TW550089B - Dispersible macromolecule compositions and methods for their preparation and use - Google Patents
Dispersible macromolecule compositions and methods for their preparation and use Download PDFInfo
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- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K9/1658—Proteins, e.g. albumin, gelatin
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
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Description
550089 經濟部中央標準局員工消費合作社印製 B7 __五、發明説明(1 ) 發明背景 1.發明領域 本發明概略而言係關於一種巨分子組成物及其製法及 用法。特別,本發明係關於一種於可保有蛋白質純度的控 制條件下經由噴乾而而製備巨分子組成物之方法,結果獲 得良好粉末分散性和其它所需特性。 多年來,有些藥物係呈適合形成經口吸入(經肺輸藥) 的藥物分散體來治療人體各種病情的組成物出售。此種經 肺輸藥組成物係設計適合由病人藉吸入藥物分散體輸藥, 使分散體内的活性藥物可到達肺臟。發現某些輸送至肺臟 的藥物易經由肺泡區直接吸收入血循環。經肺輸藥對於輸 送巨分子(蛋白質,多肽,高分子量多醣,和核酸)其難以 藉其它投藥途徑輸送者特別有展望。此種經肺輸藥可有效 供系統輸藥與局部輸藥來治療肺臟疾病。 經肺輸藥本身可藉不同途徑達成,包含液體霧化器, 基於氣霧劑的計量式劑量吸入器(MDI),和乾粉分散裝置 。基於氣霧劑的MDI的風采漸失,原因是其依賴氯氟碳化 物(CFC),CFC由於對臭氧層的不良影響而受非難。乾粉分 散裝置其並非仰賴CFC氣霧劑技術,其對於易調配成乾粉 的藥物輸送上有展望。多種其它易感巨分子本身或與適當 粉末載劑組合,呈凍乾或噴乾粉末安定儲存。 然而,呈乾粉輸送醫藥組成物的能力於某些方面成問 胃。多種醫藥組成物劑量常有關鍵重要性,故希望乾粉輸 送系統可正確、準確、且可靠地輸送預期量的藥物◦此外 (請先閱讀背面之注意事 1·. ,項再填< 裝-- 寫本頁) 訂·- it 本紙張尺度適用中國國家榡準(CNS ) A4規格(210X 297公釐) 550089 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明(2 ) ,多種醫藥組成物相當昂貴◦如此,可有效配方、加工、 包裝、與輸送乾粉而藥物的損失極少相當具有關鐽重要性 。雖然天然巨分子於肺臟的透過性為眾所周知,但巨分子 製法和巨分子輸送合併無效,對經肺輸藥的巨分子乾粉的 商業化產生限製。 經肺輸送乾粉藥物的特別有展望的方法利用附有手動 唧筒的手持裝置提供加壓氣體源。加壓氣體遽然經由粉末 分散裝置如文氐管噴嘴釋放,而分散的粉末供病人吸入。 雖然就多方面而言優異,但此種手持裝置於多種其它方面 成問題。輸送粒子大小通常小於5iim,使粉末的處置與分 散比較較大粒子更因難。問題因相當小量加壓氣體(可使 用手動唧筒獲得)而惡化。特別,當僅有小量加壓氣體可 Μ手動唧筒獲得時,文氏管分散裝置不適合難Μ分散粉末 。另一種手持輸藥裝置和其它粉末輸送裝置的需求有效。 Μ最佳大小分布供經肺輸藥輸送藥物給病人的高裝置效率 乃市售產品。習知輸送藥物技術不具有商業化所需輸送效 率。達成充分分散與小分散容積乃有意義的技術挑戰,該 挑戰要求各單位劑量粉狀組成物容易且可靠地分散。 噴乾乃習知化學加工單元操作,其用Μ由多種液體和 漿液起始物料生產乾粒狀固體。使用噴乾調配乾粉藥物為 已知,但通常僅限於小分子和其它對照分解和其它激烈處 理條件較不敏感的安定藥物。使用噴乾製備生物巨分子組 成物,含蛋白質,多肽,高分子量多醣,和核酸可能成問 題,原因是此等巨分子易感,暴露於高溫及噴乾製程的其 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) I 裝-----—V -訂·--------- 550089 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明(3 ) 它態樣時易分解。巨分子分解過度可能導致藥物配方缺所 需純度。也難Μ控制由噴乾產生的組成物之粒子分散和粒 子大小分布◦供經肺輸藥要緊地,平均粒徑須維持於〈Silm ,較佳0.4-5/im,而包括目標大小範圍以外的粒子之組成 物數量也須減至最低◦較佳,至少90社%粉末具有粒徑於 0·1-7*πη之範圍。更佳,至少95%之粒徑係於〇.4-5iim之範 圍。此外,偶爾難K對粒狀產物成品的物理與化學安定性 達成所需低水含量,特別K經濟方式達成。最後且或許最 要緊地,難有效方式生產經肺輸藥所需的小粒子。對 高價位巨分子藥物而言,收集效率(亦即,呈有用形式由 製程回收的粒狀藥物數量)須高於80wt%,較佳高於90社% ,滿意地高於95wU。雖然如下述,噴乾曾用於實驗室規 模設備製備巨分子粉末,但商用噴乾機未設計供生產肺用 大小範圍的粉末。霧化、乾燥粉末、和收集方法須修改而 可Μ有效產率和Μ商業可接受的生產速率(超率30克/小 時)經濟地生產附有所需經肺輸藥產品物性的蛋白質粉末 0 因此,希望提供一種改良方法供噴乾巨分子供用於經 肺輸藥及其它輸藥。特別,希望提供一種改良製程方法和 粉末組成物其可解決至少部分前述缺憾。 2.背景技術說明 U.S· 5,260,306 , 4,590,206 , GB 2 105 189 ,和ΕΡ 072 046敘述噴乾1^(^〇(^〇111丨1鈉形成小粒較佳於2-15/1111之 範圍供經肺輸藥之方法。美國專利第5,376,386號敘述供 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ---------裝-----i--訂·------ (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 550089 A7 B7 五、發明説明(4 ) 經肺輸藥用之粒狀多醣載劑之製備,此處載劑包括粒子大 小於5-1000um之範圍且具縐摺度小於1.75 ° Mumenthaler et al. (1994) Pharm. Res. 11:12敘述重組人類生長激素 和重組組織型胞質素原活化劑。研究驗證蛋白質可能於噴 乾期間分解,因而無法保有治療用的充分活性^ W0 95/ 23613敘述使用實驗室規模設備藉噴乾製備DNase吸入粉末 。W0 91/16882敘述一種噴乾蛋白質和其它藥物於脂小體 載劑之方法。 下列讓與本案受讓人之申請案各別敘述噴乾可用Μ製 備生物巨分子乾粉;申請案第08/423,515號,申請日1995 年4月14日;申請案第08/383,475號(其為08/207,472號申 請案,申請日1994年3月7日之部分連續案);申請案第08/ 472,563號,申請日1995年4月14日(其乃申請案第08/417, 507號,申請日1995年4月4日現已放棄之部分連續案;申 請案第08/044,358號,申請日1993年4月7日現已放棄之連 續案);申請案第號,申請日年月日;申請案第08/232, 849,申請之1994年4月25日(其乃申請案第07/953,397號 現已放棄之連續案)。TO 94/07514請求申請案第07/953, 397號之優先申請之。W0 95/24183請求申請案第08/207, 472和08/383,475號之優先申請日。 發明概述 根據本發明,噴乾生物巨分子之方法可提供醫藥組成 物,其具有改良之特性,該方法可克服至少部分前述先前 本纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) --------^^裝-----It -訂-------AW (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 550089 A7 B7 五、發明説明(5 ) 技術之噴乾方法之缺點。本發明之方法包括提供預定濃度 之巨分子,及選擇性其它賦形劑呈於液體介質之溶液、漿 液、懸浮液等,通常於水圼水溶液。巨分子可選擇性視需 要與相容賦形劑如糖、媛衝液、鹽和其它蛋白質調配成溶 液而提供治療有效劑量,抑制乾燥過程的分解,促進粉末 分散性,及達成於室溫粉末之可接受的物理與化學安定性 。液體介質於特選條件下霧化,形成小滴具有於或低於預 定值的平均粒徑,然後,小滴於特選條件下乾燥而形成水 含量低於預定閾值的配方粒子。乾粒子經收集與包裝成適 合使用形式,典型為單位劑量容座。霧化與乾燥條件較佳 選擇使粒子於單一乾燥步驟乾燥至低於目標水含量,粒子 具有所需大小範圍而無需於包裝前進一步分離(例如,大 小篩選)粒子。 本發明之方法之第一較佳態樣中,液體介質內之總固 體含量(含巨分子和賦形劑)低於10%,通常係於0.5-lOwt% 介質包括水溶液。發現控制總固體濃度低於5%可顯著增進 之範圍。較佳,濃度係於約之範圍,液體獲得具所 需大小範圍亦即,〈5/im,較佳〇.4-5*im之範圍的乾粒子。 本發明之方法之第二較佳態樣中,溶液經霧化而生產 具有中等小滴大小於或小於11/im的小滴◦霧化器設計與操 作條件的最適化可使固體含量增至前述濃度而使高量生產 變實際且經濟。較佳,霧化步驟係經由Μ預定氣:液質量 流比較佳高於5,使溶液和霧化氣體流經雙流體噴嘴進行 。空氣孔口上游的氣壓維持高於25 psig。雖然氣壓高於 本紙張尺度適用中國國家標準(CNS ) M規格(21Q χ 297公釐) (請先閱讀背面之注意事項再填寫本頁) ▼裝---- 訂-------0 經濟部中央標準局員工消費合作社印製 550089 A7 ____ B7_ 五、發明説明(6 ) 獲得音速所得氣壓,亦即,速度未續增至高於音波,發現 較高壓霧化氣體密度增高可使產生的小滴大小減少。 本發明之方法之另一個態樣中,霧化小滴乾燥而形成 終水含量低於5wU的粒子。較佳,粒子於單次乾燥操作乾 燥至此程度,典型於單次噴乾操作進行,小滴係與具有足 量熱能的熱氣流同流流動,水位粒子內蒸發至所需濃度, 隨後,粒子由乾燥燥作收集。通常,熱氣流典型熱空氣流 具有入口溫度至少90°C,較佳至少120°C,更佳至少135°C ,又更佳至少145°C,常為175°C,或高達200¾ ,依接受 乾燥的巨分子而定。至少部分熱氣體乾燥流入口溫度依接 受處理的生物巨分子的可靠性而定。胰島素範圍中入口溫 度為140-150°C之範圍。 欲控制乾燥操作中產生的粒子的終水含量,也需控制 氣體出口溫度。氣體出口溫度為入口溫度、產物乾燥步驟 加諸的熱負載(依液體介質入口溫度、蒸發水量等)及其它 因素之函數。較佳氣體出口溫度維持至少50°C或K上,較 佳至少70°C,通常係於60-80°C之範圍。 本發明之方法之又另一個特定態樣中,乾燥條件係選 擇可控制粒子形態俾增進粉末分散性。特別,乾燥條件經 選擇而提供縐摺度至少2的粒子。縐摺度測量表面盤旋, 值愈高表不表面不規則性程度愈高。絕非欲限制本發明之 範圍,目前相信藉縐摺度測得之表面不規則性增高導至毗 鄰粒子間之内聚力減低。表面交互作用減少,改良所得粉 末的分散性。粒子縐摺度受個別小滴乾燥速率和溶解固體 本纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) --------裝-----L--訂·------ (請先閱讀背面之注意事項再填寫本頁) 550089 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(7 ) 組成的影響。 小滴最初於相當高速率乾燥,形成環繞液滴外部的黏 稠層。隨著乾燥的持續,黏層無法如溶液蒸發時粒子收縮 般快速流動’结果導致粒子表面盤旋(趨摺)。黏層M iiLF 方程式(Williams, Landel, Ferry方程式)參見K. Alexander & C. J. King, Drying Technology, Vol· 3, No. 3, 1985,與材料之玻璃轉變溫度相關◦乾燥區段内的溫 度梯度須控制使粒子乾燥夠快而使表面萎縮和盤旋而非快 速至使粒子破裂。 本發明之方法之又另一特定態樣中,乾燥妥的粒子藉 由氣體流分離大體整個乾燥步驟。發現妥為控制霧化與乾 燥條件產生乾粉具有至90%粒子之大小範圍為O.l-7/un,更 佳至少95%係於0.4-5*im之範圍,如此可使乾燥步驟輸出經 收集而粉末於包裝前無需作尺寸過篩。然後,收集的粉末 可Μ習知方式用作粉末藥物。通常,部分粒子輸出包裝於 適當容器,例如,用於乾粉吸入器之單位劑量容器。 本發明之方法之又另一特定態樣中,粉末分離步驟包 括整個氣體流通經分離器,分離器由氣體流去除至少約90 wt%大小為Ι/m的粒子。分離器包括高效旋風器,特別設計 及於條件下操作而對藉本發明之方法生產的超細粒子獲得 所需高去除效率。另外,分離器包括過濾元件,例如,燒 结金屬纖維過濾器、膜過濾器(例如,袋濾器)等。 本發明之方法可用於生產生物巨分子典型為適合藥用 ,亦即,作為人與動物用藥的巨分子乾粉。生物巨分子包 (請先閲讀背面之注意事 I# 項再填· 裝-- 填寫本頁) -訂· it 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 經濟部中央標準局員工消費合作社印製 550089 A7 B7 五、發明説明(8 ) 含蛋白質,多肽,寡肽,高分子量多醣(典型分子量高於2 kD),和核酸等。特定生物巨分子列舉於下表1。該方法 特別可用於生產胰島素,其為分子量約7.5kD或Μ上之多 肽激素◦根據本發明製備之胰島素粉末可衍生自動物源, 例如,牛胰島素或重組製備。重組胰島素含有同天然人類 胰島素的胺基酸序列,或可修改至某種程度同時維持所需 胰島素活性。 根據本發明之組成物包括供經肺輸藥,亦即,由病人 吸入病人肺臟肺泡區的可分散巨分子粉末。組成物包括粒 子之平均粒徑〈lOum而縐摺度>2,較佳>3,偶爾>5,通常 係於2-6,較佳於3-6,偶爾於4-6之範圍◦較佳,組成物 粒子之水含量<5wt%,更佳<3wt%,典型<2wU。縐摺度可 藉BET或其它習知粒子表面分析技術測量。較佳,g〇wt%組 成物包括粒子之粒徑於0·1-7μιη,更佳95¾於0.4-5um之範 圍◦組成物常包裝為單位劑型,治療有效量之組成物存在 於單位劑量容座,例如,泡胞、明膠膠囊等。 圖式之簡單說明 第1圖為方塊圖,示例說明本發明之方法之主要單元 操作; 第2圖為細節流程圖,示例說明適合進行根據本發明 之範例方法之系統; 第3圖為示意說明圖,闡明可用於執行本發明之方法 之霧化步驟的較佳霧化噴嘴; 第4圖示例說明第2圖系統之替代裝置,其係供執行 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨0X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 一裝- 丁 _ -:'口 經濟部中央標準局員工消費合作社印製 550089 A7 B7 五、發明説明(9 ) 本發明之方法之分離步驟。 較佳具體例之說明 本發明係關於一種組成物之製法,該組成物包括主要 供經肺輸藥給病人供多種治療與臨床用途之生物巨分子超 细乾燥粉末。本發明之第一主要態樣係關於控制粉末特性 促進粉末用於預期用途◦本發明之第二主要態樣係關於組 成物本身和包裝妥的組成物,特別包含組成物單位劑量。 本發明之第三態樣係關於可Μ支撐特定藥物之市場需求而 生產具有所需特性之粉末。 「生物巨分子」一辭表示包含具有療效和其它有用活 性之已知和未來生物化合物。生物巨分子典型為蛋白質, 多肽,寡呔,和核,和相當高分子量多醣;本發明之方法 可修改化合物成為具有所需特性,特別供經肺輸藥的超細 乾燥粉末。根據本發明之方法適用於製備成超細乾燥粉末 的生物巨分子若干範例示於下表1。生物巨分子最初經溶 解、懸浮、或Μ其它方式分散於可揮發液體介質,然後, 根據本發明之方法霧化、乾燥、和收集。較佳生物巨分子 包含胰島素,介白素-1受體,副甲狀腺激素(ΡΤΗ-34),α -1抗胰蛋白酶,抑鈣素,低分子量肝素,肝素,干擾素, 和核酸。使用本發明之方法製備胰島素組成物之細節例示 於如下實驗乙節。 本紙張尺度適用中國國家標準(CNS ) Α4規格(210 X 297公藶) --一,-------^-裝-- (請先閱讀背面之注意事項再填寫本頁) 訂' 550089 A7 B7五、發明説明(10 ) 表1 生物巨分子藥物範例 經濟部中央標準局員工消費合作社印製 藥物 谪應症 抑鈣素 預防鬆骨病 巴吉特氏病 高鈣血症 紅血球生成素(ΕΡ0) 貧血 第IX因子 Β型血友病 粒狀细胞群落剌激因子 嗜中性血球減少 (G-CSF) 粒狀细胞巨噬细胞群落 骨髓移植失敗 剌激因子(GM-CSF) 生長激素 矮小 腎臟衰竭 肝素 血液凝固 氣喘 肝素(低分子量) 血液凝固 胰島素 第一和第二型糖尿病 干擾素α 肝炎Β和C 髮细胞白血病 卡波西氏肉瘤 干擾素Θ 多發性硬化 (請先閱讀背面之注意事項再填寫本頁) —0 項再填. 裝· aw*-·· 一 V · . 、-V5 4 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 550089 A7 B7 五、發明説明(11 ) 經濟部中央標準局員工消費合作社印製 干擾素7 慢性肉芽腫病 介白素-2 腎癌 黃體化激素釋放激素 前列腺癌 (LHRH) 子宮內膜癌 生長抑制素類似物 胃腸癌 增壓素類似物 糖尿病 尿床 濾泡剌激激素(FSH) 受孕 Amyl in 第一型糖尿病 睫狀嗜中性因子 Lou Gehri 氏病 生長激素釋放因子(GRF) 矮小 仿胰島素生長因子 鬆骨病 營養支持 促胰島素激素 第二型糖尿病 干擾素冷 B和C型肝炎 干擾素7 類風濕性關節炎 介白素-1受體拮抗劑 類風濕性關節炎 介白素-3 化學治療佐藥 介白素-4 免疫缺乏病 介白素-6 血小板減少症 巨噬细胞群落剌激因子 真菌病 (M-CSF) 癌症 高膽固醇血症 神經生長因子 周邊神經病變 : : 批衣-- (請先閲讀背面之注意事項再填寫本頁) •訂: •4 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 550089 A7 B7 五、發明説明(12 ) 副甲狀腺激素 鬆骨病 生長抑制素類似物 頑固腹瀉 胸腺素αΐ B和C型肝炎 Ilb/IIIa抑制素 不穩的心絞痛 α -1抗胰蛋白酶 囊腫纖維變性 抗RSV抗體 呼吸融合病毒 囊腫纖維變性穿膜調節子 囊腫纖維變性 (CFTR)基因 去氧核糖核酸酶(DNase) 慢性支氣管炎 殺菌性/透過性增高蛋白質 成人呼吸窘迫症候群 (BPI) ' (ARDS) 抗CMV抗體 细胞巨病毒 介白素-1受體 氣喘 介白素-1受體拮抗劑 氣喘 (請先閱讀背面之注意事 ΙΦΙ 項再填· 裝-- 填寫本頁) 丁 經濟部中央標隼局員工消費合作社印製 「超细乾燥粉末」一辭表示粉末組成物包括具有下示 特徵的多數分立乾粒子◦特別,乾粒子具有平均粒徑〈5Wm ,更佳於0.4-5jum之範圍,較佳0,4_4um,最佳0.4-3]Lim之 範圍。粉末平均粒徑係藉習知技術以質量平均直徑(MMD) 測量。特殊粉末篩選技術係使用離心沈澱粒子大小分析儀 (Horiba Capa 700)。粉末易分散於吸入裝置,隨後,由 病人吸入,使粒子可穿透肺臟肺泡區。 本發明特別要緊地,藉本發明之方法生產的超细乾燥 粒子組成物具有粒徑分布,使組成物鎖定肺臟肺泡區目標 供經肺輸藥系統作用蛋白質。此等組成物較佳攙混於單位 .曠 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 550089 A7 B7 五、發明説明(13 ) 劑型和其它劑量而未經篩選。通常超细乾燥粉末之大小分 布為至少90wt%粉末包括平均粒徑0.1-7uni之範圍之粒子, 較佳至少95wU係於0.4-5wra之範圍。此外,希望粒徑分布 可避免過量粒子具極小平均直徑,亦即,〈〇.4im。 相反地,已知吸入供治療氣喘和慢性支氣管炎的治療 化合物粉末須輸送至呼吸道更中心(亦即,非輸送至肺泡 區)。粉末產生氣霧劑具有明顯較大粒徑分布,平均直徑 於◦此種大小的粉末比較具有最佳經肺輸藥粒徑的 粉末,更易Μ高產率收集於習知噴乾器。 「乾」一辭表示粉末粒子之水含量使粉末儲存於室溫 時之物理和化學性質安定,易分散於吸入裝置形成氣霧劑 。通常粒子水含量低於10wt%水,常見低於,較佳低 於,更佳低於2wU,選擇性低於約lwt%或以下。水含 量通常由乾燥條件控制(容後詳述)。 經濟部中央標準局員工消費合作社印製 —------丨裝-- (請先閱讀背面之注意事項再填寫本頁) •嘈 「乾」一辭表示粉末粒子之水含量使粉末易分散於吸 入裝置形成氣霧劑。通常粒子水含量低於10wt%水,常見 低於5vrU,較佳低於,更佳低於2社%,選擇性低於約 lwU或以下。水含量通常由乾燥條件控制(容後詳述)。但 某些情況下,非水介質用於分散生物巨分子,該種情況下 ,水含量趨近於零。 「治療有效量」一辭組成物内存在量其乃於接受治療 個體獲得預期生理反應提供所需藥物濃度之需要量。此量 對各藥物係依案例決定。「生理有效量」一辭表示投予個 體獲得所需緩解或治療效果的輸藥量。此量乃各種藥物及 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 550089 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(14 ) 其最終核准劑量之特定量。 組成物內之治療有效量活性藥物將依所用生物巨分子 之生物活性和單位劑型之需要量改變。因本粉末可分散, 故高度較佳係製造成易由配方人與使用人操控的單位劑型 。通常表示單位劑量為乾粉組成物之總物料量約0.5-15mg ,較佳2-10mg。通常組成物之巨分子量為約0.05wt%至約 99.0wU。最佳組成物含約0.2wt%至約97.0wU巨分子。 醫藥可接受性載劑選擇性攙混於粒子(或作為粒子之 本體載劑)提供安定、分散、稠度及/或本體特性而促進 均勻經肺輸送組成物給有需要的個體◦「醫藥可接受性載 劑」一辭表示載劑可攝入肺臟而對肺並無顯著不良毒性。 數字上依使用藥物活性而定,數量為約0.05wU至約99.95 wt%。較佳約5wt%至約95wt%。 醫藥可接受性載劑可為一種或兩種或多種醫藥賦形劑 之組合,但通常大體不含「滲透促進劑」。滲透促進劑為 表面活性化合物,其可促進藥物穿過黏膜或內襯,提議用 於鼻內、直腸、和陰道內投藥藥物配方。滲透促進劑範例 包含膽鹽,例如,牛磺膽酸鹽,甘油膽酸鹽,和去氧膽酸 鹽;fusidates例如牛磺去氫fusidate ;和生物相容清潔 劑,例如,Tweenx, Laureth-9等。但肺用配方使用滲透 促進劑通常非所需,原因是肺臟的上皮血液障壁受界面活 性化合物之不良影響。本發明之方法乾粉組成物易吸收入 肺而無需使用滲透促進劑。 可用於本發明作為醫藥賦形劑之類型包含安定劑,例 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ---r--:---雙II (請先閱讀背面之注意事項再填寫本頁) 訂---- 550089 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(15 ) 如,人血清白蛋白(HSA),緩衝劑,例如,碳水化合物, 胺基酸,和多呔;pH調節劑或緩衝劑;鹽類如氯化鈉等。 載劑可呈結晶形或不定形,或可為二者之混合物。 發規HSA特別可作為載劑而提供改良分散性。 可與本發明之方法粉末併用的本體劑包含相容碳水化 合物、多肽、胺基酸或其組合。適當碳水化合物包含單醣 ,例如,半乳糖,D-甘露山梨等;雙醣,例如,乳糖,海 藻糖,等;環糊精,例如,2-羥丙基-0-環糊精;和多醣 ,例如,鼠李糖,麥芽糊精,葡萄聚糖,等;醛糖醇,例 如,甘露糖醇,木糖醇,等。較佳碳水化合物包含乳糖, 海藻糖,鼠李糖,麥芽糊精和甘露糖醇。適當多呔包含阿 斯巴甜。胺基酸包含丙胺酸和甘胺酸,Μ甘胺酸為佳。 添加劑乃本發明之組成物之次要成分,可包含於其中 供獲得噴乾期間的形穩性與改良分末分散性。添加劑包含 疏水胺基酸,例如,色胺酸,酪胺酸,苯基丙胺酸,等。 適當pH調節劑或緩衝劑包含製自有機酸和鹼的有機鹽 ,例如,檸檬酸鈉,抗壞血酸鈉等;及檸檬酸鈉為佳。 本發明之方法可提供粒子,其可分散,其又可對抗處 理與包裝操作期間粒子的附聚與非期望的壓密。發現與改 良分散性和處理性有關的特性為產品縐摺度。縐摺度為比 面積(藉BET,分子表面吸附,或其它習知技術)與表面積 之比,而表面積係假定無孔球形粒子,由粒徑分布(藉離 心沈積粒徑分析儀Horiba Capa 700測量)與粒子密度(藉 比重瓶測量)求得◦若已知粒子形狀概略结節,如同噴乾 本紙張尺度適用中國國家標準(CNS )八4規格(2 i 0 X 297公釐) --------裝--------訂------ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 550089 A7 B7 五、發明説明(16 ) 之例,則縐摺度係測量表面盤旋或摺疊程度◦此可由SEM 分析藉本發明之製造的粉末獲得證實。縐摺度丨表示粒子 表面球形且無孔。縐摺度值大於1表示粒子表面不均勻, 盤曲至至少某種程度,值愈高表示不均勻度愈大^對本發 明之粉末而言,發現縐摺度至少為2,更佳至少3,通常係 於2-6,較佳3-6,更佳4-6之範圍。 可分散乾粉生物巨分子之經肺輸藥單位劑型包括含有 前述乾粉的單位劑量容座。粉末置於適當劑量容座内,其 量足夠使個體接受單位劑量治療。劑量容座嵌合於適當吸 入裝置,使乾粉組成物氣霧化,係經由分散乾粉於氣體流 ,形成氣霧劑,然後,捕集如此生產的氣霧劑於腔室内, 腔室附接有口件供隨後由需要治療的個體吸入。劑量容座 包含業界已知之任一種包圍組成物的容器,例如,明膠或 塑膠膠囊附有可去除部分,可使氣體流(例如,空氣流)導 入容器內而分散乾粉組成物。此等容器範例例如美國專利 第4,227,522號,1980年10月14日獲頒;美國專利第4,192 ,309號,1980年3月11日獲頒;美國專利第4,105,027號, 1978年8月8日獲頒所示。適當容器亦包含與Glaxo’s Ventolin Rotohaler品牌粉末吸入器或FisorTs Spinhaler 品牌粉末吸入器併用者。另一種可提供優異水障壁的單位 劑量容器係由鋁箔/塑膠層合物形成。以藥物為主的粉末 係Μ重量或容積計填充於可成形箔的凹部内,及Μ蓋材箔 -塑膠層合物氣密封閉。此種用於粉末吸入裝置的容器述 於美國專利第4,778,〇54號並併用〇1^〇、〇丨3心3101^(美 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐) AWI ^----- L--:tT----- (請先閱讀背面之注意事項再填寫本頁) —19 — 550089 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(17 ) 國專利第4,627,432,4,811,731,和5,035,237號)◦較佳乾 粉吸入器述於讓與本發明之受讓人的美國專利申請案第08 /309,691 和08/487,184號,後案公告為W0 96/09085。 現在,參見第1圖,根據本發明之製備生物巨分子可 分散乾粉之方法,包括一種霧化操作10,其生產液體介質 小滴,小滴於乾燥操作20乾燥。乾燥液體小滴,導致形成 分立粒子,其形成乾粉組成物,然後,於分離操作30收集 。各個單元操作容後詳述。 霧化操作10可使用任一型習知霧化器。霧化過程增加 起始液體表面積。结果導致液體表面能增高,增高幅度係 與表面積增加直接成正比,而表面積的增加又與小滴直徑 平方成反比。能量增加源依使用的霧化器類型而定。任何 可產生質量平均直徑小於約lUm的小滴的霧化器(離心、 音振、加壓、雙流體)皆可使用◦本發明之較佳者為使用 雙流體霧化器,此處,液體介質與高壓氣體流同流輸送經 噴嘴◦特性使用雙流體霧化噴嘴(容後詳述),其可產生質 量平均直徑小於lOiim的小滴。 霧化氣體通常為空氣,其已經過濾或Μ其它方式清潔 去除微粒和污染物。另外,可使用其它氣體如氮。霧化氣 體將加壓輸送經霧化噴嘴,典型至高於25 psig壓力,較 佳高於50 paig ◦雖然霧化氣體流通常限於音速,但輸送 壓力愈高導致霧化氣體密度增高。氣體密度增高可減小霧 化操作形成的小滴大小。小滴大小愈小,又導致粒子大小 愈小。霧化條件包含霧化氣體流速、霧化氣體壓力、液體 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) — ^-- (請先閱讀背面之注意事項再填寫本頁)
、言 經濟部中央標準局員工消費合作社印製 550089 A7 B7___ 五、發明説明(18 ) 流速等,控制成可產生質量平均直徑小於Π Wm的液體 ,藉相位都卜勒速度儀測量◦界定較佳霧化器設計與操作 條件時,液體噴霧的小滴大小分布直接使用氣體比重相位 都卜勒粒徑分析儀測量◦小滴大小分布亦可由乾粒徑分布 (Horiba Capa 700)和粒子密度測量值求出。兩種方法的 結果符合一致。較佳,霧化小滴之平均直徑係於5-llirn, 較佳6-8μιπ之範圍◦氣:液質量流量比較佳較佳維持大於5 ,更佳於8至10之範圍。控制氣:液質量流量比於此範圍 對於粒子小滴大小控制特別重要。 至今為止,一般認為習知噴乾機的霧化裝置不適用於 生產本發明使用的極細小滴011/im) ◦例如參見Masters, Handbook of Spray Drying, 4th ed., Wiley & Sons 1985。但發現於前述參數範圍内的雙流體霧化噴嘴可可靠 地獲得於所需大小範圍的噴霧小滴。 液體介質可為生物巨分子於適當液體載劑的溶液、懸 浮液或其它分散液。較佳,生物巨分子係合併醫藥可接受 性載劑存在於液體溶劑呈溶液,液體載劑較佳為水◦但較 佳使用其它液體溶劑,例如,有機液體、乙醇等。總溶解 固體(含巨分子和其它載劑、賦形劑等存在於最終乾粒子) 存在於廣泛濃度範圍,典型O.l-lOwt%。但通常希望放大 粒徑於可吸入大小範圍的固體濃度且具有所需分散特性, 典型固體濃度係於0.5-10%,較佳1.0-5¾。含相當低濃度 生物巨分子的液體介質可得具有相當小直徑的乾粒(容後 詳述)。 本紙張尺度適用中國國家標準(CNS ) A4規格(210x297公釐) --------裝----Ί ----:訂----- (請先閱讀背面之注意事項再填寫本頁) 550089 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(19 ) 其次,進行乾燥操作20而由霧化操作10產生的小滴蒸 發液體。通常,乾燥需將能量引至小滴,典型係經由混合 小滴與引起水或其它液體介質氣化的加熱氣體。較佳,混 合係於嗔乾機或相當腔室內其中已經引進加熱氣體進行。 較佳,熱氣流與霧化液體同流流動,但亦可使用逆流、交 叉流或其它流類型。 乾燥操作控制成獲得具有特殊特性的乾粒,例如,如 前述縐摺度大於2。縐摺度大於2可經由控制乾燥速率獲得 ,故黏性材料層於小滴外表快速形成。隨後,乾燥速率須 夠快可使水分經由材料外層去除,结果導致外層萎縮盤曲 而得高度不規則外表面。但乾燥不可太快而致材料外層破 裂。乾燥速率須基於多種變因控制,含小滴大小分布,氣 體流入口溫度,氣體流出口溫度,液滴入口溫度,以及霧 化噴嘴與熱乾氣體混合方式。較佳,乾燥氣體流之入口溫 度至少90°C,更佳於前述範圍◦出口溫度通常至少約70°C ,較佳於前述範圍。乾燥氣體通常為經過濾或經其它處理 去除微粒和其它污染物的空氣。空氣將使用習知鼓風機或 壓縮機經系統移除。 分離操作30係選擇可以極高效率收集乾燥操作20生產 的超细粒子◦可用習知分離操作條件,但某些情況下,可 修改俾確保收集次微米粒子。範例具體例中,分離係使用 過濾介質如膜介質(濾袋)、燒结玻璃纖維濾器等達成。另 外且常較佳,分離係使用旋風分離器達成,但通常希望提 供高能分離俾確保有效收集次微米粒子。分離操作可達成 --------_-- (請先閱讀背面之注意事項再填寫本頁) -口 本紙張又度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標隼局員工消費合作社印製 550089 B7 五、發明説明(20 ) 收集的全部粒子中至少80¾之平均粒徑大於Um,較佳大於 85%,更佳大於99%,又更高於95%之收集效率。 某些情況下,旋風分離器可用於由最終收集粒子分離 極细粒子,例如,O.Um。旋風操作參數可經選擇而得適 當截留,收集大於約O.lum的粒子,而小於O.lMm粒子載於 頂排放物。肺臟粉末存在有小於O.Um粒子不合所需,原 因是其通常未沈積於肺臟肺泡區反而被排出。 本發明之方法之特殊優點為乾燥操作產生的和分離操 作30收集的全部粒子可用於包裝於所需藥包而無需進一步 分離或篩選粒子成所需大小範圍。结果為霧化條件與乾燥 條件組合,產生超细乾粉組成物具有於經肺輸藥所需個別 粒徑範圍。如此,分離操作30僅由乾燥氣體流分離粒子 (選擇性截留0.4iim),分離係K儘可能高效率達成,原因 是大體全部收集物料皆適用於醫藥配方。 現在,參照第2圖,敘述進行本發明之方法之範例製 程流程圖。製程流程圖包含噴乾器50,可為市售噴乾器 (設計適合本發明之方法)例如得自Buchi, Niro, APV, Yamato化學公司,Okawara Kakoki公司等供應商。噴乾器 50經由供應唧筒52,過濾器54,和供應管路56進料前述液 體介質溶液(溶液進料)。供應管路56連接至雙流體霧化噴 嘴57,如下就第3圖所述。霧化空氣係由壓縮機58,過濾 器60,及管路62供應至噴嘴57。乾燥空氣也經由加熱器65 和過濾器66供應給噴乾器50。 本紙張尺度適用中國國家標李(CNS ) A4規格(210X 297公釐) --------裝----Ί -----^訂------ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 550089 A7 B7 五、發明説明(21 ) 來自噴乾器50的乾燥粒子由氣流經由導管70載至過濾 器殼體72。過滤器殼體72包含多個内部過濾元件74,其乃 過濾袋或燒结金屬纖維濾器,例如,Smale,製造化學師 29頁,1992年4月所述類型燒结不鏽鋼纖維濾器。替代過 濾介質包括濾袋、濾布、和濾匣。所有情況下,載有乾粒 子的氣體流流入過濾器殼體72,載氣通經過濾元件74 ◦但 乾燥妥的粒子的通過被過濾元件阻斷,乾燥妥的粒子藉重 力落至過濾器殼體72底,收集於粒子收集罐76。罐76定期 取出替換,罐內乾粉用Μ呈單位劑型或其它型式包裝◦載 氣由過濾器殻體72頂經由管路80和通風扇84排出。過濾器 82收集任何意外通經過濾介質74的粒子。高壓氣體源90供 定期經由過濾介質74產生逆流空氣脈衝流。此種反向脈衝 空氣流鬆脫黏附於過濾介質入口側的粒子以防结塊。根據 本發明之並使用第2圖之流程圖生產胰島素粉末之範例系 統示於如下實驗乙節。 現在參照第3圖,示例說明範例雙流體霧化噴嘴。流 動管路56包含內導管100和外導管102 ◦內導管100載有 進料溶液並止於孔口 104,依液體流速而定,孔口直徑於 0.015-0.075吋,較佳0.025-0.05吋之範圍。外導管102套 住内導管100同軸設置,載有來自管路62的霧化氣體。導 管62止於孔口 110,孔口 110係同心套於內導管100的孔口 104 ◦孔口110直徑典型大於孔口104直徑,孔口110通常剖 面積夠大而可產生附所需上游壓力的所需空氣質量流速。 選擇性地,冷卻夾套120設於噴霧噴嘴周圍(或霧化氣 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X 297公釐) --------裝----J—-訂------ (請先閱讀背面之注意事項再填寫本頁) 550089 經濟部中央標準局員工消費合作社印製 A7 B7_五、發明説明(22 ) 體與進料溶液間)俾於進料溶液進入噴乾器50時維持相對 低溫進料溶液。冷卻夾套120典型載有冷卻水而其溫度和 數量足Μ維持進料溶液低於生物巨分子分解程度,通常4-45°C。冷卻通常僅需熱敏巨分子。更高進料溶液溫度獲得 低黏度,低黏度可縮小經由霧化操作形成的小滴大小。 玆參照第4圖,至於使用過濾分離器72(如第2圖之 示例說明)之替代之道,收集操作可藉旋風器150進行。旋 風器150經由導管70接受乾燥妥的粒子,載氣經由管路80 向上行,其方式類似第2圖之示例說明。旋風器150係以 可確保經由本發明之方法生產的超细粒子極高收集效率的 方式設計與操作。使用旋風器可使極细粒子略攜載通過頂 出口80。雖然某些情況下,此乃非期望者,需進一步分離 去除過而可達肺臟肺泡區的粒子,例如,小於7wm的粒子 〇 下列實例僅供舉例說明而絕非視為囿限本發明之範圍 〇 貫驗 實驗1 噴乾設備構造如第2和4圖所示,該回合共處理20升 溶液。溶液含有250克(1.25wU)總固體,其中20%為胰島 素。固體之差額為甘露糖醇、氯化鈉和甘胺酸混合物。溶 液於4°C使用Watson Marlow脈動唧筒與矽膠管以約44ml/ min速率進料霧化器。真正進料速率係藉PID回路使用噴 乾器出口溫度作為控制變因控制◦霧化器溫控循環夾套有 本紙張尺度適用中國國篆系^(€奶)八4規格(210\ 297公釐) (請先閱讀背面之注意事項再填寫本頁) 錚 項再填. 裝· ,·--:1Τ 噃 -- 550089 A7 B7____ 五、發明説明(23 ) 4。0水循環通過其中。霧化器空氣經控流,使用針閥和轉 子流速計M12 scfm和38 psig測量。空氣和液體恰於流進 霧化器(Millipak 60和Millipore Wafergard II F-40線 上氣體過濾器)之前通過拋光濾器。粉末於55吋水柱壓 降收集於高效率旋風器。乾燥空氣流速藉交流控速系統於 100 scfm鼓風機傳動馬達控制,使用孔板和差壓轉換器於 鼓風機出口測量◦乾燥空氣溫度於時間分配PID回路和7.5 kW加熱器控制於130°C。四部收集器共回收225克粉末獲得 總產率90%。各個收集器内粉末分析示如表2。 表2 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製
屬性/方法 單 位 收集器1 收集器2 收集器3 收集器4 水,卡爾費雪 H2O %wt. 3·4% 2.8¾ 2Μ 3.0% 粒徑,Horiba Capa 700 MMD % < 5ym Ι.δμπι 100 1·4μι 100 100 1·4μπι 100 氣霧劑粒徑, 串級衝擊器 MMAD 3·3μιη 68% ND ND ND 輸藥劑效率, 重力吸入裝置 % ± SD 83±3 84±5 84±4 81±6 表面積 ra2/g 11.3 11.7 ND ND 縐摺度 3.8 3·9 ND ND 本紙張尺度適用中國國家榡準(CNS ) A4規格(210X 297公釐) 550089 A7 B7_____ 五、發明説明(24 ) 實例2 共處理2.4升溶液。溶液含有100克(4.0wt%)總固體, 其中20%為胰島素。固體之差額為甘露糖醇、氯化納和甘 胺酸混合物。實驗1使用的噴乾器用於本實驗。溶液於 4°C使用Watson War low脈動唧筒與矽膠管Μ隨出口溫度改 變之速率進料霧化器。真正進料速率係藉PID回路使用噴 乾器出口溫度作為控制變因控制。霧化器溫控循環夾套有 45°C水循環通過其中。霧化器空氣經控流,使用針閥和轉 子流速計以13.8 scfm和70 psig測量。空氣和液體恰於流 進霧化器(Millipak 60和Millipore Wafergard II F-40 線上氣體過濾器)之前通過拋光濾器。乾燥空氣流速藉交 流控速系統於95 scfm鼓風機傳動馬達控制,使用孔板和 差壓轉換器於鼓風機出口測量。乾操空氣溫度於時間分配 PID回路和7·5 KW加熱器控制於150°C乾燥出口空氣於70 , 75和80°C改變。各個設定溫度更換粉末收集器。各個收集 器内粉末分析示如表3。 m nn mi ml . .- nn - n I— «- 1-1— i .....- a— mi in n (請先閎讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標隼(CNS ) A4規格(21〇X 297公釐) 550089 A7 B7 五、發明説明(25 ) 表3 經濟部中央標準局員工消費合作社印製 屬性/方法 單 位 進氣70°C 進氣75°C 進氣30°C 水,卡爾費雪 H2O %wt· 2· 28 2.02 1.63 粒徑,Horiba MMD 2.41/im 2.69/im 2-43jum Capa 700 % < 5ium 100 82.3 100 輸藥劑量效率 % ± SD 71 土 3 73±3 71 土 2 平均表面積, m2/g±SD 6.76±.19 6±0·2 8.07±.12 Gemini微計量儀 縐摺度 3.6 3.9 3.8 (請先閱讀背面之注意事項再填寫本頁) 項再填办 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 經濟部中央榡準局員工消費合作衽印製 550089 A7 _____B7 五、發明説明(26 ) 實例3 噴乾器另外構造成附有殼袋外方嵌合燒结不鏽鋼纖維 過濾元件。(Fairey Microfiltrex)噴乾設備構造如第2 圖所示。 胰島素回合共處理8升溶液。溶液含有100克(1.25wU) 總固體,其中20%為胰島素◦固體之差額為甘露糖醇、氯 化鈉和甘胺酸混合物。溶液於4°C使用Watson Marlow脈動 唧筒與矽膠管以約55 ml/min速率進料霧化器。霧化器溫 控循環夾套有4°C水循環通過其中。霧化器空氣經控流, 使用針閥和轉子流速計M12 scfm和42 psig測量。空氣和 液體恰於流進霧化器(Millipark 60和Millipore Wafer-gard II F-40線上氣體過濾器)之前通過拋光濾器。乾燥 空氣流速藉交流控速系統於100 scfm鼓風機傳動馬達控制 ’使用孔板和差壓轉換器於鼓風機出口測量。乾燥空氣溫 度於Niro 7.5 KW加熱器控制於145°C。粒子收集係於經修 改的大西洋工程公司(加州阿尼罕)自清式腔室(殼袋或濾 器殼體)進行。殼袋帶入殼内並修改而可改變濾器數目。 籠和過據織物以兩個Fairey Microfiltrex(英國漢普夏) 燒結金屬纖維濾器替代◦反向脈衝(Μ高壓空氣回沖洗袋 子)過濾元件系統建於殻袋俾輔助回收。每20秒作動脈衝 少於1秒。脈壓110 PSig。粉末因重力與機械助力(振搖) 落至殼袋底。各個收集器內粉末分析示如表4。 尺度適用中國國家榡隼(CNS) A4規格(210X297公釐) m ^ϋϋ 1^1 ϋ^— m·— ϋϋ ml —fan·' HBJA ·ϋϋι« ^ ^ >1 mu 11 111 mi nl__— (請先閲讀背面之注意事項再填寫本頁) 550089 A7 B7 五、發明説明(27 ) 表4 屬性/方法 單 位 收集器 水,卡爾費雪 H2O %wt. 4.8% 粒徑,Horiba MMD 1.34iim Capa 700 % < 5iim 100¾ % < lAum 62¾ %〈 1·0 44¾ 輸藥劑量效率, % ± SD 73±2 乾粉裝置 (請先閱讀背面之注意事項再填寫本頁) 雖然前文已藉示例說明和實例說明本發明之若干细節 Μ求清晰瞭解,但顯然易知於隨附之申請專利範圍內可做 出某些變化與修改。 經濟部中央標準局員工消費合作杜印製 本紙張尺度適用中國國家標隼(CNS ) Α4規格(210Χ 297公釐) 550089 A7 B7 五、發明説明(23 ) 元件標號對照 10.. ..霧化操作 20----乾燥操作 30——分離操作 50.. ..噴乾器 52.. ..供應唧筒 54.. ..過滤器 56.. ..供應管路 57.. ..雙流體霧化噴嘴 53.. ..壓縮機60.66.82.. ..過濾器62.. ..管路 72.. ..過濾器殼體 74.. ..過濾介質 76····筒 80.. ..管路 84.. ..通風麽 90.. ..高壓氣體源 100.·..内導管 102.. ..外導管110,104____孔口 120.·..冷卻夾套 150----旋風器 (請先閱讀背面之注意事 丨# 項再填. 裝-- :寫本頁) 丁. 經濟部中央標準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)
Claims (1)
- 550089 六、申請專利範圍 第86108261號專利再審查案申請專利範圍修正本p年h 修正日期:92年6月 1· 一種製備生物性巨分子之可分散性乾粉的方法,該方法包 含: ’ 提供-可氣化性液體介質’其含有—預定漢度之生物性 巨分子,該生物性巨分子具有一大於2kD之分子量; 將該液體介質予以霧化;及 在加熱後的氣體流中乾燥該等小滴以產生粒子,該等粒 子具有-以空氣通透率測量為至少2 〇之_纟、低於1〇 重量%之溼度含量及小於10微米之粒子尺寸。 2·如申請專利範圍第!項之方法,其中該液體介質中之總固體 濃量係低於1 〇重量%。 3.如申請專利範圍第2項之方法,其令該液體介質中之總固體 濃量係低於5重量%。 Φ 4·如申請專利範圍第w之方法,其中該霧化條件係以欲形成 具有平均小滴尺寸小於丨丨以爪之小滴來選定。 5·如申請專利範圍第㈣之方法,其更包含收集該等粒子。 6·如申請專利範圍第旧之方法,其㈣%之質量的該分散性粉 末係由具有直徑在(Μ#—” m直徑之範圍内的粒子所組 成。 7·如申請專利範圍第旧之方法,其中㈣之質量的分散性粉末 係由具有直控在〇·4 # m至5 # m直徑之範圍内的粒子所組成。 8·如申請專利範圍第W之方法,其中該等小滴係與該加熱後 -32- 550089的氣體流同步流動 口溫度。 9· 以及其中該氣體流具有一高於90°C之入 如申請專利範圍第8項 °C之間。 之方法,其中該入口溫度係在12〇_2⑻ 10. 之方法,其中該氣體流具有一高於 高於50°c之出口溫度。如申請專利範圍第8項 110°C之入口溫度以及一 U·如申請專利範圍第10項 60-80°C 之間。 之方法,其中該出口溫度係在 12. 如申請專利範圍第5項之方法,其更包含在收集步驟後, 將至v些粒子包裝於一容器内,其中該等粒子於包裝前未 經尺寸檢選。 13·如申請專利範圍第12項之方法,其中該等粒子係被包裝於 一單位劑量容器中。14.如申凊專利範圍第旧之方法,其中該巨分子係選自於由 下列所構成之群組中:抑鈣素、紅血球生成素、第ιχ因子、 粒狀細胞群落刺激因子、粒狀細胞巨噬細胞群落刺激因子、 生長激素、胰島素 '干擾素^、干擾素点、干擾素,、間白 素-2、黃體化激素釋放激素(LHRH)、生長抑制素類似物、增 壓素類似物、濾泡刺激激素(FSH)、糊精、纖毛性神經營養 因子、生長激素釋放因子(GRF)、仿胰島素生長因子、促胰 島素激素、間白素-1受體拮抗劑、間白素、間白素·4、間 白素-6、巨噬細胞群落刺激因子(M_CSF)、神經生長因子、 副甲狀腺激素、胸腺素al、Ilb/HIa抑制素、α-1抗胰蛋白-33- 550089 六、申請 1¾¾¾ — ~- ~ 酶、抗-RSV抗體、去氧核糖核酸酶(DNase)、殺菌性/通透性 增高蛋白質(BPI)、抗-CMV抗體、間白素-1受體及間白素q 受體拮抗劑。 15 •如申請專利範圍第1項之方法,其中該等粒子包含有以空 Μ氣通透率測量為在3至6之範圍中的縐摺度。 、 種巨分子組成物,其係由如申請專利範圍第卜15項之方 法所製備者。-34-
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