1243061 五、發明說明（1) 發明係有關一種包含兩個不同節段之錠劑。特別本發 明係關於兩種醫藥物質的組合以及過敏病症之治療方法。 2-[2-[4-[(4-氯苯基）苯甲基]-1-哌阱基]乙酸也稱做哂 得力畊（cetirizine)及其二鹽酸鹽由美國專利第4,525,358 號爲已知，該案也揭示其抗組織胺性質。該化合物具有 有用之藥理性質。特別可用做抗過敏劑、抗組織胺劑、 支氣管擴張劑及抗痙攣劑。 若干文獻也揭示於人體使用藥物之特定液體異構物治 療病症同時避免相對應之外消旋混合物之相關不良反應 。特別國際專利申請案公告號碼WO 94/06429及WO 9 4/0 6430，揭示於人體治療由於嗜伊紅血球增多或嗜伊 紅血球功能加強所引發或促成的疾病，該方法包含對需 要嗜伊紅血球治療病人投予定量（+)哂得力畊（另外（-)哂 得力畊）或其醫藥可接受性鹽，其實質上不含其（-)立體 異構物（另外不含其（+)立體異構物），及用量係足夠該 改善嗜伊紅血球增多或嗜伊紅血球功能加強，但不足以 引發不良影響。 它方面，化合物假麻黃素眾所周知爲擬交感神經作用 藥物，已知爲有效緩解鼻塞之安全治療劑。 熟諳技藝人士也眾所周知組合用藥需審慎，原因在於 組合用藥相當容易於人體誘發無法預測的不良影響。於 某些病例，組合用藥引發治療效果低於單獨投予個別藥 物。 治療過敏病症例如花粉引起之過敏性鼻炎-結膜炎時 1243061 五、發明說明（2) ，當組合抗組織胺劑及解充血劑時需審慎，其原因在於 組合用藥不僅提高整體治療效果，亦即整個治療期間打 噴嚏、流鼻水、鼻塞、流淚、鼻及眼搔癢等症狀不存在 或最微弱的日數百分比提高，同時也可避免例如失眠、 頭痛等不良影響。 有鑑於治療人體之多種病症，若干專利申請案已經揭 示藥物以特定用量做二元及/或三元組合。特別，英國 專利2 3 1 1 9 4 0及歐洲專利申請案〇 8 1 1 3 7 4揭示一種包 含哂得力畊及假麻黃素之醫藥組成物；美國專利6，1 71，6 18 揭示一種劑型，其含有哂得力哄做爲即刻釋放組成分以 及假麻黃素做爲控制釋放組成分，部份假麻黃素可攙混 爲即刻釋放組成分。 特別，國際專利申請案WO 9 8/41 194揭示一種醫藥組 成物，其可經口投藥，允許即刻釋放第一活性物質以及 長期釋放同一活性物質或第二活性物質，該醫藥組成物 包含： A. 至少一層包含活性物質及賦形劑，該賦形劑允許 該活性物質於投藥後即刻釋放，以及 B. 至少一第二層，其允許控制釋放同一活性成分或第 二活性成分，此層爲一種醫藥組成物，相對於組成 物總重，包含5至60%重量比至少一種賦形劑，該 賦形劑係選自惰性基質、親水基質、脂質基質、惰 性基質與脂質基質混合物、親水基質與惰性基質混 合物；以及相對於組成物總重，5至50%重量比至 1243061 五、發明說明（3) 少一種於生理pH條件下可溶於水相之鹼化劑。 由於存在有鹼化劑，故此種組成物證實有良好安定性 態樣。 今曰出乎意外地發現此種醫藥組成物可經由添加低於 5 %鹼化劑或於無鹼化劑存在下製備。 藉此方式獲得一種每日二次（1 2小時）緩慢特定釋放之 錠劑，但含有大於5 %鹼化劑之醫藥組成物則可採用每 曰一次釋放劑量。 儘管事實上添加較低量鹼化劑，但本發明錠劑也顯示 良好安定性態樣。 如此本發明之目的係提供一種於人體治療多種病症之 醫藥物質的有用的組合，該組合可提供治療效果由於個 別物質單獨效果，同時避免於治療期間發生不良影響。 本發明之另一目的係提供用於例如鼻炎。感冒、流行 性感冒；鼻炎般及流行性感冒等症兆治療之有用的藥物 組合。 本發明涵蓋一種於人類治療一種選自鼻炎、感冒、流 行性感冒、感冒般及流感般症狀之病症之方法，包含對 需要此種治療之人體投予一種錠劑，該錠劑包含有效量 之假麻黃素、其個別光學異構物或醫藥可接受性鹽，以 及有效量之哂得力畊、個別光學異構物或其醫藥可接受 性鹽。 一種於「人體治療選自鼻炎、感冒、流感感冒般及流 感般症狀之病症之方法」一語表示提供打噴嚏、流鼻水 1243061 五、發明說明（4) 、鼻塞、鼻及眼搔癢、流淚等症狀的緩解。 「醫藥可接受性鹽」一詞就哂得利劑用於此處不僅表 示其與無毒性有機及無機酸例如乙酸、檸檬酸、丁二酸 、抗壞血酸、氫氯酸、氫溴酸、硫酸及磷酸等之加成鹽 ’同時也表示其金屬鹽（如鈉或鉀鹽）、銨鹽、胺鹽及胺 基酸鹽。 「醫藥可接受性鹽」一詞就假麻黃素用於此處表示其 鹽酸鹽及硫酸鹽以及相當之無毒鹽。 「個別光學異構物」一詞用於此處表示當分子有個非 對稱中心時，其左旋及右旋對映異構物。如業界眾所周 知’依據選用之化合物製備途徑以及起始物料之光學純 度’此種對映異構物之純化相當困難。因此「個別光學 異構物」一詞用於此處表示該化合物包含至少9 0 %，較 好至少95%重量比個(以及左旋-或右旋-)光學異構物 以及至多10%，且較好至多5%重量比另一種個別（左旋-或右旋0光學異構物。個別光學異構物可經由使用習知 手段例如英國專利申請案第2,225,32 1號揭示之手段由 其外消旋混合物獲得。此外，個別光學異構物可藉酶生 物催化光學分割而由外消旋混合物製備，例如揭示於美 國專利第 4,800，162 及 5,057,427 號。 哂得力哄較佳化合物爲2-[2-[4-[(4-氯苯基）苯甲基]-1-哌哄基]乙氧基]乙酸之外消旋體及其二鹽酸鹽，稱做 哂得力畊二鹽酸鹽，及其左旋及右旋對映異構物（左哂 得力畊及右哂得力哄）。 1243061 五、發明說明（Ο 本案中「假麻黃素」一詞用於此處表示假麻黃素本身 、其個別光學異構物及其醫藥可接受性鹽。 本案中「哂得力哄」一詞表示哂得力哄本身（2 _ [ 2 _ [ 4 _ [(4-氯苯基）苯甲基卜哌哄基]乙氧基]乙酸之外消旋體） 、個別光學異構物、光學異構物之任一種混合物或其醫 藥可接受性鹽。 特疋具體貫施例中’本發明係有關一種包含至少二不 同節段之錠劑，其中一節段主要包含哂得力畊做爲活性 成分，以及第二節段主要包含假麻黃素做爲活性成分， 該等節段之組合及形成方式，讓結果所得錠劑實質上不 含經由哂得力畊及假麻黃素反應形成雜質，但相對於錠 劑總重，錠劑包含例如5%重量比鹼化劑。 於第二具體實施例中，本發明係有關一種包含至少二 不同節段之錠劑，其中一節段主要包含哂得力哄做爲活 性成分，以及第二節段主要包含假麻黃素做爲活性成分 ，該等節段之組合及形成使所得錠劑實質上不含經由哂 得力畊及假麻黃素反應形成雜質，哂得力畊及假麻黃素 之藥力學態樣（profile)實質上與含有等量個別做爲單一 活性成分之劑型相等。 「節段」一詞意圖表示個別醫藥組成物含有活性藥物 以及一或多種醫藥可接受性賦形劑。錠劑節段例如可爲 多層錠之一層(亦即雙層錠之一層）、或錠芯、或完全或 部份覆蓋錠芯之包衣。一節段可爲粒子其完全或部份由 包衣所覆蓋、或完全或部份覆蓋粒子之包衣。 1243061 五、發明說明（6) 「實質上不含」一詞需了解係小於5 %，較好小於3 % 重量比。更好小於0 · 5 %，又更好小於〇 · 2 %重量比。 較好，於本發明之錠劑，假麻黃素節段爲實質上且含 哂得力畊，表示假麻黃素節段之哂得力哄節段含量低於 5 % ’較好低於3 %及更好低於〇 · 5 %。較好於根據本發明 之錠劑，哂得力畊節段實質上不含假麻黃素，表示於哂 得力畊節段之假麻黃素節段含量低於5 %，較好低於3 % 及更好低於0.5 %。 根據本發明’假麻黃素節段於哂得力畊節段之界面表 面積低於180平方毫米，及較好由約20至約150平方 毫米。界面面積一詞表示二節段間之接觸面積計算値， 而與錠劑類型（圓形、橢圓形、方形、包衣橢圓形…）或 接觸類型無關。 本發明之另一具體實施例中，錠劑進一步包含一屏蔽 節段’其中該屏蔽節段分開哂得力哄節段及假麻黃素節 段。屏蔽節段包含熟諳技藝人士已知之物料。 本發明之另一具體實施例中，相對於假麻黃素節段總 量，假麻黃素節段包含低於5 %重量比鹼化劑。 根據本發明有用之鹼化劑，較好於生理p Η條件下可 溶於水相。鹼化劑可選自鹼金屬或鹼土金屬，氫氧化物 、碳酸鹽、碳酸氫鹽及磷酸鹽、硼酸鈉及有機酸鹼性鹽 (例如檸檬酸鈉）。它方面，於生理pH條件下不溶於水 之鹽如二鹼基磷酸鈣不適用於本發明。 本發明之另一具體實施例中，錠劑包含多數假麻黃素 1243061 五、發明說明（7) 節段。 較好錠劑之哂得力哄節段係呈壓縮包衣劑型、或另外 呈噴霧包衣劑型。「壓縮包衣」一詞需了解使用小錠做 爲第二銳壓縮之一部份，此處小錠係幾乎位在粉末壓縮 之外側的中心及差額部份。「噴霧包衣」一詞需了解錠 劑使用含活性物質之包衣製劑做外側包衣。 較好錠劑之假麻黃素節段含有惰性醫藥賦形劑之含量 爲假麻黃素本身之〇·75至4.5倍，及更好1至3倍重量 較好錠劑之哂得力畊節段含有惰性醫藥賦形劑，其含 量爲哂得力畊本身重量之5至30倍，且較好10至20倍。 較好惰性醫藥賦形劑存在之總量相對於全部活性成分 之總聚集體數量之比爲約2至6重量比。比値約爲3時 獲得最佳結果。 根據本發明之錠劑，假麻黃素對哂得力畊之重量比爲 12至30。比値爲24可獲得最佳結果。 較佳錠劑中，假麻黃素節段包含約1 0 8至1 3 2毫克及 較好120毫克假麻黃素；以及哂得力畊節段包含約4.5 至5 · 5毫克及較好5毫克哂得力畊。 本發明之較佳具體實施例中，假麻黃素節段爲緩慢釋 放調配劑。「緩慢釋放」一詞表示於U S P裝置1 (3 7 °C， 100 RPM)於500毫升水（0· IN鹽酸）於1小時釋放20至 60%，而於6小時釋放大於70% ;或於2小時釋放40至 8 0 %而於6小時釋放大於70%。 1243061 五、發明說明（8) 本發明之較佳具體實施例中’哂得力畊係呈即刻釋放 劑型。「即刻釋放」一詞表示於USP裝置1(37°C，100 RP Μ)於5 00毫升水（〇· IN鹽酸），於30分鐘之釋放大於 7 0%。 錠劑重量爲2〇〇至800毫克，及較好300至600毫克。 較好根據本發明之錠劑包含定量哂得力哄，該錠劑投 予人體時可獲得哂得力畊血漿濃度相對於時間曲線下方 哂得力畊面積爲當包含該含量哂得力畊之二鹽酸鹽哂得 力哄即刻釋放錠以相等哂得力畊劑量給藥給相同人體時 觀察得哂得力哄血漿濃度相對於時間曲線之曲線下方面 積之80%至125%。 較好根據本發明之錠劑包含定量假麻黃素，該錠劑投 予人體時可獲得假麻黃素血漿濃度相對於時間曲線下方 齒麻黃素面積爲當包含該量假麻黃素之假麻黃素持續釋 放錠劑投予相同人體時觀察得假麻黃素血漿濃度相對於 時間曲線之曲線下方面積之80%至125%。 本發明之假麻黃素/哂得力畊劑型提供假麻黃素及哂 得力畊血液或血漿濃度係等於由分開投予個別假麻黃素 及哂得力畊對照調配劑之濃度。 約1 20毫克假麻黃素對照調配劑爲以商品名蘇達非 (SUDAFED)12小時鏡（華納蘭茂曰用品；述於2001年醫 師桌面手冊）。適當哂得力哄對照調配劑爲5毫克即刻 釋放哂得力畊（吉太特（ZYRTEC))，UCB、S.A及輝瑞藥 廠出售。 -10- 1243061 五、發明說明（9) 爲了試驗於活體內之當量，進行下述試驗。一組至少 1 2個健康人平分爲二組。其中一組口服投予本發明之假 麻黃素/哂得力畊劑型，以及另一組授予蘇達非1 2小時 120毫克包衣錠（或當量）及5毫克以商品名吉太特錠劑 出售之產品。於給藥後以規則時間由個體採血，製備血 漿。 HPLC或LC/MS或LC/MS/MS檢定分析用來決定各試 樣之假麻黃素及哂得力畊濃度。 約一週後，原先接受假麻黃素/哂得力畊劑型之個體 ，現在變成投予假麻黃素對照及哂得力畊對照。原先接 受假麻黃素對照及哂得力畊對照之個體現在被投予假麻 黃素/哂得力畊組合劑型。測量假麻黃素及哂得力哄血 漿濃度。對個人準備血漿假麻黃素相對於時間作圖，準 備血漿哂得力畊相對於時間作圖。 哂得力畊CMAX爲最大哂得力畊血漿濃度。組合劑型 之哂得力畊CMAX除以即刻釋放哂得力畊對照之CMAX， 對各個個體決定平均CMAX比。本發明之假麻黃素/哂得 力畊劑型獲得平均CMAX比爲0.8至1.25。 對組合劑型以及對哂得力畊對照錠測定血漿哂得力哄 濃度相對於時間曲線下方面積（AUC)。組合劑型之哂得 力哄AUC除以即刻釋放哂得力畊對照之哂得力畊AUC ，對各個體決定平均AUC比。 本發明之假麻黃素/哂得力哄平均劑型獲得平均AUC 比爲〇·8至1.25，此外，90%信度間隔爲〇.8至1.25。 -11- 1243061 五、發明說明（10 ) 以同樣方式獲得假麻黃素之平均AUC比。本發明之 假麻黃素/哂得力畊平均劑型獲得平均假麻黃素AUC比 爲0.8至1 ·25，此外，90%信度間隔爲0.8至1.25。 哂得力畊及假麻黃素血漿分析如後。足夠提供最小5 毫升血漿（二份2·5毫升血漿）供分析哂得力畊及假麻黃 素藥力學之血液於乾式化管試管內於下列時間進行試驗 :〇 (恰在給藥前），給藥後〇 · 5、1 ' 2、3、4、6、8、1 0 、12、16、24、36及48小時。依據硏究者之裁量，個 體於第9及25日於1 2小時樣本後釋放。血樣於約4°C 離心，儲存血漿加適當標籤；蓋上螺帽之聚丙烯管於-2 〇°C於收集的1小時以內儲存。得自各別個體之血樣係 以該個體之包裝形式儲存。 AUC表示曲線下方面積，Cmax表示偵測得之最高濃 度，Tmax表示獲得Cmax所需時間。 於根據本發明之錠劑，假麻黃素之存在粒徑係選擇具 有流動指數小於2 5。「流動指數」一詞表示三次試驗中 試用可通過其中三次之最小孔洞直徑對應之流動能力指 數（設備係得自漢森（Hanson)硏究公司，確賀司）。 粒經之決定係利用於下述條件下空氣噴槍過篩：個別 篩根據ASTME 11，10克物質，設備配備有艾爾潘（Aipine) 空氣噴射篩，使用低壓，較好爲250毫米水柱（100-300 毫米水柱），過篩時間爲5分鐘，輔助爲每10克物質〇.30 克抗靜電，較好爲氣溶膠R 972 (德古司阿公司）。 根據本發明之錠劑中，假麻黃素存在之粒徑係選擇可 12- 1243061 五、發明說明（) 沉降少於30毫升。沉降能力（VlcrV5。。）係根據歐洲藥典 2.9 . 1 5 測量。 較好於根據本發明之錠劑，不超過1 〇 %的假麻黃素具 有粒子大小小於1 〇〇微米。更好假麻黃素粒子大小爲至 少9 5 %粒子小於5 0 0微米，而不超過1 5 %者小於1 〇 6微 米。 錠劑其中之假麻黃素爲結晶性，該種錠劑可獲得最佳 結果。 根據本發明之較佳具體實施例之錠劑包含甲基纖維素 醚衍生物，及較好經取代之羥化甲基纖維素做爲親水聚 合物。 甲基纖維素醚衍生物之黏度係根據歐洲藥典所述方法 於纖維素衍生物單章或根據USP方法<91 1>測量。 使用商品名米索塞爾（Methocel)Kl5 MCR出售之產品 獲得最佳結果，該產品爲羥丙基甲基纖維素（甲氧基： 19-24%，羥丙基：7-12%)，氯化物：最高0.5% ;顯著 之黏度11000至21000 mPa( = cP)，粒子大小：最少90% < 1 0 0飾目。 較好羥丙基甲基纖維素（HPMC)對假麻黃素之比爲0.5 至2重量比。 於根據本發明之較佳具體實施例之錠，含哂得力哄節 段也含有崩散劑，崩散劑含量較好係占哂得力畊節段小 於5 %重量比，最好丨至5%之範圍。適當崩散劑例如爲 乙醇酸激粉鈉、庫司卡米克司（crosscarmelose)(交聯魏 -13- 1243061 五、發明說明（12) 甲基纖維素）鈉、聚乙烯基吡咯啶酮衍生物、交聯普維 龍（保力帕司頓（P〇lyPlasdone)XL，PLP XL)。最佳結果 係以崩散劑爲交聯聚甲基纖維素獲得。 錠劑之較佳具體實施例中，哂得力哄節段含有賦形劑 其包括分子量小於4 0 0之多羥基化合物。較好多羥基化 合物爲糖。最好糖爲乳糖。 本發明之更佳具體實施例爲錠劑，錠劑爲雙層錠，以 哂得力哄節段爲一^層’而以假麻黃素節段爲一^層。較好 假麻黃素層對哂得力畊層之重量比爲0.25至10，最好 爲2至6。 較佳具體實施例中，二層個別之外表面形狀不同。較 好鍵劑有第一面，其爲假麻黃素層，有多種曲率半徑， 最好有三種曲率半徑。較好錠劑有第二面，該第二面爲 哂得力畊層，具有單一曲率半徑。曲率半徑定義於美國 製藥協會（錠劑規格手冊第4版，憲法大道2215號，NW ，華盛頓特區，DC 20037-2985，45及46頁）；杯半徑 爲由錠劑中線（中點）跨越定錠劑直徑、短軸或長軸直徑 產生的單弧；杯半徑構成杯之態樣（profile);杯於衝頭 梢端爲凹線或凹面；長軸爲中心錠長度，短軸爲中心錠 寬度。 旋劑包含額外塗層。替代例中，塗層可做爲口味遮蓋 劑。適當之口味遮蓋劑例如爲纖維素衍生物（甲基-、羧 甲基-、經甲基-、羥乙基-、羥甲基丙基-纖維素）、乙烯 系衍生物（聚乙烯醇、聚乙酸乙烯酯）、丙烯酸及甲基丙 -14- 1243061 五、發明說明（13) 烯酸系衍生物（優拉吉（Eudragits®)、順丁烯二酸共聚物 、聚氧伸乙基二醇、天然樹脂（玉米蛋白、樹膠）。 錠劑也含有若干醫藥可接受性塡充劑做爲賦形劑。適 當塡充劑例如爲澱粉及其衍生物、乳糖、甘露糖醇、蔗 糖、葡萄糖、山梨糖醇、鈣磷酸鹽、麥芽糖糊精類、聚 乙烯基吡略啶酮、聚乙二醇類、微晶纖維素、有機酸類。 本發明之較佳具體實施例中，锭劑係包裝於防水及防 氧包裝材料。 根據本發明之較佳具體實施例之錠劑，假麻黃素節段 包含至少一種賦形劑，該賦形劑係選自惰性基質、親水 基質、脂質基質、惰性基質與脂質基質之混合物、親水 基質與脂質基質之混合物、親水基質與惰性基質之混合 物。 根據本發明之較佳具體實施例之錠劑，包含選自惰性 、親水及親脂基質之基質賦形劑。 根據本發明可使用之惰性基質有：聚氯乙烯、聚乙烯 、乙酸乙烯酯/氯乙烯共聚物、聚甲基丙烯酸甲酯類、 聚醯胺類、聚矽氧類、乙基纖維素、聚苯乙烯等。 根據本發明可使用之親水基質例如爲纖維素衍生物 (經丙基甲基纖維素、羥乙基纖維素、羥丙基纖維素、 甲基纖維素等）、非纖維素多醣（半乳糖聚甘露糖、瓜爾 膠、卡洛膠（carob gum)、阿拉伯膠、梧桐膠、瓊酯、褐 藻酸鹽類等）以及丙烯酸聚合物（卡洛帕司（carb〇p〇ls)934p 以及974P等）。較好根據本發明使用之親水基質爲羥丙 -15- 1243061 五、發明說明（14) 基甲基纖維素，例如以商品名米索塞爾K或E出售之化 合物。 根據本發明有用之脂質基質例如爲甘油酯類（一-、二-或三酸甘油酯類：硬脂精、棕櫚精、月桂精、肉宣蔻精 、氫化篦麻油或氫化棉子油、派塞隆（precirol)等）、脂 肪酸類及醇類（硬脂酸、棕櫚酸、月桂酸；硬脂醇、鯨 蠟醇、鯨蠟基硬脂醇等）、脂肪酸酯類（丙二醇及蔗糖之 一酸甘油酯類、蔗糖二硬脂酸酯等）及蠟類（白蠟、抹香 鯨鱲等）。 除了前述各種組成分外，本發明錠劑也含有其它賦形 劑例如稀釋劑（如：安康帕司（Emcompress)、乳糖等）、 黏結劑（安維塞爾（Avicel)、澱粉類、聚乙烯基吡咯啶酮 等）、崩散劑（澱粉及改性澱粉、纖維素衍生物、褐藻酸 衍生物、果膠類等）、潤滑劑（滑石、硬脂酸鎂、膠體氧 化矽等）、口味遮蓋劑（α -環糊精、Θ -環糊精、r -環糊 精及其烷化衍生物）、矯味劑或著色劑以及包衣劑（例如 :纖維素衍生物、甲基丙烯酸系樹脂、聚氯乙烯、尼龍 類等）。 用於實施本發明之治療方法，前述錠劑需含有有效量 之哂得力畊及假麻黃素。有效數量方便使用習知技術經 由觀察於類似情況下所得結果決定。決定有效量時，需 考慮多項因素，此等因素包括但非限於：病患種屬；身 材、年齢及一般正常情況；特定疾病；該疾病發病程度 或嚴重程度；個別病患的反應；投予之特定化合物；投 -16- 1243061 五、發明說明（15) 藥模式；投予製劑之生物利用性特徵；選定之用法用量 ;以及伴隨用藥。 此外，錠劑中哂得力阱及假麻黃素個別比例較好爲該 錠劑包含約0.25至約2.5 %重量比哂得力哄及約1〇至約 45%重量比假麻黃素。 根據本發明之錬劑可以任一種形式或模式投予病人， 讓該錠劑經口途徑可以有效量供生物利用。熟諳製備調 配劑技巧人士容易依據欲治療之特殊疾病狀態、疾病階 段、以及其它相關情況之特殊特性選用適當劑型及投藥 模式。 本發明之錠劑包含至少一種醫藥可接受性賦形劑，其 比例及性質係由選用之錠劑之溶解度及化學性質、選用 之投藥途徑、以及標準製藥規範決定。 特別，本發明涵蓋醫藥組成物，主要係由治療有效量 之前述活性化合物組合一或多種醫藥可接受性賦形劑組 成。· 賦形劑材料可爲固體或半固體物質，可做爲活性成分 之媒劑或介質。適當賦形劑材料爲業界眾所周知。本發 明之錬劑適合經口投藥，可以銳劑或膠囊劑等劑型投予 病人。 賦形劑材料適合根據預期之投藥形式且符合習知製藥 規範做選擇。例如，用於以錠劑或膠囊劑劑型經口投藥 ，治療活性藥物組成分可組合任一種口服無毒醫藥可接 受性惰性賦形劑如乳糖或澱粉。視需要地，本發明之藥 - 17- 1243061 五、發明說明（16) 錠也含有黏結劑如微晶纖維素、西黃蓍膠或明膠、崩散 劑如褐藻酸、潤滑劑如硬脂酸鎂、滑動劑如膠體二氧化 矽、甜味劑如蔗糖或糖精、著色劑或矯味劑如薄荷或水 楊駿甲酯。 錠劑由於容易投藥，錠劑表示最佳口服單位劑型。若 有·所需，錠劑可以標準水性或非水性技術使用糖、蟲膠 、或其它腸衣劑包衣。較好，各錠或膠囊劑含有約15 毫克至約300毫克活性成分。 根據本發明之錠劑，可根據熟諳技藝人士已知之多種 方法製備。 本發明亦係有關所述錠劑之用途，其係用於製造鼻炎 、感冒、流行性感冒、感冒般及流行性感冒般症狀及過 敏性鼻炎相關病症或病情之預防或治療甩藥，用於緩解 鼻塞、季節性鼻炎、打噴嚏、流鼻水、鼻及眼部搔癢、 紅眼、流淚、打噴嚏。 本發明亦係關於一種預防或治療人體或哺乳動物病症 或病情之方法，該病症或病情係關聯鼻炎、感冒、流行 性感冒、感冒般及流行性感冒般症狀及過敏性鼻炎，用 於緩解鼻塞、季節性鼻炎、打噴嚏、流鼻水、鼻及眼部 搔癢、紅眼、流淚、打噴嚏。 將參照下列實例進一步定義本發明，下列實例說明本 發明錠劑之細節及其用途。 實例 實例1 ·雙層錠之假麻黃素緩慢釋放節段組成 -18- 12430611243061 V. Description of the invention (1) The invention relates to a tablet containing two different segments. In particular, the present invention relates to a combination of two medical substances and a method for treating allergic conditions. 2- [2- [4-[(4-chlorophenyl) benzyl] -1-piperidyl] acetic acid is also known as cetirizine and its dihydrochloride. U.S. Patent No. 4,525,358 is It is known that this case also reveals its antihistamine properties. The compound has useful pharmacological properties. Particularly useful as anti-allergic, anti-histamine, bronchodilator and anti-spasmodic agents. Several literatures have also revealed that specific liquid isomers of drugs used in humans to treat conditions while avoiding the associated adverse reactions of the corresponding racemic mixture. Special International Patent Application Publication Nos. WO 94/06429 and WO 9 4/0 6430, disclosed in the human body to treat diseases caused or promoted by increased eosinophils or enhanced eosinophil function, the method includes treating eosinophils in need The patient administers quantitative (+) 哂 effective farming (also (-) 哂 effective farming) or a pharmaceutically acceptable salt thereof, which substantially does not contain its (-) stereoisomer (other than its (+) stereoisomer Structure), and the amount is sufficient to improve the increase of eosinophils or strengthen the function of eosinophils, but not enough to cause adverse effects. In this regard, the compound pseudoephedrine is well known as a sympathomimetic drug, and is known as a safe therapeutic agent effective in alleviating nasal congestion. It is also well known to those skilled in the art that combination medication needs to be prudent because combination medication is relatively easy to induce unpredictable adverse effects in the human body. In some cases, the combination may cause a lower therapeutic effect than the individual drugs administered alone. When treating allergic conditions such as allergic rhinitis-conjunctivitis caused by pollen 1243061 V. Description of the invention (2), caution should be taken when combining antihistamines and decongestants, because the combination of drugs not only improves the overall treatment effect, that is, the entire Sneezing, runny nose, stuffy nose, tearing, itching of the nose and eyes during the treatment are absent or the percentage of the weakest days is increased. At the same time, adverse effects such as insomnia and headache can be avoided. In view of the treatment of various diseases of the human body, several patent applications have disclosed that drugs are used in binary and / or ternary combinations at specific dosages. In particular, British patent 2 31 1 940 and European patent application 0 8 1 1 3 7 4 disclose a pharmaceutical composition containing trigonel and pseudoephedrine; U.S. patent 6,171,6 18 discloses a dosage form, It contains tadpoles as an immediate release component and pseudoephedrine as a controlled release component, and some pseudoephedrine can be mixed as an immediate release component. In particular, international patent application WO 9 8/41 194 discloses a medicinal composition that can be administered orally, allowing immediate release of the first active substance and long-term release of the same or second active substance. The medicinal composition includes: A At least one layer contains the active substance and an excipient which allows the active substance to be released immediately after administration, and B. At least one second layer which allows the controlled release of the same active ingredient or the second active ingredient. This layer is A pharmaceutical composition, containing 5 to 60% by weight of at least one excipient relative to the total weight of the composition, the excipient being selected from the group consisting of an inert matrix, a hydrophilic matrix, a lipid matrix, a mixture of an inert matrix and a lipid matrix, and a hydrophilic matrix Mixture with inert matrix; and 5 to 50% by weight to 1243061 with respect to the total weight of the composition V. Description of the invention (3) One less alkalizing agent soluble in the aqueous phase under physiological pH conditions. Due to the presence of the alkalizing agent, this composition proved to have good stability. It was unexpectedly discovered that such a pharmaceutical composition can be prepared by adding less than 5% of an alkalizing agent or in the absence of an alkalizing agent. In this way, a slow and specific release lozenge is obtained twice a day (12 hours), but a pharmaceutical composition containing more than 5% of an alkalizing agent can be used in a single release dose. Despite the fact that a lower amount of alkalizing agent is added, the lozenges of the present invention also show good stability. The purpose of the present invention is thus to provide a useful combination of medicinal substances for treating various diseases in the human body, which combination can provide therapeutic effects due to the individual effects of the individual substances, while avoiding adverse effects during treatment. Another object of the present invention is to provide, for example, rhinitis. A combination of medicines useful for the treatment of symptoms such as colds and influenza; rhinitis and influenza. The present invention encompasses a method for treating a condition selected from rhinitis, cold, influenza, cold-like and flu-like symptoms in humans, comprising administering a lozenge to a person in need of such treatment, the lozenge containing an effective amount of Pseudoephedrine, an individual optical isomer or a pharmaceutically acceptable salt thereof, and an effective amount of trigonex, an individual optical isomer, or a pharmaceutically acceptable salt thereof. A method of "human body treating conditions selected from rhinitis, cold, flu-like symptoms and flu-like symptoms" means providing sneezing, runny nose 1243061 V. Description of the invention (4), nasal congestion, itching of the nose and eyes, tearing, etc. Relief of symptoms. The term "pharmaceutically acceptable salt" is used herein to mean that the beneficial agent is not only used in connection with non-toxic organic and inorganic acids such as acetic acid, citric acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and Addition salts of phosphoric acid and the like also mean metal salts (such as sodium or potassium salts), ammonium salts, amine salts and amino acid salts. The term "pharmaceutically acceptable salt" is used herein with respect to pseudoephedrine to indicate its hydrochloride and sulfate salts and equivalent non-toxic salts. The term "individual optical isomers" is used herein to indicate the left-handed and right-handed enantiomers of a molecule when it has an asymmetric center. As is well known in the industry, purification of such enantiomers, 'depending on the route of preparation of the selected compounds and the optical purity of the starting materials', is quite difficult. The term "individual optical isomers" is used herein to indicate that the compound contains at least 90%, preferably at least 95% by weight (and left- or right-) optical isomers and up to 10%, and It is preferably at most 5% by weight than another individual (L- or D-0 optical isomer. Individual optical isomers can be obtained by using conventional means such as those disclosed in British Patent Application No. 2,225,32 1 Racemic mixtures are obtained. In addition, individual optical isomers can be prepared from racemic mixtures by enzymatic biocatalytic optical segmentation, as disclosed, for example, in U.S. Patent Nos. 4,800,162 and 5,057,427. The preferred compound is 2- [ The racemate of 2- [4-[(4-chlorophenyl) benzyl] -1-piperazyl] ethoxy] acetic acid and its dihydrochloride are referred to as dihydrogen dihydrochloride , And its left-handed and right-handed enantiomers (left and right stalks) 1243061 V. Description of the invention (0 The term "pseudoephedrine" in this case is used here to indicate pseudoephedrine Itself, its individual optical isomers and their pharmaceutically acceptable salts.哂 Coaxing itself (2 _ [2 _ [4 _ [(4-chlorophenyl) benzylpiperazine] ethoxy] acetic acid racemate), individual optical isomers, optical isomers Or a pharmaceutically acceptable salt thereof. In the specific embodiments, the present invention relates to a lozenge containing at least two different segments, wherein one segment mainly contains slabs as active ingredients, and The second segment mainly contains pseudoephedrine as an active ingredient. The combination and formation of these segments make the resulting tablets not substantially contain impurities formed through the effective cultivation and pseudoephedrine reaction. The total weight of the lozenge, the lozenge contains, for example, a 5% by weight alkalizing agent. In a second specific embodiment, the present invention relates to a lozenge comprising at least two different segments, wherein one segment mainly contains tincture as The active ingredient and the second segment mainly contain pseudoephedrine as the active ingredient. The combination and formation of these segments make the obtained lozenges substantially free of impurities formed through the effective cultivation of pseudoephedrine and the reaction of pseudoephedrine. Pharmacokinetics of Tillage and Pseudoephedrine (Profile) is essentially equivalent to a dosage form containing an equal amount of an individual as a single active ingredient. The term "segment" is intended to mean that an individual pharmaceutical composition contains the active drug and one or more pharmaceutically acceptable excipients. Lozenge segments For example, it can be a layer of a multi-layered tablet (ie, a layer of a double-layered tablet), or a core, or a coating that completely or partially covers the core. A segment can be a particle that is completely or partially covered by a coating, or The coating that completely or partially covers the particles. 1243061 V. Description of the invention (6) The term "substantially free" needs to be understood to be less than 5%, preferably less than 3% by weight. More preferably less than 0.5%, and It is more preferably less than 0.2% by weight. Better, in the lozenge of the present invention, the pseudoephedrine segment is substantially effective and contains 哂, which means that the content of the pseudoephedrine segment is less than 5%. It is preferably below 3% and more preferably below 0.5%. It is better than the tablet according to the present invention that the tamarind segment is substantially free of pseudoephedrine, indicating that the ephedrine segment content in the tamarind segment is less than 5%, preferably less than 3% and more Well below 0.5%. According to the present invention, the interface surface area of the pseudoephedrine segment at the sturdy tilling segment is less than 180 square millimeters, and preferably from about 20 to about 150 square millimeters. The term interfacial area refers to the calculation of the contact area between two segments, regardless of the type of tablet (round, oval, square, coated oval ...) or the type of contact. In another specific embodiment of the present invention, the lozenge further comprises a shielded segment ', wherein the shielded segment is separated from a powerful coaxing segment and a pseudoephedrine segment. The shield segment contains materials known to those skilled in the art. In another embodiment of the present invention, the pseudoephedrine segment contains less than 5% by weight of alkalizing agent relative to the total amount of pseudoephedrine segment. The alkalizing agent useful according to the present invention is preferably soluble in the aqueous phase under physiological pΗ conditions. The alkalizing agent may be selected from alkali metals or alkaline earth metals, hydroxides, carbonates, bicarbonates and phosphates, sodium borate and basic salts of organic acids (such as sodium citrate). In this respect, water-insoluble salts such as dibasic calcium phosphate under physiological pH conditions are not suitable for use in the present invention. In another specific embodiment of the present invention, the lozenge contains the majority of pseudoephedrine 1243061 V. Description of the invention (7). The preferred tablets are capable of coaxing the segments in a compressed coating formulation or, alternatively, in a spray coating formulation. The term “compression coating” needs to be understood as the use of small tablets as part of the second sharp compression, where the small tablets are located almost at the center and balance of the powder compression outside. The term "spray coating" requires the understanding that the tablets are coated on the outside with an active substance-containing coating formulation. The pseudoephedrine segment of the better lozenges contains inert pharmaceutical excipients in an amount of from 0.75 to 4.5 times the amount of the pseudoephedrine itself, and more preferably 1 to 3 times the weight of the good lozenge segments of the good lozenges. The content of the inert pharmaceutical excipient is 5 to 30 times, and preferably 10 to 20 times, the weight of Zhiligeng itself. Preferably, the ratio of the total amount of inert pharmaceutical excipients present relative to the total number of aggregates of all active ingredients is about 2 to 6 weight ratios. Best results are obtained when the ratio is approximately 3. According to the lozenge of the present invention, the weight ratio of pseudoephedrine to effective tillage is 12-30. The best result is obtained with a ratio of 24. Among the preferred lozenges, the pseudoephedrine segment contains about 108 to 132 mg and preferably 120 mg of pseudoephedrine; and the effective farming segment contains about 4.5 to 5.5 mg and preferably 5 mg. Effective farming. In a preferred embodiment of the present invention, the pseudoephedrine segment is a slow release formulation. The term "slow release" is expressed in USP device 1 (37 ° C, 100 RPM) in 500 ml of water (0. IN hydrochloric acid) to release 20 to 60% in 1 hour, and greater than 70% in 6 hours; or Release 40 to 80% in 2 hours and release more than 70% in 6 hours. 1243061 V. Description of the invention (8) In the preferred embodiment of the present invention, the 'capable tillage system is an immediate release dosage form. The term "immediate release" means that in a USP device 1 (37 ° C, 100 RP Μ) in 5000 ml of water (0.1N hydrochloric acid), the release in 30 minutes was greater than 70%. The tablet weight is from 200 to 800 mg, and preferably from 300 to 600 mg. Preferably, the lozenge according to the present invention contains a quantitative amount of the effective hydrocolloid. When the lozenge is administered to the human body, the effective hydroponic plasma concentration relative to the time curve is below the effective hydroponic area. The effective release of ingots was administered at the same effective dose to the same human body. Observed the effective plasma concentration of 80% to 125% of the area under the curve of the time curve. Preferably, the lozenge according to the present invention contains a quantitative amount of pseudoephedrine, and when the lozenge is administered to the human body, the plasma concentration of pseudoephedrine relative to the area of the ephedrine under the time curve is the pseudoephedrine containing the amount of pseudoephedrine. When the flavin sustained release lozenge was administered to the same human body, it was observed that the pseudoephedrine plasma concentration was 80% to 125% of the area under the curve of the time curve. The pseudoephedrine / codrugate formulations of the present invention provide blood or plasma concentrations of pseudoephedrine and pupae effective farming that are equal to the concentrations of the individual pseudoephedrine and pupae effective farming control formulations. About 120 mg of pseudoephedrine control formulation is a 12-hour mirror under the trade name SUDAFED (Warner Lanmao supplies; described in the 2001 physician's desktop manual). The appropriate formulation is 5 mg of immediate release formulation (ZYRTEC), sold by UCB, S.A and Pfizer Pharmaceuticals. -10- 1243061 V. Description of the invention (9) In order to test the equivalent in vivo, the following test is performed. A group of at least 12 healthy people was evenly divided into two groups. One group was administered orally to the pseudoephedrine / coligenol dosage form of the present invention, and the other group was awarded to Sudafil 120 mg coated tablets (or equivalents) for 12 hours and 5 mg under the trade name Geitat tablets. Products for sale. Blood was collected from individuals at regular times after administration to prepare plasma. HPLC or LC / MS or LC / MS / MS verification analysis is used to determine the concentration of pseudoephedrine and canola in each test sample. About a week later, individuals who had previously received the pseudoephedrine / codextrin formulations have now become administered to the pseudoephedrine control and the pandextrin control. Individuals who had previously received the pseudoephedrine control and the tadpoles control were now administered the pseudoephedrine / tadpoles combination formulation. Measure the plasma concentration of pseudoephedrine and tincture. Plot plasma pseudoephedrine versus time for individuals, and prepare plasma plots for time versus time for plasma. Climax CMAX is the maximum Climax plasma concentration. Divide the effective CMAX of the combined dosage form by the immediate release CMAX control CMAX, and determine the average CMAX ratio for each individual. The pseudoephedrine / codine effective tillage dosage form of the present invention achieves an average CMAX ratio of 0.8 to 1.25. The area under the curve (AUC) of the plasma concentration was measured for the combined dosage form and for the control tablets. The effective AUC of the combined dosage form is divided by the effective AUC of the immediate release effective control, and the average AUC ratio is determined for each individual. The average dosage form of the pseudoephedrine / saccharine of the present invention achieves an average AUC ratio of 0.8 to 1.25, and in addition, the 90% confidence interval is 0.8 to 1.25. -11- 1243061 V. Description of the invention (10) The average AUC ratio of pseudoephedrine is obtained in the same way. The average dosage of pseudoephedrine / copper can be obtained according to the present invention with an average AUC ratio of pseudoephedrine of 0.8 to 1.25, and the 90% confidence interval is 0.8 to 1.25.哂 Delicious and pseudoephedrine plasma analysis is as follows. Enough to provide a minimum of 5 ml of plasma (two 2.5 ml of plasma) for analysis. Pharmacokinetic and pseudoephedrine blood is tested in the desiccated tube test tube at the following time: 0 (just before administration), 0.5, 1 '2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours after administration. At the discretion of the investigator, individuals were released on the 9th and 25th days after a 12-hour sample. Blood samples were centrifuged at about 4 ° C, and the stored plasma was appropriately labeled; the polypropylene tubes with screw caps were stored at -20 ° C within 1 hour of collection. Blood samples obtained from individual individuals are stored in the packaging of that individual. AUC represents the area under the curve, Cmax represents the highest concentration detected, and Tmax represents the time required to obtain Cmax. In the tablet according to the present invention, the particle size of pseudoephedrine is selected to have a flow index of less than 25. The term “flow index” refers to the flow capacity index corresponding to the minimum pore diameter that can be passed in three of the three trials (equipment obtained from Hanson Research Co., Ltd.). The determination of the granules was carried out by using an air spray gun to sifter under the following conditions: individual screens according to ASTME 11, 10 grams of substance, equipment equipped with Aipine air jet screens, using low pressure, preferably 250 mm water column (100 -300 mm water column), sieving time is 5 minutes, auxiliary is 0.30 g antistatic per 10 g of substance, preferably aerosol R 972 (Degussa). In the lozenge according to the present invention, the particle size of pseudoephedrine can be selected 12- 1243061 V. Description of the invention () Settlement is less than 30 ml. Settling capacity (VlcrV5 ...) is measured according to the European Pharmacopoeia 2.9.15. It is preferred that no more than 10% of the pseudoephedrine according to the present invention have a particle size of less than 1000 microns. More preferably, the pseudoephedrine particle size is at least 95% of the particles smaller than 500 microns, and not more than 15% of the particles smaller than 106 microns. Among the lozenges, pseudoephedrine is crystalline, and this kind of lozenges can obtain the best results. The lozenges according to a preferred embodiment of the present invention comprise a methyl cellulose ether derivative, and preferably substituted methylated cellulose as a hydrophilic polymer. The viscosity of the methyl cellulose ether derivative is measured in a cellulose derivative single chapter according to the method described in the European Pharmacopoeia or according to the USP method < 91 1 >. The best results were obtained using a product sold under the trade name Methocel Kl5 MCR. This product is hydroxypropyl methylcellulose (methoxy: 19-24%, hydroxypropyl: 7-12%), Chloride: up to 0.5%; significant viscosity of 11,000 to 21,000 mPa (= cP), particle size: at least 90% < 1 0 0 mesh. Preferably, the ratio of hydroxypropyl methylcellulose (HPMC) to pseudoephedrine is from 0.5 to 2 by weight. In the ingots according to the preferred embodiment of the present invention, the tadpole-containing effective segment also contains a dispersant. The dispersant content preferably accounts for less than 5% by weight of the tadpole-capable segment, and preferably ranges from 5% to 5% . Suitable disintegrants are, for example, sodium glycolate, crosscarmelose (crosslinked Wei-13-1243061 V. Description of the invention (12) methyl cellulose) sodium, polyvinyl pyrrolidone derivatives, Leproviron (PolyPlasdone XL, PLP XL). The best results were obtained with a dispersant as crosslinked polymethylcellulose. In a preferred embodiment of the tablet, the effective segment contains excipients which include polyhydroxy compounds having a molecular weight of less than 400. A preferred polyhydroxy compound is a sugar. The best sugar is lactose. A more specific embodiment of the present invention is a lozenge, the lozenge is a double-layered lozenge, the effective coaxing segment is one layer, and the pseudoephedrine segment is one layer. Preferably, the weight ratio of the pseudoephedrine layer to the effective tillage layer is from 0.25 to 10, more preferably from 2 to 6. In a preferred embodiment, the outer surfaces of the two layers are different in shape. A better bonding agent has a first side, which is a pseudoephedrine layer with multiple curvature radii, and preferably three curvature radii. Preferably, the lozenge has a second side, which is an effective plough layer with a single radius of curvature. The radius of curvature is defined by the American Pharmaceutical Association (4th edition of the Tablet Specification Manual, 2215 Constitution Avenue, NW, Washington DC, DC 20037-2985, pages 45 and 46); the cup radius spans the midline (midpoint) of the tablet Single arc produced by fixed tablet diameter, short axis or long axis diameter; cup radius constitutes the profile of the cup; cup is concave or concave at the tip of the punch; long axis is the length of the central ingot and short axis is the center Ingot width. The spinner contains an additional coating. In the alternative, the coating can be used as a taste masking agent. Suitable taste covering agents are, for example, cellulose derivatives (methyl-, carboxymethyl-, methyl-, hydroxyethyl-, hydroxymethylpropyl-cellulose), vinyl derivatives (polyvinyl alcohol, Polyvinyl acetate), acrylic acid and methacrylic acid 14-1243061 5. Description of the invention (13) enoic acid derivatives (Eudragits®, maleic acid copolymer, polyoxyethylene diethylene glycol) Alcohols, natural resins (zein, gum). Lozenges also contain a number of medically acceptable tinctures as excipients. Suitable tinctures are, for example, starch and its derivatives, lactose, mannitol, sucrose, glucose , Sorbitol, calcium phosphate, maltodextrin, polyvinylpyrrolidone, polyethylene glycol, microcrystalline cellulose, organic acids. In a preferred embodiment of the present invention, the tablets are packaged For waterproof and oxygen-resistant packaging materials. According to the tablet of the preferred embodiment of the present invention, the pseudoephedrine segment contains at least one excipient selected from the group consisting of an inert matrix, a hydrophilic matrix, a lipid matrix, and an inert matrix. Mixture with lipid matrix, hydrophilic group Mixtures with lipid bases, mixtures of hydrophilic bases and inert bases. Lozenges according to a preferred embodiment of the present invention comprise a matrix excipient selected from inert, hydrophilic and lipophilic bases. Inerts that can be used according to the present invention The substrates are: polyvinyl chloride, polyethylene, vinyl acetate / vinyl chloride copolymer, polymethyl methacrylates, polyamines, polysiloxanes, ethyl cellulose, polystyrene, etc. According to the present invention Usable hydrophilic substrates are, for example, cellulose derivatives (via propylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, etc.), non-cellulose polysaccharides (galactose polymannose, Guar gum, carob gum, acacia gum, sycamore gum, agar ester, alginate, etc.) and acrylic polymers (carbopouls 934p and 974P, etc.). It is good that the hydrophilic matrix used according to the present invention is hydroxypropyl-15-1243061. V. Description of the invention (14) methylmethyl cellulose, for example, a compound sold under the trade name Misoser K or E. Useful lipid matrices according to the present invention Gan Oil esters (mono-, di-, or triglycerides: stearin, palm extract, laurel, myristyl, hydrogenated ramie or hydrogenated cottonseed oil, precirol, etc.), fatty acids And alcohols (stearic acid, palmitic acid, lauric acid; stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, etc.), fatty acid esters (propylene glycol and sucrose monoglycerides, sucrose distearate Esters, etc.) and waxes (white wax, sperm whale, etc.). In addition to the aforementioned various components, the lozenges of the present invention also contain other excipients such as diluents (eg, Emcompress, lactose, etc.), cohesion Agents (Avicel, starches, polyvinyl pyrrolidone, etc.), disintegrating agents (starch and modified starch, cellulose derivatives, alginic acid derivatives, pectin, etc.), lubricants ( Talc, magnesium stearate, colloidal silica, etc.), taste masking agents (α-cyclodextrin, Θ-cyclodextrin, r-cyclodextrin and its alkylated derivatives), flavoring or coloring agents, and coatings Agents (for example: cellulose derivatives, methacrylic resins, polyvinyl chloride, nylon Class, etc.). For the implementation of the treatment method of the present invention, the aforementioned lozenges need to contain effective amounts of scopolamine and pseudoephedrine. The effective amount to facilitate the use of conventional techniques is determined by observing results obtained under similar circumstances. There are a number of factors to consider when deciding on an effective amount, including but not limited to: the patient's species; size, age, and general normal conditions; specific diseases; the incidence or severity of the disease; individual patient responses; administration Specific compounds; Dosage-16-1243061 V. Description of the invention (15) Medicine mode; Bioavailability characteristics of the administered preparation; selected usage and dosage; and concomitant medication. In addition, it is preferred that the individual ratios of tetrogen and pseudoephedrine in the lozenge are such that the troche contains about 0.25 to about 2.5% by weight of tetrid and about 10 to about 45% by weight of pseudoephedrine. The tincture according to the present invention can be administered to a patient in any form or mode, so that the lozenge can be used in an effective amount for biological use by the oral route. Those skilled in the preparation of formulations can easily select the appropriate dosage form and administration mode according to the special characteristics of the particular disease state, disease stage and other relevant conditions to be treated. The lozenges of the present invention include at least one pharmaceutically acceptable excipient, the proportion and properties of which are determined by the solubility and chemical properties of the lozenges selected, the route of administration chosen, and standard pharmaceutical specifications. In particular, the present invention encompasses pharmaceutical compositions, which are mainly composed of a therapeutically effective amount of the aforementioned active compound in combination with one or more pharmaceutically acceptable excipients. · Excipient materials can be solid or semi-solid materials and can be used as a vehicle or medium for active ingredients. Suitable excipient materials are well known in the industry. The tincture of the present invention is suitable for oral administration, and can be administered to patients in the form of sharps or capsules. Excipient materials are suitable for selection based on the intended form of administration and compliance with conventional pharmaceutical specifications. For example, for oral administration in the form of tablets or capsules, the therapeutically active pharmaceutical ingredients can be combined with any oral non-toxic pharmaceutically acceptable inert excipient such as lactose or starch. If necessary, the medicine of the present invention-17- 1243061 V. Description of the invention (16) The tablet also contains a binder such as microcrystalline cellulose, tragacanth or gelatin, a dispersant such as alginic acid, and a lubricant such as magnesium stearate Slip agents such as colloidal silica, sweeteners such as sucrose or saccharin, colorants or flavoring agents such as mint or salicylic acid methyl ester. Due to the ease of administration of lozenges, lozenges represent the best oral unit dosage form. If desired, lozenges can be coated with sugar, shellac, or other enteric agents using standard aqueous or non-aqueous techniques. Preferably, each tablet or capsule contains from about 15 mg to about 300 mg of the active ingredient. The lozenges according to the present invention can be prepared according to various methods known to those skilled in the art. The present invention also relates to the use of the tablet, which is used for the prevention or treatment of rhinitis, colds, influenza, cold-like and influenza-like symptoms and allergic rhinitis-related diseases or conditions. Relieves congestion, seasonal rhinitis, sneezing, runny nose, itching of the nose and eyes, red eyes, tearing, and sneezing. The invention also relates to a method for preventing or treating a human or mammalian disease or condition, which is associated with rhinitis, cold, influenza, cold-like and influenza-like symptoms, and allergic rhinitis, and is used to relieve nasal congestion , Seasonal rhinitis, sneezing, runny nose, itchy nose and eye, red eyes, tearing, sneezing. The invention will be further defined with reference to the following examples, which illustrate the details of the tablets of the invention and their uses. Examples Example 1 Composition of slow-release segments of double-layered tablets of pseudoephedrine -18- 1243061
Cmax (奈克 /毫升） 3 9 1 25 9 29 5 tmax (小時） 1.5 5 5 AUC(奈克·小時/毫升）3 877 3 943 4249 兩種實驗性調配劑（A及B)顯示明顯緩慢釋放側繪， 生物利用率等於參考調配劑。 選擇B調配劑進一步發展，原因在於假麻黃素層於曲 線中獲得平台時間比調配劑A更長。 實例2·錠劑B節段溶解態樣之pH相依性 於各種pH評估假麻黃素之溶解態樣（水，鹽酸n ，ρΗ=4·5，6·8 及 7.5，USP24 裝置 1，lOOrpm，37。〇 。結果示於表3。 表3 ·錠劑B節段於各種p Η之試管內溶解資料 時間（小時） 水 鹽酸〇. IN pH 4.5 pH 6.8 pH 7 0 - - - - - 1 44.1 39.4 39.6 40.4 4 1.4 2 62.1 57.0 58.0 58.2 59.4 3 74.9 68.5 70.1 70.8 7 0.5 4 84.0 77.9 79.0 79.6 7 9.2 6 92.7 89.3 92.3 90.8 90.6 8 97.8 97.3 96.7 96.7 96.2 12 一 105.3 101.2 100.9 99.9 結果顯示ρ Η相依性之試管內溶解作用。 -20- 1243061 五、發明說明（19) 實例3.哂得力哄·鹽酸鹽/假麻黃素.鹽酸鹽5毫克/12 0 毫克雙層錠之試管內溶解作用 製備經包衣之哂得力畊·鹽酸鹽/假麻黃素.鹽酸鹽雙層 錠。 假麻黃素粒子大小爲至少9 5 %粒子小於5 0 0微米，不 超過15%粒子小於1〇6微米。 此等錠劑配方示於表4。 表4·5毫克/120毫克膜衣哂得力畊·鹽酸鹽/假麻黃素. 鹽酸鹽錠劑組成 毫克/銳 心紅第一層： 心銳第二層： 包衣材料： 假麻黃素·鹽酸鹽 120 HPMC(a) 120 微晶纖維素 57 膠體二氧化矽 1.5 硬脂酸鎂 1.5 哂得力畊.鹽酸鹽 5 乳糖一水合物 43.23 微晶纖維素 19.15 交聯羧甲基纖維素鈉 1.40 膠體二氧化矽 0.52 硬脂酸鎂 0.70 歐派崔白（Opadry white) 11.1( -21 - 1243061 五、發明說明（2〇) 產品歐派崔白爲水性膜衣聚合物組合（羥丙基甲基纖 維素、二氧化欽、聚乙二醇4 0 〇)。 各芯層及組成分分開混合，然後於雙層旋轉打錠機壓 縮。然後錠劑以歐派崔包衣。 錠劑之第一面爲假麻黃素層，有多個曲率半徑。鏡劑 之第二面爲哂得力畊層，有單一曲率半徑。 假麻黃素節段與哂得力畊節段間之界面面積約爲78.f 平方毫米。錠劑直徑約爲1 0毫米。 錠劑包裝於防水及防氧包裝材料。 假麻黃素及哂得力哄之溶解態樣使用實例2所述方法 評估（介質鹽酸=〇·1 N)。結果示於表5。 表5.5毫克/120毫克哂得力畊·鹽酸鹽/假麻黃素鹽酸 鹽雙層錠之試管內溶解資料 時間（小時） 假麻黃素 溶解藥物百分比 •鹽酸鹽 哂得力哄·鹽酸鹽 0.25 16 88 0.50 26 94 0.75 33 95 1 40 97 4 8 1 99 8 97 99 12 100 99 結果顯示假麻黃素. 鹽酸鹽釋放緩慢（類似實例2結果） 以及哂得力畊·鹽酸鹽即刻釋放。 -22- 1243061 五、發明說明（21) 溶解試驗係於USP裝置1，容積5 0 0毫升，速度100 r p m，3 7 °C 進行。 安定性試驗顯示哂得力哄節段實質不含假麻黃素，假 麻黃素節段實質上不含哂得力哄（低於0.2 %重量比）。 -23-Cmax (neck / ml) 3 9 1 25 9 29 5 tmax (h) 1.5 5 5 AUC (neck · hour / ml) 3 877 3 943 4249 Two experimental formulations (A and B) showed significantly slow release On the side, the bioavailability is equal to the reference formulation. Formulation B was selected for further development because the pseudoephedrine layer obtained a plateau in the curve for a longer time than formulation A. Example 2 pH dependence of the dissolution state of the tablet B segment The dissolution state of pseudoephedrine was evaluated at various pH levels (water, hydrochloric acid n, ρΗ = 4 · 5, 6 · 8, and 7.5, USP24 device 1, 100 rpm, 37 〇。 The results are shown in Table 3. Table 3. • Dissolution time of tablet B segment in various test tubes (hours) Hydrochloric acid 0.1 pH 4.5 pH 6.8 pH 7 0-----1 44.1 39.4 39.6 40.4 4 1.4 2 62.1 57.0 58.0 58.2 59.4 3 74.9 68.5 70.1 70.8 7 0.5 4 84.0 77.9 79.0 79.6 7 9.2 6 92.7 89.3 92.3 90.8 90.6 8 97.8 97.3 96.7 96.7 96.2 12-105.3 101.2 100.9 99.9 Internal dissolution. -20- 1243061 V. Explanation of the invention (19) Example 3. Dehydration · Hydrochloride / Pseudoephedrine. Hydrochloride 5mg / 120mg double-layered in vitro test tube preparation Coated coriander. Hydrochloride / Pseudoephedrine. Bilayer tablets of hydrochloride. Pseudoephedrine particle size is at least 95%, particles smaller than 500 microns, and no more than 15% particles smaller than 106. Micron. The formula of these lozenges is shown in Table 4. Table 4 · 5 mg / 120 mg film-coated Dingli · HCI / Pseudo-hemp Composition of hydrochloride lozenge mg / heart red First layer: Heart sharp Second layer: Coating material: pseudoephedrine · hydrochloride 120 HPMC (a) 120 microcrystalline cellulose 57 colloidal silica 1.5 Magnesium stearate 1.5 Hydrogenate. Hydrochloride 5 Lactose monohydrate 43.23 Microcrystalline cellulose 19.15 Croscarmellose sodium 1.40 Colloidal silicon dioxide 0.52 Magnesium stearate 0.70 Opadry white ) 11.1 (-21-1243061 V. Description of the invention (20) The product Opalic is a water-based film-coating polymer combination (hydroxypropyl methylcellulose, dioxin, polyethylene glycol 400). Each core layer The ingredients are mixed separately, and then compressed in a double-layer rotary tableting machine. The tablets are then coated with opex. The first side of the tablet is a pseudoephedrine layer with multiple radii of curvature. The second of the mirror The surface is an effective tillage layer with a single radius of curvature. The area of the interface between the pseudoephedrine segment and the effective tillage segment is about 78.f square millimeters. The diameter of the tablets is about 10 mm. The tablets are packaged in waterproof and anti- Oxygen packaging material. Pseudoephedrine and tincture dissolve in the use case 2 Said method Evaluation (= square in HCl · 1 N). The results are shown in Table 5. Table 5.5 mg / 120 mg Dicaptan · Hydrate / Pseudoephedrine Hydrochloride Bilayer Tablets Dissolution Data Time (hours) Pseudoephedrine Dissolved Drugs Percentage • Hydrochloride Peptide Effective Hydrochloric Acid Salt 0.25 16 88 0.50 26 94 0.75 33 95 1 40 97 4 8 1 99 8 97 99 12 100 99 The results show pseudoephedrine. The release of the hydrochloride salt is slow (similar to the result of Example 2), and the effective hydroponics · hydrochloride is immediate freed. -22- 1243061 V. Explanation of the invention (21) The dissolution test was performed on USP device 1, volume 500 ml, speed 100 r p m, 37 ° C. Stability tests have shown that the tadpole effective segment is substantially free of pseudoephedrine, and the pseudoephedrine segment is substantially free of tadpole effective segment (less than 0.2% by weight). -twenty three-