍較假麻黃鹼(24〇 毫克)及氯苯《比胺(24毫克)的專著每日劑量為低。 木氺氺 本發明之範圍係非限制於在此所描述的特定實施例。 15當然,除了該等在此所描述的實施例,本發明的不同改良 對熟習此項技藝者將由前面的描述及隨附的圖式,而變得 明顯。此等改良因此係'落在後述之中請專利範_範圍内。 、上面提及的所有專利、中請案、文章、發表,和檢驗 方法係以引用的方式併入本文中。 20 【闽式簡單說明】 (無) 【圖式之主要元件代表符號表】 25
Claims (1)
1313598公告本ί 第092135802號專利申請案申請專利範圍修正本98.01.22 申請專利範圍: 1. 一種包含各有效量之(a)布洛芬、(b)解除充血劑及(c)抗 組織胺的藥學組成物,其中,相對於該布洛芬的量係對 應於一該布洛芬之標準強度核准劑量形式存在量的 5 100%,該解除充血劑或該抗組織胺或兩者的有效量係 少於或等於該解除充血劑或該抗組織胺或兩者之核准 劑量中存在量的約75%且大於1%。 2. 如申請專利範圍第1項之藥學組成物,其中各該解除充 血劑及抗組織胺係以少於75%且大於1%之該核准劑量 10 存在。 3. 如申請專利範圍第1項之藥學組成物,其中各該布洛 芬、解除充血劑及抗組織胺之核准劑量為一成人劑量。 4. 如申請專利範圍第1項之藥學組成物,其中該解除充血 劑或該抗組織胺或兩者之有效量係約核准劑量存在之 15 量的50%。 5. 如申請專利範圍第1項之藥學組成物,其中該布洛芬的 量為200毫克。 6. 如申請專利範圍第1項之藥學組成物,其中該解除充血 劑為假麻黃驗。 20 7.如申請專利範圍第1項之藥學組成物,其中該抗組織胺 為一組織胺受體拮抗劑。 8. 如申請專利範圍第7項之藥學組成物,其中該組織胺氏 受體枯抗劑為氯苯π比胺。 9. 如申請專利範圍第1項之藥學組成物,其型式為錠劑、 26 1313598 片劑、分散劑、懸浮液、溶液、糖漿、膠囊或貼片。 10.如申請專利範圍第1項之藥學組成物,其進一步含有至 少一賦形劑,該賦形劑係選自由潤滑劑、分解劑、滑動 劑、吸收劑,及其混合物所構成之組群。 5 11. 一種含有以下活性成份之組合的藥學組成物: (a) 每劑量單位之約10至約60毫克的假麻黃鹼鹽 酸鹽; (b) 每劑量單位之約1至約4毫克的氯苯吼胺馬來 酸鹽;及 10 (c)每劑量單位之約200至約400毫克的布洛芬; 其中相對於各核准劑量,該假麻黃鹼或氯苯°比胺或 兩者對布洛芬之量的比例為少於或等於約0.75:1且大於 0.01:卜 12. 如申請專利範圍第11項之藥學組成物,其中每劑量單位 15 之假麻黃鹼之量範圍係約20至約45毫克。 13. 如申請專利範圍第11項之藥學組成物,其中每劑量單位 之氯苯°比胺之量範圍係約1至約3毫克。 14. 如申請專利範圍第11項之藥學組成物,其中每劑量單位 之布洛芬之量約200毫克。 20 15.如申請專利範圍第11項之藥學組成物,其中每劑量單位 之假麻黃鹼及布洛芬的量,以毫克計,係選自由(i)30毫 克假麻黃驗、200毫克布洛芬及(ii)60毫克假麻黃驗、400 毫克布洛芬所構成之組群;且氯苯°比胺劑量為2毫克。 16.如申請專利範圍第11項之藥學組成物,其中每劑量單位 27 1313598 之氯苯吡胺及布洛芬的量,以毫克計,係選自由(i)2毫 克氯苯°比胺、200毫克布洛芬及(ii)4毫克氣苯吼胺、400 毫克布洛芬所構成之組群;且假麻黃驗劑量為30毫克。 17. 如申請專利範圍第11項之藥學組成物,其中每劑量單位 5 之假麻黃驗、鼠苯π比胺,及布洛分的置,以宅克計,係 選自由(i)30毫克假麻黃鹼、2毫克氣苯吼胺、200毫克布 洛芬及(ii)30毫克假麻黃鹼、2毫克氯苯吡胺、400毫克 布洛芬所構成之組群。 18. 如申請專利範圍第11項之藥學組成物,其型式為為一錠 10 劑、片劑、分散劑、懸浮液、溶液、糖漿、膠囊或貼片。 19. 如申請專利範圍第18項之藥學組成物,其型式為一錠 劑。 20. 如申請專利範圍第18項之藥學組成物,其型式為一膠 囊。 15 21.如申請專利範圍第18項之藥學組成物,其型式為一糖 漿。 22.如申請專利範圍第11項之藥學組成物,其進一步含有至 少一種賦形劑,該賦形劑係選自由潤滑劑、分解劑、滑 動劑、吸收劑,及其混合物所構成之組群。 20 23. —種使用 (a) —對抗組織胺之有效量的抗組織胺; (b) —解除充血之有效量的解除充血劑; (c) 一抗發炎之有效量的布洛芬 於製造一用於減輕哺乳動物之鼻炎症狀之藥物的用 28 1313598 途, 其中,相對於以相同劑量形式存在之該布洛芬的量 係對應於一該布洛芬之標準強度核准劑量形式存在量 的100%,該解除充血劑或該抗組織胺或兩者的有效量 5 係少於或等於該解除充血劑或該抗組織胺或兩者之核 准劑量中存在量的約75%且大於1%,且其中該抗組織 胺、該解除充血劑及布洛芬係以一單一劑量形式存在。 24. —種包含各有效量之(a)布洛芬、(b)解除充血劑、(c) 抗組織胺及(d)抗咳嗷劑的藥學組成物,其中,相對於該 10 布洛芬的量係對應於一該布洛芬之標準強度核准劑量 形式存在量的1 〇〇% ’ 一或多個該解除充血劑或該抗組 織胺或該抗咳嗽劑的有效量係少於或等於該解除充血 劑、該抗組織胺或該抗咳漱劑之核准劑量中存在量的約 75%且大於1%。 15 25. —種製備藥學組成物的方法,該方法包含:摻合治療上 各有效量之(a)布洛芬、(b)解除充血劑及(c)抗組織胺, 其中,相對於該布洛芬的量係對應於一該布洛芬之標準 強度核准劑量形式存在量的1 〇〇%,該解除充血劑或該 抗組織胺或兩者之有效量係少於或等於該解除充血 20 劑、該抗組織胺或兩者之核准劑量中存在量的75%且大 於1%。 29
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ZA200504908B (en) | 2006-12-27 |
NZ540289A (en) | 2006-10-27 |
RU2005122403A (ru) | 2006-01-20 |
EP1572206B1 (en) | 2014-04-23 |
AU2003301188A1 (en) | 2004-07-14 |
AU2003301188B2 (en) | 2009-07-02 |
CN102406642B (zh) | 2013-04-03 |
WO2004056320A3 (en) | 2004-09-23 |
PT1572206E (pt) | 2014-06-12 |
CA2508611A1 (en) | 2004-07-08 |
CO5640087A2 (es) | 2006-05-31 |
HK1166602A1 (en) | 2012-11-02 |
PE20040973A1 (es) | 2004-12-14 |
CN1726035A (zh) | 2006-01-25 |
ES2468217T3 (es) | 2014-06-16 |
HK1078494A1 (zh) | 2006-03-17 |
PE20081072A1 (es) | 2008-08-15 |
RU2322262C2 (ru) | 2008-04-20 |
EP1572206A4 (en) | 2007-07-18 |
TW200413004A (en) | 2004-08-01 |
EP1572206A2 (en) | 2005-09-14 |
MXPA05006331A (es) | 2005-08-26 |
CN102406642A (zh) | 2012-04-11 |
CA2508611C (en) | 2011-07-26 |
WO2004056320A2 (en) | 2004-07-08 |
AR042543A1 (es) | 2005-06-22 |
CL2003002653A1 (es) | 2005-04-22 |
JP2006515299A (ja) | 2006-05-25 |
US20040186184A1 (en) | 2004-09-23 |
US7863287B2 (en) | 2011-01-04 |
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