TWI327073B - Dry powder inhale system for pulmonary administration - Google Patents

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丄327073 坎、發明說明 [發明所屬之技術領域] 本發明係關於適於經肺投與之新穎 έ4 袖粉末吸入奂 、先。更詳言之，本發明係關於在使用收容於容号 糸 =乾燥組成物時，藉由微粒化可調製成適於經肺二： 1蜊形態，並可以該形態直接吸入投盘 又，、之 粉末吸入系統。 又一肺投與用乾燥 再者，本發明係關於與該經肺投與用乾燥 統相關之下述技術。具體而言，此等技術例如 系 :調製成適於經肺投與之微粒粉末（經肺投與用乾燥於= 製劑)之冷束乾燥組成物’該經肺投與用乾燥粉末製劑： 造方法，使用上述冷純燥組成物之吸人或㈣投血方 法，以及在使用經肺投與用乾燥粉末製劑時用以 〇 凍乾燥組成物的使用等。 7 又，以下在本說明書中所謂「微粒」意指不論 鲁粉末（微粉末）狀、針狀、板狀或纖維狀，只要具有微細形 狀者皆包括在内。 / [先前技術] -般而言’已知經肺投與之時，藉由將醫藥品所含之 有效成分之平均粒徑製成1〇微米以下較佳5 可使該有效成分效率良奸地到達肺部。因此，目前的狀況 是:先前之經肺投與用吸入劑，為了預先將醫藥品原料製 成適於經肺投與之粒徑，用噴乾法及喷射磨法等調製成微 粒，或者再進行加工處理，麸尨收社，士 处然後將其填入吸入裝置來提供。 315314 6 1327073 具體而言’ 一直以步> a A 4-JL La i 已知乾無粉末吸入劑有三種. ⑴將只由藥物微粒組成之粉末狀組成物充填於適當容器 而成之製劑；(2)將藥物微粒輕輕地造粒成較大粒徑並將其 形成之粉末狀組成物充填於摘者交哭；々 、逋田今盗而成之製劑；以及（ 將藥物微粒與比該藥物微齟 .心祖位大之賦形劑粒子（乳糖 等）均-地混合並將所得混合粒子組成之粉末狀組成物充 填於適當容器而成之製劑（例如參照曰本專利特開平"· 1 7 1 7 6 0號公報等）。在此等 寻文獻中δ己載有：若將此等乾燥 粉末吸入劑投與至呼吸道内， ’、 円，則顯不有下列之舉動··（ j) 組成物中之該藥物微粒將到童 打Α違並，儿者於氣管及支氣管等下 呼吸道> (2)造粒之藥物飛杆於名、岩&& 、— 现仃杰軋暹内時解離成微粒，且生 成之樂物微粒將到達並沉菩於名其β 儿者於軋官及支氣管等下呼吸道； (3)賦形劑沉著於口腔内 因頭或喉頭’而只有藥物微粒到 達並沉著於氣管及支氣管等下呼吸道。 如上述，先前之經肺投與用乾燥粉末吸入劑係預先 將吸入成分製造成期望之嫩私* 乂别J：之嘁粒後，或者將該微粒用任合方 法加工後，充填於吸入裝置中，然後經肺投與。 、¥ S 了將低分子藥物微粒化，可以使用噴乾法(例 如特開平1 1-1 71760號公報蓉、月略& _ a 此A報寺）及噴射磨法（例如特開 2001-151673號公報等）箄。复由 哥）寺其中所用之噴射磨法，係將以 1000 L/min以上之空齑、.*旦 又二虱机里且經由音速以上之空氣速度生 成之空氣衝擊賦與低合i鏟札、，时# _ 、-刀子樂物亚將5玄樂物微粒化之方法， 但對於以低空氣衝擊將藥物微粒化之方法則尚未知悉。 另一方面，關於月太及蛋白質等高分子藥物，已知有例 315314 7 1327073 如將包含添加劑之醫藥原液之喷霧溶液用喷乾法以單牛 驟做成平均粒徑為s w 員乾法以早一步 裝置之方法(喷，去微米以下之微粒’並將其充填於吸入 質與添加劑—起 =例如W〇95/3㈣ 等微粒化並充V於 繼而將該冷;東乾燥物用喷射磨 法，例如鄭91/16038號等）。 雙射磨 疋用上文所示之喷乾法或喷射磨法調製 •肺投與用乾燥粉末吸入劑，尤其是對於肽及蛋白質i:: 子藥物而言’未必是理想的製刻。舉例言之：： W095/31479 ^ ^ 、^ 嬈中所記載之於噴乾步驟中干擾素約25%失 活，右藉由噴乾法，可以預知在製造步驟中蛋白質等之失 活以及藥物活性之降低。又，對於高分子藥物而言，亦與 低分子樂物相同，無法得悉藉由低空氣衝擊進行微粒化 方法。 Λ ^ 再者，無論對於噴乾法或冷凍乾燥·喷射磨法，其將調 籲製之微粉末從噴乾裝置或喷射磨裝ί回收並分成小部分充 填於容器中係為必要之操作。因此，伴隨該操作，不可避 免地會產生因回收及充填耗損造成之調製收率下降及隨之 而來之成本上升，以及夾雜物混入製劑等問題。又，一浐 而言，將粉末在微量下精確地分成小部分充填頗有困難^ 因此’對於必須在粉末狀態以微量分成小部分充填之喷乾 法及噴射磨法而言，高精確度之微量粉末充填法之確立當L 然有其必要。事實上，例如在美國專利公報第 號公報中，對於將微粉末進行粉末充填之系統、裳置及方 315314 8 法均有詳細之記栽。 [發明内容] 燥粉末吸人為解決關於上述先前經肺投與用乾 供-種可用於緩肺=題。具體而言，本發明之目的為提 將收容於容器内之二新賴製劑系統及投與系統，其中 ^ ^ ώ 7凍乾燥組成物在該容器中微粒化成適 於經肺投與之粒徑並直接吸入。 本發明者為達成 到地發現將做為有：八之藥伩反覆深入研究’意想不 頁政成分之樂理活性物質充填於容器中並 二，乂,燥法所調製而成之非粉末狀態之冷凍乾燥組成 ，错較低之空氣衝擊，可將直接收納於容器中者予以 士广基於該見解，本發明者進一步反覆研究，發現藉 由將以非粉末狀態收容於容器内之冷;東乾燥組成物，與具 備=賦與=成物㈣之空氣衝擊，將特定速度及流量 氣導入谷益内之手段及將微粒化之粉末組成物從容器 中排出之手段之裝置組合使用’使用者於使用時(尤其是吸 入時)將可簡單地將冷凍乾燥之非粉末製劑調製成適於經 肺投與之微粒狀態，因此藉由將該微粒直接吸入服用，將 可達成絰肺投與。再者’本發明者發現以液態充填於容器 之含藥理活性物質組成液’不限於其中之添加成分(尤其是 為有效成伤之樂理活性物質）澄明地溶於溶媒或澄明地混 合之情況，縱使此等添加成分以未溶於溶媒或非溶解狀態 存在，藉由特定之空氣衝擊，仍可調製成適於經肺投與之 微粒之冷凍乾燥組成物。因此，本發明者則肯定若藉由該 315314 9 1327073 經肺投與用乾燥粉末吸入系統，可以完全解 肺投與用乾：粉末吸入劑之相關問題。〜上述“經 亦p若依照本發明之經肺投與系統，ώ 進行微•化後再分成小部分充填於容器中：= = :::，可以應用於經肺投與。又，若依照= ,、、肺&與用乾燥粉末吸人系統，由於不像 製造步驟中為藥效成分之蛋白質及胜肽等項9 、。之 下，因此不合有s “昱+ 肽等須暴露於高溫 此咅味對於I 而造成藥理活性降低之問題。 對於為高價藥物之胜肽及蛋白質等藥 從經濟觀點而之經肺投與系統 。方為有用。再者，若依照 =燥粉ί吸入系統，可以得到極高之有效粒二= Η 、肺之Ϊ)’可以有效率地將藥物送到達肺部。 本發明之經肺投與用乾燥粉末吸入系統，其特徵為將 =有效成分之非溶解狀態組成液經冷; 東 末之塊狀形態之冷綱組成物做為經肺投與用製：； 吸二二製之塊狀形態之冷來乾燥組成物應用於乾燥粉末 前乾朴ΓΓ成之本發明乾燥粉末吸入系統，與依照先 =w末吸入劑所採用之如嘴射磨法或喷乾法預先將粒 =粒化成所要大小以適於經肺投與之粉末狀製劑應用於 =明之乾燥粉末吸入裝置之情況相比，可以得到顯著高 :有效粒子比率。因此’本發明之乾燥粉末吸入系統可以 疋位為向性能經肺投與系統。 本發明係基於以該見解而開發者，其包含下述形態。 315314 10 1327073 (第1項）一種經肺投與用之A、占 *凍乾燥組成物，係將包含非 溶解狀態之添加成分之組点泷 成液經冷凍乾燥而調製成，且具 有下述（i)至（i i i)之特性： (i) 具有非粉末之塊狀形態； (ii) 衰變指數為〇.〇5以上；以及 (i i i)藉由承受具有至1 % / ' Sec之空氣速度及至少1 7ml/sec 之空氣流量之空氣衝擊，可成為平均粒徑在ι〇微米以 下或有效粒子比率在1〇%以上之微粒。 (第2項）如第1項之冷决私、降&上 _ 東乾知組成物，係包含做為有效成 分之冋分子藥物。 (第3:貝）_種經肺投與用乾燥粉末製劑之製造方法，包含 在收谷下述冷♦乾燥組成物之容器中，使用可將下述空氣 衝擊賦與該容器内之冷康乾燥組成物之裝置，導入具備該 空氣衝擊能力之空氣’藉此使得上述冷床乾燥組成物形成 平句：仏I 10微米以下或有效粒子比率在10%以上之微 八x、中忒冷凍乾燥組成物藉由將包含非溶解狀態之添加 成分之組成液經冷凍乾燥而調製成，且具有下述⑴至（iii) (1)具有非粉末之塊狀形態， (⑴衰變指數為0.05以上，以及 ()藉由承叉具有至少im/sec之空氣速度及至少17ml/sec 之空氣流量之空氣衝擊，可成為平均粒徑在丨〇微米以 卜下或有效粒子比率在10%以上之微粒。 (弟 項）如第3項之經肺投與用乾燥粉末製劑之製造方 11 315314 1327073 法，其中，該冷凍乾燥組成物包含做為有效成份之高分 藥物。 门刀 (第5項）如第3項之經肺投與用乾燥粉末製劑之製造方 法，其十，使用在下述（A)或（B)令記载之乾燥粉末吸入裝 置做為裴置’將冷凍乾燥組成物微粒化： (A)經肺投與用乾燥粉末吸入裝置，其係將以非粉末狀態收 容於容器中之冷凍乾燥組成物微粒化並使被驗者吸入 所得微粒用之裝置，其特徵為具備： 具有空氣噴射流路之針部，具有排出流路之針部，在上 述針部之空氣喷射流路中輸送空氣用之空氣壓送手 段，以及與上述針部之排出流路連通之吸入口； 且構成為： 使上述針部扎入供密封上述容器之口栓以將空氣喷射 錢及排出流路與上述容器内部連通，並用上述空氣壓 、乂手奴使Λ氣絰由上述空氣喷射流路噴射於上述容器 内藉由该嘴射空氣之衝擊使上述冷;東乾燥組成物微粒 化，且得到之微粒經由上述排出流路從吸入口排出；或 ⑻燥粉末吸人裝置，其係將以非粉末狀態收 ,θ 中之~凍乾燥組成物微粒化並使被驗者吸入 付到之微粒用之農置’其特徵為具備： 具有吸引流路之針部’具有空氣導入流路之針部以及盘 上述吸弓丨流路連通之吸入口·， 且構成為： 315314 12 1327073 在上述針部扎入供密封上述容器之口栓之狀態，藉由使 用者之吸氣壓從上述吸入口吸入上述容器内之空氣，同 時使空氣經由上述空氣導入流路流入已成為負壓之容 器内’藉由流入之空氣衝擊將上述冷凍乾燥組成物微粒 化’且得到之微粒經由上述吸引流路從吸入口排出。 (第6項）一種經肺投與用乾燥粉末吸入系統，係將下述（1) 及（2)組合使用： (1)收容具有冷凍乾燥組成物之容器，該冷凍乾燥組成物係 將包含非溶解狀態之添加成分之組成液經冷凍乾燥而 調製成，且具有下述⑴至之特性： ⑴具有非粉末之塊狀形態， (Π)衰變指數為〇_05以上，以及 (iii)藉由承受具有至少im/sec之空氣速度及至少 之空氣流量之空氣衝擊’可成為平均粒徑在1 0微米以 下或有效粒子比率在10%以上之微粒； ⑺具備可將上述空氣衝擊賦與於上述容器内之冷决乾燥 手段以及排出經微粒化之粉末狀冷滚乾燥組 成物之手段之裝置。 (第7項）如第6項之經肺投與用乾燥粉末吸 中’在吸入時將上述容器與上述裝置纪合使用。 、 項）如第6項之經肺投與用乾燥 十’該冷凍乾燥組成物係包含、：’其 物。 …有效成伤之[fj分子藥 (第9項）如第 6項之經肺投與用 乾燥粉末吸入系統 ，其 J15314 13 1327073 中，使用下述（A)或（B)做為裝置： (A)經肺投與用乾燥粉末吸入裝置，係將以非粉末狀態收容 於容器中之冷凍乾燥組成物經微粒化並使使用者吸入 所得微粒用之裝置，係具備： 具有空氣喷射流路之針部，具有排出流路之針部，在上 述針部之空氣噴射流路中輸送空氣用之空氣壓送手 段’以及與上述針部之排出流路連通之吸入口； 且構成為： 使上述針部扎入供密封上述容器之口栓以將空氣噴射 流路及排出流路與上述容器内部連通，並用上述空氣壓 达手段使空氣經由上述空氣喷射流路喷射於上述容器 内，藉由該噴射空氣之衝擊使上述冷凍乾燥組成物經微 粒化，且得到之微粒經由上述排出流路從吸入口排出； 或者 (B)j肺投與用乾燥粉末吸入裝置，其係將以非粉末狀態收 谷於容器中之冷凍乾燥組成物經微粒化並使被驗者吸 入得到之微粒用之裝置，係具備： 具有吸引流路之針部，具有空氣導入流路之針部以及與 上述吸引流路連通之吸入口； 且構成為： ::述針部扎入供密封上述容―，…，錯由被 之吸軋壓從上述吸入口吸入上述容器内之介 時使空氣經由上述空氣導入流路流入已 ：、二 器内’藉由流入之空氣衝擊將上述冷 :…… 牝岛組成物經微 315314 1327073 粒化，且得到之微粒經由上述吸引流路從吸入口排出。 (第項）一種經肺投與方法，包含使用冷凍乾燥組成物， 該冷;東乾燥組成物係將包含非溶解狀態之添加成分之組成 液經冷;束乾燥而調製成，具有下述特性： (i)具有非粉末之塊狀形態， (Π)衰變指數為〇‘〇5以上，以及 (出）藉=承受具有至少lm/sec之空氣速度及至少Η⑹ 之空乳流量之空氣衝擊，可成為平均粒徑在丨〇微米以 下或有效粒子比率在10°/。以上之微粒； 使用時’藉由將上述空氣衝擊賦與該冷凍乾燥組成 物，形成平均粒徑在1〇微米以下或有效粒子比率在1〇% 以上之微粒’然後藉由令使用者吸人該經微粒化之粉末而 投與。 (第11項）如第10項之經肺投與方法，其中，該冷凌乾福 組成物係收容於容器内，以及該經微粒化之粉末係用具你 下遂手段裝置調製而成‘·可將上述空氣衝擊賦與該容器产 之、東乾燥、’且成物之手段以及可從容器中排出經微粒化之 粉末狀冷凍乾燥組成物之手段。 (第12項）如第1〇項之經肺投與方法，其中，該冷凍絮 燥組成物係包含做為有效成份之高分子藥物。 (第13項）如第U項之經肺投與方法，其中，使用在飞 述(A)或⑻中s己載之乾燥粉末吸入裝置做為裝置： (A) I : t與用乾燥粉末吸入裝置’係將以非粉末狀態收笔 方、今益中之冷；東乾燥組成物經微粒化並使使用者吸力 315314 15 丄似ϋ73 所得微粒用之裝置，係具備： :有空氣嘴射流路之針部，具有排出流路之針部，在上 述針部之空氣哈身、士 、 、、、/瓜路中輸送空氣用之空氣壓送手 又以及與上述針部之排出流路連通之吸入口 且構成為： 使上述針部扎入供穷 —口。 流路及排出流路盘：比一：“之口栓以將空氣喷射 … 〃、上述谷态内部連通，並用上述空氣壓 使二+虱鉍由上述空氣噴射流路喷射於上述容器 ^由ρ射空氣之衝擊使上述冷“燥組成物經微 ;:且仔到之微粒經由上述排出流路從吸入口排出； 或者 讲m (B)經肺投與用乾燥粉末^ ^ ^ ^ ^ ^ w 戒罝係將以非粉末狀態收容 ;令器中之冷/東乾燥組成物經微粒化並使被驗者吸入 得到之微粒用之裝置，係具備： 具有吸引流路之針部’具有空氣導人流路之針部以及與 上述吸引流路連通之吸入口； 且構成為： 在上述針#人供密封上述容器之口栓之狀態，藉由被 驗者之吸氣壓從上述吸入口吸入上述容器内之空氣，同 :使空氣經由上述空氣導入流路流入已成為負壓之容 斋内’错由流人之空氣衝擊將上述冷♦乾燥組成物經微 粒化，且得到之微粒經由上述吸引流路從吸人口排出。 (第14頁）種冷凍乾燥組成物在吸入式經肺投與之使 用，其中，該冷洗乾燥組成物係將包含非溶解狀態之添加 315314 16 1327073 成分之組成液經冷凍乾燥而調製成，且 ⑴具有非粉末之塊狀形態， 特在. (ii)衰變指數為〇.〇5以上，以及 (n〇糟由承受具有至少im/sec之空氣速度及至少pm丨/sec 二氣i之空氣衝擊，可成為平均粒徑在1 〇微米以 下或有效粒子比率在1 〇 %以上之微粒；並且 將該冷凍乾燥組成物粉末化使成為具有上述平均粒徑 或有效粒子比率之微粒來使用，。 (第B項）如第14項之冷凍乾燥組成物在經肺投與之使 ^，其中，該冷凍乾燥組成物被收容於容器内，以及該經 微粒化之粉末係用纟備可將上述空氣衝擊賦與該纟器内之 束乾燥組成物之手段以及可從容器中排出經微粒化之粉 末狀冷凍乾燥組成物之手段之裝置調製而成。 (第16項）” 14項之冷凍乾燥組成物在經肺投與之使 用，其中，該冷凍乾燥組成物係包含做為有效成份之高分 子藥物。 (第項）一種冷凍乾燥組成物在製造吸入式經肺投與之 乾燥粉末製劑之使用，纟中，該冷;東乾燥、组成物具有下述 特性： ⑴將包含非溶解狀態之添加成分之組成液經冷束乾燥而 調製成， - (11)具有非粉末之塊狀形態， (ui)衰變指數為〇 〇5以上，以及 (lv)藉由承受具有至少im/sec之空氣迷度及至少17m丨/sec 315314 17 叫/073 之空氣流量之空氣衝擊，可成為平均粒徑在10微米以 下或有效粒子比率在10%以上之微粒；並且 、於使用時，將該冷凍乾燥組成物經微粒化使成為具有 上>述平均粒徑或上述有效粒子比率。 "項）如第17項之冷凍乾燥組成物在製造經肺投與 用乾燥粉末製劑之徒用，f由 W之便用其中，S亥冷凍乾燥組成物係包含 做為有效成份之高分子藥物。 項）如第17項之冷凍乾燥組成物在製造經肺投盥 粉末製劑之使用H該冷綠燥組成物錢 产於谷益内，以及該經微粒化之粉末係用具備可將上述空 :衝擊賦與該容器内之冷; 東乾燥組成物之手段以及可從容丄 327073 坎, invention description [Technical Field of the Invention] The present invention relates to a novel έ4 sleeve powder inhalation 适于 suitable for pulmonary administration. More specifically, the present invention relates to a form suitable for transpulmonary two: 1 蜊 by micronization when used in a container 糸=dry composition, and can be directly inhaled and thrown in the form, Powder inhalation system. Further lung administration and drying. Further, the present invention relates to the following technique relating to the dry system for pulmonary administration. Specifically, such techniques are, for example, preparation of a cold-dried composition suitable for pulmonary administration of a particulate powder (dried by a lung to a formulation). The dry powder preparation for pulmonary administration: The method comprises the use of the above-mentioned cold-drying composition for inhalation or (4) blood administration, and the use of the freeze-dried composition when using a dry powder preparation for pulmonary administration. Further, the term "microparticles" as used in the present specification means that it is included in the form of a fine powder, a needle, a plate, or a fiber, as long as it has a fine shape. / [Prior Art] - Generally speaking, it is known that when the lung is administered, the effective particle size of the active ingredient contained in the pharmaceutical product can be made less than 1 micron and preferably 5, and the effective ingredient can be effectively raped. The ground reaches the lungs. Therefore, the current situation is: the prior inhalation of the lungs, in order to prepare the pharmaceutical raw materials in advance for the particle size to be administered by the lungs, and to prepare the particles by spray drying and jet milling, or The processing is carried out, and the bran is collected, and the department then fills it into the inhalation device to provide it. 315314 6 1327073 Specifically, 'Always Steps' a A 4-JL La i There are three types of dry powder-free inhalers known. (1) A preparation in which a powdery composition consisting only of drug particles is filled in a suitable container; (2) Gently granulating the drug particles into a larger particle size and filling the powdered composition into a crying; sputum, sputum, and the smuggled preparation; and (the drug particles and ratio The drug is micro-cluster. The excipient particles (lactose, etc.) of the heart ancestor are uniformly mixed and the powdery composition composed of the obtained mixed particles is filled in a suitable container (for example, refer to the patent of the patent) ;· 1 7 1 7 6 0, etc.). In these documents, δ contains: If these dry powder inhalants are administered into the respiratory tract, ', 円, then the following actions are not included. · (j) The drug particles in the composition will go to the children's snoring, and the children will be in the lower respiratory tract such as the trachea and bronchi. (2) The granulated drug fly rod is named, rock && When Jie Jie rolled Siam, it dissociated into particles, and the generated music particles will arrive and sink in the name. β children in the lower respiratory tract such as rolling officials and bronchial tubes; (3) the excipients are deposited in the mouth due to the head or throat 'only the drug particles reach and sink in the lower respiratory tract such as the trachea and bronchi. As mentioned above, the previous lungs are administered. The inhalation component is preliminarily prepared into a desired powder by using a dry powder inhaler, or the microparticles are processed by any combination method, filled in an inhalation device, and then administered through the lungs. ¥ S The micromolecular drug is micronized, and the spray drying method can be used (for example, JP-A No. 11-1 71760, Rong, Yuelu & _ a, this A-ji Temple) and jet-grinding method (for example, JP-A-2001-151673) No. bulletin, etc.) 箄 复 复 复 ) 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复The method of micronizing the shovel, the shovel, the _ _, and the knives, and the method of atomizing the drug with low air impact is not known. On the other hand, regarding a polymer drug such as taiyue and protein, there is a known example of 315314 7 1327073. For example, a spray solution of a pharmaceutical stock solution containing an additive is spray-dried by a single bolus to have an average particle diameter of sw. In the method of the first step (spray, remove the particles below the micron' and fill it with the inhalation and the additive - such as W〇95/3 (four), etc., and then fill the V and then the cold; Grinding method, such as Zheng 91/16038, etc.). Double shot grinding is prepared by spray drying or jet milling as shown above. • Lung administration with dry powder inhalers, especially for peptides and protein i:: sub-drugs, is not necessarily ideal. For example: W095/31479 ^ ^, ^ 娆 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰Reduced activity. Also, for polymer drugs, as with low molecular music, it is impossible to understand the method of micronization by low air impact. Further, in the case of the spray drying method or the freeze drying/jet milling method, it is necessary to reclaim the fine powder from the spray drying device or the jet mill and fill it into a small portion. Therefore, with this operation, problems such as a decrease in the modulation yield due to recovery and filling loss, an increase in cost, and an incorporation of inclusions into the preparation are inevitably caused. Moreover, in a glance, it is difficult to accurately divide the powder into small portions under a small amount. Therefore, it is highly accurate for the spray drying method and the jet milling method which must be filled in a small amount in a powder state. The establishment of a micro-powder filling method is necessary for L. In fact, for example, in the U.S. Patent Gazette No., the system for the powder filling of the fine powder, the skirting method, and the method of the 315314 8 are detailed. [Summary of the Invention] The dry powder is inhaled to solve the problem that the above-mentioned previous lung administration can be used for slowing down the lungs. Specifically, the object of the present invention is to provide a two-in-one formulation system and a delivery system that are contained in a container, wherein the freeze-dried composition is micronized in the container into a particle size suitable for pulmonary administration. And inhaled directly. In order to achieve the discovery, the inventors will do as follows: the eight medicines and the in-depth study of the 'intentional non-page ingredients of the music active substance filled in the container and two, 乂, dry method to prepare the non-powder state The freeze-dried composition, the low-impact air impact, can be directly stored in the container, based on the knowledge, the inventors further studied and found that the container was kept in a non-powder state in the cold; The composition is combined with a device that has an air impact of ====(4), a means for introducing a specific velocity and a flow rate into the valley, and a means for discharging the micronized powder composition from the container. When used (especially when inhaled), the lyophilized non-powder formulation can be simply prepared into a particulate state suitable for administration via the lung, so that by direct inhalation of the microparticles, silicosis can be achieved. Further, the present inventors have found that the composition containing the pharmacologically active substance in the liquid state is not limited to the case where the added component (especially the active ingredient for effective wounding) is clearly dissolved in the solvent or is clearly mixed. Even though these additional ingredients are present in an undissolved or non-dissolved state, the freeze-dried composition suitable for pulmonaryly administered microparticles can be made by specific air impact. Therefore, the present inventors have confirmed that if the dry powder inhalation system is administered by the lung by the 315314 9 1327073, the problem of the dry administration of the powder: inhalation can be completely solved. ~ The above-mentioned "Phase also p according to the present invention, the sputum administration system, 进行 micro-chemicalization and then divided into small parts filled in the container: = = :::, can be applied to the lungs. Also, according to = , , , lung & and the use of dry powder inhalation system, because unlike the protein and peptides in the manufacturing step are the ingredients of the drug 9, and therefore do not have s "昱 + peptides must be exposed to High temperature This astringency causes a problem of reduced pharmacological activity for I. For peptides and proteins such as high-priced drugs, the lungs are administered from an economic point of view. The party is useful. Furthermore, if you follow the = dry powder ί inhalation system, you can get extremely high effective granules 2 = Η, lung Ϊ Ϊ) can efficiently deliver the drug to the lungs. The dry powder inhalation system for pulmonary administration according to the present invention is characterized in that the non-dissolved state composition liquid of the active ingredient is cooled; the cold form composition of the block form of the east end is used as a transpulmonary administration system; The cold-dried composition of the block form of the second and second forms is applied to the dry powder inhalation system of the present invention before drying the powder, and is sprayed or spray dried according to the first inhalation of the inhaler. The method can be obtained by previously granulating the granules to a desired size to be suitable for the application of the powdered preparation administered by the lungs to the dry powder inhalation device of the spleen, and a significantly higher ratio of effective particles can be obtained. Thus, the dry powder inhalation system of the present invention can be placed in a performance-to-performance pulmonary administration system. The present invention is based on the findings of the developer, and includes the following aspects. 315314 10 1327073 (Item 1) A composition for pulmonary administration, which comprises a composition comprising a non-dissolved additive component, which is lyophilized and has the following (i) to (iii) characteristics: (i) having a non-powder block form; (ii) a decay index of 〇.〇5 or more; and (iii) by withstanding an air velocity of up to 1% / 'sec And an air impact of an air flow rate of at least 17 ml/sec may be a particle having an average particle diameter of less than 10 μm or an effective particle ratio of 1% or more. (Item 2) The composition of the cold, the private, the lower, and the upper _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (3rd: Bay)_ A method for producing a dry powder preparation for transpulmonary administration, which is contained in a container of the following cold-drying composition of the trough, which can be used to impart the following air impact to the cold bath in the container. a device for drying a composition, introducing air having the air impact capability', thereby causing the above-mentioned cold-bed-dried composition to form a flat sentence: 仏I 10 μm or less or an effective particle ratio of 10% or more. The composition is prepared by freeze-drying a composition liquid containing an additive component in an undissolved state, and has the following (1) to (iii) (1) a non-powder block form ((1) a decay index of 0.05 or more, And () by means of an air impact having an air velocity of at least im/sec and an air flow rate of at least 17 ml/sec, the particles having an average particle diameter of 丨〇micron or an effective particle ratio of 10% or more can be obtained. (Personal) The method for producing a dry powder preparation for transpulmonary administration according to the third aspect of the invention, wherein the freeze-dried composition comprises a high-scoring drug as an active ingredient. The door knife (item 5) Item 3 A method for producing a dry powder preparation, which is obtained by using a dry powder inhalation device described in the following (A) or (B) as a device to micronize the freeze-dried composition: (A) for pulmonary administration a dry powder inhalation device which is a device for atomizing a freeze-dried composition which is contained in a container in a non-powder state and inhaling the obtained fine particles, and comprising: a needle portion having an air jet flow path, a needle portion of the discharge flow path, an air pressure feed means for conveying air in the air injection flow path of the needle portion, and a suction port communicating with the discharge flow path of the needle portion; and configured to: thread the needle portion a port plug for sealing the container to communicate the air ejection money and the discharge flow path with the inside of the container, and the air pressure is used to spray the helium gas into the container by the air jet flow path by the air jet The impact of the air causes the above-mentioned cold; the east dried composition to be micronized, and the obtained fine particles are discharged from the suction port through the discharge flow path; or (8) the dry powder inhaling device, which is to be in a non-powder state, θ In the case where the freeze-dried composition is micronized and the subject inhales the particles to be used, the present invention is characterized in that: the needle portion having the suction flow path has a needle portion having an air introduction flow path, and the suction plate of the disk a suction port that communicates with the flow path, and is configured as: 315314 12 1327073. The needle is inserted into the mouth of the container to seal the mouth of the container, and the air in the container is sucked from the suction port by the suction pressure of the user. At the same time, air is introduced into the container which has become a negative pressure through the air introduction flow path, and the freeze-dried composition is atomized by the inflowing air impact, and the obtained fine particles are discharged from the suction port through the suction flow path. (Item) A dry powder inhalation system for pulmonary administration, which is used in combination with the following (1) and (2): (1) accommodating a container having a freeze-dried composition, which will contain a non-dissolved state The component liquid of the added component is prepared by freeze-drying, and has the following characteristics (1): (1) having a non-powder block form, (Π) decay index being 〇_05 or more, and (iii) borrowing An air impact capable of with an air velocity of at least im/sec and at least an air flow rate can be a particle having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; (7) having the above-mentioned air impact can be imparted to the above A means of drying in a container and means for discharging the micronized powdered cold-rolled composition. (Item 7) The lungs are administered by dry powder according to item 6. The container is used in combination with the above device at the time of inhalation. (Item) The transpulmonary administration of the sixth aspect of the invention is as follows: The freeze-dried composition comprises: ...effective wounds [fj molecular medicine (item 9), as in item 6, the dry powder inhalation system for transpulmonary administration, in J15314 13 1327073, using the following (A) or (B) as a device: A) A dry powder inhalation device for pulmonary administration, which is a device for micronizing a freeze-dried composition contained in a container in a non-powder state and allowing a user to inhale the obtained microparticles, having: an air jet flow path a needle portion having a needle portion for discharging a flow path, an air pressure feed means for conveying air in the air injection flow path of the needle portion, and a suction port communicating with the discharge flow path of the needle portion; The needle portion is inserted into the mouth plug for sealing the container to communicate the air jet flow path and the discharge flow path with the inside of the container, and the air is sprayed into the container through the air jet flow path by the air pressure means. The impact of the jet air causes the freeze-dried composition to be micronized, and the obtained fine particles are discharged from the suction port through the discharge passage; or (B) j the dry powder inhalation device for lung administration, which is not The device for pulverizing and drying the freeze-dried composition in the container in the container and allowing the sample to be inhaled by the subject includes a needle portion having a suction flow path, a needle portion having an air introduction flow path, and the above a suction port that is connected to the suction passage; and is configured to:: the needle portion is inserted into the sealing chamber for sealing, and the air is passed through the air when the suction pressure is sucked into the container from the suction port. The inflow of the introduction flow path has been carried out: "The inside of the two devices is cooled by the inflow of air: ... The composition of the island is granulated by the micro-315314 1327073, and the obtained fine particles are discharged from the suction port through the suction flow path. (Item) A method of pulmonary administration comprising using a freeze-dried composition, wherein the composition of the additive component comprising an additive component in an undissolved state is prepared by cold drying; : (i) having a non-powdered block form, (Π) decay index of 〇'〇5 or more, and (out) borrowing; bearing an air impact with an air velocity of at least lm/sec and an air flow of at least Η(6), It may be an average particle diameter below 丨〇micron or an effective particle ratio of 10°/. The above particles; when used, by applying the above air impact to the freeze-dried composition, forming particles having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more, and then by inhaling the user The micronized powder is administered. (11) The method according to claim 10, wherein the cold-drying composition is contained in a container, and the micronized powder is prepared by means of a squatting device. The above-mentioned air impact imparts to the container, the means of drying, and forming, and means for discharging the micronized powdery freeze-dried composition from the container. (12) The method of transpulmonary administration according to the first aspect, wherein the frozen flocculating composition comprises a polymer drug as an active ingredient. (Item 13) The method of transpulmonary administration according to item U, wherein a dry powder inhalation device loaded in the fly (A) or (8) is used as the device: (A) I : t with dry powder The inhalation device is a device that will receive the pen in a non-powder state and is cooled in the present; the device that is micronized by the east drying composition and allows the user to suction 315314 15 like ϋ73, has:: air nozzle jet The needle portion of the road has a needle portion for discharging the flow path, and the air pressure feed hand for conveying air in the air body, the air, the body, the body, the body, and the melon road of the needle portion is connected to the discharge flow path of the needle portion. The suction port is configured to: insert the needle portion into the poor port. Flow path and discharge flow path disk: ratio one: "the port plug is used to spray air... 〃, the above-mentioned valley state is connected internally, and the air pressure is used to cause two + 喷射 to be sprayed into the container by the air jet flow path. The impact of the injected air causes the above-mentioned cold "dry composition to pass through;; and the particles that have been taken out are discharged from the suction port through the above-mentioned discharge flow path; or m (B) through the lung for dry powder ^ ^ ^ ^ ^ ^ w The sputum sputum system is housed in a non-powder state; the device for pulverizing the cold/east dry composition in the device and allowing the subject to inhale the obtained particles has: a needle portion having a suction flow path having an air guide a needle portion of the human flow path and a suction port that communicates with the suction flow path; and configured to suck the container from the suction port by the suction pressure of the subject in a state in which the needle is sealed by the needle The air inside is the same as that: the air is introduced into the flow path through the air into the negative pressure, and the cold-drying composition is atomized by the air impact of the flowing person, and the obtained particles pass through the suction flow. The road is discharged from the population. (p. 14) a lyophilized composition for use in an inhaled pulmonary administration, wherein the cold-washed dry composition is prepared by freeze-drying a composition comprising an undissolved component of 315314 16 1327073. And (1) has a non-powder block form, in particular. (ii) the decay index is 〇.〇5 or more, and (n〇 is subjected to an air velocity of at least im/sec and at least pm丨/sec. The air impact may be a fine particle having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more; and the freeze-dried composition may be powdered to be a fine particle having the above average particle diameter or effective particle ratio, and used. (Item B) The freeze-dried composition of Item 14 is administered by pulmonary administration, wherein the freeze-dried composition is contained in a container, and the micronized powder is used in preparation The above-mentioned air impact imparts a means for imparting a bundle drying composition in the crucible and a means for discharging the micronized powdery freeze-dried composition from the container. (Item 16)" 14 items of freezing Drying group The product is administered by transpulmonary administration, wherein the freeze-dried composition comprises a high molecular drug as an active ingredient. (Part 1) A freeze-dried composition is produced in an inhaled dry powder formulation for pulmonary administration Use, 纟中, the cold; East dry, the composition has the following characteristics: (1) The composition liquid containing the additive component in an undissolved state is prepared by cold-blown drying, - (11) has a non-powder block form, (ui) the decay index is 〇〇5 or more, and (lv) can be average particle size by withstanding an air impact having an air density of at least im/sec and an air flow of at least 17 m丨/sec 315314 17/073 Particles having a ratio of 10 μm or less or an effective particle ratio of 10% or more; and, at the time of use, the freeze-dried composition is micronized to have an average particle diameter of the above > or the above effective particle ratio. The freeze-dried composition of item 17 is used for the manufacture of a dry powder preparation for transpulmonary administration, and the composition of the lyophilized composition of the hexa-containing freeze-dried composition contains a polymer drug as an active ingredient. As the 17th The freeze-dried composition is used in the manufacture of a pulmonary-administered powder preparation. The cold-green dry composition is produced in Guyi, and the micronized powder is used to impart the above-mentioned void: impact to the container. Cold; East means of drying the composition and calm

::排出經微粒化之粉末狀冷来乾燥組成物之手 凋製而成β τ I (第20項）一種包含非溶解狀態之添加成分之組成液之使 •I燥=製造供調製經肺投與用乾操粉末製劑用之冷束 、' 冷凍乾燥組成物具有下述特性： (0具有非粉末之塊狀形態， (1丨）衰變指數為0·05以上，以及 ㈣藉=受，有至少lm/，之空氣速度及至少丨一 之王轧流ir之空氣衝擊，可成為平均粒徑在1 下或有效粒子比率在10%以上之微粒； …卡 子比^且於使用時經微粒化為上述平均粒徑或上述有效粒 (第21 項）如第20項之包含非溶解狀態之添加成分之組 315314 18 1327073 成液之使用，其中， 份之南分子藥物。 s亥冷;東乾燥組成物 係包含做為有效成 (第22項）如第20項之包含非 成液之使用1中，該冷束乾==之：加成分之組 以及該經齡化之粉末係用具 容器内’ 容器内之冷康乾燥組成物之手段以及可：：：衝擊賦與該 粒化之粉末狀冷康乾燥組成物之手段之裝置調製而: [實施方式] 堂施發明之最佳开4能 (1)冷来乾燥組成物 本發明之冷康乾燥組成物，係藉由將包含非溶解狀態 之添加成分之組成液以液態充填於容器並直接將其冷凌乾 無而調製成之非粉末之乾燥狀態組成物。其較佳為將包含 早次或數次投與有效量（以包含單次投與份之有效量為特 佳）之有效成分之非溶解狀態組成液經冷凍乾燥而調製成 之冷凍乾燥組成物。 本發明之冷凍乾燥組成物，藉由選擇及調製上述組成 液之組成（有效成分，以及與有效成分併用之載劑之種類及 用量）以使冷凍乾燥處理所得之非粉末組成物之衰變指數 在0.05以上，將可藉著被導入（流入）容器内之空氣衝擊（空 氣衝擊、喷射壓），瞬間或快速地微粒化成適於經肺投與之 其中’在本發明中所謂之哀變指數，係對於冷;東乾燥 组成物’依照下述方法測得之該冷凍乾燥組成物之固有 !9 315314 1327073 值： <衰變指數> 在筒徑018 mm或筒徑0 23贿之容器中，以液態充 填0.2至〇.5 ml之組成液（該組成液含有以才籌成冷來乾燥电 成物為標的之成份）並將其冷；東乾燥。繼而，在得到之非粉 末狀冷凍乾燥組成物中，經由容器壁靜靜地滴入正己烷丨 nU。將其於3_ rpm授拌約1()秒所得之混合液投入光路 長1職，総寬Π)随之㈣室，快速地用分光光度計 測定在波長500 nm $ ^ 之濁度。將所得濁度除以構成冷凍乾 燥組成物之成份之總量（重量），其所得之值定義為衰變指 數。 ”中本發明之冷/東乾燥組成物所具有之衰變指數 下限值為上述之0.05,其理想依序以〇 〇8 〇 〇9 〇 Η "、 〇·12為佳，又以013為最佳。 又，關於本發明之冷束乾燥組成物之上限值，雖 別限定，但以1 5盔龢杜 …、付 .、較佳’其理想依序以〇. 9、〇. 8、〇 7 〇·6’特別是G·5為最佳。本發明之冷;東乾燥組成物宜以005 以上為限度，以及期望 m具有在從上述者任意選出之下 44上限值構成之範圍内 值 關内之哀變指數。衰變指數之範圍，且 體而…"。為 〇.〇5 至 Μ，0.08^.5,〇 〇…；、 至。.9’O.iO 至。.8,至。7,〇1至〇6 及。 本發明之以乾燥組成物為可藉由冷康乾燥 粉末之塊狀形態者。在太 攻非 組成物意指將含有效成八二S'非粉末狀之冷束乾燥 成刀之組成液經冷凍乾燥所得之乾燥 315314 20 iW7073 固體’通常被稱為冷凍乾焯 之處理中，塊體產生===乾燥步驟或其後 分破損成為粉狀者，只要不r :固大塊者、M及部 明所針對之非粉末狀冷;東乾；=明；效果，皆係本發 非粉末之塊狀形態之冷凌乾燥、组成物巾。 、有 本發明之Μ乾燥組成物’為將上述包含非溶解狀能 之添加成分之組成液經冷凍 心' …以上之衰變指數以Λ 製 其特徵為具 ， 扎數以及非粉末之塊狀形態，而且Λ於 以上述哀變指數表現之該冷純燥組成物之时性了 由承受具有至少一之空氣速度及至少17 : 轧流量之空氣衝擊，可 工 乂形成為平均粒徑為J 〇微米以 有效粒子比率為10%以上之微粒。 一飞 就理想之冷康乾燥組成物而言，藉由承受上述空氣之 列如可以形成平均粒徑為10微米以下（較佳5微米 以下）’或者有效粒子比率A 1G%以上（較佳2G%以上，更 佳25/°以上’最佳3〇%以上，特佳35%以上）之微粒。 又賦與冷凍乾燥組成物之空氣衝擊，若藉由具有丄 油“以上之空氣速度及17ml/se。以上之空氣流量之空氣 產生之衝擊’則無特別限制。具體而言上述之空氣衝擊 例如為藉由1 m/seC以上，較佳為-2 m/sec以上，更佳為5 m/secu上’最佳為1〇m/sec以上之空氣速度生成之衝擊。 其中，關於空氣速度之上限，雖無特別限制，但通常為3〇〇 :/s:c ’較佳為250 m/sec以上，更佳為2〇〇 m/sec以上， 最佳為150 m/sec以上。又，空氣速度，只要在從上述中 315314 21 1327073 ^壬意選出之下限及上限所構成之範圍内，則無特別限制。 具體而言，為 1 至 300 m/sec ’ 1 至 250 m/sec，2 至 250 m/sec ’ 5 至 250 m/sec，5 至 200 m/sec，1〇 至 200 m/sec， 至150 m/sec之範圍。 又，上述之空氣衝擊，例如通常藉由17 ml/sec以上， 奴佳20 ml/sec以上’更佳25 ml/sec以上之空氣流量產生 之衝擊。其中，空氣流量之上限’雖無特別限制，例如可 為 900 L/min，依序以 15 L/sec、1〇 L/sec、5 L/sec、4 L/See 為佳，又以3L/Sec為最佳。具體而言，空氣流量只要在上 述中任思選出之下限及上限所構成之範圍内，則無特別限 制。該範圍例如為17 ml/sec至15 L/sec，2〇 mi/sec至Μ L/sec > 20 ml/sec 5 L/sec > 20 ml/sec J. 4 L/sec > 20 ml/sec 至 3 L/Sec，25 ml/sec 至 3 L/sec。 在本發明中所使用之有效成分，原貝·]上只I可作為妙 :技，用乾燥粉末吸人劑之成份之具有任何藥理活性 • ^ 活：物質：以下亦可簡稱為藥物)’則無特別限 分子藥物二低分子藥物及高分子藥物。又高 酵$、激素及抗體4蛋白質（包含胜肝 及多肽）以及DNA月月肽 八及rna等核酸（包含基因及cDN 生理活性成分。 ，」< 又’做為藥物之f « „ . 子象疾病者，視情況，可為全身療法 及局部療法二種。 % m击 做為低分子藥物纟，例如為皮f cortisone)、去 ~ 反貝％ (hydro- 風可體醇（prednisol〇ne)、去炎於 315314 22 1327073 (triamcinolone)、***（dexamethas〇ne)、倍他米松 (betamethasone)、倍氣米松（bec丨〇methas〇ne) ' 氟提卡松 (fluticasone) ^ 莫美他松（mometasone)、可滅喘 (budesonide)、沙 丁胺醇（salbutam〇1)、沙美特羅 (salmeterol)、丙卡特羅（pr〇cater〇i)、鹽酸丁丙諾非 (buprenorphine hydr〇chloride)、阿嘆嗎啡（ap〇m〇rphine)、 紫杉醇（taxol)及妥布黴素（t〇bramycin)等抗生物質。 做為咼分子藥物（蛋白質類及核酸等生理活性成分） 者，例如干擾素U，/5，7 )、間白素（例如間白素]、2 ' 3、4、5、6、7、8、9、10、η、12、13、14、15、16、17、 18等）、抗間白素-1α抗體、間白素“受體、間白素受體 拮抗劑、間白素-4受體 '抗間白素_2抗體、抗間白素-心 受體抗體、間白素-4拮抗劑、間白素_6_拮抗劑、抗間白素 -8抗體、化學趨素受體拮抗劑、抗間白素_7受體、抗間白 素-7抗體、抗間白素-5抗體、間白素_5受體、抗間白素_ 9抗體、間白素-9受體、抗間白素_1〇抗體、間白素-1〇受 體、抗間白素-14抗體、間白素_14受體、抗間白素_丨5抗 體、間白素-受體、間白素_18受體、抗間白素_18抗體= 紅血球生成素（ΕΡΟ)、紅血球生成素衍生物、顆粒球群落 刺激因子（G-CSF)、顆粒球巨嗟細胞·群落刺激因子 CSF)、巨噬細胞·群落刺激因子（M_CSF)、降鈣素、胰島 素、騰島素衍生物（LisPro、NovoRapid、h〇E9〇1、NN 3〇4 等）、促胰島素激素、類胰島素生長因子、升糖素、生長抑 素（somatostatin)或其之類似物、血管升壓素（vas〇pre =幻 315314 23 1327073 或…之類似物、騰激粉樣酵素請、人 黃體《激素釋出激素、卵泡刺激激素、成二 子、田曱狀腺激素、血管内皮細胞成長因子、血小板衍生 -增殖因子、角質細胞成長因子、上皮細胞成長因子、纖維 •母細胞成長因子、來自腦之神經營養因子、毛樣體神經營 養因子、腫瘤壞死因子(TNF)、TNF受體、TNF抑制劑、 轉形成長因子(TGF)、肝細胞成長因子(HGF)、神經成：因 籲子（GF)血液幹細胞成長因子、企小板增殖因子、納利 尿胜肽、血液凝固因子、血液肝細胞成長因子（s_Ca)、 FLT3配位體、抗血小板凝聚抑制單株抗體、組織•纖維蛋 白/令酶原•活化因子或其之衍生物、超級歧化氧化酶、反 義醫藥、免疫抑制劑（例如環孢素、塔可羅利姆斯（tacr〇Hms) 水合物等）、癌抑制基因p53、囊胞性纖維症膜貫通型調節 蛋白（CFTR)基因、RNA干擾素（RNAi)、架橋核酸、 α二抗胰蛋白酶、促血小板生成素（thr〇mb〇p〇ietin，丁p〇)、 •血&生成抑制素（metastasin)、去氧核糖核酸酶（膽、 催礼激素、催產素、促甲狀腺激素釋放激素、殺菌 性/透過性增加蛋白質(Βρι)以及流行性感冒疫苗、愛滋病 疫苗、輪狀病毒疫苗' 瘧疾疫苗以及Mtb72f等結核疫苗等 疫苗製劑等。 此等有效成分可以使用單獨一種，或組合使用2種以 上又，上述各種胜肽類亦包含天然型多肽、基因重組型 多肽、藉由化學合成之多肽等。 又，此等有效成分，可以使用本身游離態或鹽狀態者。 315314 24 1327073 又可以使用被保持為任意之保持 1 八％有 關於該俘拄 體，右為可使有效成分（例如包 、夺 一此 匕3蛋白^類及核酸等高分早 樂物及合成低分子藥物)以任意之附著，存在形態(吸 包、包接、離子結合等)保持者，則無特別限制，例 脂質膜構造體、微膠囊、環糊精、樹狀分子(dendri_、’: 微米球粒、奈米膠囊及奈米球粒等…其中脂質膜構造 體包含單層膜脂質體及多層脂質體等脂質體、〇/w型或 w/o/w型礼液、球狀膠體粒子、細带狀膠體粒子及層狀j 造物等。 又，所謂「樹狀分子」，一般而言，為分子之鏈依據— 定之規則，從中心向外方三次元地形成規則擴大之形狀之 分子。樹狀分子具有球狀構造，在其之内部具有攝入藥物 之空間，並有做為奈米膠囊之機能。為了在樹狀分子内部 中保持藥物，已知有下述方法：1)利用樹狀分子内部與藥 物之相互作用（疏水性相互作用及靜電相互作用等），或2) 在樹狀分子表面形成緻密胞室構造，物理性地捕集藥物等 (文獻：河野健司：Drug Delivery System，17-6，462-470 (2 002))。又’實施例所使用之Superfect係由具有一定形 狀之活性型樹狀分子形成（文獻：Tang，M.X，Redem.ann， C.T·以及 Szoka，Jr. F.C : In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjugate Chem. 7,703 (1 996))。此等分子從中心分枝，藉由在終端具有带正電荷 之胺基’並與核酸之碌酸基（带負電）交互作用而構成。又， SuperFect為了容易將DNA及RNA導入細胞中，具有將 25 315314 1327073 DNA及RNA凝縮成緻密形態之性質。 做為較佳之保持體者，可例舉如：脂質體、樹狀分子、 反錄病毒載體、腺病毒載體、腺病毒-伴隨病毒、慢病毒 (lentlVlrUS)、單純疱疹病毒載體、HVJ(仙台病毒）-脂質體 (例如HVJ外套載體套組等）。 其中脂質膜構造體及樹狀分子等之保持體，由於可將 外來基因導入細胞内，所以比先前應用廣泛。在本發明中， 鲁可同樣地使用基因導入用脂質體及基因導入用樹狀分子。 又，此等可從商業上獲得。 又保持體之粒徑（幾何學之平均粒徑：用動態光散射 或田射折射及散射法測定），若在1 0微米以下，則無特 别限制。較佳為5微米以下。例如脂質體及乳液，粒徑（幾 何予之平均粒杈）為50 nm至數从m，球狀膠體粒徑為5至 50 nm。 又，關於幾何學之平均粒徑之測定方法，一般而言， •對於數十奈米領域之粒子之粒度分布，可使用動態光散射 去對於數十微米以上之粒子之粒度分布，可使用雷射折 射及散射法測定，其間數百奈米與數微米領域之粒子之粒 度分布測定，皆可使用任一測定方法。 關於有效成分在此等保持體中之保持形態，雖無特別 J例如在月曰貝膜構造體之情況，例如有在脂質膜構造 體之膜中、表面、内部、脂質層中或脂質層表面任意附著/ 存在之形態。 關於形成該保持形態之方法，例如為在脂質膜構造體 315314 26 1327073 等保持體與有效成分(基因等)之混合乾燥物中添加水系溶 媒，然後用均質器等乳化機乳化或懸浮之方法；在將脂質 膜構造體等保持體溶於有機溶媒後，餾去溶媒所得到之乾 燥物中，再添加包含基因之水系溶媒以乳化之方法在已 分散於水系溶媒之脂質膜構造體等保持體中，再添加白含 有效成分（基因等）之水系溶媒之方法；將脂質膜構造^等 保持體分散於水系溶媒後乾燥所得之乾燥物添加於包含有 效成分（基因等）之水系溶媒之方法（參照特開2〇〇ι_2592號 公報）。 b 又，在控制大小（粒徑）之情況，使用孔徑相同之膜式 過，器’在高麼下進行押出過遽之方法，或使用加壓型整 粒器之方法（參照例如特開平6_238142號公報卜 …本發明之冷减乾燥組成物之特徵之一係將包含非溶解 狀態之添加成分之組成液經冷康乾燥而調製成。其中所謂 非溶解狀態意指添加成分在構成組成液之溶媒中無法以澄 ^之狀態溶解或者以澄明之狀態混合之狀態。該非溶解狀 ’包含在溶媒中固形物以可用任意手段檢測出之狀態存 :。具體而言，例如在溶媒中，具有〇〇1心以上，較 :〇.05…上，更佳01…上，再更佳0.2…上， 圭〇.5…上之幾何學平均粒裡(用動態光散射法或雷 。斤射及散射法測定)之固形物之存在可以檢測之情況。若 可以達成本發明之目的，此耸阳 此寻固形物之幾何學平均粒徑（用 ^先散射法或雷射折射及散射法測定）之上限雖無特別 限制’但通“20…下，較佳15 ”以下，更佳ι〇 315314 27 1327073 // m。更具體而言，本發明中所謂之「非溶解狀態」包含 在溶媒中，幾何學平均粒徑（用動態光散射法或雷射折射及 散射法測定）在0.01至20// m、0.05至15 # m、〇.1至15 U . U J iE- 1 (J β 0.2 至 15 // m、0.5 至 16 μ 至10 /zm、0.2至10 "m*〇 5至10#m之範圍内之固 形物以可用任意手段檢測出之狀態存在之狀態。關於該非 溶解狀態之具體形態，例如為添加成分不斷地溶於溶媒中 成為飽和以上之狀態，以及添加成不溶於溶媒之狀態，亦 即對於溶媒為非溶解性或難溶解性之有效成分懸浮或混濁 於溶媒中之狀態。又，具體評價非溶解狀態之方法，測定 試料之濁度雖為-般之方法，但可以使用以粒度分布測定 裝置測定不溶解物之粒度分布之方法。後者之方法，且體 而言，藉由將做為對象之非溶解狀態之組成液用蒸鶴水或 生理食鹽液稀釋成適於粒徑測定之濃度後，裝入小室 分攪拌’然後用粒度分布測定胜 刀邛利疋裝置測定在所得稀釋液中存 在之粒子之粒徑而實施。 入，卉1F所謂 人士 刀马非溶解狀態」意指不僅包 ..牙，肯 ， 身在洛劑申為非溶解狀態之情 ,亦匕3上述脂質體、微膠囊、淨糊_ 执吡\ 持體中所保持之有效成分在糊精、樹狀分子等保 態’但脂質體等保持體為非溶解狀 媒之狀 加成分為非溶解狀態之限定 ：，，關於添 成分限定為有效成分，…玄非溶解狀態之添加 之保持體或其他任意成分 成刀起调配成組成液 (下述)之外’沒有特別限制。 315314 28 1327073 又，對於與添加成分同時構成組成液之溶媒，並無特 別限制，但可例如為水及生理食鹽液等等張液、培養基或 缓衝液等。又，在該溶媒中可包含有機溶媒，但以最終調 製物（經肺投與用冷凍乾燥組成物）不會對人體產生不良影 響為限。該有機溶媒例如為曱醇、乙醇、異丙醇' 丙酮及 乙二醇等。 本發明之冷凍乾燥組成物’只要最終調製物之上述衰 變指數足夠’將可為單獨之上述有效成分或有效成分與保 持體組合而成者，或添加適當载劑者。在有效成分中加入 載劑之情況，使用之載劑之種類及量，若可使包含其與有 效成分之非溶解狀態之組成液藉由冷凍乾燥所調製成之最 終冷凍乾燥組成物滿足下述⑴至（iii)之特性：. (i)具有非粉末之塊狀形態， (Π)衰變指數為0.05以上，以及 (in)藉由承受具有至少lm/sec之空氣速度及至少i7mi/sec 之二氣极畺之空氣衝擊，可成為平均粒徑在1 〇微米以 下或有效粒子比率在10%以上之微粒， 立並且可以達成本發明之效果者，則無特別限制，可以 任意使用先前冷凍乾燥所使用之載劑或期望量。 做為該載劑者，具體而言，例如纈胺酸、白胺酸、異 白胺酸及苯基丙胺酸等疏水性胺基酸或彼等之鹽或醯胺； 甘胺酸、脯胺酸、丙胺酸、精胺酸、榖胺酸等親水性胺基 酸或此等鹽或醯胺；胺基酸之衍生物；具有2個以上相同 或相異之上述胺基酸之二肽、三肽或者彼等之鹽或酿胺。 315314 29 1327073 β寻彼等1種或2種以上組合使用。其中，做為胺基酸或 者例如為納及斜等鹼金屬及劈等驗土金屬類金 屬之鹽，與磷酸及鹽酸等無機酸以及磺酸等有機酸形成之 專’又’做為醯胺者，例如為L -白胺酿胺鹽酸鹽。 又’做為載劑者’可以添加α -胺基酸以外之胺基酸，該等 胺基馱例如為点·丙胺酸' 了 _胺基丁酸、高絲胺酸及牛磺 酸等。 、 再者’做為其他載劑者，例如為葡萄糖等單糖類；簾 糖、麥芽糖、乳糖及海藻糖等雙糖類；甘露醇等糖醇；環 糊精等寡糖類；葡聚糖40及聚三葡萄糖等多糖類；聚乙二 醇等多元醇；以及癸酸鈉等脂肪酸鈉等。又此等載劑，可 以添加單獨一種，或添加二種以上之組合。 其中’關於可使有效成份效率良好地到達肺部之載 Μ 具體而5，為異白胺酸、纈胺酸、白胺酸、苯基丙胺 酸等疏水性胺基酸或者彼等之鹽或醯胺；白胺醯基-纈胺 酸 '白胺醯基-苯基丙胺酸及苯基丙胺醯基_異白胺酸等疏 水性二肽等；以及白胺醯基-白胺醯基-白胺酸，白胺醯基_ 白胺醯基-纈胺酸等疏水性三肽等。此等亦可以一種單獨添 加’亦可以2種以上之組合添加。 又，干擾素-γ之情況，從微粉·末化及製劑安定性之觀 點言之’較佳除上述疏水性胺基酸或其之鹽或醯胺、疏水 性二肽及疏水性三肽之外，可以組合使用鹼性胺基酸或彼 等之鹽或醯胺、鹼性二肽及鹼性三肽。其中，做為鹼性胺 基酸者’例如為精胺酸、離胺酸、組胺酸及其之鹽。較佳 3Ι53Ι4 30 為笨基丙胺酸與鹽酸籍妝Λ 胺酸之組合、苯基丙胺酸、白胺酸 與鹽酸精胺酸之組合。 冷凍乾燥組成物所^人々+ 匕3之有效成分（藥物）之含有比率 …、特別限制，該含量例如在 π如為20 mg以下，較佳丨〇 mg以下， 更佳5叫以下，再更佳2mg以下，特佳—以下。 物滿載劑之添加比率’若可使最終冷珠乾燥組成 定 以1至（111)之特性，則無特別限制。雖然沒有限 比旦：：標準為當冷束乾燥組成物定為1〇〇重量％時， °茨比率為0· 1至不到i 〇 較佳， 重量/°，以1至不到100重量。/〇為 ，旦。 不到1〇〇重量％為更佳，以20至不到100::Extracting the hand of the micronized powdery cold to dry the composition to form β τ I (Item 20) A composition liquid containing an additive component in an insoluble state • I dry = manufactured for modulation of the lung The cold-blown composition used for dry powder preparations has the following characteristics: (0 has a non-powder block form, (1丨) decay index is 0.05 or more, and (4) borrows, receives, At least lm /, the air velocity and at least the air impact of the 轧一王轧流 ir, can be an average particle size of 1 or an effective particle ratio of 10% or more of the particles; ... clip ratio ^ and in use by the particles The use of the above-mentioned average particle diameter or the above-mentioned effective particles (Item 21) as in Item 20 of the group containing the insoluble state of the additive component 315314 18 1327073 liquid, wherein, the portion of the southern molecular drug. s Hai cold; The dry composition comprises, as an effective ingredient (Item 22), in the use of non-liquid forming, as in Item 20, the cold-drying ==: the group of added components and the aged powdered utensil container Inside the inside of the container, the means of drying the composition and can be::: impact The apparatus for imparting the granulated powdery cold-dried composition is prepared by the following: [Embodiment] The best energy of the invention is (1) cold-dried composition, the cold-kneading composition of the present invention, A non-powder dry state composition prepared by filling a container containing an additive component in an undissolved state in a liquid state and directly cooling it to a non-powder composition. It preferably contains one or several times. A freeze-dried composition prepared by lyophilizing an insoluble amount of an active ingredient (in an effective amount comprising a single dose of the active ingredient), which is prepared by lyophilization. Selecting and modulating the composition of the above composition liquid (the active ingredient, and the kind and amount of the carrier used together with the active ingredient) so that the non-powder composition obtained by the freeze-drying treatment has a decay index of 0.05 or more, and can be introduced by ( Influx) air impact (air impact, jet pressure) in the container, instantaneously or rapidly micronized into a lung suitable for the administration of the 'in the present invention, the so-called sorrow index, for cold; The dry composition 'is inherent in the freeze-dried composition measured according to the following method! 9 315314 1327073 Value: <decay index> In a container having a diameter of 018 mm or a diameter of 12 23, the liquid is filled with 0.2 to 5. 5 ml of the composition liquid (the composition liquid contains the components which are cooled to dry the electroformed product as a target) and is cooled; the east is dried. Then, in the obtained non-powdered lyophilized composition, The container wall was quietly dropped into n-hexane 丨nU. The mixture obtained by mixing it at 3 rpm for about 1 () seconds was put into the optical path length 1 position, and then (), followed by (4) chamber, and quickly measured with a spectrophotometer. Turbidity at a wavelength of 500 nm $ ^ . The obtained turbidity is divided by the total amount (weight) of the components constituting the freeze-dried composition, and the obtained value is defined as a decay index. The lower limit of the decay index of the cold/east dry composition of the present invention is 0.05, and the ideal order is 〇〇8 〇〇9 〇Η ", 〇·12 is preferred, and 013 is Further, the upper limit of the cold-dried composition of the present invention is not limited, but is preferably 15 和 and ..., 付., preferably 'the ideal order is 〇. 9, 〇. 8 〇7 〇·6', especially G·5 is optimal. The cold of the present invention; the east dry composition is preferably limited to 005 or more, and the desired m has the upper limit of 44 selected from the above-mentioned ones. The sorrow index within the range of values. The range of the decay index, and the body..." is 〇.〇5 to Μ, 0.08^.5, 〇〇...;, to .9'O.iO to. .8, to .7, 〇1 to 〇6 and. The dry composition of the present invention is a block form which can be dried by a dry powder. In the case of a non-competitive composition, it means that it will be effective as an eight-two S. 'The non-powdered cold-bundled dry-formed liquid is dried by lyophilization. 315314 20 iW7073 Solid' is usually referred to as freeze-dried, block production === drying step Or if it is broken into powdery, as long as it is not r: solid bulk, M and Min Ming are not powder-like cold; Donggan; = Ming; effect, are the non-powder block form of the hair Cold-drying, composition towel. The dry composition of the present invention is characterized in that the composition liquid containing the additive component containing the non-dissolving energy is subjected to a decay index of the frozen core to be characterized as The number and the non-powder block form, and the time of the cold pure composition represented by the above-mentioned sorrow index is tempered by the air impact with at least one air velocity and at least 17: the rolling flow rate. It is formed into fine particles having an average particle diameter of J 〇 micron and an effective particle ratio of 10% or more. The ideal cold-dried composition can form an average particle diameter of 10 μm or less by receiving the above air column. (preferably 5 micrometers or less) or particles having an effective particle ratio of A 1 G% or more (preferably 2 G% or more, more preferably 25/° or more, preferably 3 % by weight or more, particularly preferably 35% or more). Air impact of the dry composition, if by means of Shang oil "above the air speed and 17ml / se. There is no particular limitation on the impact of the air flow of the above air flow. Specifically, the above-described air impact is generated by, for example, an air velocity of 1 m/se C or more, preferably -2 m/sec or more, more preferably 5 m/secu, which is preferably 1 〇 m/sec or more. Shock. The upper limit of the air velocity is not particularly limited, but is usually 3 〇〇: /s:c ' is preferably 250 m/sec or more, more preferably 2 〇〇 m/sec or more, and most preferably 150 m. /sec or above. Further, the air velocity is not particularly limited as long as it is within the range consisting of the lower limit and the upper limit of the above-mentioned 315314 21 1327073. Specifically, 1 to 300 m/sec '1 to 250 m/sec, 2 to 250 m/sec '5 to 250 m/sec, 5 to 200 m/sec, 1 to 200 m/sec, to 150 The range of m/sec. Further, the above-mentioned air impact is, for example, usually caused by an air flow rate of 17 ml/sec or more and a slave of 20 ml/sec or more and more preferably 25 ml/sec or more. The upper limit of the air flow rate is not particularly limited, and may be, for example, 900 L/min, preferably 15 L/sec, 1 〇 L/sec, 5 L/sec, 4 L/See, and 3 L/. Sec is the best. Specifically, the air flow rate is not particularly limited as long as it is within the range of the lower limit and the upper limit which are selected as described above. The range is, for example, 17 ml/sec to 15 L/sec, 2 〇mi/sec to Μ L/sec > 20 ml/sec 5 L/sec > 20 ml/sec J. 4 L/sec > 20 ml /sec to 3 L/Sec, 25 ml/sec to 3 L/sec. In the present invention, the active ingredient used in the present invention can be used as a technique: the composition of the dry powder inhaling agent has any pharmacological activity. • The substance: the following may also be referred to as a drug) There are no special restrictions on molecular drugs, low molecular drugs and high molecular drugs. Also high-fermented $, hormone and antibody 4 proteins (including Sheng liver and peptide) and DNA such as DNA and peptides and rna (including genes and cDN physiologically active ingredients.) < Also as a drug f « „. According to the situation, it can be two kinds of systemic therapy and topical therapy. % m is used as a low molecular drug, such as skin f cortisone, and ~ is anti-bey% (hydro-wind alcohol (prednisol〇) Ne), de-inflammation in 315314 22 1327073 (triamcinolone), dexamethasone (dexamethas〇ne), betamethasone, bec丨〇methas〇ne 'fluticasone ^ ^ Mometasone, budesonide, salbutam 1 (salbutam), salmeterol, pr〇cater〇i, buprenorphine hydr〇chloride Anti-biomass such as ap〇m〇rphine, taxol, and tobramycin. It is used as a molecular drug (physiologically active ingredient such as protein and nucleic acid), such as interferon. U,/5,7 ), interleukin (eg, interleukin) 2 '3, 4, 5, 6, 7, 8, 9, 10, η, 12, 13, 14, 15, 16, 17, 18, etc.), anti-interleukin-1α antibody, interleukin "receptor , interleukin receptor antagonist, interleukin-4 receptor 'anti-interleukin-2 antibody, anti-interleukin-heart receptor antibody, interleukin-4 antagonist, interleukin _6_ antagonism Agent, anti-interleukin-8 antibody, chemonectin receptor antagonist, anti-interleukin-7 receptor, anti-interleukin-7 antibody, anti-interleukin-5 antibody, interleukin-5 receptor , anti-interleukin -9 antibody, interleukin-9 receptor, anti-interleukin-1 〇 antibody, interleukin-1 〇 receptor, anti-interleukin-14 antibody, interleukin-14 receptor , anti-interleukin _丨5 antibody, interleukin-receptor, interleukin _18 receptor, anti-interleukin _18 antibody = erythropoietin (ΕΡΟ), erythropoietin derivative, particle ball community stimulation Factor (G-CSF), granule megaloblast cell/community stimulating factor (CSF), macrophage-community stimulating factor (M_CSF), calcitonin, insulin, and temsin derivatives (LisPro, NovoRapid, h〇E9〇 1, NN 3〇4, etc.), insulinotropic hormone, insulin-like growth factor, sucrose Somatostatin or its analog, vasopressin (vas〇pre = analog of 315314 23 1327073 or ..., stimulating powder-like enzymes, human corpus luteum "hormone release hormone, follicle stimulation" Hormone, bismuth, scorpion scorpion hormone, vascular endothelial growth factor, platelet-derived-proliferation factor, keratinocyte growth factor, epithelial cell growth factor, fibroblast growth factor, neurotrophic factor from the brain, hairy body Neurotrophic factor, tumor necrosis factor (TNF), TNF receptor, TNF inhibitor, transforming long-factor (TGF), hepatocyte growth factor (HGF), neurogenic: yue (GF) blood stem cell growth factor, enterprise Platelet proliferation factor, nalagidine peptide, blood coagulation factor, blood hepatocyte growth factor (s_Ca), FLT3 ligand, anti-platelet aggregation inhibitor monoclonal antibody, tissue fibrin/proenzyme/activating factor or Derivatives, super disproportionated oxidase, antisense medicine, immunosuppressive agents (such as cyclosporine, tacr〇Hms hydrate, etc.), cancer suppressor gene p53, Cytoplasmic membrane-regulated regulatory protein (CFTR) gene, RNA interferon (RNAi), bridging nucleic acid, alpha-antitrypsin, thrombopoietin (thr〇mb〇p〇ietin, butyl p〇), blood &; production of statins (metastasin), deoxyribonuclease (biliary, stimulating hormone, oxytocin, thyrotropin releasing hormone, bactericidal / permeability-enhancing protein (Βρι) and influenza vaccine, AIDS vaccine, round Vaccine vaccines such as malaria vaccines and tuberculosis vaccines such as Mtb72f. These active ingredients may be used alone or in combination of two or more. The above various peptides also include a natural polypeptide, a recombinant polypeptide, a chemically synthesized polypeptide, and the like. Further, these active ingredients can be used in their own free state or in a salt state. 315314 24 1327073 can also be used to keep it arbitrarily 1 8% related to the captive body, right to make the active ingredients (such as the package, take a 匕3 protein class and nucleic acid and other high scores early music and synthesis The low-molecular drug is not particularly limited as long as it is attached to the form (absorbent, inclusion, ion-bonding, etc.), such as a lipid membrane construct, a microcapsule, a cyclodextrin, or a dendrimer (dendri_, ' : micron spherules, nanocapsules, nanospheres, etc. Among them, lipid membrane structures include liposomes such as monolayer membrane liposomes and multilamellar liposomes, 〇/w type or w/o/w type ritual fluid, spherical Colloidal particles, fine-banded colloidal particles, and layered j-forms, etc. In addition, the "dendrimer" is generally a shape in which a chain of molecules is formed in a three-dimensional manner from the center to the rule of the molecule. Molecule. The dendrimer has a spherical structure, and has a space for ingesting the drug inside, and functions as a nanocapsule. In order to maintain the drug in the interior of the dendrimer, the following methods are known: Using the inside of dendrimers and drugs Interactions (hydrophobic interactions, electrostatic interactions, etc.), or 2) Formation of dense cell structures on the surface of dendrimers, physical capture of drugs, etc. (Reference: Nagano Kenji: Drug Delivery System, 17-6, 462 -470 (2 002)). Further, the Superfect used in the examples was formed from active dendrimers having a certain shape (Documents: Tang, MX, Redem.ann, CT· and Szoka, Jr. FC: In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjugate) Chem. 7, 703 (1 996)). These molecules are branched from the center, by having a positively charged amine group at the terminal and interacting with the acid group of the nucleic acid (negatively charged). In addition, SuperFect has the property of condensing 25 315314 1327073 DNA and RNA into a dense form in order to easily introduce DNA and RNA into cells. As a preferred holder, for example, liposome, dendrimer, retrovirus vector, adenovirus vector, adenovirus-associated virus, lentivirus (lentlVlrUS), herpes simplex virus vector, HVJ (Sendai virus) - liposomes (eg HVJ coat carrier sets, etc.). Among them, a lipid membrane construct and a cage such as a dendrimer are widely used because they can introduce a foreign gene into a cell. In the present invention, a liposome for gene introduction and a dendrimer for gene introduction are used in the same manner. Again, these are commercially available. Further, the particle diameter of the body (the average particle diameter of the geometry: measured by dynamic light scattering or field refracting and scattering) is not particularly limited as long as it is 10 μm or less. It is preferably 5 microns or less. For example, liposomes and emulsions, the particle size (the average particle size of the particles) is from 50 nm to several m, and the globular colloid has a particle size of 5 to 50 nm. Further, regarding the measurement method of the average particle diameter of the geometry, generally, for the particle size distribution of the particles in the field of several tens of nanometers, dynamic light scattering can be used to determine the particle size distribution of particles of several tens of micrometers or more, and Ray can be used. Any measurement method can be used for the measurement of the particle size distribution of particles in the field of several hundred nanometers and several micrometers by the measurement of the refracting and scattering method. Regarding the retention form of the active ingredient in these holders, there is no particular J, for example, in the case of a mussel membrane structure, for example, in the membrane of the lipid membrane structure, in the surface, in the interior, in the lipid layer, or on the surface of the lipid layer. Any form of attachment/existence. The method of forming the above-described holding form is, for example, a method in which a water-based solvent is added to a mixed dried product of a lipid membrane structure 315314 26 1327073 and an active ingredient (gene or the like), and then emulsified or suspended by an emulsifier such as a homogenizer; After a carrier such as a lipid membrane structure is dissolved in an organic solvent, the dried product obtained by distilling off the solvent is added to a water-based solvent containing a gene to emulsify it, and a carrier such as a lipid film structure which has been dispersed in an aqueous solvent In addition, a method of adding an aqueous solvent containing an active ingredient (gene or the like) in white, and a method of adding a dried product obtained by dispersing a carrier such as a lipid film structure to an aqueous solvent and then drying it to an aqueous solvent containing an active ingredient (gene or the like) (Refer to Unexamined 2〇〇ι_2592). b Further, in the case of controlling the size (particle size), a membrane type having the same pore diameter is used, a method of performing the extrusion at a high level, or a method using a pressurized granulator (refer to, for example, JP-A-6_238142) One of the characteristics of the cold-drying composition of the present invention is that a composition liquid containing an additive component in an insoluble state is prepared by cold-drying. The so-called non-dissolved state means that the added component is in the constituent liquid. The solvent may not be dissolved in a state of being dissolved or mixed in a clear state. The insoluble form is contained in a solvent in a state in which it can be detected by any means: Specifically, for example, in a solvent, it has a ruthenium 〇1 heart or more, compared with: 〇.05...上,更更01...上,更更更0.2...上, 〇 〇.5...the geometry of the average grain (using dynamic light scattering or lightning. The presence of the solid matter determined by the scattering method can be detected. If the object of the present invention can be achieved, the geometric mean particle size of the solid object (measured by the first scattering method or the laser refraction and scattering method) Upper limit There is no particular limitation 'but it is 20", preferably 15" or less, and more preferably ι 315314 27 1327073 // m. More specifically, the so-called "non-dissolved state" in the present invention is included in the solvent, geometry. The average particle size (measured by dynamic light scattering or laser refraction and scattering) is 0.01 to 20 // m, 0.05 to 15 # m, 〇.1 to 15 U. UJ iE-1 (J β 0.2 to 15 / The state in which the solid matter in the range of /m, 0.5 to 16 μ to 10 /zm, 0.2 to 10 "m*〇5 to 10#m exists in a state detectable by any means. The specific form of the insoluble state For example, the additive component is continuously dissolved in the solvent to be saturated or higher, and added to a state in which it is insoluble in the solvent, that is, a state in which the active component which is insoluble or poorly soluble in the solvent is suspended or turbid in the solvent. Further, in the method of specifically evaluating the non-dissolved state, the method of measuring the turbidity of the sample is a general method, but a method of measuring the particle size distribution of the insoluble matter by the particle size distribution measuring device can be used. The latter method, and physically, borrows Insoluble state that will be the object The composition liquid is diluted with a steamed crane water or a physiological saline solution to a concentration suitable for particle diameter measurement, and then charged into a chamber and stirred. Then, the particle size distribution is measured by a particle size distribution measurement method to determine the particle diameter of the particles present in the obtained diluent. Implementation. In, 1F, the so-called "non-dissolved state of the human knife" means not only the package, the tooth, the Ken, the body is in the undissolved state, but also the above-mentioned liposome, microcapsule, net paste _ The active ingredient held in the pyridinium support is in a state in which the dextrin, the dendrimer or the like is in a state of being preserved, but the retaining body such as a liposome is in an insoluble state, and the component is in a non-dissolved state: The active ingredient, ... the addition of the support or any other component of the non-dissolved state is formulated as a constituent liquid (described below), which is not particularly limited. Further, the solvent constituting the composition liquid at the same time as the additive component is not particularly limited, and may be, for example, a liquid, a culture medium or a buffer solution such as water or a physiological saline solution. Further, the solvent may contain an organic solvent, but the final preparation (freeze-dried composition for pulmonary administration) does not adversely affect the human body. The organic solvent is, for example, decyl alcohol, ethanol, isopropanol 'acetone, ethylene glycol or the like. The freeze-dried composition 'of the final preparation of the present invention' may be a combination of the above-mentioned effective ingredient or active ingredient and the support, or a suitable carrier, as long as the above-mentioned decay index of the final preparation is sufficient. When the carrier is added to the active ingredient, the type and amount of the carrier to be used may be such that the final freeze-dried composition prepared by freeze-drying the composition liquid containing the insoluble state of the active ingredient satisfies the following (1) to (iii) characteristics: (i) having a non-powdered block form, (Π) a decay index of 0.05 or more, and (in) by withstanding an air velocity of at least lm/sec and at least i7 mi/sec The air impact of the two gas jets may be fine particles having an average particle diameter of 1 μm or less or an effective particle ratio of 10% or more, and the effect of the present invention may be achieved without any particular limitation, and the prior freeze drying may be arbitrarily used. The carrier or desired amount used. As the carrier, specifically, a hydrophobic amino acid such as lysine, leucine, isoleucine or phenylalanine or a salt or guanamine thereof; glycine, guanamine a hydrophilic amino acid such as an acid, alanine, arginine or valine; or a salt or a guanamine; a derivative of an amino acid; a dipeptide having two or more of the same or different amino acids, Tripeptides or their salts or amines. 315314 29 1327073 One or two or more types are used in combination. Among them, it is used as an amino acid or a salt of a metal such as an alkali metal such as nano or slant, and a mineral acid such as a mineral acid such as phosphoric acid or hydrochloric acid or an organic acid such as a sulfonic acid. For example, it is L-leucine toluene hydrochloride. Further, as the carrier, an amino acid other than the ?-amino acid may be added, and the amino group is, for example, a-alanine, methic acid, tauronic acid or tauroic acid. Further, 'as other carriers, such as monosaccharides such as glucose; disaccharides such as curtain sugar, maltose, lactose and trehalose; sugar alcohols such as mannitol; oligosaccharides such as cyclodextrin; dextran 40 and poly Polysaccharides such as triglucose; polyhydric alcohols such as polyethylene glycol; and sodium fatty acid such as sodium citrate. Further, these carriers may be added singly or in combination of two or more. Wherein 'the carrier can be efficiently delivered to the lungs, and 5 is a hydrophobic amino acid such as isoleucine, valine, leucine or phenylalanine or a salt thereof or Indoleamine; alkalamine-proline-' leucine-phenylalanine and phenylpropylamine hydrazino-isoleucine and other hydrophobic dipeptides; and leucine-alkamine-based Hydrophobic tripeptides such as leucine, leucine, leucine, valine and the like. These may be added singly or in combination of two or more. Further, in the case of interferon-γ, it is preferable to remove the above-mentioned hydrophobic amino acid or its salt or guanamine, hydrophobic dipeptide and hydrophobic tripeptide from the viewpoints of fine powder and finalization and formulation stability. Further, a basic amino acid or a salt thereof or a guanamine, a basic dipeptide, and a basic tripeptide may be used in combination. Among them, those which are basic amino acids are, for example, arginine, lysine, histidine and salts thereof. Preferably, 3Ι53Ι4 30 is a combination of streptoalanine and hydrochloric acid, phenylalanine, leucine and arginine hydrochloride. The content ratio of the active ingredient (drug) of the lyophilized composition is preferably limited to, for example, π is 20 mg or less, preferably 丨〇 mg or less, more preferably 5 or less, and further Good 2mg or less, especially good - below. The addition ratio of the full load agent is not particularly limited as long as the final cold bead drying composition is set to the characteristics of 1 to (111). Although there is no limit to denier:: The standard is when the cold-beam drying composition is set to 1% by weight, the ratio is 0. 1 to less than i 〇 better, weight / °, with 1 to less than 100 weight . /〇为,旦. Less than 1% by weight is better, from 20 to less than 100

重量0/〇為特佳。 王个SJ iUU 又’本發明做為對象 述⑴至(iii)之特性且：本：：組成物只要能滿足上 乾燥前之組成液中之有J本發明之效果’ 使冷来 安定化及防止= 安定化、乾燥後之有效成分 各鞴、天V·如, 者於令益，可在上述成分中添加 白、！二：只例言之，此等添加劑可包含人類血清白蛋 若為通二’面’舌性劑及緩衝劑等。關於界面活性劑， 右為通常適用於醫藥0 丨w 面活性劑、陽離子性：面、支面活性劑，則不論陰離子性界 均可卢A豳 1 '性劑及非離子性界面活性劑， (例如Tweeni!lK 、為聚乳化乙烯山梨糖醇酐脂肪酸酯 性界面活性劑/面活性劑）及山梨醇肝三油儀等非離子 又’將該包含古4 a 燥之方法則無特別㈣，刀及任意成分之組成液經冷;東乾 义_ ’可以使用一般製造冷凍乾燥製劑 315314 31 1327073 (冷凍乾燥組成物）’如用時溶解型注 =。雖無限制，但視情況，調整冷康之冷澡 速地冷凍乾燥。 条件，可急 本發明之冷束乾燥組成物，藉由 擊’可以形成達到適於經肺投與之微粒。因此，=空氣衝 冷;東乾燥組成物係適於調製經肺投與用之粉 發明之 可提供做為經肺投與粉末製劑之前調製物：，亦即 籲製劑調製用之冷凍乾燥組成物）。 又與粉末 樣：又’本發明之冷康乾燥組成物包含下文揭示之具體態 Μ經肺投與用之冷决乾燥組成物，係將包含非溶解 狀t之添加成分之組成液經冷束乾燥而調製成者且具有 下述（1)至（iii)之特性： ” (i)具有非粉末之塊狀形態；Weight 0/〇 is especially good. The king SJ iUU also has the characteristics of the present invention (1) to (iii) and: the composition: as long as it satisfies the effect of the present invention in the composition liquid before drying, 'the cold is stabilized and Prevention = Stabilization, drying of the active ingredients, 天, days V ·,, in the case of benefits, you can add white, the above ingredients! 2: In other words, these additives may contain human serum white eggs, such as Tong's side's tongue agent and buffer. Regarding the surfactant, the right is generally applied to the pharmaceutical 0 丨w surfactant, cationic: surface, and the surfactant, regardless of the anionic boundary, and the non-ionic surfactant. (For example, Tweeni!lK, a polyemulsified ethylene sorbitan fatty acid ester surfactant/surface active agent) and a non-ionic sorbitol liver oil meter, etc. (d), the composition of the knife and any component is cold; Dongganyi _ 'can be used to generally manufacture lyophilized preparation 315314 31 1327073 (freeze-dried composition) 'if dissolved type Note =. Although there is no limit, depending on the situation, the cold bath can be adjusted to freeze and dry quickly. Conditions, it is possible to rush the cold-dried composition of the present invention, by which the particles suitable for pulmonary administration can be formed. Therefore, the air-cooling composition is suitable for preparing a powder for pulmonary administration. The invention can be provided as a preparation for the preparation of a pulmonary preparation by a pulmonary preparation: a freeze-dried composition for preparing a preparation. ). Further, with the powder sample: 'The cold-dried composition of the present invention comprises the cold-drying composition for the specific application of the lungs as disclosed below, and the composition liquid containing the non-dissolved t-added component is subjected to a cold bundle. It is prepared by drying and has the following characteristics (1) to (iii): "(i) has a non-powder block form;

(ii)衰變指數為〇.〇5以上；以及 ㈣藉由承受具有至少lm/sec之空氣速度及至少 之玉氣/;丨L里之二氣衝擊，可成為平均粒徑在1 〇微米以 下或有效粒子比率在1 〇%以上之微粒。 102.如態樣101項記載之冷凍乾燥組成物，其中，衰 變指數為〇.〇5至1.5。 - 1〇3.如態、樣1〇1項記载之冷决乾燥組成物，其中，藉 .由承受具有至少2m/Sec之空氣速度及至少17m"sec之空 氣流置之空氣衝擊，可成為平均粒徑在丨〇微米以下或有效 粒子比率在1 〇%以上之微粒。 315314 32 1327073 1(Μ·如態樣1G1項記載之冷床乾燥組成物，其中，藉 由承受1至3-範圍之空氣速度及至少Uml/sec之 空氣流量之空氣衝擊，可# & τ & _ 了成為平均粒徑在丨〇微米以下或有 效粒子比率在10。/。以上之微粒。 105.如態、樣101項記載之冷康乾燥組成物，其中，藉 由承受具有至少lm/sec之空氣速度及至少20ml/sec之空 氣流量之空氣衝擊，可成為平均粒徑在10微米以下或有效 粒子比率在1 0 %以上之微粒。 1 0 6.如態樣1 〇 1項$恭4、人、A 4 。载之冷凉·乾燥組成物，其中，藉 由承受具有至少1 m/sec之空氣速度及至少17 ml/sec至 15Usec之空氣流量之空氣衝擊，可成為平均粒徑在Π)微 水以下或有效粒子比率在1〇%以上之微粒。 1:7.:態樣101項記載之冷凍乾燥組成物，其中，藉 由承受空氣之衝擊，可忐立 _ 成為干均粒徑在5微米以下或有效 粒子比率在20%以上之微粒。 係包含做 係包含做 係具有做 係含有做 少一種選 如態樣1〇1項記載之冷;東乾操组成物 為有效成分之低分子藥物。 .1〇9:如態樣1〇1項記載之冷;東乾燥組成物 為有效成分之蛋白質類及核酸等高分子藥物。 110.如態樣1〇9項記載之冷來乾燥組成物 為有效成分之呈保持於保持體狀態之核酸。 ⑴·如態樣⑽項記載之冷康乾燥組成物 為有效成分之低分子藥物以及載劑，該載劑為 自胺基酸、二肽、三肽及糖類組成之群者。 315314 33(ii) a decay index of 〇.〇5 or more; and (iv) an average particle size of less than 1 μm by withstanding an air velocity of at least lm/sec and at least a gas impact of at least J/M Or particles with an effective particle ratio of more than 1%. 102. The freeze-dried composition according to aspect 101, wherein the decay index is 〇.〇5 to 1.5. - 1〇3. The cold-dried composition of the sample, as described in paragraph 1〇1, wherein the air impact by an air flow having a velocity of at least 2 m/Sec and an air flow of at least 17 m" It is a fine particle having an average particle diameter of less than 丨〇micrometer or an effective particle ratio of 1% by weight or more. 315314 32 1327073 1 (Μ) The cold-bed drying composition as described in Item 1G1, wherein the air impact by the air velocity in the range of 1 to 3 and the air flow rate of at least Uml/sec can be # & τ & _ is a fine particle having an average particle diameter of less than 丨〇 micron or an effective particle ratio of 10% or more. 105. The cold-dried composition of the sample 101, wherein, by bearing at least lm The air velocity of /sec and the air impact of air flow of at least 20ml/sec can be particles with an average particle size below 10 microns or an effective particle ratio of more than 10%. 1 0 6. If the pattern is 1 〇 1 item $ Christine 4, person, A 4 . The cold and dry composition, which can be averaged by bearing an air impact with an air velocity of at least 1 m/sec and an air flow of at least 17 ml/sec to 15 Usec. Particles with diameters below 微) below micro water or with effective particle ratios above 1%. 1:7. The freeze-dried composition according to the aspect 101, which is capable of standing on a particle having a dry average particle diameter of 5 μm or less or an effective particle ratio of 20% or more by being subjected to an impact of air. It is a low-molecular drug that contains the following ingredients: .1〇9: As described in paragraph 1〇1 of the cold; East dry composition is an active ingredient protein and nucleic acid and other polymer drugs. 110. A cold-dried composition according to the aspect 1-9, which is an active ingredient, which is a nucleic acid which is maintained in a retainer state. (1) The cold-kneading composition as described in the aspect (10) is a low-molecular-weight drug and a carrier which are active ingredients, and the carrier is a group consisting of amino acids, dipeptides, tripeptides and saccharides. 315314 33

11 2 _如態樣i o q馆I 為有效成分之蛋^ 凍乾燥組成物’係含有做 載=、Γ 核酸等高分子藥物以及载劑，該 者。 一肽、三肽及糖類組成之群 11 3 .如恶樣1 u項記菊夕久、占&。 為右砷&八 、 f凍乾燥組成物，係含有做 *成刀之低分子藥物以及載 ώ ^ 入戟W ’省載劑為至少一種撰 自疏水性胺基酸、疏水性種、 氣水性二肽組成之群者。 > 1 14.如恶樣丨12項 ,載之冷凍乾燥組成物，係含有做 為有效成分之蛋白 ^ ^ 文4尚分子藥物以及載劑，螻 載知彳為至少一種選自疏水性 三肽組成之群者。 陡胺基^疏水性二肽及疏水性 11 5 ·如態樣1 〇 1項印都 性組成物。 、。”東乾燥組成物’係為水溶 如隸iG1項記載之冷;東乾燥組成物，係含有1 次投與量之有效成分。 117.如態樣1〇1項記載之冷康乾燥組成物，係將包含 非溶解狀態之添加成分之組成液經冷魏燥而調 具有下述⑴至（iii)之特性： (i) 具有非粉末之塊狀形態； (ii) 衰變指數為〇.〇5至1.5 ;以及 ㈣藉由承受1至3〇—範圍之空氣速度及17mI/sec 至I5L/SeC之空氣流量之空氣衝擊’可成為平均粒徑 在1〇微米以下或有效粒子比率在】〇%以上之微粒。 η 8.如態樣】1 7項記載之冷凍乾燥組成物，其中，空 315314 34 1327073 氣速度為1至250 m/see。 __ I樣11 7項記載之冷;東乾燥組成物，直中，办 氣流量為2〇ml/sec至1〇1^“。 ^ 工 (2)經肺投與用乾燥粉末製劑之製造方法 、又本發明係關於藉由將以非粉末狀態收容於容器内 ，冷：乾燥組成物在該容器内微粒化，製造具有適於藉由 〇 ，又’、之粒徑之乾燥粉末製劑（經肺投與用乾燥粉 ^製⑷之方法。該方法可藉由對於以非粉末狀態收容於容 。。内之冷束乾燥組成物賦與特定空氣衝擊而實施。 ° 本發明之經肺投與用乾燥粉末製劑之製造 方法I上述⑴料述之包含非溶解狀態之添加成分之組 成液經冷珠乾燥，調製成具有上衰變指數之本發明 非粕末狀冷凍乾燥組成物’然後對其賦與具有至少^ 速度及至少17ml/see之空氣流量之空氣衝擊而實 藉此可將°玄非粉末狀之冷;東乾燥組成物調製成具有平 均粒徑4 1〇微米以下（較#5微米以下）或者有效粒子比率 為ίο%以上（較佳2G%以上，更佳25%以上，還要更佳 特佳3 5 /。以上）之微粒形態之乾燥粉末製劑。 在本發月中所谓之微粒之平均粒徑意指在吸入劑 相關產業中通;ii所採用之平均粒⑮，具體而言，非為幾何 學之粒徑，而係表示空氣力學之平均粒徑（MMAD)。該空 氣力子之平均粒徑可以藉由習用方法求得。具體而言，空 氣力學之平均粒徑’例如用安裝人工肺型空氣呼吸器之乾 315314 35 1327073 式粒度分佈 s十（美國 Amberst Process Instrument, Inc.公司 製）、二段式塵埃測定器（G.W. Hallworth and D.G.11 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A group consisting of a peptide, a tripeptide, and a saccharide 11 3. As a bad sample, the 1 u item is recorded by Ju Xiu, Zhan & For the right arsenic & 八, f freeze-dried composition, is a low-molecular drug that is used as a knife, and contains ώ ' ' ' ' ' ' carrier carrier is at least one from hydrophobic amino acids, hydrophobic species, gas A group of aqueous dipeptides. > 1 14. If the lyophilized composition contains 12 substances, the lyophilized composition contains the protein as an active ingredient, and the carrier is at least one selected from the group consisting of hydrophobic three. A group of peptides. Steep amine group Hydrophobic dipeptide and hydrophobicity 11 5 · As in the case of 1 〇 1 item. ,. The "East Dry Composition" is a water-soluble solution as described in item iG1; the East-dried composition contains the active ingredient in one dose. 117. The cold-dried composition as described in paragraph 1〇1, The composition liquid containing the additive component in a non-dissolved state is adjusted by cold-drying to have the following characteristics (1) to (iii): (i) having a non-powdered bulk form; (ii) a decay index of 〇.〇5 To 1.5; and (d) by subjecting an air velocity of 1 to 3 〇-range air velocity and air flow of 17 mI/sec to I5L/SeC, the average particle diameter is below 1 〇 micron or the effective particle ratio is 〇% The above particles. η 8. As in the case] The freeze-dried composition of the seventeenth item, wherein the air velocity is 315314 34 1327073, the gas velocity is 1 to 250 m/see. __ I sample 11 7 items of cold; Object, straight, air flow rate is 2〇ml/sec to 1〇1^”. ^ (2) A method for producing a dry powder preparation by pulmonary administration, and the present invention relates to a method for preparing a cold-dried composition in a container by being placed in a container in a non-powder state, and having a suitable composition A dry powder preparation having a particle size of 〇, and a dry powder prepared by a lung (4). The method can be carried out by using a dry powder in a non-powder state. The method of producing a dry powder preparation for pulmonary administration according to the present invention is as follows. The composition liquid containing the additive component in the undissolved state described in the above (1) is dried by cold beads to prepare an upper decay index. The non-tantal freeze-dried composition of the present invention is then subjected to an air impact having an air flow rate of at least a speed and a flow rate of at least 17 ml/see, whereby the powder can be cooled in a powder form; the east dry composition It is prepared to have an average particle diameter of 4 1 μm or less (more than #5 μm or less) or an effective particle ratio of ίο% or more (preferably 2 G% or more, more preferably 25% or more, and even more preferably 3 5 /. Particle form Dry powder preparation. The average particle size of the particles in the present month means the average particle size 15 used in the inhalant-related industry; specifically, it is not the geometric particle size, but the air Average particle size of mechanics (MMAD). The average particle size of the air force can be obtained by conventional methods. Specifically, the average particle size of aerodynamics is used, for example, by the installation of an artificial pulmonary air respirator 315314 35 1327073 Particle Size Distribution s (Amberst Process Instrument, Inc., USA), two-stage dust detector (GW Hallworth and DG)

Westmoreland: J. Pharm. Pharmacol., 39, 966-' 美國專利公報第6 1 53224號）、多段硬式塵埃測定器、大理 石磨衝擊器、安德森多段衝擊器等測定。又，B. Olsson等 人報告隨著空氣力學之平均粒徑在5" m以下之粒子之比 率 ^ 力對肺之輸送增加（B. Olsson et al: Respiratory Drug _ Dehvety V’ 273-281 (1996)。像這樣推定可輸送至肺之量 方法例如為用乾式粒度分佈計、二段式塵埃測定器、 多。段硬式塵埃測定器、大理石磨衝擊器或安德森多段衝擊 器等測定所得之有效粒子比率及細粒量等。 本發明之製造方法，較佳係藉由將包含非溶解狀態之 添加成分之級成液收容於容器中，藉由在該狀態冷束乾燥 生成粉末之冷凍乾燥組成物，繼而藉著將空氣導入收容該 ^成物之谷益内，以對於該冷凍乾燥組成物賦與上述空氣 ·=而實施。在該情況’由於乾燥處理及粉末製劑化處理 =用同-容器實施，因此不會因分成小份而造成 矢及 >可染之問體。 、 段，：::：Γ氣衝擊賦與於上述冷来乾燥組成物之手 粉末吸人裝置i ’但較佳係使^下述（3)中說明之乾燥 為，投與用乾燥粉製劑之製造方法之-特徵 時)，可以二二^乾燥㈣劑之患者於自行使料(吸入 、谷於容器中之冷;東乾燥組成物調製成適於經 315314 36 1327073 沛投與之粒徑之粉末製劑。 又，本發明之經肺投與用弘 乾燥粉末製劑之製造方法包 含下文揭示之具體態樣： 20 1.經肺投與用乾燥粉絮逾丨丨♦制 Α 衣Μ之製造方法，該製劑係將 包含有非溶解狀態之添加成分夕^上 取刀之乡且成液經冷凍乾燥調製而 成’且具有下述⑴至（iii)之特枓夕、人土 + Θ f生之冷凍乾燥組成物收容於 容器中： (丨）具有非粉末之塊狀形態， ⑴）衰變指數為〇.〇5至1.5，以及 (出）藉由承受具有至少lm/sec之处#由 θ 之二軋速度及至少17ml/sec 之空氣流里之空氣衝擊，可占炎τ,仏 # 了成為平均粒徑在1 0微米以 下或有效粒子比率在1〇%以上之微粒； 藉由使用對於上述容器内之 ^ ^東乾燥組成物可賦盘上 述空氣衝擊之裝置，將具有哕允 W、丄 有°亥空乳衝擊之空氣導入； 藉此將上述冷凍乾燥組成物 取物彳政粒化成平均粒徑 〇 微米以下或有效粒子比率在丨〇%以上。 202.::樣201項記載之經肺投與用 造方法’”，收容於容器内之冷珠乾燥組成物 投與量之有效成分。 切3有1 一入 2 0 3 .如態樣2 0 1項却渐 m "，J: 與用乾燥粉末製劑之 製…，其中，調製成之微粒之平均粒徑 或有效粒子比率在20%以上。 次水以下 204.如遙樣201項記載之經肺投與㈣_ 製造方法’其中’該冷凍乾燥組成物之衰變指數;劑之 又知數在0.05至 315314 37 1327073 1.5之範圍内。 205_如態樣201項記載之經肺投與用乾俨 製造方法，其中，該冷;東乾燥組成物包^末製劑之 低分子藥物。 1 2做為有效成分之 206. 如態樣2()1項記載之經肺投與用乾之 製造方法’其中’該冷;東乾聽成物包含做 成 蛋白質類及核酸等高分子藥物。 錢n 207. 如態樣2()1項記載之經肺投與用乾燥粉末势劑之 製造方法’其中’該冷;東乾燥組成物包含做為有效^分之 呈保持於保持體狀態之核酸。 208. 如態樣205項記載之經肺投與 制-土 Hir甘Λ » , 孔你粉末製劑之 h方H该冷;東乾燥組成物含有做為有效成分之 低分子藥物以及載劑’該載劑為至少_種選自胺基酸、二 肽、三肽及糖類組成之群者。 =如=2G6項記載之經肺投與用乾燥粉末製劑之 ，該冷凍乾燥組成物含有做為有效成分之 蛋白質類及核酸等高分子藥物以及載 ^ , ^ β载劑為至少一 種選自胺基酸、二肽、三肽及糖類組成之群者。 38 1 1 0.如恶樣2 0 8項記載之經肺找愈田灿 & ，，肺缸/、用乾燥粉末製劑之 t k方法’其中，該冷凍乾焯έ4 m 一 m组成物合有做為有效成分之 低刀子樂物以及載劑，該載劑為少一 缺 月』巧玉v種選自疏水性胺基 文ilL水性一肽及疏水性三肽組成之群者。 2 2 1 1.如態樣2 0 9項記萤夕铖昧m 制！+ ‘戟之經肺扠與用乾燥粉末製劑之 法’其巾，該冷凌乾燥組成物含有做為有效成分之 315314 1327073 蛋白質類及核酸等高分子藥物以及載劑，該栽劑為至+ 種選自疏水性胺基酸、疏水性二肽及疏水性= —肽組成之鮮 2 12.如態樣201項記載之經肺投與用乾燥粉末擎劑 製造方法’其中’該冷/東乾燥組成物為水溶性組成物 2 1 3 .如態樣20 1項記載之經肺投與用乾燥粉末製劑 製造方法’係在容量為0.2至50 ml之容器内將Α1之 魟成物微粒化之方法。 L燥 χ、 孔你杨末製劑之 製造方法，其中，藉由使用具有可對容器内之冷凍乾燥名 成物賦與具有至少2 m/sec之空氣速度及至. / w ml/sec 之 空氣流量之空氣產生衝擊之手段之裝£，並將具備該" 衝擊之空氣導入收容冷凍乾燥組成物之容器而進行。氣 215.如態樣201項記載之經肺投與用乾燥粉末 之製造方法，其中，藉由使用具有可對容器内之冷東二 組成物賦與具有i至300m/sec之空氣速度及至少 之空氣流量之空氣產生衝擊之手段之裝置，並將具：::： 氣衝擊之空氣導人收容冷“燥組成物之容器而针了.工 2 1 6.如態樣2 0 1項’ fp截★彡―从 貞记載之經肺投與用乾燥粉 之製造方法，I中，鋅Λ诂m K ^ 之h方Π精由使用具有可對容器内 組成物賦與具有至少lm/sec之空氣速度及至 广 之空氣流量之空氣產生衝擊之手段之裝置，並將具備二 氣衝擊之空氣導入收容冷;^ Μ工 果罕L炼組成物之容器而進 217.如態樣201項印番★ α & 、。己载之經肺投與用乾燥粉末製劑 315314 39 1327073 之製造方法，其中，藉由使用具有 八巧j對谷态内之冷康齡 組成物賦與具有至少lm/see之空 ’、 工乳速度及17ml/sec至 —之空氣流量之空氣產生衝擊之手段之裝置且 備該空氣衝擊之空氣導入收容冷來乾 八 不礼炼組成物之容器而進 行0 218. 如態樣2(H項記載之經肺投與用乾燥粉末製劑之 製造方法，其中，使用後述（3)乾燥粉末吸入裝置中記載之 態樣301或302項之乾燥粉末吸入裝置做為裝置， 乾燥組成物微粒化。 '令丨 219. 如態樣218項記載之經肺投與用乾燥粉末製劑之 製造，法’其中’使用乾燥粉末吸人裝置後述（3)章之中記 載之態樣309項之乾燥粉末吸入裝置做為裝置，將冷康 燥組成物微粒化。 220·如態樣218項記載之經肺投與用乾燥粉末製劑之 製造方法，係使用後述（3)章乾燥粉末吸入裝置一節中記載 之態樣3(U項之乾燥粉末吸入用裝置將冷;東乾燥組成物微 粒，之乾燥粉末製劑之製造方法，其中’該裳置對容器内 之母次空氣喷射量為5至i〇〇mi。 221. 如態樣218項記載之經肺投與用乾燥粉末事咧之 製造方法，係使用後述（3)章之乾燥粉末吸入裝置中記^之 態樣302項之乾燥粉末吸入裝置將冷康乾燥紅成物微粒化 之乾紐粉末製劑之製造方法’其中該裝置對吸入口之 流量為5至300L/min。 工 222. 如態樣201項記載之經肺投與用乾燥粉末製劑之 315314 40 1327073 刀之組成液經冷 性之冷凍乾燥組 製造方法，包含將為非溶解狀態之添加成 凍乾燥調製而成之具有下述（丨）至（丨丨丨）之特 成物收容於容器中： (I) 具有非粉末之塊狀形態， (II) 具有0,05至1.5之衰變指數，以及 (出）藉由承受具有i至300 m/sec之空氣速度及η mi/sec 至15L/sec之空氣流量之空氣衝擊，可成為平均粒: 在1〇微米以下或有效粒子比率在1〇%以上之微粒. 藉由使用對於上述容器内之冷束乾燥組成物可"賦盘上 述空，衝擊之裝置，並將具有該空氣衝擊之空氣導入 '藉此使上述冷凍乾燥組成物形成平均粒徑在丨〇微米 以下或有效粒子比争·在10。/❶以上之微粒。 223土如態# 222項記載之經肺投與用乾燥粉末製劑之 ^方法’其中，收容於容器内人* 次投與量之有效成分。……束^組成物含有1 2 =如態# 222項記載之經肺投與用乾燥粉末製劑之 “方法，其中’空氣速度為i至25〇_“。 ^如⑽⑵項記載之經肺投細乾燥粉末製劑之 、^ ’其中’空氣流量為2〇 ml/sec至1〇仏“。 (3)乾燥粉末吸入裝置- 传用Λ造…發明之經肺投與用乾燥粉末製劑時適 _粉末吸入裝置，係不僅可將以非粉末狀態收 方；^内之冷隸燥製劑（冷純燥組成物）在該容器内 315314 41 1327073 用之装置广::::由之二:粉末製劑亦可供使用者吸入服 成物可賦與能將其：粒：二粉末狀之冷康乾燥組 經微粒化〇 i # A 6 #二乳衝挲之手段，以及（2)可將 之手段，可η * — 、，成物精由吸入投與至使用者 可同時貫施冷;東乾择έ日士〜 之吸人β 且成物之微粒化及對使用者 叹八钕與一者。又，上述π 空氣衝擊之”導入此—手奴亦可謂「將具備上述 卜：：乳導入收容冷康乾燥組成物之容器内手 又」 ，上述（2)之手段亦可★賈+ ± ^ 月將在谷态内經微粒化之 私末製劑從容器中排出之手 ^ 4. ^ 奴」在本發明中，若為具備此 ^㈣又者，將可使用先前公知者或未來開發者中之任一褒 ⑴之手段’具體而言，藉由將可對收容於容器内之冷 康乾燥組成物賦與上述空氣衝擊之空氣導入該容器之心 而實現。又’該⑴之手段可為將具有至少i 之空氣 速度及至少1 7 ml/sec之空氣流量之空氣衝擊賦與容器内 之冷束乾燥組成物之手段。藉由⑺之手段或經由該手段， 可將調製成適於經肺投與之形態之乾燥粉末製劑吸入投與 至患者等使用者。又，可將（2)之手段例如工作室及流路， 設計成組成物可進一步微粒化或分散。 該乾燥粉末吸入裝置包含在下述（a)中揭示之噴射型 乾燥粉末吸入裝置’以及在（b)中揭示之自己吸入型乾燥粉 末吸入裝置。 噴射型裝置（active powder inhaler) (a-1)乾燥粉末吸入裝置，其係將以非粉末狀態收容於 315314 42 1327073 :器中之冷凍乾燥組成物微粒化並供吸入用之裝置，其具 有空氣噴射流路之針部，有排出流路之針部，在上述 針部之空氣喷射流路中輸送空氣用之空㈣送手段，以及 與S亥排出流路連通之吸入σ : 且構成為： 上述針部扎入供密封上述容器之口检並將空氣喷射流 路及排Μ路與上述容器内部連通，藉由上述空氣壓送手 段使空氣從上述空氣喷射流路噴射於上述容器π，藉由該 喷射空氣之衝擊使上述冷凍乾燥組成物微粒化得到之微 粒經由上述排出流路從吸入口排出。 产(a-2)如（a-1)記載之乾燥粉末吸入裝置，其中，上述空 氣壓送手段為手動式，其具備設有吸入閥之吸進口及設有 吐出閥之吐出口之風箱體，且構成為在關閉吸進閥之狀 態，藉由壓縮該風箱體並開放吐出閥，可將上述風箱體内 之空氣經由連通於吐出口之針部之空氣喷射流路壓送至容 器内’在關閉上述吐出閥及打開吸進閥之狀態，藉由彈性 復原力·使上述風箱體擴張，及將空氣導入風箱體内。 (a-3)如上述（心丨）或（a_2)記載之乾燥粉末吸入裝置其 中，將上述空氣喷.射流路及上述排出流路形成在—根針部 中 〇 - (b)自己吸入型裝置（Passive p〇wdei· inhaier) (b-1)乾燥粉末吸入裝置，係將以非粉末狀態收容於容 器中之冷/東乾燥組成物微粒化並供吸入用之裝置，其且 315314 43 1327073 備·· 具有吸引流路之針部，具 與上述吸引流路連通之吸入口丨 L路之針部以及 且構成為： 在上述針部扎入供密封上述容器之口栓能 使用者之吸氣麼從上述 心，糟由 攸上述及入口吸入上述容器 a 時使空氣經由上述空氣導 之二軋，同 内，藉由流入之空氣之流入已成為負壓之容器 ' 等上述冷;東乾燥纟且成 ，侍至|之微粒經由上述吸引流路從吸入口排出。’、 (b-2)如（b-l)記載之兹檢办、士 ^ 使用者之-次吸入置，係構成為藉由 化並從mi、冷;東乾燥組成物之大部分微粒 (b-3)如（b_!)或（b_2)記載之乾㈣末吸 述吸引流路及上述空氣導入流路形成在一根針部中其將上 —將空氣導入容器内之手段（上述⑴之手段），係只 可從外部導入空氣之手段’而無須特別使 =縮空氣…從外部導入空氣之手段無特別限制， 例如上述料型乾燥粉末吸人裝置之情況 地將外部空氣喷射導入容器内之手段；又，自己 乾燥粉末吸入裝置之情況，藉由使用者之吸入服用所伴隨 =令益内負壓化’可以採用將外部空氣自然地吸引導入容 器内之手段。又’在前者喷射型乾燥粉末吸入裝置之情況合 將外部空氣人為地嗔射導入容器内之方法，可為手動，亦 可為使用任意之機械自動進行之方法。 ’' 315314 44 本發明所使用之乾燥粉末吸入 是自己吸入型，均可藉由用h :置，無論疋噴射型還 容奖内之外3 述空虱導入（流入）手段導入 合。。内之外。P空虱產生之 器内之冷咖製劑微粒化。^非粉末狀態收容於容 又，關於其中所使用之裒 σ 對於材質及形狀等將I特別"丨：要可供冷珠乾燥者’ 例如為以聚乙烯上舉例言之’就材質而言， ^ , Λ 本乙烯等聚烯烴系為主之塑 给，破璃及紹等…就形狀而 之j 狀、三角柱(三角錐)、正 D可為因同狀、杯 八角妇h 往（正方錐）、六角柱（六角錐）、 角柱（八角錐）等多角柱（多角錐）。 為了可以效率良好地得到該效 成物之容器之容量言之，可以使用02二谷广乾燥組 25刎為較佳，以i至15ml為 一m ’以0.2至 徑）言之，期望 ，，.、土又，就容器之筒徑（内 佳，以/吏㈣2至1〇01⑽，以必2至”咖為較 乂 2至5〇mm為更佳。 包人。。又“於泫容器内之冷凍乾燥組成物之量，較佳為 投盘Γ立投與量0次投與量）或數次（具體而言2至3次） 量又;之里有之有效成分之量。更佳為包含單位投與量(〗次投斑 ，東乾燥效成分之f。又，冷，東乾燥組成物之具體量，视冷 且成物所包含之有效成分之種類及添加量而里 f可吸人量中適當選擇者，將無特別限^ 、 从下，較佳A on 〇 mg 以下。^為20.mg以下’更佳為1〇邮以下，特佳為— 又 ，藉由導入容器内之外部空氣所產生之空氣衝擊， 3153 J4 45 係由至少人類丨次或數次 之空氣流量及其所產生之空氣流入容器内 =对久性之限度内’導入之外部二之= 及空氣速度超過上述者並未受到特別限制、t之一里 之空氣流量通常為5至3()() 人類1次吸入 勹主300L/分，更詳細言之 分。又，在喷射型之乾燥粉 ，.、、0至2〇〇L/ 1:欠空氣之喷射量為5至刚;^裝置之情況，可以使用 者。較佳調整成對於充填於容Γ內/較佳為10至50 ml 表面造成相當於至少/:益奴冷;東乾燥組成物之 〇 f # ^ ^ msec之空氣速度產生之空氣衝 名。更佳之空氣衝擊為至少 氣衝擊，爯争估5丨 V 2 m/SeC之空氣速度產生之空 還要更佳至！ 1η>5〜之空氣逮度產生之空氣衝擊， ^ “之空氣速度產生之空氣衝擊。其中 之空氣速度產生之衝擊:關如為一C ^ ^ ώ 關於5亥上限，較佳為250 m/sec 产生之空氣衝擊，更佳為2。。—之空氣速 空氣衝擊。 & 150 ⑽之空氣速度產生之 孔衝冑右為藉由具備在從上述任—者選出之下限 艮構成之範圍内之空氣速度之空氣產生者，則無特別 、，別如在 1 至 3〇〇 m/sec ’ 1 至 250 m/sec，2 至 25〇 pa ’ 5 至 250 lWSeC，5 至 2〇〇 m/sec，10 至 2〇〇 m/sec， 〇至丨5〇 m/sec之範圍内之空氣產生之衝擊。 、一其中賦與於冷凍乾燥組成物之空氣之速度可如下述 疋亦即’在下述之實施形態例1中所示之喷射型乾燥 315314 46 1327073 粉末吸入裝置中，採用將蓄積於風箱體1〇中 办 '^氣從空氣 t射流路3強制地導入充填於容器内之洽番 ,二 乾燥組成物 (塊狀之冷凍乾燥組成物：以下亦稱為「冷凌乾燦塊 以賦與空氣衝擊，結果生成之微粒從排出流路 」）上’ ί 4排出之機 構。此b ’流經空氣喷射流路3之空氣流 y A 里错由蓄積於風 相體1 0之空氣量除以將該空氣送進容器 丁间而舁出。繼 而藉由將該空氣流量除以將空氣導入容器之流路諸如空氣 喷射流路3等之截面積，可以算出對於冷凍乾燥組成物1 = 康乾無塊）賦與衝擊之空氣速度。 空氣速度（cm/sec)=空氣流量（nU = cm3/sec)+空氣導入流路 之截面積（cm2) 具體而言，例如在設計成空氣噴射流路3之孔徑為必 m排出机路之孔控為分1 8爪m及蓄積於風箱體j 〇 之i氣里為約20 mi之喷射型乾燥粉末吸入裝置之情況， 當將蓄積於風箱體10之約2〇m丨之空氣量以約〇 5秒從空 氣噴射淚路3強制地導入容器内之冷康乾燥組成物時，空 氣洲·里成為約40 ml/sec。其中若將該值除以空氣導入流路 (二氣噴射流路）之截面積（0,06 X 0,06 X 3.14 = 0. Oil 3 cm2) 將成為3540 cm/sec，即空氣速度為約35 m/sec。 0又，在下述之實施形態例2 ' 3及*所示之自己吸入型 :末吸入裝置中，由於採用從空氣導入流路】[流·入之 空氣賦與冷凍乾燥塊衝擊後，生成之微粗從吸引流路16 排出之機構’因此由空氣導入流路1 7及吸引流路】6之孔 钍來規疋流經該流路之空氣流量。因此，帶給收容於容器 47 315314 1327073 内之冷凍乾燥組成物之空氣速度，可藉由測定流經空氣導 入流路1 7之空氣^11•里 並將其除以空氣導入流路1 7之喷 嘴之截面積而算出。 空氣速度（cm/sec) =空氣流量（ml = cm3/sec)+空氣導入流路 17之截面積（cm2) 具體而言’將包含谷器之吸入裂置安裝於在歐洲藥局 方（European Pharmacopoeia, Third Edition Supplement 籲2001，Pll3-II5)中記載之裝置A(裝置A)(二段式塵埃測定 器.英國Copley公司製）之截面部分，使用流量計（K〇FL〇c D P Μ - 3 )測定流經空氣導入流路1.7之空氣流量。 例如，在設計成空氣導入流路17之孔徑為0 199mm 且吸引流路之孔徑為0丨.99 mm之自己吸入型乾燥粉末吸 入裝置中用/;,L虽6十（k〇FLOC DPM-3)測得之流經空氣導 入流路17之空氣流量為17·7 L/min(亦即295 ml/sec)之情 况’空《I速度可藉由將該值除以空氣導入流路之截面積 _ (0‘0995χ 〇·〇995Χ 3.14 = 0.G311cm2)而得到（9486 em/Sec，即 95 m/sec)。 給充填於容器内部之冷减乾燥組成 氣流罝’例如至少為 ml/sec , f V,.…ml/sec。空氣之流量較佳為至少20 mi/sec ’更佳為至. 限，無特別限制，例：Γ 於空氣流量之上 L/sec，更佳為〗0T 〇 L/min。該上限較佳為15Westmoreland: J. Pharm. Pharmacol., 39, 966-'US Patent Publication No. 6 1 53224), multi-stage hard dust tester, marble impactor, Anderson multi-stage impactor, etc. Moreover, B. Olsson et al. reported an increase in the transport of lungs with a ratio of particles with an average aerodynamic particle size below 5 " m (B. Olsson et al: Respiratory Drug _ Dehvety V' 273-281 (1996) The method for estimating the amount that can be transported to the lungs is, for example, an effective particle measured by a dry particle size distribution meter, a two-stage dust measuring device, a multi-stage hard dust measuring device, a marble grinding impactor or an Anderson multi-stage impactor. The production method of the present invention is preferably a freeze-dried composition in which a powder containing a component in an insoluble state is contained in a container, and a powder is formed by cold beam drying in this state. Then, by introducing air into the glutinous rice containing the product, the air-refining composition is applied to the freeze-dried composition. In this case, 'drying treatment and powder formulation treatment=using the same container It is implemented, so it will not be caused by being divided into small portions and being able to be dyed. Section, ::::: The impact of helium gas on the hand-applied device of the above-mentioned cold-dried composition i 'but The drying agent described in the following (3) is used as a method for producing a dry powder preparation, and the patient can be dried (four) in a self-made material (inhalation, in a container) The cold; East dry composition is prepared into a powder preparation suitable for particle size of 315314 36 1327073. Further, the method for producing a pulmonary dry powder preparation for use in the present invention comprises the following specific aspects: 20 1. The method for manufacturing the sputum by using the dry powder pulverized by the lung, and the preparation method comprises the method of adding the undissolved additive component to the home of the knives and lyophilizing the liquid. 'The freeze-dried composition having the following (1) to (iii), the human soil + Θ f raw is contained in a container: (丨) has a non-powder block form, (1)) the decay index is 〇.〇 5 to 1.5, and (by) having an air impact in an air flow having at least lm/sec# from θ and a flow rate of at least 17 ml/sec, may constitute an average particle diameter Particles below 10 microns or with an effective particle ratio above 1%; by using The drying composition of the above-mentioned container can be used to introduce the above-mentioned air impact device, and the air having the impact of 亥 W 丄 ° ° 空 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; The average particle diameter is below 〇 micron or the effective particle ratio is 丨〇% or more. 202.:: The method for producing lungs by the method of lung injection according to the item 201, and the effective component of the amount of the cold-ball-dried composition contained in the container. Cut 3 has 1 into 2 0 3 . 0 1 is gradually m ", J: and dry powder preparation ..., wherein the average particle size or effective particle ratio of the prepared particles is above 20%. Below the secondary water 204. If the remote sample 201 records The lung is administered (4) _ manufacturing method 'where 'the decay index of the freeze-dried composition; the known number of the agent is in the range of 0.05 to 315314 37 1327073 1.5. 205_ as shown in paragraph 201 of the lung administration The dry preparation method, wherein the cold; the east dry composition comprises a low molecular medicine of the final preparation. 1 2 as an active ingredient 206. The appearance of the lung production and dry manufacturing as described in the aspect 2 () The method 'where' the cold; the Donggan listener comprises a polymer drug such as a protein and a nucleic acid. Qian n 207. The method for producing a dry powder potential for pulmonary administration according to the aspect 2 (1) 'Where' the cold; the eastern dry composition contains nucleic acids that remain in the retaining state as effective. According to the 205 items of the lung-administered system - soil Hir Ganzi », the hole H of the powder preparation of the cold H; cold; East dry composition contains low molecular weight drug as an active ingredient and carrier 'the carrier a group consisting of at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides. = A dry powder preparation for pulmonary administration as described in paragraph 2G6, the freeze-dried composition containing as an active ingredient A polymer drug such as a protein or a nucleic acid, and a carrier containing β, ^β are at least one selected from the group consisting of an amino acid, a dipeptide, a tripeptide, and a saccharide. 38 1 1 0. If the evil sample is 2 0 8 The lungs are found in the lungs &, the lung cylinders/the tk method using dry powder preparations, wherein the freeze-dried 4 m-m composition is combined with a low knife and a carrier as an active ingredient. The carrier is a group consisting of a hydrophobic amine group ilL aqueous one peptide and a hydrophobic tripeptide. 2 2 1 1. As the aspect 2 0 9 items m system! + '戟之经肺叉 and the method of using a dry powder preparation', the cold-dried composition contains as an active ingredient 3 15314 1327073 Polymeric drugs such as proteins and nucleic acids, and carriers, which are selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic = peptides. The method for producing a dry powder medicinal preparation for transpulmonary administration by the lungs, wherein the cold/east dry composition is a water-soluble composition 2 1 3 . The method for producing a dry powder preparation for pulmonary administration according to the aspect 20 1 'A method of micronizing the ruthenium of Α1 in a container having a capacity of 0.2 to 50 ml. The invention relates to a method for manufacturing a dry and sputum aging preparation, wherein an air flow having an air velocity of at least 2 m/sec and an air flow of up to / w ml/sec is provided by using a freeze-dried product in the container. The air is subjected to an impact means, and the air having the impact is introduced into a container for accommodating the freeze-dried composition. 215. The method for producing a dry powder for pulmonary administration according to the aspect 201, wherein the air velocity having i to 300 m/sec is imparted to the composition of the cold east container in the container and at least The air flow of the air to generate a means of impact, and will have:::: air impact of the air to guide people to accept the cold "dry composition of the container and needle. Work 2 1 6. If the situation 2 0 1 item" Fp 彡 彡 彡 贞 贞 贞 贞 贞 贞 贞 贞 贞 经 经 经 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺The air speed of the sec and the air of the wide air flow to generate a shock device, and the air with the two-gas impact is introduced into the cold; ^ The container of the raw material of the L-refining composition is entered into the 217.印番★α &, a method for the manufacture of a dry powder preparation 315314 39 1327073, which has a minimum of lm by using a cold-aged composition in the valley state /see air', air temperature and air flow of 17ml/sec to - air flow The apparatus for the means of impact and the air impinging on the air are introduced into a container for accommodating the cold and sterilized composition. 0 218. The aspect 2 (manufacturing method of the dry powder preparation for pulmonary administration according to item H) Here, the dry powder inhalation device of the aspect 301 or 302 described in (3) the dry powder inhalation device described later is used as a device, and the dry composition is atomized. '丨 丨 219. For the production of a dry powder preparation, the method of using a dry powder inhalation device of the item 309 described in Chapter (3) of the dry powder inhalation device is used as a device to atomize the cold-kneaded composition. 220. The method for producing a dry powder preparation for pulmonary administration according to the aspect 218 is to use the method described in section (3) of the dry powder inhalation device (the dry powder inhalation device of U) is cold. The method for producing a dry powder preparation of the east dry composition particles, wherein the amount of the mother air spray in the container is 5 to i〇〇mi. 221. The lung injection according to the aspect 218 Dry powder The manufacturing method is a method for producing a dry powder powder preparation in which a dry powder inhalation device is formed by using a dry powder inhalation device of the aspect 302 in the dry powder inhalation device described in the above (3). The flow rate to the suction port is 5 to 300 L/min. 222. The method of manufacturing the cold-dried lyophilized group of the 315314 40 1327073 knives of the dry powder preparation according to the aspect 201, including the method of 201 The special product having the following (丨) to (丨丨丨) prepared by adding the non-dissolved state to freeze-drying is contained in a container: (I) has a non-powder block form, and (II) has 0 , the decay index of 05 to 1.5, and (out) by the air impact with an air velocity of i to 300 m / sec and an air flow of η mi / sec to 15 L / sec, can become an average particle: at 1 〇 micron The following or particles having an effective particle ratio of 1% or more. By using the cold-blown composition for the above container, the above-mentioned air, impact device can be placed and the air having the air impact can be introduced. Forming the above freeze-dried composition The average particle size is below 丨〇micron or the effective particle ratio is at 10. / ❶ above the particles. 223 土如态# The 222 method for the administration of a dry powder preparation by the lungs, wherein the active ingredient contained in the container is administered in a dose of *. The composition of the bundle contains 1 2 = the method of transdermal administration of a dry powder preparation as described in Item 222, wherein the air velocity is i to 25 〇 _. ^ (1) The air flow rate of the finely-dried dry powder preparation as described in (10) (2), wherein the air flow rate is 2 〇ml/sec to 1 〇仏. (3) Dry powder inhalation device - Transmitting ...... When applying a dry powder preparation, the powder-inhalation device can not only be used in a non-powder state; the cold-drying preparation (cold-pure dry composition) in the container is widely used in the container: 315314 41 1327073: :::Second: The powder preparation is also available for the user to inhale the service. It can be used to: granules: two powder-like cold-cold dry group by micronization 〇i # A 6 #二乳冲挲And (2) the means by which η * — , , the fine substance can be administered by inhalation to the user at the same time, and the cold can be applied at the same time; The user is sighed and sighed. In addition, the above-mentioned π air impact is introduced into this - the slave can also be said to "have the above-mentioned:: the milk is introduced into the container containing the cold-dried composition", the above (2 The means can also be ★ Jia + ± ^ month will be in the valley state through the micronized private preparations discharged from the container ^ 4. ^ slave In the present invention, if it is provided with this (4), the means of any one of the previously known or future developers (1) may be used, specifically, by being able to be contained in a container. The drying composition is carried out by introducing air impinging on the air into the center of the container. Further, the means of (1) may be a means for imparting an air impact having an air velocity of at least i and an air flow of at least 17 ml/sec to the cold-dried composition in the container. By means of (7) or by means of this means, a dry powder preparation prepared in a form suitable for pulmonary administration can be administered to a user such as a patient. Further, the means (2) such as the working chamber and the flow path can be designed such that the composition can be further atomized or dispersed. The dry powder inhalation device comprises the spray type dry powder inhalation device disclosed in (a) below and the self-inhalation type dry powder inhalation device disclosed in (b). Active powder inhaler (a-1) a dry powder inhalation device which is housed in a non-powder state in a device of 315314 42 1327073: a freeze-dried composition for atomization and for inhalation, having air The needle portion of the jet flow path has a needle portion for discharging the flow path, an air (four) feeding means for conveying air in the air jet flow path of the needle portion, and a suction σ for communicating with the S Hai discharge flow path: The needle portion is inserted into the mouth for sealing the container, and the air jet flow path and the drain passage are communicated with the inside of the container, and the air is sent from the air jet flow path to the container π by the air pressure feeding means. The fine particles obtained by atomizing the freeze-dried composition by the impact of the jet air are discharged from the suction port through the discharge flow path. (a) The dry powder inhalation device according to (a-1), wherein the air pressure feeding means is a manual type, and includes a suction port provided with a suction valve and a bellows having a discharge port of a discharge valve The body is configured to close the suction valve, and by compressing the air box body and opening the discharge valve, the air in the air box body can be pressure-fed to the air injection flow path that communicates with the needle portion of the discharge port to In the state in which the discharge valve is closed and the suction valve is opened, the air box body is expanded by the elastic restoring force, and air is introduced into the wind box body. (a-3) The dry powder inhalation device according to the above aspect (a), wherein the air jet flow path and the discharge flow path are formed in a needle portion - (b) self-inhalation type (Passive p〇wdei·inhaier) (b-1) A dry powder inhalation device is a device for atomizing and cooling a cold/east dry composition which is contained in a container in a non-powder state, and 315314 43 1327073 a needle portion having a suction flow path, a needle portion having a suction port 丨L path communicating with the suction flow path, and a needle portion that is inserted into the needle portion to seal the container can be sucked by a user From the above-mentioned heart, the above-mentioned and the inlet are sucked into the container a, so that the air is rolled through the air guide, and the inside of the container is filled with a negative pressure by the inflow of air. The particles that are formed into the air are discharged from the suction port through the suction flow path. ', (b-2) as described in (bl), the sub-inhalation of the user, and the sub-inhalation of the user, consisting of the majority of the particles of the composition (b- 3) If (b_!) or (b_2) the dry (4) end suction suction flow path and the air introduction flow path are formed in one needle portion, the means for introducing air into the container (the means (1) above The means for introducing air from the outside is not required to specifically reduce air. The means for introducing air from the outside is not particularly limited. For example, the above-mentioned dry powder inhalation device introduces external air into the container. Means; in addition, in the case of drying the powder inhalation device by itself, the negative pressure in the user's inhalation can be used to naturally attract the outside air into the container. Further, in the case of the former spray-type dry powder inhalation device, the method of manually introducing the outside air into the container may be manual or automatic using any machine. '' 315314 44 The dry powder inhalation used in the present invention is a self-inhalation type, and can be introduced by means of h: set, regardless of the inside of the squirt type. . Inside and outside. The cold coffee preparation in the P open space is micronized. ^The non-powder state is contained in the capacity, and the 裒σ used for the material and shape will be I special "丨: to be used for the drying of the cold beads, for example, in the case of polyethylene, in terms of material , ^ , Λ The polyolefins such as vinyl are mainly used for plastics, broken glass and sho... etc. The shape is j-shaped, triangular prism (triangular cone), positive D can be the same shape, cup octagonal woman h (square Cone), hexagonal column (hexagonal cone), corner column (octagonal cone) and other polygonal columns (polygonal pyramid). In order to obtain the capacity of the container of the effect product efficiently, it is preferable to use 02 二谷广 drying group 25 刎, preferably i to 15 ml as a m ' to 0.2 to diameter), expect, ., soil, the diameter of the container (internal, to / 吏 (four) 2 to 1 〇 01 (10), from 2 to "coffee is better than 至 2 to 5 〇 mm. Bao people." and "in the container The amount of the lyophilized composition is preferably the amount of the active ingredient in the amount of the dose of the tablet or the amount of the dose of the dose of the dose of the dose of the amount of the active ingredient. More preferably, it includes the unit dosage (the number of times of spotting, the east drying effect component f. In addition, the specific amount of the cold, east dry composition, depending on the type and amount of the active ingredient contained in the cold and the product. f can be selected in the appropriate amount of people, there will be no special limit ^, from below, preferably A on 〇mg below. ^ is below 20.mg 'better than 1 〇 post below, especially good - again, by The air impact generated by the external air introduced into the container, 3153 J4 45 is the air flow from at least human times or several times and the air generated by it flows into the container = within the limit of the durability And the air speed is higher than the above, and the air flow rate is usually 5 to 3 () (). The human inhalation is 300 L/min, which is more detailed. In addition, in the spray type Dry powder, ., 0 to 2 〇〇 L / 1: The amount of under-air injection is 5 to just; ^ device, user can be better adjusted for filling in the volume / preferably 10 to 50 ml surface caused at least /: Yinu cold; East dry composition 〇f # ^ ^ msec air velocity generated by the air The name is better. The better air impact is at least the gas impact. It is better to estimate the air velocity generated by 5 丨V 2 m/SeC to be even better! 1η>5~The air impact caused by the air catch, ^" The air impact generated by the air velocity. The impact of the air velocity is as follows: a C ^ ^ ώ about 5 hp upper limit, preferably 250 m / sec generated air impact, more preferably 2 - air speed Air impact. & 150 (10) The air velocity generated by the hole is right by the air generator having the air velocity in the range of the lower limit 选 selected from any of the above-mentioned ones. 1 to 3〇〇m/sec ' 1 to 250 m/sec, 2 to 25 〇pa ' 5 to 250 lWSeC, 5 to 2 〇〇 m/sec, 10 to 2 〇〇 m/sec, 〇 to 丨 5〇 The impact of the air generated in the range of m/sec. The speed of the air imparted to the freeze-dried composition may be as follows: 'jet type drying 315314 46 1327073 shown in the following embodiment example 1 In the powder inhalation device, it is used to accumulate in the wind box body 1 The flow path 3 is forcibly introduced into the container to be filled in the container, and the second dry composition (block-like freeze-dried composition: hereinafter also referred to as "cold dry block to impart air impact, and the resulting particles are discharged from the flow path" The mechanism of the ' ί 4 discharge. This b' flows through the air jet flow path 3 y A by dividing the amount of air accumulated in the wind phase body 10 by dividing the air into the container Then, by dividing the air flow rate by the cross-sectional area of the flow path for introducing the air into the container, such as the air injection flow path 3, etc., the air velocity for imparting an impact to the freeze-dried composition 1 = Kanggan no block can be calculated. Air speed (cm/sec) = air flow rate (nU = cm3/sec) + cross-sectional area of the air introduction flow path (cm2) Specifically, for example, the hole diameter designed as the air injection flow path 3 is a must discharge path The hole control is a case of a spray type dry powder inhalation device which is divided into 18 claws m and accumulated in the air of the wind box body j of about 20 mi, and is about 2 〇m of air which is accumulated in the wind box body 10. When the amount was forcibly introduced into the cold-dried composition in the container from the air jet tearing path 3 in about 5 seconds, the air was about 40 ml/sec. If the value is divided by the cross-sectional area of the air introduction flow path (two gas injection flow path) (0,06 X 0,06 X 3.14 = 0. Oil 3 cm2), it will become 3540 cm/sec, that is, the air velocity is about 35 m/sec. In addition, in the self-inhalation type: the last inhalation device shown in the following Example 2 '3 and *, the air is introduced into the flow path] [the flow of air into the freeze-dried block is generated, and the resulting The mechanism that is slightly discharged from the suction flow path 16 is thus regulated by the holes of the air introduction flow path 17 and the suction flow path 6 to regulate the flow rate of the air flowing through the flow path. Therefore, the air velocity of the freeze-dried composition carried in the container 47 315314 1327073 can be measured by passing through the air into the air introduction channel 17 and dividing it by the air introduction channel 17 Calculated by the cross-sectional area of the nozzle. Air velocity (cm/sec) = air flow rate (ml = cm3/sec) + cross-sectional area of the air introduction flow path 17 (cm2) Specifically, the inhalation split containing the grain is installed in the European Pharmacy (European) Pharmacopoeia, Third Edition Supplement 2001, Pll3-II5), the device A (device A) (two-stage dust detector. manufactured by Copley, UK), using a flow meter (K〇FL〇c DP Μ - 3) The flow rate of air flowing through the air introduction flow path 1.7 is measured. For example, in a self-inhalation type dry powder inhalation device designed to have an air introduction flow path 17 having a hole diameter of 0 199 mm and a suction flow path of 0 丨.99 mm, L is 60 (k〇FLOC DPM- 3) The measured air flow rate through the air introduction flow path 17 is 17·7 L/min (that is, 295 ml/sec) 'empty' I speed can be divided by the air introduction flow path The cross-sectional area _ (0'0995χ 〇·〇995Χ 3.14 = 0.G311cm2) is obtained (9486 em/Sec, ie 95 m/sec). The cooling drying composition filling the inside of the container has a gas flow 罝' of, for example, at least ml/sec, f V, ....ml/sec. The flow rate of air is preferably at least 20 mi/sec ‘more preferably to the limit, and is not particularly limited, for example, L above the air flow rate L/sec, more preferably 〖0T 〇 L/min. The upper limit is preferably 15

Wee，特佳為3⑻’再更佳為5 L/SeC，還要更佳為4 述者中任意選出之^。具體而言，空氣流量只要在從上 下限及上限構成之範圍内，將無特別限 315314 48 1327073 制。該範圍例如為17 ml/s L/sec’ 20 ml/sec 至 5 L/see 至 3 L/sec，25 ml/sec 至 3 ec 至 15 L/sec，20 ml/sec 至 ι〇 ’ 20 mi/sec 至 4 L/sec，2〇 如/… L/sec 。 八 令% r/T 1文用之 氡以接近收容於容器底部之東：：入哀4彳具備將空 之吐出口 (較佳具備細孔之吐？乾燥組成物之狀態從流路 ._ 土出口）吐出空氣之手段，諸如 在貫施例中詳述之具備空氣 渚士 崢，以做為提高從外部導人 * 卞 也油 等入之空氣衝擊壓之手段。又，嗲 机路吐出口之孔徑，由於隨。。 备蜱#Λ β ^ λ* 谷态之大小等，其較佳範圍 曰資動，所以無特別限制，亩 杜η 直從0可在0.3至10 mm，較 佳 0.5 至 5mm，更佳 〇·8$ <： 内。 mm ’特佳1至4 mm之範圍 以將以非粉末狀態收容 。其中微粒化之程度， 例如平均粒徑在丨〇以m 藉由將空氣導入該容器内，可 於容器内之冷凍乾燥組成物微粒化 各成為適於經肺投與之粒徑即可， 以下’較佳5" m以下。 又，在本發明中所使用之乾燥粉末吸入裝置包含下文 揭示之具體態樣物·· 屢、慨經肺投與用之乾燥粉末吸人裝置係藉由空氣衝 、非私末狀收谷於容器内之冷凍乾燥組成物，並使受 驗者吸入所得微粒。 · 3〇1.如態樣300項記載之經肺投與用乾燥粉末吸入裝 置，其係將以非粉末狀態收容於容器中之冷凍乾燥組成物 微极化並將得到之微粒供被驗者吸入用之裝置，其具備： 315314 49Wee, especially good for 3 (8)' and more preferably 5 L/SeC, and even better selected for any of the four. Specifically, the air flow rate is not limited to 315314 48 1327073 as long as it is within the range from the upper and lower limits and the upper limit. The range is, for example, 17 ml/s L/sec' 20 ml/sec to 5 L/see to 3 L/sec, 25 ml/sec to 3 ec to 15 L/sec, 20 ml/sec to ι〇' 20 mi /sec to 4 L/sec, 2 such as /... L/sec. Eight orders of % r / T 1 used to close to the bottom of the container to the east:: into the sorrow 4 彳 has the empty spit outlet (preferably with fine pores? dry composition of the state from the flow path. _ Soil outlets. The means of spitting out air, such as the air gentleman's knives detailed in the examples, as a means of increasing the impact of air from the outside. In addition, the aperture of the spout of the machine is due to the aperture. .备蜱#Λ β ^ λ* The size of the valley state, etc., the preferred range is 曰, so there is no particular limitation, and the acre η can be from 0.3 to 10 mm, preferably from 0.5 to 5 mm, more preferably. 8$ <: inside. Mm 'extra good range of 1 to 4 mm to be contained in a non-powder state. The degree of micronization, for example, the average particle diameter is 丨〇m into the container by introducing air into the container, and the lyophilized composition in the container can be atomized into a particle size suitable for transpulmonary administration, 'Better 5" m below. Further, the dry powder inhaling device used in the present invention comprises the specific state disclosed below. The dry powder inhaling device for repeated administration of the lungs is air-blown, non-private. The composition is freeze-dried in the container and the subject is inhaled into the resulting microparticles. · 3〇1. A dry powder inhalation device for transpulmonary administration according to the aspect 300, which microtilizes the freeze-dried composition contained in a container in a non-powder state and obtains the microparticles for the subject Inhalation device with: 315314 49

丄JZ/U/J 具有空氣噴射流路之針部，且 上述針部之空氣嘴射流路中輸送空'氣二針部，在 以及與上述針部之排出流路連通之吸入口工送手段， 且構成為·· ’ 上述針部扎入供密封上述容器之口 路及排出产技彻u 检以使空氣喷射流 段佶*齑铋精由上述空氣壓送手 使二乱厶由上述空氣喷射流路喷射 該噴射空氣之衝擊使上诚Α、φ妒上玫今益内，藉由 n r,. + 7凍乾焯組成物微粒化，得到之 极粒經由上述排出流路從吸入口排出。 3 態樣3⑽項記載之經肺投與用乾 ==非粉末狀態收容於容器中之冷來乾燥組成物 並將仔到之微粒供被驗者吸人用之|置’盆豆備. 具有吸引流路之針部’具有空氣導入流路之針部以及 舁上述吸引流路連通之吸入口； 且構成為： ^上述針部九入供密封上述容器之口栓之狀態，藉由 被驗者之吸氣壓從上述吸 4及入口吸入上述容器内之空氣，同丄JZ/U/J has a needle portion of the air jet flow path, and the air nozzle flow path of the needle portion conveys the air two-needle portion, and the suction port delivery means that communicates with the discharge flow path of the needle portion And the configuration is as follows: ' The needle portion is inserted into the mouth of the container for sealing the container, and the discharge is made to check the air jet flow segment. The air is sent by the air pressure to cause the air to be smashed by the air. The jet stream jets the impact of the jet air so that the upper Α, φ 妒 玫 玫 今 , , , , , , , , , , , , , , n n n n n n n n n n n n n n n n n n n n n n n n . 3 Aspect 3 (10) The transpulmonary administration is carried out by using a dry == non-powder state to be stored in a container to cool the composition and to take the particles into the subject for inhalation. The needle portion of the suction flow path has a needle portion having an air introduction flow path and a suction port through which the suction flow path communicates; and is configured to: ^ the needle portion is inserted into the state of sealing the mouth of the container, and is tested The suction pressure of the person is sucked into the air in the container from the suction 4 and the inlet,

%使空氣經由上述空氣導 A ^ t 虱導入，爪路流入已成為負壓之容器 =’ '由流人之空氣衝擊將上述冷;東乾燥虹成物微粒化， 侍到之微粒經由上述吸引流路從吸入口排出。 3.U 301項§己載之經肺投與用乾燥粉末吸入裝 置’係構成為藉由將空氣噴射至上述容器内一次，使得上 述冷凍乾燥組.成物經微粒化並從上述吸入口排出。 3 0 4 ·如態樣3 0 1項印哉夕城8七 、。己載之，，二肺技與用乾燥粉末吸入裝 315314 50 1327073 置，〃係構成為藉由將空氣噴射至上述容器内’使得上述冷 凍乾燥組成物經微粒化成平均粒徑在1〇冑来以 ： 粒子比率S 10%以上，並從上述吸入口排出。 =·如態樣3CH項記載之經肺投與用乾燥粉末吸入裝 :::為將上述空氣噴射流路及上述排出流路 針部中之形態。 π 胤如態樣如項記載之經肺投與用 置，係構成為藉由被驗者之 刀禾及入裝 物經微粒化並從上述吸入口排出。 …乾燥組成 置，項記载之經肺投與用乾燥粉末吸入裝 ”被構成為藉由被驗者之—次吸人 成物經微粒化成平^] 4^_ + 上达冷凍乾餘組 攻干均拉杈在1〇微米以 在1〇%以上，並從上^入口㈣。切結子比率 3 0 8.如態樣3〇2一 置，其為將上述吸引沪：經肺投與用乾燥粉末吸入裝 針部中之形態。μ及上述空氣導入流路形成在一根 ·如態樣3〇8項記载 置，係具備下列構株* ± 巾？又>、用乾無粉末吸入裝 保持容器用之f末吸入裝置： 擊以進行微粒化之非：丨中該容器收容待接受空氣衝 用口栓密封；以及、末塊狀形態之冷凍乾燥組成物，且 賦與該容器内之、 上述容器内吸弓丨藉由* :〉東乾垛組成物空氣衝擊’並從 組成物之手段； ％衝覃而微粒化之粉末狀冷凍乾燥 315314 51 1327073 其具備： 針部’其具有供從上述容 之吸引流路以及供將外部氣體導边冷; 東乾燥組成物 流路， 導入上述容器内之空氣導入 針部之吸引流路連通之吸引口部’ 保持部運轉部，其呈心“轴線方向之弓,導部， 之時，使該容器向該針部之針小卞、隹:保㈣上述保持部 述針尖札入，或從上 大引並使谷器之口栓被上 4從上述針尖後退而 針尖之機構部，以芬pλ .奋益之口栓拉離上述 被構成為可用比使上述針部扎，作體’且该機構部 小之力操作上述操作體，以及…栓所需要之力為 支持上述針部且供設置上述吸引口部 上述保持部運㈣之外H且 W丨導。Ρ及 其於上述針部扎入上述口 及空氣導入流路與上述容4針部之吸引流路 組成物定位成在空氣導入2通，同時將上述冷凌乾燥 被@ ^ ^阿·， 別力而之狀態時，藉由利用 被驗者之及術上述吸引口部吸八上 並使空氣經由空氣導入泣效、ώ π之工風 ……α 流入上述容器内，可對上述容 °°内之7凍乾燥組成物賦與空氣衝擊。 310.如態樣309項記載之 置，其係構成為： 末吸入裝 該外殼形成為筒狀，上述 端，㈣外殼心=成在該外殼之前 k保符。Ρ形成供收容上述容器之收 315314 52 1327073 納室’將上述針部以針尖朝向上述收納室之方式配設在上 迷外殼θ ’將肖上述針部之空氣導入流路$通並供導入外 氣用之導入口設置在上述外殼之壁部；並且 /、 藉由上述保持部運轉部，使上述保持部在上述收 以上述外殼之軸線方向前進及後退。 U .如態樣3 1 0項記載之經肺投與用乾燥粉末吸入 其係構成為 :述外殼’由在上述保持部後退之位置形成有上述容 二：口之外殼本體，以及用絞鏈連結於上述外殼本體 上述出入口之蓋子而形成；以及 閉之轉部，具備在蓋上上述蓋子使上述出入口關 述蓋子Hitt保持部向㈣部之針线進，且在拉起上 ”吏退之卜 打開之時M吏上述保持部從針部之針 :體。返機構部，且上述蓋子兼做為上述機構部之操 (4)經肺投與用乾燥粉末吸入*** 燥組= = ::乾燥粉末吸入系統’係將冷-中，該… 入裝置組合而成之系統，其 斑在容組成物所具有之組成，係在將空氣衝擊賊 冷細且未進行粉碎處理之以非粉末狀態 微米以二4組成物時，在容器内可形成平均粒徑在1丨 肺投盘用效粒子比率在1〇%以上之微粒者。依照該經 肺與用乾餘粉末吸入系統，使用者於使用(吸入)以非救 315314 53 πI “提供之冷來乾燥組成物時，可自行調製成適於經肺 又:，劑型’即由平均粒徑在〗〇微米以下或有效粒子比率 用）。％上之U粒組成之乾燥粉末製劑，且可自行投與（服 兮旲為I可有效率地得到經肺投與用乾燥粉末吸入系統之 等頗為重要。 “成物之組成，吸入裝置及容器 做為該冷凍乾燥組成物者，較佳# # μ 1 + ^ t 溶解狀態之添加成分之^係使用#由將包含非 .+ 之組成液經冷凍乾燥而調製成，且且 有下述特性之冷凌乾燥㈣f I成且八 (1)具有非粉末之塊狀形態； (ii)衰變指數為〇.〇5以上；以及 (in)藉由承受具有至少lm/sec 之*名，6曰 工風速度及至少1 7ml/Sec 之工軋流S之空氣衝擊， ^ L 成為+均粒徑在10微米以 下或有效粒子比率在1〇%以上之微粒。 關於該冷凍乾燥組成物之組 以援用右卜·+. η、立 ，成U及其之調製方法，可 乂後用在上述（1)章中詳述之内容。 該冷凍乾燥組成物，係在容 收容於啰1> 隹谷盗内經冷凍乾燥處理且被 叹合於遙夺益内。被收容於容器 較佳包合置彳fr讲rt θ 巧’東乾燥組成物之量 平又1 土 EL含早位投與量（i次投鱼 -欠）於盘θ 、 或數ζ人（具體而言2至3 -人）技與夏之有效成分之量。更佳為包 與量）之有效成分之量。收容於 早位4與量（1次投 具體量，視冷康乾燥組成物所包;之燥組成物之 加量而異’若為從可吸入量 ;㈣及添 、佴W無特別限定，通 315314 54 1327073 常為30 mg以下，軔杜 牲佔Μ 為20 mg以下，更佳為10 mg以下， 特佳為5 mg以下。 有下二：面’做為乾燥粉末吸入裝置者，較佳係採用I 有下述特徵之乾焯扒士 '、 〇 + / 知叔末裝置：具備（1)空氣衝擊賦盥手# (或空氣導入手段、月啊-、千& '(2)政粒排出·手段（或吸入投鱼车队、 藉由上述⑴空氣衝擊 ：山)， 粉末狀態之冷來乾烤电：机“乱導入(、-入)收容非 *翁播離rβ 物之容器内，利用導入（流入）之 二”、· 、壓），將該冷凍乾燥組成物微粒化，再者获 由上述(2)微粒排出手段’使被⑴之手段微粒‘ :成物從容"排出，且可以直…入法投=: 吸入2置之—例，例如為在上:·述（3)章中詳述之乾燥粉末 亦即’本發明之適當經肺投與用乾 至少於使用時，為缸人姑m 木及入糸統， ,,., ' 。使用收容上述本發明之冷凍乾焊组 成物之容器以及上述繫 果也各組 上这乾刼粉末吸入裝置之系統。 明之經肺投與用乾燥粉 Ρ本發 備收容上述本發明之Α、击私。 使用刖，具 ν凍乾燥組成物之容器以及上 粉末吸入裝置。 35 u及上述乾燥 右依,¾本發明之該系統藉由使用 萝窨祐從办#播 馬杨末吸入 :置1將4導入收容本發明之冷; 東 中，以對存在於i内卹+、A 现柳 < 各益 、' ° 、凍乾燥組成物賦盘呈有至，卜】 πι/sec之空氣速度及 …' 王夕1 擊，可以調製成且備可： '空氣流量之空氣衝 U了错吸入經肺投與之粒徑或可有效用 315314 55 1327073 於藉吸入經肺投與之有效粒子比率之乾 關於可藉吸入經肺投與之粒徑，例如、早”製劑。 言，空氣力學之平均粒徑，ΜΜΑ_ !。均粒徑（具體而 微米以下。又’關於可有效用於藉吸入經肺：：下奴佳5 子比率，例如1G%以上，較佳2G%以上，又」、之有效粒 再更佳30%以上，特佳35%以上。 更仏25/。以上， 又若依照該系統，可以將調製得之 經肺投與(藉由吸入)至使用者。此 ° 、製劑直接 用乾燥粉末吸入系統可謂「適於夢二本’明之經肺投與 ,.. 9 及入經肺投盘之乾燥 粉末製劑之製造系統，同時為將 /、之乾各 至使用者之投與系統」。 一末製劑經肺投與 又，本發明之經肺投與用乾燥粉末吸入***包含下文 揭示之具體形態： 乐、、兄包3下文 401.—種經肺投與用乾燥粉 及⑺組合使用： …入糸統，係將下述⑴ (1)收容冷凍乾燥組成物之容写， ^ Λ 益该冷凍乾燥組成物係將包 含非；谷解狀態之添加成分之 ^ '，且成液經冷凍乾燥而調製 成，且具有下述⑴至（iii)之特性： (1) 具有非粉末之塊狀形態； (Π)衰變指數為〇·〇5以上；以及 賴由，受具有至少lm/sec之空氣速度及至少旧⑽ 之空氣流量之空氣衝擊，可 J战為平均粒徑在1 0微米以 下或有效粒子比率在10%以上之微粒； (2) 具備可m氣衝⑼與上述容Μ之冷;東乾燥組 315314 56 1327073 成物之手段以及排出經微粒化之粉末狀冷束乾燥組成 物之手段之裝置。 ♦如態# 4〇1項記載之經肺投與用乾燥粉末吸入系 與及其中收容冷凍乾燥組成物之容器，為收容含有】次投 里之有效成分之冷凍乾燥組成物之容器。 统，403·如隸401項記載之經肺投與用乾燥粉末吸入系 、於吸入時為組合使用上述容器與上述裂置之形態。 缽，：4·如態# 401項記載之經肺投與用乾燥粉末吸二系 圍内^中’冷;東乾燥組成物之衰變指數在Μ之範 如態樣術項記載之經肺投與用乾燥粉末吸入系 <二綱中記載之空氣衝擊係藉由具有至少一 :速度及至少17ml/sec之空氣流量之空氣產生。 殊，如諸術項記載之經肺投與用乾燥粉末吸入卒 、中，在㈣中記載之空氣衝擊係藉由具 〇〇 之空氣速度及至少17 ml/see 生。 二乳、夏之空氣產 统，^07.如態樣401項記載之經肺投與用乾燥粉末吸入系 ，、中，在（m)中記載之空氣衝擊係藉 夂空知±一 , 田具有至少1 m/sec <氣速度及至少20ml/sec之空氣流 * 〜工虱產生。 08.如態樣術項記載之經肺投與用乾燥 其中’在(m)中記載之空氣衝擊係藉由具有 糸 空氣速度及17ml/seC至i5L/sec之* V mSec 生。 二乳^量之空氣產 315314 57 1327073 409. 如態樣4〇1項記載之經肺投與心 統’其中’該冷來乾燥組成物具有承受空氣衝4 =%, the air is introduced through the air guide A ^ t ,, and the claw path flows into the container which has become a negative pressure = ' 'The cold is hit by the air of the flow person; the east dry rainbow is atomized, and the particles that are served are attracted by the above The flow path is discharged from the suction port. 3. U 301 § The Pulmonary Drying Inhalation Device for Pulmonary Injection is configured to spray the air into the container once, so that the freeze-dried group is micronized and discharged from the suction port. . 3 0 4 · As in the case of 3 0 1 item, Yin Xi Xi Cheng 8 Qi. As it is, the two lung technology and the dry powder inhalation device 315314 50 1327073, the lanthanum system is configured to spray the air into the above container, so that the freeze-dried composition is micronized into an average particle size of 1 〇胄The particle ratio S is 10% or more and is discharged from the above-mentioned suction port. =: The dry powder inhalation device for lung administration according to the aspect 3CH item:: is a form in which the air jet flow path and the discharge flow path needle portion are formed. The π 胤 态 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如...the dry composition, the lung injection according to the item, the dry powder inhalation device is configured to be micronized into a flat by the subject's absorbing body]] 4^_ + The attack and dryness is pulled at 1 〇 micron to be above 1〇%, and from the upper ^ entrance (four). The cut knot ratio is 3 0 8. If the pattern is 3〇2, it will attract the above-mentioned Shanghai: through the lungs The form in which the dry powder is sucked into the needle-loading portion. The μ and the air introduction flow path are formed in one piece, as shown in the following paragraphs, and the following structures are provided: *There are the following structures *±巾? a powder inhalation holding container for the end of the suction device: hitting to perform micronization: the container is to be received by the air to be sealed with the mouth seal; and the final block form of the freeze-dried composition, and the The inside of the container, the suction bow of the container is made by *:> Donggan 垛 composition air impact 'and means from the composition; % pulverized and micronized powder freeze-dried 315314 51 1327073 which has: needle portion It has a suction flow path for the above-mentioned volume and a cold side for the outer gas to be guided; The flow path is introduced into the suction port portion of the air introduction needle portion of the container into the suction port portion. The holding portion operation portion is formed into a bow in the axial direction and a guide portion, and the container is guided to the needle portion. Needle 卞, 隹: 保 (4) The above-mentioned holding part of the tip of the needle, or from the upper and the mouth of the bar is pushed back from the needle tip by the upper 4, the mechanism of the needle tip, to the mouth of Fen. The bolt is pulled away from the above-mentioned needle portion, and the force required to operate the body and the plug is small, and the force required for the plug is to support the needle portion and to provide the suction port portion. Keep the Ministry of Transportation (4) outside of H and W. The crucible and the suction channel formed in the port and the air introduction flow path and the volume 4 needle portion are positioned to be in the air introduction 2, and the cold shaft is dried by @^^阿·, In the state of force, by using the above-mentioned suction port of the subject and sucking air through the air into the weeping effect, the work wind of ώ π ... into the container, the above tolerance can be The inner 7 freeze-dried composition imparts an air impact. 310. The method of claim 309, wherein the outer casing is formed into a cylindrical shape, and the end, (4) outer casing core = is in front of the outer casing. Ρ 315 314 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 The gas introduction port is provided in a wall portion of the outer casing; and/or the holding portion is moved forward and backward in the axial direction of the casing by the holding portion operation portion. U. According to the aspect of the invention, the transpulmonary administration is carried out by inhalation of the dry powder, and the outer casing is formed by the outer casing body having the above-mentioned capacity: the mouth is formed at the position where the retaining portion retreats, and the hinge is formed. a lid that is coupled to the inlet and outlet of the outer casing body; and a closed portion that includes the lid on the lid, and the needle inlet of the lid hitting portion to the (four) portion of the inlet and outlet, and is pulled up When opening, the above-mentioned holding portion is from the needle portion of the needle portion, the body is returned to the mechanism portion, and the lid is also used as the mechanism portion. (4) The dry powder inhalation system for lung administration is dry group == :: The dry powder inhalation system is a system in which a combination of cold and medium, which is incorporated into a device, the composition of which is contained in a volume composition, which is in a non-powder state in which the air impact thief is cold and not pulverized. When the micron has a composition of two or four, a particle having an average particle diameter of 1% or more of the lung-spraying effect particle ratio can be formed in the container. According to the transpulmonary and dry powder inhalation system, the user Use (inhalation) to save 315314 53 πI Providing cooling to the dried composition, to prepare a self pulmonary and adapted to: dosage form 'i.e. the ratio or effective particle with an average particle diameter in microns square〗). A dry powder preparation consisting of U particles on a %, and can be self-administered (it is important to obtain a dry powder inhalation system for pulmonary administration by the treatment of I. "Composition of the composition, inhalation device And the container as the freeze-dried composition, preferably # # μ 1 + ^ t in the dissolved state, the added component is used to prepare the composition liquid containing non-.+ by freeze-drying, and has The characteristic cold-drying (IV) f I and eight (1) have a non-powder block form; (ii) the decay index is 〇.〇5 or more; and (in) by bearing a name of at least lm/sec, 6 曰 wind speed and air impact of at least 1 7ml / Sec work flow S, ^ L becomes particles with a mean particle size below 10 microns or an effective particle ratio of 1% or more. About the freeze-dried composition The group uses the right ··+. η, 立, 立 U and its modulation method, which can be used later in the above (1). The freeze-dried composition is contained in 啰1> The pirates are freeze-dried and sighed in the distance. They are contained in containers and better packaged. Fr rt θ 巧 巧 'East dry composition of the amount of flat and 1 soil EL with early cast (i fish-owed) on the disk θ, or several people (specifically 2 to 3 - people) And the amount of the active ingredient in summer, preferably the amount of the active ingredient of the package. It is contained in the early 4 and the amount (1 shot of the specific amount, depending on the composition of the dry composition of the cold; the addition of the dry composition) The amount is different from the inhalable amount; (4) and the addition of 佴W is not particularly limited, and the 315314 54 1327073 is usually 30 mg or less, and the sputum is more than 20 mg, more preferably 10 mg or less. It is less than 5 mg. There are the following two: face 'as a dry powder inhaler, preferably I use a dry gentleman with the following characteristics', 〇 + / know the end of the device: with (1) air impact盥手# (or air introduction means, month ah-, thousand & '(2) political granule discharge means (or inhaled fish fleet, by the above (1) air impact: mountain), powder state of cold to dry roasting : The machine "introduces (--) the container that contains the non-* sown from the rβ substance, and uses the introduction (inflow) of the two", ·, pressure) to lyophilize the composition. The granulation is further obtained by the above-mentioned (2) particle discharge means 'dissolving the particles of the means (1): the contents are taken out, and can be directly injected into the method =: inhaled 2 - for example, on The dry powder detailed in the chapter (3), that is, the appropriate transpulmonary administration of the present invention is at least used when it is used, and is used to contain the above-mentioned The container of the lyophilized dry-welded composition of the invention and the system of the above-mentioned system are also used in the system of the dry powder inhalation device. The dried granules of the present invention are used for accommodating the sputum and smuggling of the present invention. Use 刖, a container with a freeze-dried composition and a powder inhalation device. 35 u and the above-mentioned dry right, 3⁄4 The system of the present invention is inhaled by using the 窨 窨 从 从 播 播 播 播 播 播 : : : : : : : : : : 吸入 吸入 吸入 吸入 吸入 吸入 吸入 吸入 东 东 东 东 东 东 东 东 东 东 东+, A is now Liu < each benefit, ' °, freeze-dried composition is presented to the disk, b] πι / sec air speed and ... 'Wang Xi 1 hit, can be prepared and prepared: 'air flow The air is rushed into the wrong diameter of the lungs or can be effectively used 315314 55 1327073 for the ratio of the effective particles administered by inhalation through the lungs, regarding the particle size that can be administered by inhalation through the lungs, for example, early preparation The average particle size of aerodynamics, ΜΜΑ _ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Above, "," the effective granules are better than 30%, especially better than 35%. More than 25 /. Above, according to the system, the modulated lung can be administered (by inhalation) to use This °, the preparation directly with the dry powder inhalation system can be described as "suitable for the dream of the second" Mingzhi lung,.. 9 And a manufacturing system for a dry powder preparation for pulmonary delivery, and a system for administering the dried product to the user." The final preparation is administered by the lung, and the dry powder for pulmonary administration of the present invention is used. The inhalation system includes the specific forms disclosed below: Le, brother package 3 below 401. - type of dry powder for lung administration and (7) combination: ... into the system, the following (1) (1) contain the freeze-dried composition The composition of the freeze-dried composition will contain non-additional components in the state of the solution, and the liquid is prepared by freeze-drying and has the following characteristics (1) to (iii): 1) having a non-powder block form; (Π) a decay index of 〇·〇5 or more; and relying on, by an air impact having an air velocity of at least lm/sec and an air flow of at least the old (10), Particles having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; (2) having a gas-capable (9) and a cold of the above-mentioned volume; East Drying Group 315314 56 1327073 means of forming and discharging micronized A device for the means of powdered cold-bundled composition. The dry powder inhalation system and the container in which the freeze-dried composition is contained in the lungs according to the above paragraph #4〇1, is a container for accommodating the freeze-dried composition containing the active ingredient in the sub-injection. For example, the dry lung inhalation system for transpulmonary administration according to Item 401 is used in combination with the above-mentioned container and the above-mentioned splitting form when inhaled. 钵,: 4·如## The dry powder for transpulmonary administration described in Item 401 In the second line of the system, the decay index of the composition of the east dry matter is as described in the article. The air impact system described in the dry lung inhalation system is described in the article. At least one: a velocity and an air flow of at least 17 ml/sec. In particular, if the lungs are administered by the lungs and the dry powder is inhaled, the air impact recorded in (4) is produced by the air velocity of at least 17 ml/see. Two milk, summer air production system, ^07. According to the 401 items of the lungs, the dry powder inhalation system is used, and the air impact system described in (m) is by the hollow space. At least 1 m/sec < gas velocity and air flow of at least 20 ml/sec* are produced. 08. Transplantation of lungs as described in the aspect of the art. The air shock described in (m) is produced by having a helium air velocity and a flow rate of 17 ml/seC to i5 L/sec*V mSec. The amount of air produced by two milks 315314 57 1327073 409. If the lungs are administered to the heart as described in paragraph 4〇1, the cold-dried composition has the ability to withstand air rushing 4 =

為平均粒徑在5微米以下或有效粒子比率在咖 粒之特性。 工疋U 410. 如態樣4〇1項記載之經肺投與用乾 統’其中，該冷柬乾燥組成物包含做為有效成：;二二 藥物。 他刀子The average particle size is below 5 microns or the effective particle ratio is characteristic of the coffee grains. Work unit U 410. According to the aspect of the invention, the transpulmonary administration system is described in the above paragraph, wherein the cold-dried composition comprises as an effective ingredient: a two-two drug. His knife

用乾燥粉末吸入系 有效成分之蛋白質 用乾燥粉末吸入系 有效成分之呈保持 4 1 1.如態樣40 1項記載之經肺投與 統’其中，該冷凍乾燥組成物包含做為 類及核酸等高分子藥物。 4 1 2 ·如態樣4 0 1項記載之經肺投與 統’其中’該冷凍乾燥組成物包含做為 於保持體狀態之核酸。 三 4U.如態樣410項記載之經肺投與用乾燥粉末 統’其中，該冷凍乾燥組成物包含做為有效成分之低八： 藥物以及載劑，該載劑為至少—種選自胺基酸、二肽刀于 肽及糖類組成之群者。 ' 414. 如態樣4U項記載之經肺投與用乾燥粉末吸入 統，其中，該冷;東乾燥組成物包含做為有效成分之蛋㈠ 類及核酸等高分子藥物以及載劑，該裁劑為至少—種選^ 胺基酸、二肽、三肽及糖類組成之群者。 415. 如態樣4i3項記載之經肺投與用乾燥粉末吸入系 統，其中，該冷珠乾燥組成物包含做為有效成分之低〇 藥物以及載劑，該載劑為至少一種選自疏水性胺基酸、 315314 58 1327073 水性二肽及疏水性三狀組成之群者。 =·如態樣414項記載之經肺投與用乾燥粉末吸入系 統，其令，該冷决乾燥組成物包含做為有效成分之蛋白質 類及核酸等南分子藥物以及載劑，該載劑為至少一種選自 疏水性胺基酸、疏水性二肽及疏水性三狀组成之群者； 統Γ中如項記載之經肺投與用乾燥粉末吸入系 Ί、中’戎冷凍乾燥組成物為水溶性組成物。 =如態樣401項記載之經肺投與用乾燥粉末吸入系 統，/、中，該裝置係採用下列丨）及ii): i)經肺投與用乾燥粉末 容於六哭由、人、 其係將以非粉末狀態收 # 之東乾燥組成物經微粒化並將得到之微粒 供被驗者吸入用之裝置，其具備： 2空氣嘴射流路之針部，具有排出流路之針部，在 以及心空乳嘴射流路中輸送空氣用之空氣壓送手段， /、上述針部之排出流路連通之吸入口； 且被構成為<Inhalation of the active ingredient of the protein with a dry powder, the inhalation of the active ingredient in the dry powder is maintained as 4 1 1. According to the aspect 40, the pulmonary administration system described in paragraph 1 1 wherein the freeze-dried composition comprises as a class and nucleic acid And other polymer drugs. 4 1 2 · The lung administration system as described in the aspect of the invention, wherein the freeze-dried composition contains nucleic acid as a state of maintenance. Three 4U. According to the aspect 410, the transpulmonary administration uses a dry powder system, wherein the freeze-dried composition comprises as a low component of the active ingredient: a drug and a carrier, the carrier being at least one selected from the group consisting of amines A group of peptides and saccharides composed of a base acid and a dipeptide knife. ' 414. According to the aspect 4U, the lung is administered by a dry powder inhalation system, wherein the cold; the east dry composition comprises an egg (a) as an active ingredient, a polymer drug such as a nucleic acid, and a carrier. The agent is at least one selected from the group consisting of amino acids, dipeptides, tripeptides and saccharides. 415. The dry powder inhalation system for transpulmonary administration according to the aspect 4, wherein the cold bead dry composition comprises a low hydrazine drug as an active ingredient and a carrier, the carrier being at least one selected from the group consisting of hydrophobicity Amino acid, 315314 58 1327073 Aqueous dipeptide and a group of hydrophobic tri-forms. = a dry powder inhalation system for transpulmonary administration according to the aspect 414, wherein the cold-dried composition comprises a southern molecule drug such as a protein or a nucleic acid as an active ingredient, and a carrier, wherein the carrier is At least one selected from the group consisting of a hydrophobic amino acid, a hydrophobic dipeptide, and a hydrophobic tri-form; wherein the lung is administered by a dry powder inhalation system, and the medium lyophilized composition is A water soluble composition. = According to the 401 item, the dry powder inhalation system for transpulmonary administration, /, the device uses the following 丨) and ii): i) via the lung, with dry powder for six crying, human, It is a device for inhaling the dry composition of the east of the non-powder state, and the obtained microparticles are supplied to the subject for inhalation, which has: 2 a needle portion of the air nozzle flow path, and a needle portion having a discharge flow path And an air pressure feed means for conveying air in the heart-empty nipple jet flow path, / a suction port through which the discharge flow path of the needle portion communicates; and configured as <

上述針部扎入供來去+ P 路及排出流路與上述容二 =之:；以將空氣喷射流 段 4盗内邛連通，肖由上述空氣壓送手 該嘴述空氣喷射流路喷射於上述容器内，藉由 η粒έ: λ札之衝擊使上述冷凍乾燥組成物微粒化，得到之 微粒經由上述排出流路從吸入口排出。 η)Π:!用乾燥粉末吸入裝置，係將以非粉末狀態收容 祐I之冷4乾燥組成物經微粒化並將得到之微粒供 破^者吸入用之褒置，其具備： 315314 59 1327073 /、有吸引机路之針部，具有空氣導 與上述吸引流路連通之吸人口 ； 《針相及 且構成為： 在上述針部扎入供密封上述容器 被驗者之吸氣壓從上；+、B 之狀悲，错由 時使空氣經由二…容器内之空氣，同 内，藉由流入之：二^ 已成為負壓之容器 得到之微粒經由上：：=述燥組成物微粒化， 上攻及引流路從吸入口排出。 19.如愁樣418項記载之經肺投與 統’其中’該裝置㈣I經肺投㈣之乾朴入糸 其係具備下列構件之裝置’ 再干之乾紐粉末吸入裝置： 保持容器用之保 擊以進行忾牿几 ”中。玄合益收容待承受空氣衝 U粒化之非粉末塊狀形 用口栓密封，以及 7果钇煸組成物，且 職與該容器内之上述冷凍乾 上述容器内吸引藉由空氣===物空氣衝擊，並從 組成物之手段； ❹化之粉末狀冷凌乾燥 其具備： 針部，具有供從上述容5! 0刀弓丨μ、+·人Α 之吸彡丨f 1、/ β 。引上述Θ凍乾燥組成物用 流路㈣心及供將外部氣體導人上述容㈣之空氣導Ζ 與上述針部之吸㈣路連通之吸引 將上述保持部導向上述針部二 保持部運轉部，其具有將上/二方向之引導部， ’谷盗保持於上述保持部 315314 60 之時’使該容器向該針 述針尖扎入，及從卜二 並使容器之口栓被上 針尖用之機構π广退而將容器之口栓拉離上述 部被構成為可用 料體，且该機構 .,^ 述針部扎入容器之口拴所需要之Λ 為小之力操作上述操作體，以及 ㈣而要之力 上it. if上述針部且供設置上述吸引口部、上述引導部及 上述保持部運轉部之外殼；而且 於上述針部扎入上述口栓 ^ ^ 4 枉Μ便上述針部之吸引流路及The needle portion is inserted into the supply + P path and the discharge flow path and the above-mentioned volume 2:; the air jet flow segment 4 is stolen and connected, and the air jet flow path is sprayed by the air jet flow path. In the above-mentioned container, the freeze-dried composition is atomized by the impact of η έ : λ , and the obtained fine particles are discharged from the suction port through the discharge flow path. η)Π:! A dry powder inhalation device is used to store the dried composition in a non-powder state by micronization and to obtain a microparticle for inhalation, which has: 315314 59 1327073 /, a needle portion having a suction path, and a suction portion having an air guide and the suction flow path; the needle phase is configured to: the suction pressure of the subject in the needle portion is sealed from the upper portion; +, B is sad, when the error is caused by the air in the container, through the inside of the container, by the inflow: two ^ particles that have become a container of negative pressure through the above:: = dry composition micronization The upper attack and drainage path are discharged from the suction port. 19. For example, in the case of 418, the lungs are administered by the Department of Health, in which the device (4) is administered by the lungs (4), and the device has the following components. The smashing of the smashing is carried out in a non-powder block shape, and 7 钇煸 composition, and the above freezing in the container Drying the above-mentioned container to attract air by air === air impact, and from the means of the composition; ❹化的粉状冷凌干 It has: Needle part, with a supply from the above 5! 0 knife bow 丨μ, + ·The suction of the human 彡丨F 1 , / β. The suction channel of the above-mentioned freeze-dried composition is attracted by the heart of the flow path (4) and the air guide for guiding the external air to the above-mentioned volume (4) and the suction (four) of the needle. The holding portion is guided to the needle portion holding portion operating portion, and has a guiding portion in the upper/two directions, and when the "grass is held in the holding portion 315314 60", the container is inserted into the needle tip, and From the second and the container of the container is used by the mechanism of the needle tip The mouth bolt is pulled away from the above portion to be formed into a usable body, and the mechanism, the needle portion is required to be inserted into the mouth of the container, the operation body is operated with a small force, and (4) the force is required If the needle portion is provided with a casing for providing the suction port portion, the guiding portion, and the holding portion operating portion; and the needle portion is inserted into the needle portion to facilitate the suction flow path of the needle portion and

Li广’:路與上述容器内連通，同時將上述冷凍乾燥組 疋位成在空氣導入流路之前端之狀態時，藉由利用被 驗者，吸氣壓從上述吸引口部吸入上述容器内之空氣，並 使空氣經由空氣導入流路流入上述容器内，可對上述容器 内之冷凍乾燥組成物賦與空氣衝擊。 420.如態樣401項記載之經肺投與用乾燥粉末吸入系 統’其中，組合使用下列（1)及: (1)收容冷凍乾燥組成物之容器，該冷凍乾燥組成物係將包 含非溶解狀態之添加成分之組成液經冷凌乾燥而調製 成’且具有下述⑴至（iii)之特性： (i) 具有非粉末之塊狀形態； (ii) 衰變指數在0.05至1.5之範圍内；以及 (iii)藉由承受具有1至300m/sec之空氣速度及i7ml/sec 至15L/sec之空氣流量之空氣衝擊，可成為平均粒徑 在1 〇微米以下或有效粒子比率在1 〇%以上之微粒； 以及 315314 61 1327073 (2)具備可將上述空氣衝擊賦與上述容器内之冷凍乾燥組 成物之手段以及排出經微粒化之粉末狀冷凍乾燥組成 物之手段之裝置。 ^ 421.如態樣420項記載之經肺投與用乾燥粉末吸入系 、’先，其中，收容該冷凍乾燥組成物之容器，為收容含有工 人才又與里之有效成分之冷凍乾燥組成物之容器。 422. 如態樣420項記載之經肺投與用乾燥粉末吸入系 統’其中’該空氣速度為1至25〇m/sec。 423. 如態樣420項記載之經肺投與用乾燥粉末吸入系 、、先其中’該空氣流量為20 ml/sec至1 〇L/sec。 (5)經肺投與方法 再者，本發明係關於經肺投與方法，其包含在使用（投 與）非粉末狀態之冷凍乾燥組成物時，調製成可經肺投與之 微粒之狀態，並吸入該微粒形態之乾燥粉末製劑。該經肺 投與方法可藉由使用在（4)章中詳述之本發明經肺投與用 乾蚝軋末吸入系統進行，該系統宜為由收容（1 )章中詳述之 將包含非溶解狀態之添加成分之組成液經冷凍乾燥所調製 成之本發明冷凍乾燥組成物之容器，以及在（3)章中詳述之 乾燥粉末吸入裝置組成之經肺投與用乾燥粉末吸入系統組 成》 本發明之經肺投與方法包含在下文中揭示之具體態 樣： 八心 501.—種經肺投與方法，包含使用冷凍乾燥組成物， 62 315314 1327073 =来乾燥組成物係將包含非溶解狀態之添加成分之組成 液、及冷4乾燥而調製成，且具有下述特性： (0具有非粉末之塊狀形態； (11)衰變指數為0 05以上；以及 (Hi)藉由承受具有至少W之空氣速度及至少Uml/sec 之空氣流量之空氣衝擊’可成為平均粒徑在ι〇微米以 下或有效粒子比率在1 0%以上之微粒； 寺肖由將上述空氣衝擊賦與於該冷;東乾燥組成 平均粒M 1G微米以下或有效粒子比率在ι〇% 與。之微拉’然後藉由令使用者吸入該微粒化之粉末而投 502·如5G1項記載之經肺投與方法其中，該冷 凍“組成物含有丨次投與量之有效成分。 5。〇3.如錄5G1項記載之經肺投與方法，其中，該冷 衣乾燥組成物被收容於交 r 呈備心以及被微粒化之粉末係用 八備對於谷益内之命六，占 冷凍乾燥組成物可賦與上述空氣衝擊 之手^又以及將經料私儿*1· u拉化之粉末狀冷凍乾燥組成物從容哭中 排出之手段之裝置調製而成。 …。中 5 0 4.如態樣5 〇 1 jgΛLi Guang': the road is connected to the inside of the container, and when the freeze-drying group is clamped into the state of the front end of the air introduction flow path, the suction air is sucked into the container from the suction port by using the subject. Air and air are introduced into the container through the air introduction flow path to impart an air impact to the freeze-dried composition in the container. 420. The dry powder inhalation system for transpulmonary administration according to aspect 401, wherein the following (1) and (1) containers for lyophilizing the composition are contained, the freeze-dried composition system comprising non-dissolving The composition of the added component of the state is prepared by cold drying to have 'the characteristics of the following (1) to (iii): (i) having a non-powdered bulk form; (ii) having a decay index in the range of 0.05 to 1.5 And (iii) by subjecting an air impact having an air velocity of 1 to 300 m/sec and an air flow of i7 ml/sec to 15 L/sec, the average particle diameter is below 1 〇 micron or the effective particle ratio is 1 〇%. The above microparticles; and 315314 61 1327073 (2) are provided with means for imparting the above-mentioned air impingement to the freeze-dried composition in the container and means for discharging the micronized powdery freeze-dried composition. ^ 421. According to the aspect 420, the transpulmonary administration uses a dry powder inhalation system, 'first, wherein the container for accommodating the freeze-dried composition is a freeze-dried composition for containing the active ingredient of the worker. Container. 422. The air velocity of the transpulmonary administration using the dry powder inhalation system as described in item 420 is 1 to 25 μm/sec. 423. According to paragraph 420, the lungs are administered with a dry powder inhalation system, and the air flow rate is 20 ml/sec to 1 〇L/sec. (5) Transpulmonary administration method Further, the present invention relates to a pulmonary administration method comprising the state of being prepared into a particle which can be administered through the lung when the (ly) lyophilized composition in a non-powder state is used (administered) And inhaling the dry powder preparation in the form of the microparticles. The method of pulmonary administration can be carried out by using a dry-pulling inhalation system for pulmonary administration according to the present invention as described in detail in (4), which system is intended to contain a non-dissolved state as detailed in containment (1). The container of the component of the present invention is prepared by freeze-drying the container of the freeze-dried composition of the present invention, and the dry powder inhalation system consisting of the dry powder inhalation device detailed in the chapter (3). The pulmonary administration method comprises the specific aspects disclosed below: Baxin 501. - A method of pulmonary administration, comprising using a freeze-dried composition, 62 315314 1327073 = to dry the composition will contain an additive component in an undissolved state. The composition liquid and the cold 4 are dried to be prepared, and have the following characteristics: (0 has a non-powder block form; (11) a decay index is 0 05 or more; and (Hi) by withstanding an air velocity of at least W And an air impact of at least Uml/sec air flow can be a particle having an average particle diameter below ι〇micron or an effective particle ratio of 10% or more; The east dry composition is equal to the average particle M 1G micron or the effective particle ratio is ι〇% and the micro pull 'and then by the user inhaling the micronized powder and cast 502 · as described in the 5G1 lung injection method Wherein, the frozen "composition contains the active ingredient of the sputum administration amount. 5. 〇 3. The method for the pulmonary administration according to the item 5G1, wherein the cold-drying composition is contained in the argon And the micronized powder is used for the preparation of the glutinous rice, the lyophilized composition can be given the above-mentioned air impact, and the powdered lyophilized powder can be pulled by the granules. The composition is prepared from the device of the means of discharging from the crying. .... 5 0 4. If the state is 5 〇 1 jgΛ

d 員s己載之經肺投與方法，其中，該A 柬乾燥組成物之衰變户與_ / λ ^ 7 农又札數在0.05至i.5之範圍内。 5 0 5.如態樣 5 (Π is 4 中m p t 載之經肺投與方法，其中，在（叫 m w 八有至乂 2 m/sec之空氣速度及 ml/sec之空氣流量之空氣產生。 5 0 6 ·如態樣 5 (Π 、 項^己载之經肺投與方法，其中，在（iii) 315314 63 1327073 中。己載之空乳衝擊係藉由具有丄至3〇〇 m/sec之空氣速度 及至少17ml/sec之空氣流量之空氣產S。 、、又 507. 如怎樣503項記載之經肺投與方法其中，在（⑴） 己載之工A衝擊係藉由具有至少丨之空氣速度及 至>、2〇ml/sec之空氣流量之空氣產生。 508. 如態樣 503 jg 4 ^ ^ 項5己载之經肺投與方法，其中，在（iii) 〒屺載之空氣衝擊係, 、㈢由具有至少1 m/sec之空氣速度及 m sec 至 15L/Sec 之空氣流 &。 如態# 5〇3項記載之經肺投與方法，其中，該冷 /東乾燥組成物包含做& ^ 又馬有效成分之低分子藥物。 510.如隸503項記載之經肺投與方法，其中，該卜 /東乾燥組成物包含做氧 7 子藥物。 文為有效成分之蛋白質類及核酸等高分 5 11.如態樣503瑁4A ^ .^ 項圮載之經肺投與方法，其中，該冷 核酸。 為有效成分之呈保持於保持體狀態之 512.如態樣5〇91^匕 東乾燥組成物包含做為：載：：肺投與方法，”，該冷 該載劑為至少-種選t有效成…分子藥物以及載劑， 群去 k自胺基酸、二肽、三肽及糠類組成之 5 1 3 ·如態樣 5 1 〇 - . _ Ά ^ 、記載之經肺投與方法，其中，該冷 子藥物以及載劑心有效成分之蛋白質類及核酸等高分 三肽及糖類組成之群：劑為至少—種選自胺基酸、二肽、 315314 64 5 1 4.如態樣5 12項 象乾燥組成物包含做為 該載劑為至少一種選自 性三肽組成之群者。 έ己載之經肺投與方法，其中，該冷 有效成分之低分子藥物以及載劑， 疏水性胺基酸、疏水性二肽及疏水 5如㈣513項記載之經肺投與方法，其中，該冷 子：：且成物包含做為有效成分之蛋白質類及核酸等高分 千樂物以及載劑，兮# 士，& , 載洌為至 >、一種選自疏水性胺基酸、 肌水性二肽及疏水性三肽組成之群者。 5 16.如態樣 ;東乾燥組成物為 503項記載之經肺投與方法，其中，該冷 水〉谷性組成物。 ,5 1 7.如％ # 503 1貝記載之經肺投與方&，其係微粒化 成平均粒徑在5微米以下或有效粒子比率在观以上之微 粒之投與方法。 5 1 8·如態樣503項記載之經肺投與方法，其中，該裝 置係採用（3)乾燥粉末吸入裝置之章中記載之形態項3〇 j或 302之乾燥粉末吸入裝置。 5 1 9.如態樣5 1 8項記載之經肺投與方法，其中，該裝 置係採用（3)乾燥粉末吸入裝置之章中記載之形態項3〇9之 乾燥粉末吸入裂置。 520.如態樣5〇3項記載之經肺投與方法其中，冷凍 乾燥組成物係將包含非溶解狀態之添加成分之組成液經冷 凍乾燥而調製成，且具有下述特性者： (1)具有非粉末之塊狀形態； :以及 (ii)衰變指數在〇·〇5至1.5之範圍内 315314 65 1327073 ㈣藉由承受具有！至300 m/sec之空氣速度及旧⑹ 至15L/sec之空氣流量之空氣衝擊，可成為平均粒徑 在1〇微米以下或有效粒子比率在1〇%以上之微粒； 經微粒化之粉末，係使用具備可將上述空氣衝擊賦與容器 内之上述冷凍乾燥組成物之手段以及從容器排出經微粒化 之粉末狀冷凍乾燥組成物之手段之裝置調製而成。 521.如態樣520項記載之經肺投與方法其中該空氣 速度為1至25〇m/sec。 ； 曰522,如態樣52〇項記載之經肺投與方法，其中該空氣 流量為 20 ml/sec 至 l〇L/sec。 (6)冷/東乾無組成物在吸入式經肺投與之使用 再者，本發日月係關於非粉末狀態之冷來乾燥组成物在 吸入式經肺投與上之使用。該使用包含在下文中揭示 體態樣： 〃 601.冷凍乾燥組成物在吸入式經肺投與之使用，其 中，該冷凍乾燥組成物係將包含非溶解狀態之添加成分之 、、且成液經冷/東乾燥而調製成，且具有下述特性· (i) 具有非粉末之塊狀形態； (ii) 衰變指數為〇.〇5以上；·以及 (山）藉由承受具有至少lm/sec之空氣速度及至少 之空氣流量之空氣衝擊’可成為平均粒徑在ι〇微米以 下或有效粒子比率在1 〇%以上之微粒； 該冷凍乾燥組成物係粉末化成具有上述平均粒徑或有 315314 66 1327073 效粒子比率之微粒來使用。 602.如態樣601項記載之冷凍乾燥組成物在經肺投與 上之使用，其中，該冷凍乾燥組成物為含有j次投與量之 有效成分者。 603.如態樣601項記载之冷凍乾燥組成物在經肺投與 上之使用，其中，該冷凍乾燥組成物被收容於容器内，以 及經微粒化之粉末係用具備對於容器内之該冷凍乾燥組成 物可賦與上述空氣衝擊之手段以及將經微粒化之粉末狀冷 凍乾燥組成物從容器中排出之手段之裝置調製而成。7 04·如心樣603項6己載之冷凍乾燦組成物在經肺投與 上之使用，其中，該冷凌乾操組成物之衰變指數在〇 〇5至 1.5之範圍内。 6〇5.如態樣6〇3項記載之 上之使用，其中，該冷凍乾燥 2 m/sec之空氣速度及至少17 擊’可形成平均粒徑在丨〇微米 以上之微粒者。 冷凍乾燥組成物在經肺投與 組成物係藉由承受具有至少 ml/sec之空氣流量之空氣衝 以下或有效粒子比率在丨〇0/〇 606.如態樣603項記恭夕.人、*私β , 、載之冷凍乾燥組成物在經肺投與 上之使用，其巾，該冷凍乾燥組成物係藉由承受呈有1 : 3〇〇m/SeC之空氣速度及至少1.…C之空氣流量之空氣 衝擊，可形成平均粒徑在1〇 飞 1 υ域木以下或有效粒子比率在 10 %以上之微粒者。 607·如態樣603項記 戰之冷凍乾燥組成物在經肺投與 上之使用，其中’該冷凍乾 乾炼，.且成物係精由承受具有至少 3Ι53Ι4 67 1327073 咖之空氣速度及至少2〇mi/sec之空氣流量之空氣衝 形成平均粒徑在！ 0微米以下或有效粒子比 以上之微粒者。 心樣603項兄載之冷凍乾燥組成物在經肺投與 -、中°玄冷凍乾燥組成物係藉由承受呈有至少 lm/sec之空氣速度及π ―、 _ n ml/seC至15L/sec之空氣流量之空 乳衝擊，形成平均粒徑在 邮以上之微粒者。 下或有效粒子比率在 609.如態樣6〇3項記都夕A、去私^ ^ ^ 载之令凍乾燥組成物在經肺投與 可形成平均粒徑在5微乎以下=#由承受空氣衝擊， 之微粒者。， ^下或有效粒子比率在20%以上 6 1 〇·如態樣6〇3項記載冷凌 之使用，装由…“ 組成物在經肺投與 低分子藥物者。 勹已“故為有效成分之 611. 如態樣603項夺哉々、人社 之使用，JL中，^r A^ 7 / L燥組成物在經肺投與 便用# ϋ冷4乾燥組成物 白質類及核酸等高分子藥物。 為有效成为之蛋 612. 如態樣603項記冷 之使用，其中，該冷凍款皮？ 且成物在經肺投與 保持於保持體狀態之核酸。 ‘，，、有效成刀之呈 6!3·如態樣610項記栽之冷凍 之使用，"’該冷;東乾燥組成物包含做為：在=投與 分子藥物以及載劑’該載劑為至少-種選自胺基v:r太低 315314 68 1327073 三肽及糖類組成之群者。 614.如態樣611項記載之冷来乾燥址成物在經肺投斑 之使用，Μ，該冷;東乾燥組成物包含做為有效成分之蛋 白寅類及核酸專面分子藥物以及載劑，該載劑為至少一種 選自胺基酸、二肽、三肽及糖類組成之群者。 6 1 5.如L樣6 13項§己载之冷凍乾燥組成物在經肺投與 之使用，#中，該冷凍乾燦組成物包含做為有效成分之低 分子藥物以及載劑’該載劑為至少—種選自疏水性胺基 酸、疏水性二肽及疏水性三肽組成之群者。 616.如態樣614項記载之冷純燥组成物在經肺投盘 之使用，彡中，該冷洗乾燥組成物包含做為有效成分之蛋 白質類及核酸等兩分子藥物以及載劑，該載劑為至少—種 :自疏水性胺基酸、疏水性二肽及疏水性三肽組成之群 者0 617·如態樣603項記載之冷减乾燥組成物在經肺投與 之使用，其中，該冷來乾燥組成物為水溶性組成物。 618.如態樣6G3項記載之冷純燥組成物在經肺投與 之使用’其中’該裝置係採用前述（3)章乾燥粉末吸入裝置 中5己載之悲樣3 0 1或3 02項之乾燥粉末吸入裝置。 619•如態樣⑽項記载之冷珠乾燥組成物在經肺投與 之使用’其中’戎裝置係採用前述(3)章乾燥粉末吸入裝置 中έ己載之態樣3 0 9項之乾燥粉末吸入裝置。 620.如悲樣603項記載之冷凍乾燥組成物在經肺浐血 之使用，纟中，該冷隸燥組成物係將包含非溶解狀= 315314 69 1327073 添加成分之組成液經冷凍乾燥而調製成，且具有下述特性 者： (1)具有非粉末之塊狀形態； (ii)衰變指數在0.05至1.5之範圍内；以及 (111)藉由承受具有1至300m/sec之空氣速度及17ml/sec 至15L/Sec之空氣流量之空氣衝擊，可成為平均粒徑 在微米以下或有效粒子比率在10%以上之微粒· 々哭經微粒化之粉末，係使用具備可將上述空氣衝擊賦與 之上述冷凍乾燥組成物之手段以及從容器排出經微 粒化之粉末f冷康乾燥組成物之手段之裝置調製而成/ 心樣620項記載之冷凍乾燥組成物在經肺投盥 ’該空氣流量為1至25〇m/sec。 ” 々心樣62〇項記載之冷凍乾燥組成物在經肺投與 用，其中，該空氣流量為20 ml/sec至10L/sec。 燥組成物在製造吸入式經肺投與用乾燥粉末製 再者，明係關於非粉末狀態之冷康乾 製造吸入式經肺投盥用仏P “ ^ 含在丁t L燥粕末製劑上之使用。該使用包 3在下文中揭不之具體態樣： 701·冷凍乾燥組成物太制^ 主 在製&吸入式經肺投與用乾燥粉 末製劑之使用，該冷凌妒 乾無組成物具有下述特性： (1)係將包含非溶解狀能 而調製成， …、加成分之組成液經冷康乾燥 315314 70 丄义/073 (II) 具有非粉末之塊狀形態， (III) 衰變指數為0.05以上，以及 ㈣藉由承受具有至少丨m/sec之空氣速度及至少ι: = l/sec之空氣流量之空氣衝擊，可成為平均粒徑在 微=以下或有效粒子比率在1〇%以上之微粒；以及 於使用時，將該冷凍乾燥組成物經微粒化成具有上述平均 粒徑或上述有效粒子比率。 7〇2.如悲、樣701項記載之冷;東乾燥組成物之使用其 ’該冷凍乾燥組成物為含有！次投與量之有效成分者:、 士 t樣7〇 1項圮載之冷凍乾燥組成物在製造經肺 指:與用乾燥粉末製齋丨卜 + 一 上之使用，其中，該冷凍乾燥組成物 之衣變指數在〇.〇5至1,5之範圍内。 704.如態樣701項記載之冷凍乾燥組成物在製造經肺 :用乾燥粕末製劑之使用，其該冷凍乾燥組成物係 f =具有至少2 一之空氣速度及至少旧/…之 空乳流量之空氣衝擊，可形成平均粒徑在1〇微米以下或有 效粒子比率在1〇%以上之微粒者。 ^ 7〇5·如_ 7〇1我載之冷束乾燥組成物在製造經肺 用乾Μ末製劑之使用’其中，該冷;東乾燥組成物係 稭！！ΐί有1至300m/sec之空氣速度及至少17 — 氣机里之二氣衝擊’可形成平均粒徑在1 〇微米以下或 有效粒子比率纟10%以上之微粒者。 706•如態樣7〇1項記載之冷;東乾燥組成物在製造經肺 投與用乾燥粉末製劑之使用，其令，該冷凍乾燥組成物係 315314 1^27073 2罗又八有至J lm/sec之空氣速度及至少Μ出…“之 空氣流量之空氣衝擊，可形成平均粒徑在ι〇微米以下或有 效粒子比率在10%以上之微粒者。 〜、樣70 1項記载之冷凍乾燥組成物在製造經肺 =用乾㈣末製劑之使用，其中，該冷隸燥組成物係 ，承又具有至少lm/sec之空氣速度及17ml/seC至 、L/sec之空氣流量之空氣衝擊，形成平均粒徑在1〇微米 、下或有效粒子比率在！ 〇%以上之微粒者。 士心樣70 1項記載之冷凍乾燥組成物在製造經肺 乞燥粉末製劑之使用，其中，該冷束乾燥組成物為 =承受空氣衝擊，可形成平均粒徑在5微米以下或有效 粒子比率在20%以上之微粒者。 Π 士 &樣7〇 1項記載之冷凍乾燥組成物在製造經肺 燥粉末製劑之使用，其中，該冷來乾燥組成物為 包3做為有效成分之低分子藥物者。 L'樣701項記載之冷凍乾燥組成物在製造經肺 又人用乾燥粉末製 ^ ^ 製"丨之使用，其中，該冷凍乾燥組成物包 二有效，蛋白質類及核酸等高分子藥物。 投返用7G1項記載之冷束乾燥組成物在製造經肺 冬κ ^之使用，其中，該冷凍乾燥組成物包 效成分之呈保持於保持體狀態之核酸。 投 樣709項δ己載之冷凍乾燥組成物在製造經肺 含做2燥粉末製劑之使用，其中，該冷凌乾燥組成物包 效成分之低分子藥物以及載劑，該載劑為至少一 315314 72 1327073 種選二胺基酸、二肽、三肽及糖類組成之群者。 3.如&樣71G項記載之冷束乾燥組成物在製造經肺 才又與用乾燥粉末f 含傲 、 吏用，/、中，该冷凍乾燥組成物包 :::效成分之蛋白質類及核酸等高分子藥物以及栽 成之群者Μ為至少一種選自胺基酸、二肽、三肽及糠類組 π盘2如悲冑712項記載之冷來乾燥組成物在製造經肺 才又，、用乾燥粉末製劑 含傲…；、 其中’該冷凍乾燥組成物包 種、巽白· ^/文刀之低分子藥物以及載劑’該载劑為至少一 者？疏水性胺基酸、疏水性二肽及疏水性三肽組成之群 t 〜樣713項圮載之冷凍乾燥組成物在製造經肺 ‘與用乾燥粉末製劑之使用，其 劍，核酸等高分子藥物以及載 J錢別為至少—種選自疏水性胺 疏水性三肽組成之群者。 ^性一肽及 m.如態樣701項記載之冷康乾燥組 投與用乾燥粉末製 肺 水溶性組成物。 其中’該冷來乾·燥組成物為 717.如態樣701項記載之冷凍 投與用乾燥粉末製劑之使用 製造經肺 末製劑之微粒之平該經肺投與用乾燥粉 子比率為鳩以上。為^以下’或微粒之有效粒 718_如態樣Μ項記載之冷决乾燥組成物在製造經肺 315314 73 1327073 投^用乾燥粉末製劑之使用，其中，該冷來乾燥組成物被 枚容於容器内，以及經微粒化之粉末係用具備對於該容器 内之冷凍乾燥組成物可賦與上述空氣衝擊之手段以及將經 微粒化之粉末狀冷凍乾燥組成物從容器中排出之手段之裝 置調製而成。 7 1 9.如態樣7 1 8項記載之冷凍乾燥組成物在製造經肺 投、與用乾燥粉末製劑之使用’其中，職置係採用（3)乾燥 _粉末吸入裝置之章中記載之形態項3〇1或3〇2之乾燥粉末 吸入装置。 ^ 72〇_如態樣719項記載之冷凍乾燥組成物在製造經肺 投與用乾燥粉末製劑之使用，其中該裝置係採用（3)乾燥粉 末吸入襞置之章中記載之形態項3〇9之乾燥粉末吸入 置。 、 72 1 ·如態樣70 1項記載之冷凍乾燥組成物在製造經肺 投與用乾燥粉末製劑之使用，其中使用具有下述特性之冷 鲁’東乾餘組成物d The admin has a method of transpulmonary administration, wherein the decaying composition of the A-card dry composition and the number of _ / λ ^ 7 are in the range of 0.05 to i. 5 0 5. As in the case 5 (Π is 4 in mpt, the method of transpulmonary administration, in which air is generated at an air velocity of mw eight to 2 m/sec and air flow of ml/sec. 5 0 6 · As in the case of 5 (Π, 项 己 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载The air velocity of sec and the air flow rate of air flow of at least 17ml/sec S., 507. How to record the lung injection method of 503, in which (A) has a work A impact by at least The air velocity of the air and the air flow to >, 2 〇 ml/sec. 508. If the pattern is 503 jg 4 ^ ^ item 5, the method of lung administration, wherein, in (iii) The air impact system, (3) the air flow with an air velocity of at least 1 m/sec and m sec to 15 L/Sec. The lung administration method according to the state #5〇3, wherein the cold/ The east dry composition comprises a low molecular drug which is an active ingredient of & ^ horse. 510. The method according to 503, wherein the preparation of the lung is dry The substance comprises an oxygen-based 7-drug. The protein is an active ingredient of a protein and a nucleic acid, etc. 5 11. If the 503瑁4A ^ .^ item is a lung-administered method, wherein the cold nucleic acid is effective. The component is maintained in the state of the retaining body 512. If the composition is 5〇91^匕东 dry composition is included as: loading:: lung administration method,", the cold carrier is at least - selected t effective ...molecular drug and carrier, group k from amino acid, dipeptide, tripeptide and anthraquinone 5 1 3 · as in the case of 5 1 〇 - . _ Ά ^, the recorded transpulmonary administration method, wherein a group consisting of a protein and a nucleic acid such as an active ingredient of the carrier and a high-quality tripeptide and a saccharide: the agent is at least one selected from the group consisting of an amino acid, a dipeptide, and 315314 64 5 1 4. 5th dry composition comprises, as the carrier, a group consisting of at least one selected from the group consisting of tripeptides. The pulmonary administration method, wherein the cold active ingredient is a low molecular drug and a carrier, Hydrophobic amino acid, hydrophobic dipeptide, and hydrophobic 5, as described in paragraph 513 of the method of pulmonary administration, wherein the cold: And the product comprises a high-grade Thousand music and a carrier such as a protein and a nucleic acid as an active ingredient, 兮#士,&, 洌为至>, one selected from hydrophobic amino acids, myosin dipeptide And a group of hydrophobic tripeptides. 5 16. As the aspect; the east dry composition is the 503 method of pulmonary administration, wherein the cold water> gluten composition. 5 1 7. 503 1B, the pulmonary administration method is a method of administering microparticles into microparticles having an average particle diameter of 5 μm or less or an effective particle ratio of more or more. 5 1 8 . The method according to aspect 503, wherein the device is a dry powder inhalation device according to the item 3〇 j or 302 described in the chapter (3) of the dry powder inhalation device. 5 1 9. The method according to the aspect of the invention, wherein the device is a dry powder inhalation split of the shape item 3〇9 described in the chapter (3) of the dry powder inhalation device. 520. The pulmonary administration method according to the aspect 5, wherein the freeze-dried composition is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state, and has the following characteristics: (1) ) has a non-powder block form; : and (ii) the decay index is in the range of 〇·〇5 to 1.5 315314 65 1327073 (d) by withstanding! The air impact at an air velocity of 300 m/sec and an air flow of the old (6) to 15 L/sec may be particles having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more; It is prepared by using a device having means for imparting the above-described air impingement to the freeze-dried composition in the container and means for discharging the micronized powdery freeze-dried composition from the container. 521. The method according to aspect 520, wherein the air velocity is 1 to 25 〇m/sec.曰522, a method according to the aspect of the invention, wherein the air flow rate is from 20 ml/sec to l〇L/sec. (6) Cold/East dry ingredients are used in inhaled transpulmonary administration. Further, this is the use of a cold-dried composition in a non-powder state for inhaled transpulmonary administration. This use includes the following aspects: 〃 601. The freeze-dried composition is administered by inhalation via the lung, wherein the freeze-dried composition will contain the added component in an undissolved state, and the solution is cooled. / East dry and prepared, and has the following characteristics: (i) has a non-powder block form; (ii) decay index is 〇. 〇 5 or more; · and (mountain) with at least lm / sec The air velocity of the air velocity and the at least air flow rate may be particles having an average particle diameter below ι〇micron or an effective particle ratio of more than 1% by weight; the freeze-dried composition is powdered to have the above average particle diameter or has 315314 66 1327073 Particles of the effect particle ratio are used. 602. The freeze-dried composition according to aspect 601, which is administered by pulmonary administration, wherein the freeze-dried composition is an active ingredient containing j administration amount. 603. The freeze-dried composition according to aspect 601, which is used for pulmonary administration, wherein the freeze-dried composition is contained in a container, and the micronized powder is used in the container. The freeze-dried composition can be prepared by means of the above-described means of air impact and means for discharging the micronized powdery freeze-dried composition from the container. 7 04·If the chilled dry composition of the 603 item 6 is used in the administration of the lung, the decay index of the cold-drying composition is in the range of 〇 5 to 1.5. 6〇5. Use as described in paragraphs 6.3, wherein the freeze-dried air velocity of 2 m/sec and at least 17 strokes can form particles having an average particle diameter above 丨〇micron. The lyophilized composition is administered to the composition via the lungs by subjecting the air to have an air flow rate of at least ml/sec to the following or effective particle ratio at 丨〇0/〇606. * private β, and the freeze-dried composition is used in the administration of the lung, the towel, the freeze-dried composition is subjected to an air velocity of 1:3〇〇m/SeC and at least 1.... The air impact of the air flow of C can form particles having an average particle diameter of less than 1 〇 1 υ domain wood or an effective particle ratio of 10% or more. 607. If the lyophilized composition of the 603th record is used in the pulmonary administration, wherein the freeze-drying is performed, and the adult system is subjected to an air velocity of at least 3Ι53Ι4 67 1327073 and at least The air flow of the air flow of 2〇mi/sec forms an average particle size! Those below 0 microns or having effective particles above the above. The freeze-dried composition of the heart-shaped 603 brothers is administered in the lungs, and the medium freeze-drying composition is subjected to an air velocity of at least lm/sec and π ―, _ n ml/seC to 15 L/ The air flow of the sec air is impacted by the air, forming a particle with an average particle size above the post. The ratio of the effective particle or the effective particle is 609. If the state is 6〇3, it is recorded in the evening, and the free-drying composition is placed in the lung to form an average particle size of 5 micro or less =# Those who withstand the impact of air, the particles. , ^ or the effective particle ratio is above 20% 6 1 〇 · If the state of 6 〇 3 items describes the use of cold ling, loaded by ... "The composition of the drug in the lungs of low molecular drugs. 勹 has been "effective Ingredients 611. If the 603 items are used, the use of human society, JL, ^r A^ 7 / L dry composition in the lungs can be used to dry #4 cold 4 dry composition white matter and nucleic acids, etc. Polymer drugs. To be effective as an egg 612. If the 603 items are used in the cold, where is the frozen skin? Further, the adult is administered a nucleic acid which is maintained in a maintained state by the lung. ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The carrier is at least one selected from the group consisting of an amine group v:r too low 315314 68 1327073 tripeptide and a saccharide. 614. If the cold-dried dry matter recorded in the 611th aspect is used in the lungs, the cold-dried composition contains the peptone and the nucleic acid-specific molecular drug and the carrier as active ingredients. The carrier is at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides. 6 1 5. If the lyophilized composition contained in the L-class 6 § 1:1 is used in the lung, the lyophilized composition contains the low-molecular drug as an active ingredient and the carrier. The agent is at least one selected from the group consisting of a hydrophobic amino acid, a hydrophobic dipeptide, and a hydrophobic tripeptide. 616. The cold-pure dry composition according to aspect 614 is used in a lung-dropping, wherein the cold-washed dry composition comprises two molecules of a protein such as a protein and a nucleic acid as an active ingredient, and a carrier. The carrier is at least one species: a group consisting of a hydrophobic amino acid, a hydrophobic dipeptide, and a hydrophobic tripeptide. 0 617. The cold-dried composition described in Section 603 is used in the lung. Wherein the cold-dried composition is a water-soluble composition. 618. If the cold and pure dry composition described in the 6G3 item is used in the lung, the device is used in the dry powder inhalation device of the above (3), and the sadness of the sample is 3 0 1 or 3 02 Dry powder inhalation device. 619•If the cold-bead-dried composition described in the aspect (10) is used in the lung, the 'where' device is used in the dry powder inhalation device of Chapter (3) above. Dry powder inhalation device. 620. The lyophilized composition according to the 603th item of sadness is used in the blood of the lung, and the composition of the cold stalk is contained in the non-dissolving form = 315314 69 1327073. And having the following characteristics: (1) having a non-powder block form; (ii) a decay index in the range of 0.05 to 1.5; and (111) by withstanding an air velocity of 1 to 300 m/sec and The air impact of the air flow rate from 17ml/sec to 15L/Sec can be a particle with an average particle diameter of less than micrometer or an effective particle ratio of 10% or more. The powder is cryogenically micronized, and the air impact can be used. The lyophilized composition described in the above-mentioned means for lyophilizing the composition and the means for discharging the micronized powder from the container, and the lyophilized composition described in Item 620, is injected into the lung The flow rate is 1 to 25 〇 m/sec. The freeze-dried composition described in the above paragraph 62 is administered by transpulmonary administration, wherein the air flow rate is from 20 ml/sec to 10 L/sec. The dry composition is manufactured by using a dry powder for inhaled transpulmonary administration. Furthermore, the use of the cold-dry dry in the non-powder state for the manufacture of inhaled transpulmonary sputum P "^ is contained in the preparation of the sputum-dried sputum. The use package 3 is not disclosed in the following: 701· freeze-dried composition is too much to be used in the main & inhaled lung-administered dry powder preparation, and the cold-cold dry composition has the following composition Characteristics: (1) The composition will contain non-dissolving energy, and the composition of the added component will be dried by cold drying. 315314 70 丄 / 073 (II) has a non-powder block form, (III) decay index 0.05 or more, and (d) by subjecting an air impact having an air velocity of at least 丨m/sec and an air flow of at least ι: = l/sec, the average particle diameter may be micro== or the effective particle ratio is 1%% The above microparticles; and, at the time of use, the freeze-dried composition is micronized to have the above average particle diameter or the above effective particle ratio. 7〇2. If sorrow, sample 701 is cold; use of east dry composition. 'The freeze-dried composition is contained! The sub-injection and the effective component of the dose:, the t-sample 7〇1 item of the freeze-dried composition in the manufacture of the lung finger: and the use of dry powder for the use of 丨 丨 + 一 , The clothing index of the object is in the range of 〇.〇5 to 1,5. 704. The lyophilized composition of aspect 701, wherein in the manufacture of transpulmonary: a dry mash composition, the lyophilized composition f = having an air velocity of at least 2 and at least an old air emulsion The air impact of the flow rate can form particles having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more. ^ 7〇5·如_7〇1 The cold-dried composition of my use is used in the manufacture of dried sputum preparations for the lungs. Among them, the cold; the eastern dry composition is straw! ! Ϊ́ί has an air velocity of 1 to 300 m/sec and at least 17 - a gas impact in the gas engine can form particles having an average particle diameter of less than 1 〇 micrometer or an effective particle ratio of 纟 10% or more. 706• The cold as described in paragraph 7〇1; the dry composition of the east is used in the manufacture of a dry powder preparation for transpulmonary administration, and the freeze-dried composition is 315314 1^27073 2 Luo and eight to J The air velocity of lm/sec and at least the air impact of the air flow can form particles with an average particle diameter below 10 μm or an effective particle ratio of 10% or more. The freeze-dried composition is used in the manufacture of a transpulmonary = dry (four) final formulation, wherein the cold-drying composition has an air velocity of at least lm/sec and an air flow of 17 ml/seC to L/sec. The air is impinged to form particles having an average particle diameter of 1 μm or less, or an effective particle ratio of !% or more. The freeze-dried composition described in 1971, in the manufacture of a pulmonary dry powder preparation, wherein The cold-dried composition is subjected to air impact and can form particles having an average particle diameter of 5 μm or less or an effective particle ratio of 20% or more. The freeze-dried composition described in the & && sample 7〇1 Manufacture of a pulmonary dry powder preparation for use The cold-dried composition is a low-molecular drug containing the active ingredient of the package 3. The freeze-dried composition of the L' sample 701 is used in the manufacture of a lung and a dry powder. The freeze-dried composition package 2 is effective, and a polymer drug such as a protein or a nucleic acid is used. The cold-dried composition described in the 7G1 item is used for the production of a lung-dried composition, wherein the freeze-dried composition is used. The bacteriological component is a nucleic acid which is maintained in a state of being in a retaining body. The lyophilized composition of 709 δ is used in the manufacture of a dry powder containing 2 dry powder preparation, wherein the cold-blooming composition has an effect component a low molecular drug and a carrier, the carrier being at least one of 315314 72 1327073 selected from the group consisting of diamine acids, dipeptides, tripeptides and saccharides. 3. Cold beam drying composition as described in & 71G In the manufacture of the lungs and the use of dry powder f, the lyophilized composition package::: protein components of nucleic acids and nucleic acids and other high-molecular drugs and planted groups are at least One selected from the group consisting of amino acids, dipeptides, Peptide and anthraquinone group π disc 2, such as the cold-dried composition described in Item 712, is produced in the lungs, and is used in a dry powder preparation. In which, the 'freeze-dried composition is packaged, white ^/文刀的低分子药物和载剂' The carrier is at least one of the group consisting of hydrophobic amino acids, hydrophobic dipeptides and hydrophobic tripeptides t ～ 713 圮 之 freeze-dried compositions In the manufacture of transpulmonary and dry powder preparations, the sword, nucleic acid and other high-molecular medicines and the group of J-types are at least one selected from the group consisting of hydrophobic amine hydrophobic tripeptides. ^Sexual peptide and m The cold-cold drying group described in Item 701 is administered with a dry powder to prepare a lung water-soluble composition. Wherein the cold-dried dry composition is 717. The use of a dry powder preparation for cold-supplied administration as described in Item 701 to produce a finely divided powder of the lung preparation has a dry powder ratio of the lung for administration. the above. The dry-dried composition described in the following paragraphs or the granules of the granules 718 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the container, and the micronized powder, a device having means for imparting the above-described air impact to the freeze-dried composition in the container and means for discharging the micronized powdery freeze-dried composition from the container Modulated. 7 1 9. The lyophilized composition according to the aspect 7 1 8 is used in the manufacture of a pulmonary injection and a dry powder preparation, wherein the occupation is carried out in the chapter (3) Drying_Powder inhalation device. A dry powder inhalation device of the form item 3〇1 or 3〇2. ^ 72 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 9 dry powder is placed inhaled. 72 1 · The use of the freeze-dried composition according to the aspect 70 1 in the manufacture of a dry powder preparation for transpulmonary administration, wherein a cold-rubber composition having the following characteristics is used

(0其係將包含非溶解狀態之添加成分之組成液經冷束乾 燥而調製成， L (II) 具有非粉末之塊狀形態； (III) 衰變指數在0 〇5至1 5之範圍内；以及 (山）藉由承受具有1至300 m/sec之空氣速度及i7mi/see 至15L/Sec之空氣流量之空氣衝擊，可成為平均粒徑 在1 〇微米以下或有效粒子比率在丨〇%以上之微粒。 7 2 2.如態樣7 2 1項記載之冷凍乾燥組成物在製造經 315314 74 1^27073 才又與用乾燥粉末製劑之使用，其中該空氣速度為1至250 爪/sec 〇 723.如態樣721項記載之冷凍乾燥組成物在製造經肺 才又與用乾燥粉末製劑之使用，其中該空氣流量為20ml/sec 至 1 〇L/sec。 (8)添加成分非溶解組成液在製造調製經肺投與用乾燥粉 末製劑所需之冷凍乾燥組成物之使用。 再者，本發明係關於一種添加成分非溶解組成液在製 造調製經肺投與用乾燥粉末製劑所需之冷綠燥組成物之 使用。其中，在製造冷凍乾燥組成物時使用之添加成分非 办解組成液’其調製方法及使用彼等之冷凍乾燥組成物之 調衣方法，以及冷凍乾燥組成物之使用方法（經肺投與用乾 燥粉末製劑之調製方法）係如前述。 ^ 實施例 但本發明並不限 以下，列舉實施例具體說明本發明 於此等實施例。 又，在以下之實施例中 燥組成物（冷凍乾燥塊）之衰 評價經微粉末化之乾燥粉末 述方法計算出。 <衰變指數之計算> ’本發明之非粉末狀之冷凍乾 變指數以及有效粒子比率（係 製劑對送達肺之指標）依照下 乾燥組成物（冷凍乾燥塊） ·〇 ml正己烷。將其用自動 在调製之非粉末狀之冷P東 中，經由容器之壁靜靜地滴入1 315314 75 1327073 實驗室混合器NS-8(Pas()lina公司製）於3_ rpm約授摔ι〇 秒。將得到之混合溶液投入光路長i顏，光路寬1〇麵 之uv至（島津GLC公司製）中，並快速地用分光光度計 (UV 240 ’島津製作所製）於測定波長測定該混合液 ’又將得到之，蜀度除以總處方量（有效成分與載劑之總 量（重量））所得之值做為衰變指數。 <有效粒子比率之算出> 籲 將充填有調製之非粉末狀冷凍乾燥組成物之容器安裝 於乾燥知末吸入裝置中。將使用該裝置並賦與特定之空氣 衝擊所微粉末化而得之粉末製劑於歐洲藥局方 Pharmacopoeia, Third Edition Supplement 2001, pll3-115) 中圯載之裝置A(二段式塵埃測定器：英國c〇pley公司製） 中直接排出。之後，分別回收裝入該裝置之第丨段及第2 段之溶媒.，藉由生物測定法及HpLC等適於測定冷滚乾燥 組成物中之有效成分之方法，定量第丨段及第2段之各溶 •媒中所包含之有效成分[Lucas彡人之報告⑽随· r“， 叫），562·569(1998))及飯田等人之報告（參照藥學雜誌 1 19(1 0)752-762 (1999))]。又可以期待送達肺之部分為第2 段（在該部分中所回收之空氣力學之粒徑為6 4 #爪以 下）’通常達到其之第2段所甶收之有效成分之比率稱為有 效粒子比率（可期待達到肺之量，即.細粒比率），其被做為 评價經肺投與用之吸入劑之適用性之基準。 在下述之實施例及比較例中，定量第丨段及第2段各 含之有效成分之重量，並將得到之第2段中有效成分之重 315314 76 1327073 里除以被噴射之有效成分之總重量（第i段及第2段所含之 有效成分之總重量：以下稱為「第…第2段」），以得 到之值做為有效粒子比圭，Q/、 ，扭十比羊（/°)。又，原則上，在歐洲藥局方 中使用二段式塵埃測定器(英國c〇pley公司製)之情況，由 方、，疋工氣之吸引流置為6〇 ，因此下述 之實施例及比較例亦比照此。 乾燥粉末吸入裝置（噴射型1} 本發明所用之喷射型齡，原伞 主乾展叔末吸入裝置之一實施形態 用第1圖說明。 乾燥粉末吸入裝置，係眩 〇〇 係將收容於容器1之底部之非粉 末性之單位或數次投愈I夕、人、± k 、 ^里之冷凍乾燥組成物2予以微粒化 並送達.肺器官之空氣嗜斯剂。。θ '、’ ^益具’其具備設有空氣噴射流 路3及排出流路4之釙邱 t邛5，有吸入口 6且裝設在針部5 之基端之吸氣構件7，圍繞斜 固、免針5且兼具容器1之保持之 同狀女全罩8以及空氣壓送手段9。 空氣壓送手段9，失主* 七n — 為手動式且具備筒狀之風箱體10， 在風相體1 0上設置附有 喇及進閥11之吸進口 12以及附有吐 出閥1 3之吐出口 1 4，吐 η- 2 ^ ^ 14設置在於針部5之空氣噴 对机路’3之基端側所形 成之接續口 1 5，並與空氣噴射流路 3連通。而且，在關閉吸 於ϋΐ & _ , Λ 阀11之狀悲，猎由施加壓縮力 於風相體1 〇使之收給 允511出閾13將開放，風箱體-:10内之 工乳攸吐出口 14經由办 一 ，，由二軋噴射流路3排出至容器丨内。另 方面，若解除壓縮力，藉由 體1〇 *由風相體10之彈性復原力風箱 υ將伸張’吐出間i 3成盍 或為關閉狀態且吸入閥丨丨打開， 315314 77 1327073 於是空氣被導入風箱體10中。 使用該乾燥粉末吸入裝置時， .^ . 弟1圖所示’將容器 1裝入筒狀安全罩8中，使針部5 L八4态1之口栓部1 a 並使空氣噴射流路3及排出流路4鱼六„。 '、谷态1之内部連通。 在該狀悲’若使空氣壓送手段9之 1相體1 〇收縮以使空氣 從吐出口 14排出，該空氣將經由 工虱賀射流路3從針部5 之前端朝向容器内之冷凍乾燥組成 ^ ^ 取物噴射’藉由該空氣衝 擊’冷凍乾燥組成物2將成為微粒 又杻，經由針部5之排出流 路4從吸氣構件7之吸入口 6排ψ .. 才非出。使用者（患者）藉由從 吸氣構件7之吸入口 6吸入該料初、人土 Λ养’冷凍乾燥組成物2之 微粒可送達患者之肺器官内。又， 。。 人對於本發明所使用之容 器之口栓之材質並無特別限制，你丨 利例如可任意選擇橡膠、塑 膠或鋁等通常做為收容藥物及彳卜人仏α — 奶及化合物之容器之口栓所使用 之材質。 在該喷射型之吸入襄置中，設定成空氣喷射量為約20 ♦刎，容器之容量為約5⑹，空氣噴射流路3之孔徑（直徑） 為約1.2 mm以及排出流路4之孔徑（直徑）為約18丨⑽。 但是非限定於此’空氣喷射流路3及排出流路4之孔 徑由於視容器之大小等較佳範圍而變動，所以並無特別限 制，直徑可從0_3至1〇 mm，較佳〇 3至-7 mm，更佳 至5 mm之範圍内適當選擇。 又，空氣壓送手段9，藉由調整風箱體10之壓縮速度， 可以凋卽吸入投與所需要之微粒之排出量，又藉由該空氣 噴射可以調整成使冷凍乾燥組成物2之大部分微粒化。 78 315314 1327073 實施形態例乾燥粉末吸入裝置（自己吸入型υ 本發明所用之自己吸入型乾燥粉末吸入裝置之一實施 形態(其1)用帛2圖說明。第2圖所示之乾燥粉末吸入裝 置，具備有吸引流路1 6及空氣導入流路丨7之針部5、筒 狀安全蓋8、以及有與吸引流路丨6連通之吸入口丨8之吸 氣構件1 9，吸氣構件1 9與針部5之吸引流路丨6之基端侧 連結。 使用乾燥粉末吸入裝置時，如第2圖所示’將容器】 裝入筒狀安全蓋8中，使針部5札入容器丨之口栓u並使 吸引流路16及空氣導入流路17與容器丨之内部連通。在 該狀態，藉患者之吸氣壓從吸入口 18經由吸引流路16吸 引容窃1内之空氣，同時使外氣從空氣導入流路17流入因 此成為負壓之谷器1内。此時，藉由作用於冷凍乾燥組成 物2之空氣衝擊，將冷凍乾燥組成物2微粒化，調製得之 微粒經由吸引流路丨6從吸入口丨8送達患者之肺器官内。 又，该乾燥粉末吸入裝置被設定成藉由患者之丨次吸 入，冷凍乾燥組成物2之大部分可微粒化並從吸入口 j 8 排出。又，雖然患者之1次吸A之空氣流量為5至3〇〇l/ 分，以至200 L/分為較佳，以1〇至1〇() L/分為更佳， 不過，本發明之自己吸入型乾燥粉末吸入裝置可依照使用 之患者之呼吸能力而適當地變更設計。第2圖所示之吸入 裝置ίτ'依照某患者之呼吸能力設定成容器之容量為約i 〇 ml,空氣導入流路17及吸引流路16之孔徑（直徑）為約i 5 mni者。藉此設定成藉由患者之丨次吸入，冷凍乾燥組成 79 315314 1327073 物2可大致無殘留地完全微粒化並從吸入口 1 8排出。 形態你i__l乾燥粉末吸入裝置（自己吸入型2) 本發明所用之自己吸入型乾燥粉末吸入裝置之一實施 形態（其2)用第3圖說明。第3圖所示之乾燥粉末吸入裝 置’與第1圖所示之喷射型乾燥粉末吸入裝置從接續口 15 取下用於壓送空氣之風箱體1 〇時之形態相同；又第丨圖之 噴射型乾燥粉末吸入裝置之排出流路4相當於吸引流路 鲁1 ό ’空氣噴射流路3相當於空氣導入流路1 7，有吸入口 6 之吸氣構件7相當於有吸入口 1 8之吸氣構件1 9。 因此’使用該自己吸入型乾燥粉末吸入裝置時，以與 第2圖所示之乾燥粉末吸入裝置相同之要領，藉患者之吸 氣壓從吸入口 1 8經由吸引流路1 6吸引容器1内之空氣， 同時使外氣從空氣導入流路1 7流入藉此成為負壓之容器1 内’藉由伴隨該空氣流入所產生之空氣衝擊，將冷凍乾燥 組成物2微粒化。之後，所得之微粒從吸入口 1 8送達患者 _之肺器官内。又，如上述患者之1次吸入之空氣流量為5 至3 00L/分，不過，第3圖所示之吸入裝置可依照使用之 患者之呼吸能力設定成容器之容量為約5 m卜空氣導入流 路1 7之孔徑（直徑）為約1 _ 2 m m ’以及吸引流路1 6之孔徑 (直徑）為約1.8 mm者。藉此設定成藉由患者之1次吸入， 冷凍乾燥組成物2之大部分經微粒化並從吸入口 1 8排出。 若構成此種自己吸入型之乾燥粉末吸入農置，由將 風箱體10等空氣壓送手段9以裝卸自如之方式安裝在接^ 口 15上，可將該自己吸入型之吸入裝置變更為噴射型。藉 315314 80 1327073 此對同一個乾燥粉末吸入裝置，可按照所需適宜選擇自 己吸入型及噴射型之任—形態來使用。 乂上之本發明之乾燥粉末吸入裝置可為自己吸入型或 噴射！之任一型，冷凍乾燥組成物可被構成為藉由選擇設 疋二氣衝擊之大小，而形成平均粒徑為丨〇微米以下（較佳5 微米以下）之微粒且大體無殘留之飛散。 施形』_复_£乾燥粉末吸入裝置（自己吸入型3) 用第4圖至第丨〇圖說明本發明所用之自己吸入型乾燥 粉末吸入裝置之一實施形態（其3)。又’第4圖為顯示該乾 燥粉末吸入裝置之透視圖，第5圖為顯示該乾燥粉末吸入 裝置之剖面圖。又，第6圖之（a)為顯示該乾燥粉末吸入裝 置之針部5及吸引口 3丨之部分剖面圖，（b)為針部5之側 面圖。再者，第7圖至1 〇係說明各個乾燥粉末吸入裝置之 運轉之剖面圖。 乾燥粉末吸入裝置具備吸引流路1 6及空氣導入流路 1 7形成之針部5、供保持容器1之保持部22、經由該保持 部22收容容器1用之收納室20、供將保持部22導向針部 5之轴線方向且設置在收納室20之引導部23、以及使保持 部22沿著引導部23前進及後退之保持部運轉部24，且此 等被收容在筒狀之外殼21中。又’在該外殼21之前端具 備咬嘴32 ’該咬嘴32具有與針部5之吸引流路16連通之 吸引口 3 1。 如第7圖所示，外殼2 1，詳細言之，具有在保持部22 後退之位置形成有出入口 25之外殼本體26，以及開關出 315314 81 ^^/073 ^^/073 入 26 25之蓋子27。蓋子27以絞鏈21A連結於外殼本體 又在蓋子27上設置供確認容器1之裝填之窗28。 入 32 在外殼21之壁部設置導入外氣用之導入口 29 ,在導 Μ中裝設逆止閥30。又，在外殼门之前部安裝咬嘴 咬嘴32，於不使用本乾燥粉末吸入裴置時，將吸引口 31用蓋子32a塞住。 土在針部5之基端部形成凸緣狀之隔壁部33，空氣導入 :路17之端部經由隔壁部33内並開口在隔壁部33之外周 之„向。又，周壁部34從隔壁部33之外周緣朝向咬嘴32 可：::：31延伸’藉由將隔壁部33嵌進外殼21之前端部 了將針部5安裝在外殼21内。 峋士二t 错由5玄女裝，外殼2 1之軸 、、象方向與針部5之軸線方向—致。 在保持部22中安奘供膝六。。， 走… 女m盗1從保持部22之底部拉 起取出之取出體35，在該取Ψ牌。c 之控制桿36。在絲出體35上形成拉起容器1用 運轉部24具備使保持部22在外殼^轴線方 向往復移動用之機構部37、摔 a ^ ^ '、乍機構。P 37之操作控制桿。 機構部37.具備連結體39。連社 Ά Jh A3. 4* 。體3 9之—端用絞鏈4 0連 ，.、〇在保持部22上，連結體39之 .97 , μ ? 之另—端用絞鏈41連結在蓋 子27上。盍子27兼做為上 pa ga ,, + 細作控制桿。藉由蓋子27 開關才木作，使得保持部 妨下笔2 π 者引導部23前進及後退。 放下盍子27之力之作 fi 〇 # gp , ,Λ ^ ^ Λ Μ為苐7圖之箭頭C所示之 ‘亦即，攸紋鏈ΜΑ至該作用點之 绞赫41夕且电e λ* 長度比攸纹鍵2 1Α至 鏈41之長度長’藉由「 了、埋」可以比針部5扎入容 315314 82 1327073 器1之口栓la所需之力為小之力操作蓋子（操作控制 桿）2 7 〇 又’如第6圖所示，形成將空氣補助性地導入乾燥粉 末吸入裝置之第2導入路42»在由吸嘴32吸引粉末化之 冷凍乾燥組成物時，外氣經由該第2導入路42流入直接咬 嘴32之吸引口 3 1。藉此，肺活量低之患者或兒童患者可 以無負.擔地使用該乾燥粉末吸入裝置。又，可以省略第2 導入路42。 第2導入路42 ’係藉由將導入溝42a裝設在針部5之 隔壁部33,將導入溝42b裝設在周壁部34並將咬嘴32嵌 進針部5之周壁部34,而由咬嘴32以及導入溝42&及4孔 形成者。 在咬嘴32與外殼2 1之間形成小間隙43，第2導入路 42之一端44經由間隙43開口至外部第2導入路竹之 另一端45開口於咬嘴32之吸引口 3 }。 又，如第6圖所示，在吸引口 31設置有通氣孔46之 壁47。因此，縱使藉由吸引力不足等賦與冷凍乾燥組成物 2、之空氣衝擊力變小’乾燥組成物2之—部分產生非 #末部分之情況，該非粉末部分通過壁47之通氣孔^之 時可以粉末化。 &又’如第6⑷圖所示，針部5之空氣導入流路17之前 、口 m比吸弓丨流⑬16《前端。i6a更靠近冷凍乾燥組成 物2 η ’可儘可能地壓抑從空氣導入流路17之前端口 谷器1内之空氣之流速降低，而可有效地將空氣 315314 83 1327073 衝擊賦與冷凍乾燥組成物2。又，由於針部5之吸引流路 1 6之岫端口 1 6a比空氣導入流路1 7之前端口 1 7a遠離冷 凍乾燥組成物2，在針部5之吸引流路16中進行吸引之 月’在容器1内可儘可能地將冷凍乾燥組成物2微粉末化。 因此’乾燥粉末吸入裝置係如下述使用。首先，如第 7圖所不，藉由拉起蓋子27並打開外殼21之出入口 25， 使保持部22後退靠近至外殼21之出入口 25。繼而將容器 1以口检la向前之方式安裝在保持部22中。接下來如第8 圖所不’藉由放下蓋子以關閉外殼21之出入口 2 5，利用 $。體3 9將保持部22朝針部5之方向壓入並使針部5之 =端扎入各器1之口栓la，以使針部5之吸引流路1 6及 氣導入机路1 7與容器！之内部連通。接下來，藉由患者(0) The composition liquid containing the additive component in an undissolved state is prepared by cold beam drying, L (II) has a non-powder block form; (III) The decay index is in the range of 0 〇 5 to 15 And (mountain) by an air impact with an air velocity of 1 to 300 m/sec and an air flow of i7mi/see to 15L/sec, the average particle size is below 1 〇 micron or the effective particle ratio is 丨〇 More than % of the particles. 7 2 2. The lyophilized composition described in paragraph 7 2 1 is used in the manufacture of 315314 74 1^27073 in combination with a dry powder formulation, wherein the air velocity is from 1 to 250 claws/ Sec 〇 723. The lyophilized composition according to the aspect 721 is used in the manufacture of transpulmonary and dry powder preparations, wherein the air flow rate is from 20 ml/sec to 1 〇L/sec. The use of a lyophilized composition for preparing a dry powder preparation for pulmonary administration is prepared by dissolving a composition liquid. Further, the present invention relates to a non-dissolving composition liquid for adding an ingredient in the preparation of a dry powder preparation for pulmonary administration The use of cold green dry ingredients is required. Method for preparing a component for preparing a freeze-dried composition, a method for preparing the same, a method for preparing a freeze-dried composition using the same, and a method for using the freeze-dried composition (dried powder for pulmonary administration) The preparation method of the preparation is as described above. ^ EXAMPLES The present invention is not limited to the following examples, and the examples of the invention are specifically described in the examples. Further, in the following examples, the dry composition (freeze-dried cake) is used. The fading evaluation was calculated by the method of dry powder which was micronized. <Calculation of Decay Index> The non-powdered freeze-dried index and effective particle ratio of the present invention (indicator for delivery to the lungs) were in accordance with the dried composition (freeze-dried cake), 〇ml-hexane. It is automatically dropped into the 1 315314 75 1327073 laboratory mixer NS-8 (manufactured by Pas () Lina Co., Ltd.) in a non-powdered cold P East which is prepared in a non-powder form at a 3 rpm. Wreak 〇 second. The obtained mixed solution was placed in the optical path length i, and the uv of the optical path width was 1 to the surface (manufactured by Shimadzu GLC Co., Ltd.), and the mixture was quickly measured by a spectrophotometer (UV 240 'Shimadzu Corporation) at the measurement wavelength. In addition, the value obtained by dividing the twist by the total prescription amount (the total amount (weight) of the active ingredient and the carrier) is taken as the decay index. <Calculation of effective particle ratio> The container filled with the prepared non-powder-shaped freeze-dried composition was attached to a dry-end inhalation device. The device A (two-stage dust detector) which is used in the Pharmacopoeia, Third Edition Supplement 2001, pll3-115) of the powder preparation obtained by using the device and imparting specific air impact. Directly discharged from the British c〇pley company. Thereafter, the solvent charged in the second stage and the second stage of the apparatus is separately recovered, and the second stage and the second part are quantified by a method suitable for measuring the active ingredient in the cold-rolled dry composition such as bioassay and HpLC. The active ingredients contained in each of the solvents and media [Lucas's report (10) with r ", called), 562.569 (1998)) and the report of Iida et al. (Ref. Pharmacy Journal 1 19 (1 0) 752-762 (1999))]. It can be expected that the part of the lung that is delivered to the second stage (the particle size of the aerodynamics recovered in this part is 6 4 #爪#)" usually reaches the second paragraph of it. The ratio of the effective ingredient is called the effective particle ratio (the amount of lungs that can be expected to be obtained, that is, the fine particle ratio), which is used as a benchmark for evaluating the applicability of the inhalation agent for pulmonary administration. In the examples and comparative examples, the weight of the active ingredient contained in each of the second and second stages is quantified, and the weight of the active ingredient in the second stage is 315,314,76,1,327,073 divided by the total weight of the active ingredient to be sprayed (the first The total weight of the active ingredients contained in paragraphs i and 2: hereinafter referred to as "the second paragraph") The value is used as the effective particle ratio Kyu, Q /,, more than ten sheep twist (/ °). In addition, in principle, in the case of using the two-stage dust measuring device (manufactured by British company c〇pley) in the European Pharmacopoeia, the suction flow of the square and the working gas is set to 6〇, so the following examples And the comparative example is also the same. Dry powder inhalation device (injection type 1) The spray type used in the present invention, an embodiment of the original umbrella main exhibition and the inhalation device is described with reference to Fig. 1. The dry powder inhalation device is in a container for glare The non-powder unit at the bottom of 1 or several times of freeze-dried composition 2 of human, human, ± k, ^ is micronized and delivered to the air organ of the lung organ. θ ', ' ^ The utility model has a suction member 7 provided with an air jet flow path 3 and a discharge flow path 4, a suction port 6 and a base end provided at the base end of the needle portion 5, surrounding the oblique fixing and needle-free 5 and the same female full cover 8 and the air pressure feeding means 9 which are held by the container 1. The air pressure feeding means 9, the owner * seven n - is a manual type and has a tubular wind box 10 in the wind phase body The suction inlet 12 with the pull-in valve 11 and the discharge port 1 4 with the discharge valve 13 are provided on the 10, and the η- 2 ^ ^ 14 is disposed on the base of the air jet pair path '3 of the needle portion 5 The joint port 15 formed on the end side is in communication with the air jet flow path 3. Moreover, the sorrow of sucking in the ϋΐ & _, Λ valve 11 is closed The hunting is performed by applying a compressive force to the wind phase body 1 收 to the 511. The threshold 13 will be opened, and the nipple discharge port 14 in the wind box body: 10 is discharged through the second rolling jet flow path 3. In the container 。. On the other hand, if the compression force is released, the elastic recovery force of the wind phase body 10 by the body 1 〇 * will be stretched out 'spit out i 3 盍 or closed and the suction valve 丨丨 opened , 315314 77 1327073 The air is then introduced into the wind box body 10. When the dry powder inhalation device is used, . . . 1 shows the container 1 into the cylindrical safety cover 8 so that the needle portion 5 L 8 The plug portion 1 a of the state 1 and the air jet flow path 3 and the discharge flow path 4 are connected to each other. The inner state of the valley state 1 is connected. In this case, if the air pressure is sent to the first phase of the body 1 The crucible is contracted to allow air to be discharged from the discharge port 14, which will be ejected from the front end of the needle portion 5 toward the freeze-drying portion of the container through the work beam channel 3 by the air impact 'freeze-dried composition 2, the particles are further broken, and are discharged from the suction port 6 of the air suction member 7 via the discharge flow path 4 of the needle portion 5. The user (patient) can be delivered to the lung organ of the patient by inhaling the material from the inhalation port 6 of the inspiratory member 7, and the particles of the freeze-dried composition 2 can be delivered to the patient's lung. Further, the present invention The material of the mouth plug used in the container is not particularly limited. For example, you can choose any material such as rubber, plastic or aluminum, which is usually used as a medicine for accommodating medicines and sputum 仏α-milk and compound containers. In the injection type suction device, the air injection amount is set to about 20 ♦ 刎, the capacity of the container is about 5 (6), the aperture (diameter) of the air injection flow path 3 is about 1.2 mm, and the diameter of the discharge flow path 4 is (diameter) is about 18 丨 (10). However, the diameter of the air jet flow path 3 and the discharge flow path 4 is not limited to a preferred range such as the size of the container, and is not particularly limited. The diameter may be from 0 to 3 mm, preferably from 3 to 3. Suitable for selection in the range of -7 mm, more preferably 5 mm. Further, by adjusting the compression speed of the wind box body 10, the air pressure feeding means 9 can withstand the discharge amount of the fine particles required for the suction and can be adjusted to make the freeze-dried composition 2 large by the air injection. Partially micronized. 78 315314 1327073 Embodiment of the dry powder inhalation device (self-inhalation type 实施 One embodiment of the self-inhalation type dry powder inhalation device used in the present invention (the 1) is illustrated by a 帛 2 diagram. The dry powder inhalation device shown in Fig. 2 The needle portion 5 having the suction flow path 16 and the air introduction flow path 丨7, the cylindrical safety cover 8, and the suction member 186 having the suction port 8 communicating with the suction flow path 丨6 are provided, and the suction member is provided. 1 9 is connected to the proximal end side of the suction flow path 丨 6 of the needle portion 5. When the dry powder inhalation device is used, the container is placed in the cylindrical safety cover 8 as shown in Fig. 2, and the needle portion 5 is inserted. The port plug u of the container is connected to the inside of the container port by the suction flow path 16 and the air introduction flow path 17. In this state, the air in the handcuff 1 is sucked from the suction port 18 via the suction flow path 16 by the suction pressure of the patient. At the same time, the outside air is introduced from the air introduction flow path 17 and thus becomes the inside of the barn 1 of the negative pressure. At this time, the freeze-dried composition 2 is atomized by the air impact acting on the freeze-dried composition 2, and is prepared. The particles are delivered to the patient from the suction port 8 via the suction flow path 6 Further, the dry powder inhalation device is set to be inhaled by the patient, and most of the freeze-dried composition 2 can be micronized and discharged from the suction port j 8. Further, although the patient sucks once The air flow rate of A is preferably 5 to 3 〇〇 l/min, and even 200 L/min, preferably 1 〇 to 1 〇 () L /, more preferably, the self-inhalation type dry powder inhalation device of the present invention The design can be appropriately changed according to the breathing ability of the patient to be used. The inhalation device ίτ' shown in Fig. 2 is set so that the capacity of the container is about i 〇 ml, the air introduction flow path 17 and the suction flow path according to the breathing ability of a certain patient. The aperture (diameter) of 16 is about i 5 mni, whereby the composition is set to be inhaled by the patient, and the freeze-dried composition 79 315314 1327073 can be completely micronized substantially without residue and discharged from the suction port 18. Your i__l dry powder inhalation device (self-inhalation type 2) One embodiment of the self-inhalation type dry powder inhalation device used in the present invention (the 2) is illustrated in Fig. 3. The dry powder inhaling device shown in Fig. 3 and the Spray dry powder shown in Figure 1 The suction device is in the same form when the air box body 1 for pumping air is removed from the connection port 15; and the discharge flow path 4 of the spray type dry powder inhalation device of the second drawing is equivalent to the suction flow path Lu 1 ό 'air The jet flow path 3 corresponds to the air introduction flow path 17, and the getter member 7 having the suction port 6 corresponds to the getter member 19 having the suction port 18. Therefore, when using the self-inhalation type dry powder inhaler, In the same manner as the dry powder inhaling device shown in Fig. 2, the air in the container 1 is sucked from the suction port 18 through the suction flow path 16 by the suction pressure of the patient, and the external air is introduced from the air introduction flow path 17 Thereby, in the container 1 of the negative pressure, the freeze-dried composition 2 is atomized by the air impact generated by the inflow of the air. Thereafter, the obtained microparticles are delivered from the inhalation port 18 to the lung organ of the patient. Further, if the above-mentioned patient has an inhaled air flow rate of 5 to 300 L/min, the inhalation device shown in Fig. 3 can be set to a container capacity of about 5 m in accordance with the breathing ability of the patient to be used. The aperture (diameter) of the flow path 17 is about 1 _ 2 mm 'and the aperture (diameter) of the suction flow path 16 is about 1.8 mm. Thereby, the majority of the freeze-dried composition 2 is micronized by one inhalation by the patient and discharged from the suction port 18. When the dry powder constituting such a self-inhalation type is sucked into the farm, the air suction means 9 such as the bellows body 10 can be detachably attached to the port 15, and the self-inhalation type inhaler can be changed to Spray type. By 315314 80 1327073 The same dry powder inhalation device can be used in any form suitable for the type of suction and spray. The dry powder inhalation device of the present invention can be inhaled or sprayed by itself! In either form, the freeze-dried composition may be formed so as to form fine particles having an average particle diameter of not more than 丨〇 micrometer (preferably 5 μm or less) and having substantially no residual scattering by selecting the size of the impact of the second gas. FORM TYPE _ _ _ dry powder inhalation device (self-inhalation type 3) An embodiment (3) of the self-inhalation type dry powder inhalation device used in the present invention will be described with reference to Figs. 4 to 丨〇. Further, Fig. 4 is a perspective view showing the dry powder inhaling device, and Fig. 5 is a cross-sectional view showing the dry powder inhaling device. Further, Fig. 6(a) is a partial cross-sectional view showing the needle portion 5 and the suction port 3' of the dry powder inhaling device, and Fig. 6(b) is a side view showing the needle portion 5. Further, Fig. 7 to Fig. 1 are sectional views showing the operation of each dry powder inhalation device. The dry powder inhalation device includes a needle portion 5 formed by the suction flow path 16 and the air introduction flow path 17 , a holding portion 22 for holding the container 1 , a storage chamber 20 for accommodating the container 1 via the holding portion 22 , and a holding portion for holding the container 1 The guide portion 23 provided in the storage chamber 20 in the axial direction of the guide needle portion 5 and the holding portion operating portion 24 that advances and retracts the holding portion 22 along the guide portion 23, and are housed in the cylindrical outer casing 21 in. Further, the mouthpiece 32 is provided at the front end of the casing 21. The mouthpiece 32 has a suction port 31 which communicates with the suction flow path 16 of the needle portion 5. As shown in Fig. 7, the outer casing 2 1, in particular, has a casing body 26 having an inlet and outlet 25 formed at a position where the holding portion 22 is retracted, and a cover of 315314 81 ^^/073 ^^/073 into 26 25 27. The cover 27 is coupled to the casing body by a hinge 21A. A window 28 for confirming the filling of the container 1 is provided on the cover 27. Into 32, an inlet port 29 for introducing an outside air is provided in a wall portion of the outer casing 21, and a check valve 30 is installed in the guide. Further, the mouthpiece mouthpiece 32 is attached to the front portion of the casing door, and the suction port 31 is closed by the lid 32a when the dry powder suction device is not used. The soil forms a flange-shaped partition wall portion 33 at the base end portion of the needle portion 5, and the air introduction: the end portion of the passage 17 passes through the partition wall portion 33 and opens to the outer circumference of the partition wall portion 33. Further, the peripheral wall portion 34 is separated from the partition wall portion. The outer periphery of the portion 33 faces the mouthpiece 32 and can be extended by:::31. The needle portion 5 is mounted in the outer casing 21 by inserting the partition wall portion 33 into the front end of the outer casing 21. The gentleman is wrong. The shaft of the outer casing 21 and the direction of the image are aligned with the axial direction of the needle 5. The ampule is placed in the holding portion 22 for the knee. The female thief 1 is pulled out from the bottom of the holding portion 22 and taken out. The body 35 is provided with a control lever 36 for picking up the card c. The pulling unit 1 is formed on the wire body 35. The operation unit 24 is provided with a mechanism portion 37 for reciprocating the holding portion 22 in the axial direction of the casing. a ^ ^ ', 乍 mechanism. Operation control lever of P 37. Mechanism unit 37. Having a connecting body 39. Lianshe Ά Jh A3. 4*. Body 3 9-end with a hinge 4 0,. On the holding portion 22, the other end of the connecting body 39, .97, μ is connected to the cover 27 by a hinge 41. The dice 27 is also used as the upper pa ga , and + as a fine control lever. wood Therefore, the holding portion can move the pen 2 π guide portion 23 forward and backward. The force of the force of the scorpion 27 is fi 〇# gp , , Λ ^ ^ Λ Μ is the arrow C of the 苐7 diagram, that is, The ΜΑ ΜΑ ΜΑ ΜΑ 该 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 The force required for the plug 1 of the device 1 is a small force operation cover (operation control lever) 2 7 〇 and 'as shown in Fig. 6, forming a second introduction path 42 for introducing air into the dry powder inhalation device in a supplementary manner » When the powdered freeze-dried composition is sucked by the suction nozzle 32, the outside air flows into the suction port 31 of the direct mouthpiece 32 via the second introduction path 42. Thereby, the patient or the child patient with low lung capacity can use the dry powder inhalation device without any burden. Further, the second introduction path 42 can be omitted. The second introduction path 42' is attached to the partition portion 33 of the needle portion 5 by the introduction groove 42a, and the introduction groove 42b is attached to the peripheral wall portion 34, and the mouthpiece 32 is fitted into the peripheral wall portion 34 of the needle portion 5, and It is formed by the mouthpiece 32 and the introduction groove 42& and 4 holes. A small gap 43 is formed between the mouthpiece 32 and the outer casing 2, and one end 44 of the second introduction path 42 is opened to the outside of the outer second introduction path through the gap 43 to the suction port 3 of the mouthpiece 32. Further, as shown in Fig. 6, the suction port 31 is provided with a wall 47 of the vent hole 46. Therefore, even if the air impact force of the freeze-dried composition 2 is reduced by the insufficient attraction or the like, the portion of the dry composition 2 is not the last portion, and the non-powder portion passes through the vent hole of the wall 47. It can be powdered. & Again, as shown in Fig. 6(4), before the air introduction path 17 of the needle portion 5, the mouth m is larger than the suction turbulence 1316 "front end. The i6a is closer to the freeze-dried composition 2 η ' as much as possible to suppress the flow rate of the air in the port barn 1 before the air introduction channel 17 is lowered, and the air 315314 83 1327073 can be effectively applied to the freeze-dried composition 2 . Further, since the port 16a of the suction channel 16 of the needle portion 5 is farther from the freeze-dried composition 2 than the port 17a before the air introduction channel 17, the month of attraction in the suction channel 16 of the needle portion 5' The freeze-dried composition 2 can be micronized as much as possible in the container 1. Therefore, the 'dry powder inhalation device' is used as follows. First, as shown in Fig. 7, the holding portion 22 is retracted to the inlet and outlet 25 of the outer casing 21 by pulling up the lid 27 and opening the inlet and outlet 25 of the outer casing 21. The container 1 is then mounted in the holding portion 22 in a manner that the oral inspection la is forward. Next, as shown in Fig. 8, the $ is used by closing the lid to close the inlet and outlet 2 of the outer casing 21. The body 39 presses the holding portion 22 in the direction of the needle portion 5, and the end portion of the needle portion 5 is inserted into the mouth plug 1 of each of the devices 1, so that the suction flow path 16 of the needle portion 5 and the gas introduction path 1 7 with the container! Internal connectivity. Next, by the patient

之·吸氣壓從咬嘴32$ <59 2丨η A 為32之及引口 31經由針部5之吸引流路16 及引容器1内之空氣, m 孔此時今益1内成為負壓且逆止閥30 打開’外氣經由針部5之空氣導入产故】1 士 Μ . 工軋V入机路U流入容器1内。 在各盎1内產生空氣衝擊，冷;東 _ 粒化，1制 不钇各組成物2經微 凋製之微粒經由吸引流路16從吸 之肺器官内伯田4 4 1运至患者 之出入口 25德，·用抻制π u κ P 22罪近外殼21 後用控制;^ 36拉起取 從保持部22取出。 體35並將容器1 另—方面，縱使從咬嘴32之吸y d 器1内，微粒化之冷束乾燥組成物21將空氣吹進容 到逆止閥3〇擋住。 4之排出將會受 又，雖然如上述患者之丨次吸入 <氣流量通常在5 315314 84 至300L/分鐘之筋图咖 较置可依照患者之二’但從第4圖至第10圖所示之吸入 如，空氣導入流路Γ能力，設定成容器之容董為約5 路16之口徑（心）^σ#(直徑）為約2.5mm，吸引流 吸入，冷;東乾燥:成二2.5mm。、藉此，藉由患者之1次 31排出。 ' 之大部分將經微粒化並從吸引口 乾無粉末吸入梦罢 第"圖至第13圖所、示。己吸入型)之其他實施形態例如 第11圖所不之乾燥粉 箭頭所示，將摔作研及入裝置（自已吸入型4)，如 *向。未圖示出=1迴轉自如地設置在外般21之圓周 其扣合之隨_件，\=轉部之機構部具有螺旋溝及與 …變換為:針雜…轉運動，可以將保 j計口P 5之軸線方向首 48之迴轉角度為約18〇度。 ，、泉運動。又，操作體 又，第U圖及帛圖戶斤 "入型…係將環狀之操作體吸入裝置(自己 21中，未®示出之保持A 轉自如地安裝在外殼 藉由操作體49之回轉運動，將:之_部具有送料螺旋’ 之轴線方向直線運動。保持部2.2係：22變換為向針部5 後部自由取出者。 、^成為可從外殼2 1之 將為基因導入用陽性脂質 (invitrogen 公司 、五 WokctAMiNE 2〇〇< 4) 7以及為質體職之pEGFp_c2 315314 85 1327073 (Clontech公司製）24 添加至為細胞培養液之〇ρτι_ MEM I無血清培養基（Invitr〇gen公司製，伊格氏最少必須 &養基之改良培養基）丨2〇〇 " 1中，並懸浮混合，在該培養 • 液存在下形成複合體。該複合體之幾何學平均粒徑用動態 ' 光散射光度計（ELS-8000,大塚電子公司製）測定。接下來， 將包含該複合體之懸浮液各1〇〇// 1分別添加混合於1〇個 容器（筒徑0 18 mm)中（檢體數：1〇)，其中各容器預先收容 籲L-白胺酸溶於水之水溶液（5 mg/ml)4〇〇 "卜之後，使用棚 狀冷凍乾燥機（LYOVAC GT-4，LEYB0LD公司製）進行冷 束乾燥’對於得到之非粉末狀冷凍乾燥組成物（冷凍乾燥 塊），計算出衰變指數。接下來，將含有得到之非粉末狀冷 床乾燥組成物（冷凍乾燥塊）之容器安裝在被設計成空氣噴 射流路3之孔徑為0 1.2 mm，排出流路4之孔徑為0 1.8 mm 之噴射型乾燥粉末吸入裝置（具有可供給空氣量約2〇 ml之 風箱體10，參照實施形態例1，第1圖）中。 φ 轉認藉由將空氣量約20ml從吸入裝置導入容器内（賦 與由空氣速度約35m/sec及空氣流量約40ml/sec之空氣所 產生之衝擊）’可將容器内之非粉末狀之冷凍乾燥塊微粒 化，並瞬間從容器經由微粒排出流路4噴射排出。使用安 裝有為人工肺型空氣呼吸器（美國Amherst ProcessThe suction pressure is 32 from the mouthpiece 32$ <59 2丨η A and the inlet 31 passes through the suction flow path 16 of the needle portion 5 and the air in the container 1, and the m hole becomes negative in the current 1 The pressure and the check valve 30 are opened, and the air is introduced into the container 1 through the air of the needle portion 5. The worker's rolling V inlet path U flows into the container 1. Air shock is generated in each ang 1 , cold; east granulation, 1 钇 钇 钇 2 2 2 2 2 2 2 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒The entrance and exit 25 de, the sputum π u κ P 22 sin near the outer casing 21 is used for control; ^ 36 is pulled up and taken out from the holding portion 22. The body 35 and the container 1 are otherwise provided, and even in the suction device 1 from the mouthpiece 32, the micronized cold-beam drying composition 21 blows air into the check valve 3 to block it. The discharge of 4 will be affected again, although the inhalation of the above-mentioned patients is usually in the range of 5 315 314 84 to 300 L / min. The ribs can be placed according to the patient's second 'but from the 4th to the 10th The inhalation shown, for example, the ability of the air to be introduced into the flow path, set to a container of about 5 channels of 16 caliber (heart) ^ σ # (diameter) is about 2.5 mm, suction flow inhalation, cold; Two 2.5mm. By this, the patient is discharged by one time. Most of the particles will be micronized and sucked from the mouth of the mouth without powder inhalation. Other embodiments of the inhaled type, such as the dry powder indicated in Fig. 11, are thrown into the device (self-inhalation type 4), such as *. It is not shown that it is arbitrarily set to the circumference of the outer 21, and it is fastened with the _ piece, and the mechanism part of the turning part has a spiral groove and is transformed into: a needle... The angle of rotation of the first 48 in the axial direction of the mouth P 5 is about 18 degrees. , spring sports. In addition, the operating body, the U-shaped figure and the 户 户 & quot 入 入 入 入 入 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状In the slewing motion of 49, the _ section has a linear motion in the direction of the axis of the feed screw. The holding portion 2.2 is: 22 is converted to be freely taken out to the rear of the needle portion 5. The ^ becomes a gene that can be extracted from the outer casing 2 Positive lipid for introduction (invitrogen, five WokctAMiNE 2〇〇 < 4) 7 and pEGFp_c2 315314 85 1327073 (manufactured by Clontech) 24 for cytoplasmic culture were added to 〇ρτι_MEM I serum-free medium (Invitr) 〇gen company, Ig's minimum necessary & nutrient improvement medium) 丨2〇〇" 1 , and suspension mixing, forming a complex in the presence of the culture solution. The geometric average of the complex The diameter was measured by a dynamic 'light scattering photometer (ELS-8000, manufactured by Otsuka Electronics Co., Ltd.). Next, each suspension containing the composite was added and mixed in one container (1 tube). 18 mm) (number of samples: 1〇), its Each of the containers was preliminarily contained in an aqueous solution (5 mg/ml) of L-leucine dissolved in water, and then subjected to cold beam drying using a shed-type freeze dryer (LYOVAC GT-4, manufactured by LEYB0LD). 'For the obtained non-powdered freeze-dried composition (freeze-dried cake), the decay index was calculated. Next, the container containing the obtained non-powdered cold-bed dried composition (freeze-dried cake) was installed in the air designed to be air An injection type dry powder inhalation device having a diameter of 0 1.2 mm and a hole diameter of 0 1.8 mm in the discharge flow path 3 (having a bellows body 10 capable of supplying an air amount of about 2 μm, see Example 1 Fig. 1) The φ transposition can be carried out by introducing an air volume of about 20 ml from the inhalation device into the container (giving the impact of air having an air velocity of about 35 m/sec and an air flow of about 40 ml/sec). The non-powdered freeze-dried cake inside is micronized and instantaneously ejected from the container through the particle discharge flow path 4. The artificial lung type air respirator (Amhrst Process, USA) is installed.

Instrument 公司製，R.W. Niven:Pharmaceutical Technology， 72-78( 1993))(測定條件，呼吸速率：60L/min;呼吸體積： 1L;加速：19)之粒度分布計（氣膠分析儀（aerosizer广美國 Amherest Process Instrument 公司製，R.W. Niven· 315314 86 1327073Instrumentation, RW Niven: Pharmaceutical Technology, 72-78 (1993)) (measurement conditions, respiration rate: 60 L/min; respiration volume: 1 L; acceleration: 19) particle size distribution meter (aerogel analyzer (aerosizer) Amherest Process Instrument, RW Niven· 315314 86 1327073

Pharmaceutical Technology，72-78(1993))將其回收，測定經 微粒化之粒子之粒度分佈，並從其算出空氣力學平均粒徑 U m± SD)。將以非溶解狀態存在於懸浮液中之粒子之幾 何學平均粒徑，及各冷凍乾燥組成物之衰變指數，及從該 裝置噴射之粒子之空氣力學平均粒徑（//m± SD)示於表j <表1> i凍ιΐ燥組成物幾何 均粒徑（μιη) a 空氣力學之平 均粒徑（pm±SD,Pharmaceutical Technology, 72-78 (1993)) was recovered, and the particle size distribution of the micronized particles was measured, and the aerodynamic mean particle diameter U m ± SD) was calculated therefrom. The geometric mean particle size of the particles present in the suspension in an undissolved state, and the decay index of each freeze-dried composition, and the aerodynamic mean particle diameter (//m ± SD) of the particles ejected from the device In Table j <Table 1> i frozen ι dry composition geometric mean particle size (μιη) a aerodynamic mean particle size (pm ± SD,

白胺酸 如表1 所 藉由空氣速度約35m/sec及空氣流量約40ml/se :::產生之衝擊而衰變，形成為空氣力學之平均㈣ 於經肺投與之微粒狀乾㈣末製劑^ 果縱使在冷;東乾燥前之試料為非溶解 狀態)’藉由在本發明中所規定之特定空氣 “製適於經肺投與之微粒化乾燥粉末之 ^ 物’亦即顯讀使在冷凍乾燥前之試料為非溶：’ 本發明之經肺投與用乾燥粉末吸入系統令亦適用，… :地經肺投與。又，藉由使用癌抑制劑基因ρ53:? 纖維症臈貫通型調節蛋白(c 囊月』 使用之質體顧_P_C2)，可將能二 』/口療效果之基因 315314 87 1327073 或反義分子等藉由經肺投與導入體内。所以本發明之經肺 投與用乾燥粉末吸入系統被認為可有效地利用做為基因治 療。 ‘ 實施例2、出齡例1 將為基因導入用1%性脂質體之Lip0fectAMIN£ 2000 (InWtrogen 公司製）72//§及〇Ug〇_RNA 1〇"g(大塚製藥 公司製）1〇 #g，於OPTI-MEMI無血清培養基（Invitr〇gen 籲公司製，伊格氏最少必須培養基之改良培養基）存在下混合 %浮，以形成複合體。該複合體之幾何學平均粒徑用動態 光散射光度計（ELS-8000,大塚電子公司製）測定。接下來， 將包含該複合體之懸浮液各丨00 #丨分別添加混合於丨〇個 容器（筒徑0 18 mm)中，其中各容器預先加入l—白胺酸溶 於水調製而成之L-白胺酸水溶液（5 mg/mi) 4〇〇// 1，調製得 冷凍乾燥用試料（實施例2)。又，關於比較例，用葡聚糖 40之水溶液（5 mg/mi)4〇〇 # i代替上述白胺酸水溶液， 籲並同樣地調製冷凍乾燥用試料（1〇個）（比較例丨）。 之後’各個試料用棚狀冷凍乾燥機（ly〇vac gt_4， LEYBOLD公司製）進行冷凍乾燥，對於得到之非粉末狀冷 凍乾燥組成物（冷凍乾燥塊）計算出衰變指數。接下來將 含有非粕末狀冷凍乾燥組成物（冷;東乾燥塊）之容器安裝在 破設計成空氣喷射流路3之孔徑為分丨2 mm，排出流路4 之孔徑為0 1.8 mm之喷射型乾燥粉末吸入裝置（具有可供 給空氣量約20 ml之風箱體10，參照實施形態例1，第j 圖）中。 315314 88 1327073 其結果，對於實施例2之冷凍乾燥組成物，確認藉由 將空氣量約20ml從吸入裝置導入容器内（賦與由空氣速度 約3 5m/sec及空氣流量約40 ml/sec之空氣所產生之衝擊）， 可將谷器内之非粉末狀之冷凍乾燥塊微粒化，並瞬間從容 器經由微粒排出流路4喷射排出。與實施例丨同樣地，使 用安裝空氣呼吸器（美國Amherst Pr〇cess Insuument公司 製）（測定條件，呼吸速率：60L/min ;呼吸體積：il ;加 速：19)之粒度分布計（氣膠分析儀（aer〇sizer):美國The leucine is decayed by the impact of an air velocity of about 35 m/sec and an air flow of about 40 ml/se::, as shown in Table 1, and is formed into an aerodynamic average. (IV) A particulate dry (four) final formulation administered via the lung. ^ If the sample is in a cold state before the east; the sample before the drying in the east is in a non-dissolving state, 'by the specific air specified in the present invention, the product is made suitable for the micronized dry powder administered by the lung. The sample before lyophilization is non-soluble: 'The dry powder inhalation system for pulmonary administration of the present invention is also applicable, ...: by the lungs. Also, by using the cancer inhibitor gene ρ53:? The through-regulatory protein (the cytoplasm of the capsule) can be used to introduce the gene 315314 87 1327073 or the antisense molecule into the body by pulmonary administration. The lung-administered dry powder inhalation system is considered to be effective for gene therapy. 'Example 2, Age-old Example 1 Lip0fect AMIN £ 2000 (InWtrogen) 72 for introduction of a gene into a 1% liposome //§ and 〇Ug〇_RNA 1〇"g (made by Otsuka Pharmaceutical Co., Ltd.) 1 #g, in the presence of OPTI-MEMI serum-free medium (Invitrogen, Inc., modified medium of the least necessary medium of Ig's), mixed % float to form a composite. The geometric mean particle size of the composite is dynamic. A light scattering photometer (ELS-8000, manufactured by Otsuka Electronics Co., Ltd.) was measured. Next, each suspension containing the composite was separately mixed and mixed in one container (bore diameter 0 18 mm), wherein Each container was previously added with an aqueous solution of L-leucine (5 mg/mi) prepared by dissolving l-leucine in water to prepare a sample for freeze-drying (Example 2). In the comparative example, an aqueous solution of dextran 40 (5 mg/mi) 4 〇〇 # i was used instead of the above aqueous leucine solution, and the samples for freeze-drying were prepared in the same manner (Comparative Example). Each sample was freeze-dried by a shed-type freeze dryer (ly〇vac gt_4, manufactured by LEYBOLD Co., Ltd.), and a decay index was calculated for the obtained non-powder freeze-dried composition (freeze-dried cake). Freeze-dried composition (cold; Donggan The container of the block is installed in a spray type dry powder inhalation device having a pore diameter of 2 mm and a pore diameter of 0 1.8 mm which is designed to be an air jet flow path 3 (having a wind supplyable amount of about 20 ml) The case 10 is referred to in the first embodiment and the first embodiment. 315314 88 1327073 As a result, it was confirmed that the freeze-dried composition of Example 2 was introduced into the container from the inhalation device by the amount of air of about 20 ml. The impact of the air at a speed of about 35 m/sec and an air flow of about 40 ml/sec, the non-powdered freeze-dried cake in the trough can be atomized and instantaneously ejected from the container through the particle discharge flow path 4. discharge. In the same manner as in Example ,, a particle size distribution meter (gas gel analysis) using an air breathing apparatus (manufactured by Amherst Prence Insuument Co., Ltd.) (measurement conditions, respiration rate: 60 L/min; respiratory volume: il; acceleration: 19) was used. Instrument (aer〇sizer): United States

Amherest Process Instrument公司製））將其回收測定經微 粒化之粒子之粒度分佈，並從其算出空氣力學平均粒徑（以 m土 SD)。 另一方面，比較例1之冷凍乾燥組成物，藉由空氣这 度約35m/see及空氣流量約4Qmi/see之空氣所產生之種 擊’完全未分散，因此無法測定线力學之平均粒徑。 ，、非，合解狀態存在於各懸浮液中之粒子之幾何學平 均粒徑’各冷凍乾燥組成物(實施例2、比較你! 1)之衰變γ 數’及從該裝晋哈, θ 示於表2:。'射之粒子之空氣力學平均粒經(一 315314 89 1327073 <表2> 冷東乾燥組成物 煢何學之平衰變指數 均粒徑（μιη) 空氣力學之平 均粒徑（pm±SD， mmad) 實施例2) LipofectAMINE2 000 + 〇lig〇-RNA + 白胺酸 1.19 0.165 1.633±1.496 比 較 例 1)1.19 LipofectAMINE2 000 + Oligo-RNA+ 葡聚糖40 0.002 完全不分散無 法測定 如表2所示’顯示衰變指數為〇165之非粉末狀冷凍 乾燥塊（實施例2)，與實施例丨同樣地，縱使在冷凍乾燥前 之試料為非溶解狀態（在其中為懸浮狀態），藉由空氣速度 約3 5m/sec及空氣流量約4〇mi/sec之空氣所產生之衝擊而 崩壞，形成為空氣力學之平均粒徑為5微米以下之適於經 肺投與之微粒狀乾燥粉末製劑。 相對於此’顯示衰變指數為〇〇〇2之非粉末狀冷束乾 籲燥塊（比較例D，藉由上述衝擊，完全未分散及微粒化，不 適於調製成為經肺投與用之乾燥粉末製劑。 實施例3至5、比較例2 將為基因導入用活性型樹狀分子（陽性聚合物）之 Supeifect (Qlagen 公司製）36〇" g 及 QUgo RNA(大塚製藥 公司製）5 Η (實施例3,比較例2)或為質體DNA : PEGFP-C2 (Clontech公司製）心以實施例4及5)，於 OPTI-MEM 存在下混合懸浮，以形成複合體。該 315314 90 1327073 複合體之幾何學平均粒徑用動態光散射光度計（ELS-8000 ’大塚電子公司製）或雷射折射及散射式粒度分佈測定 裝置（SALD-3000J，島津製作所製）測定。 接下來’將包含此等複合體之懸浮液各1 00 // 1，如表 3所不’分別添加於裝有預先調製之L_白胺酸水溶液（5 mg/ml) 40 0 //1之容器（筒徑必18爪爪）（實施例3及4)中以及 哀有★解乳糖之水溶液（5 4〇〇 “I之容器（筒徑必Η )(Λ知例5)中（對於各實施例，使用1 〇個容器），調製 得冷’東乾燥用試料°又，關於比較例，用葡聚糖40之水溶 液（mg/ml)400 μ代替實施例3之l_白胺酸水溶液，並 同樣地調製冷凍乾燥用試料(1 〇個)(比較例2)。 之後對於用棚狀冷康乾燥機（LYOVAC GT-4， = Β〇^5Ί製）進行冷隸燥所得到之 :組成物(冷滚乾燥塊)，計算出衰變指數。接下來，將： 有得到之非粉末狀冷凍乾燥組 裝在被吟辞Λ介# + 取物（冷凍乾燥塊）之容器安 装在被。又计成工氣賀射流路3之孔 路4之孔妒A r/】1 〇 仏為必12 mm，排出流 二‘”、0 .8 mm之喷射型乾燥 可供仏空翕吾的木及入裝置（具有 J仏，.·。工轧3:約2〇nU之風箱體1〇， 第1圖）中。 參照貫施形態例1及 其結果，對於實施例3 ; τ犮5 認藉由將空氣量约2_丨從吸人 4乾燥組成物，確 氣速度们5WSec及空氣流量約:入容器内（賦與由空 衝擊），可將容器内之非粉末狀之 二之空氣所產生之 間從容器經由微粒排出a 7 '乾燥塊微粒化，並瞬 徘出机路4贺射排 轉只把例I同樣 315314 91 1327073 地，使用安裝空氣呼吸器（美國Amherst Process Instrument 公司製）（測定條件’呼吸速率：60L/min ;呼吸體積：1L ; 加速：19)之粒度分布計（氣膠分析儀（aerosizei·):美國 Amherest Process Instrument公司製））將其回收，測定經微 粒化之粒子之粒度分佈，並從其算出空氣力學平均粒徑（" m土 SD)。 另一方面，比較例2之冷凍乾燥組成物，藉由空氣速 籲度約35m/sec及空氣流量約40ml/sec之空氣所產生之衝 擊，完全未分散，因此無法測定空氣力學之平均粒徑。 將以非溶解狀態存在於各懸浮液中之粒子之幾何學平 句才仏各冷;東乾燥組成物（實施例3至5及比較例2)之衰 變指數，及從該裝置噴射之粒子之空氣力學平均粒徑（//m 土 SD)示於表3中。Amherest Process Instrument Co., Ltd.)) The particle size distribution of the microgranulated particles was measured and recovered, and the aerodynamic average particle diameter (in m soil SD) was calculated therefrom. On the other hand, in the freeze-dried composition of Comparative Example 1, the seed shot produced by the air having an air of about 35 m/see and an air flow rate of about 4 Qmi/see was completely undispersed, and thus the average particle diameter of the line mechanics could not be determined. . ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Shown in Table 2:. 'The aerodynamic mean grain of the particles of the shot (a 315314 89 1327073 < Table 2 > cold east dry composition 茕 何学 flat decay index average particle size (μιη) aerodynamic mean particle size (pm ± SD, mmad) implementation Example 2) LipofectAMINE2 000 + 〇lig〇-RNA + leucine 1.19 0.165 1.633±1.496 Comparative Example 1) 1.19 LipofectAMINE 2 000 + Oligo-RNA+ Dextran 40 0.002 Completely non-dispersible cannot be determined as shown in Table 2 'Showing decay index In the non-powdered freeze-dried cake of Example 165 (Example 2), the sample before the freeze-drying was in an insoluble state (in which it was in a suspended state), in the same manner as in Example 藉, by an air velocity of about 35 m/ The sec and the air flow rate collapsed by an impact of air of about 4 〇mi/sec, and formed into a particulate dry powder preparation suitable for pulmonary administration with an aerodynamic average particle diameter of 5 μm or less. Relative to this, a non-powdered cold-baked dry-blocking block having a decay index of 〇〇〇2 (Comparative Example D, completely undispersed and micronized by the above-mentioned impact, is not suitable for preparation for drying by transpulmonary administration) Powder preparations. Examples 3 to 5 and Comparative Example 2 Supeifect (manufactured by Qlagen Co., Ltd.) 36 〇" g and QUgo RNA (manufactured by Otsuka Pharmaceutical Co., Ltd.) 5 for the introduction of the active dendrimer (positive polymer) for gene introduction (Example 3, Comparative Example 2) or plastid DNA: PEGFP-C2 (manufactured by Clontech Co., Ltd.), and Examples 4 and 5) were mixed and suspended in the presence of OPTI-MEM to form a complex. The geometric mean particle diameter of the 315314 90 1327073 composite was measured by a dynamic light scattering photometer (ELS-8000' manufactured by Otsuka Electronics Co., Ltd.) or a laser refracting and scattering type particle size distribution measuring apparatus (SALD-3000J, manufactured by Shimadzu Corporation). Next, 'the suspension containing these complexes is 1 000 // 1, as shown in Table 3, respectively, added to the pre-conditioned L_leucine solution (5 mg/ml) 40 0 //1 The container (the diameter of the tube must be 18 claws) (Examples 3 and 4) and the aqueous solution of the lactose solution (5 4 〇〇 "I container (tube diameter)" (for example 5) In each of the examples, one container was used to prepare a cold sample for the east drying. Further, with respect to the comparative example, 400 μ of an aqueous solution (mg/ml) of dextran 40 was used instead of the leucine of Example 3. The aqueous solution was prepared in the same manner as in the freeze-drying sample (Comparative Example 2). Then, it was obtained by cold-drying with a shed-type cold-drying machine (LYOVAC GT-4, = Β〇^5). : The composition (cold-rolled dry block) was used to calculate the decay index. Next, the obtained non-powder-like freeze-dried product was assembled in a container of the 吟 吟 Λ + + + + + + 冷冻It is also counted as the hole of the hole 4 of the work flow channel 3, 妒A r/】1 〇仏 is 12 mm, and the discharge type is '2', and the spray drying type of 0.8 mm is available for hollowing out the wood of the scorpion. Into the device (with J仏, .., work rolling 3: about 2〇nU wind box 1〇, Fig. 1). Refer to the example 1 and its results, for Example 3; τ犮5 By arranging the air quantity about 2_丨 from the suction 4 drying composition, the gas velocity 5WSec and the air flow rate are about: into the container (giving the impact by the air), the non-powder type in the container can be The air is generated from the container through the particles discharged a 7 'dry block micronized, and instantaneously out of the machine path 4, the ball is only transferred to the same example 315314 91 1327073, using the installed air respirator (Amherst Process Instrument, USA) (measurement condition 'respiration rate: 60 L/min; respiratory volume: 1 L; acceleration: 19) particle size distribution meter (aerosizei (aerosizei·): Amherest Process Instrument, Inc.)) The particle size distribution of the micronized particles, and the aerodynamic mean particle diameter (" m soil SD) was calculated therefrom. On the other hand, the freeze-dried composition of Comparative Example 2 was completely undispersed by the impact of air having an air velocity of about 35 m/sec and an air flow rate of about 40 ml/sec, and thus the aerodynamic average particle diameter could not be measured. . The geometrical rhyms of the particles present in each suspension in an undissolved state are each cold; the decay indices of the East dried compositions (Examples 3 to 5 and Comparative Example 2), and the particles ejected from the device The aerodynamic mean particle size (//m soil SD) is shown in Table 3.

315314 92 1327073 &lt;表3&gt; 冷束乾* I组成物~學之平旨-數空氣力學之军： 均粒徑（μπι) 均粒徑（gm±SD, 實施例 3) Superfect 11.12 + 〇lig〇- RNA+ 白 胺酸 4) Superfect + pEGF 3.74 P-C2+白胺酸 MMAD) 0.225 1.578±1,403 0.189 1.646±1.420 5)Superfect + pEGF 3.74 P-C2 +乳糖 0.080 2.848土 1.837 比較例 2)Superfect+01ig〇 11.12 -RNA+葡聚糖40 0-003 完全不分散無 法測定 ' ‘不哀支扣數為〇.08〇至〇 225(亦即衰 變指數為0.080以上非机士〜 非如末狀冷凍乾燥塊，與實施例1 同樣地’縱使在冷凌乾燥前之試料為非溶在 懸浮狀態）且很易凝隼虑铿打以 'Τ ^ 子，亦可藉由空氣^Π之7粒㈣11微米之粒 之空氣所產生之衝擊而崩壞m 4約— 為5微米以下之適於细肺〜成為空氣力學之平均粒徑 相對於此，顯示衰變粒狀乾燥粉末製劑。 -叫藉…衝 調製成為經肺投與用之乾燥粉末製劑❹化，不適於 結果’縱使在冷康乾燥前之試料為非溶解狀態(“中 315314 93 —㈣態）’藉由在本發明中所規定m氣衝擊，可 =供能調㈣於經肺投與之微粒化乾燥粉末之冷滚乾燥 ::物’π即’在本發明之經肺投與用乾燥粉末吸入系統 Π適用，且可有效地經肺投與。又，藉由使用癌抑制劑 基因Ρ53(適用於肺癌)及囊胞性纖维症膜貫通型調節蛋白 (:R)基因（適用於囊胞性纖維症）等代替本實施例所使用 之貪體職（pEGFP_C2)，可將能得到治療效果之基因或 反義分子等藉由經肺投與導入體内。又，〇Ug〇_RNA為 RNAi(RNA干㈣）之—，係可心罐^術之雙股 RNA’稭由導入對應於標的基因之短雙股rna，可以特昱 性抑制標的基因之傳信職之機能，亦可適用於肺癌等之 治療。 所以，本發明之經肺投與用乾燥粉末吸入系統被認為 於基因治療中可有效地利用。 • 實施例6 、將為基因導入用活性型樹狀分子之Superfect (Qiagen 公司製）3 60 /^及〇丨4〇_111^(大塚製藥公司製）5#层，於 〇 ΤΙ MEM I 12〇〇 # kgacobrl公司製）存在下混合懸 芋、开^成複s體。遠複合體之幾何學平均粒徑用雷射折 射及散射式粒度分佈測定裝置（SALD_3〇〇〇J，島津製作所 氣則定。接下來，將包含此等複合體之懸浮液各1 00 // 1， 分別添加於裝有預先調製之L-纈胺酸水溶液（2.5 mg/ml) 4〇〇//1之容器（筒徑必18 mm)( 1 0個）中，調製得冷凍乾燥 315314 94 1327073 用试料。之後，用棚狀冷凍乾燥機（LY〇VAC G丁_4， LEYBOLD公司製）進行冷凍乾燥，對於所得到之非粉末狀 冷凍乾燥組成物（冷凍乾燥塊），計算出衰變指數。 接下來，將含有得到之非粉末狀冷凍乾燥組成物（冷凍 乾燥塊）之容器安裝在被設計成空氣喷射流路3之孔徑為 0 1.2 mm，排出流路4之孔徑為0丨8 mm之噴射型乾燥粉 末吸入裝置（具有可供給空氣量約2〇 ml之風箱體1〇，參照 實施形態例1及第1圖）。 結果，對於實施例6之冷凍乾燥組成物，確認藉由將 空氣量約2〇ml從吸入裝置導入容器内（賦與由空氣速度約 35m/SeC及空氣流量約4〇ml/sec之空氣所產生之衝擊），可 將谷器内之非粉末狀之冷凍乾燥塊微粒化，並瞬間從容器 經由微粒排出流路4噴射排出。與實施例丨同樣地，使用 安裝空氣呼吸器（美國Amherst Pr〇cess Instrument公司 製）（測定條件，呼吸速率：60L/min ;呼吸體積：1L ;加速： 19)之粒度分布計（氣膠分析儀（aer〇sizer):美國Amherest Process InStrument公司製））將其回收，測定經微粒化之粒 子之粒度分佈，並從其算出空氣力學平均粒徑（V m± SD) 〇 將以非溶解狀態存在於各懸浮液中之粒芊之幾何學平 均粗徑，及各冷凍乾燥組成物之衰變指數，及從該裝置噴 射之粒子之空氣力學平均粒徑爪土 SD)示於表4中。 95 315314 1327073 〈表4&gt; 冷 組成物 ~~系何 --- 均粒衣變指數空氣力學之平 ____μ } 均粒徑（μηι 土 SD, 6) Sniper fect+Olig 13 9 ' ~---MAD)_ \RNA +纈胺酸 0.275 1.589 士 1.553 如表4所示，顯示-- ^ 支知數為0.275之非粉末狀冷凍 乾燥組成物（冷凍乾燥塊），斑 …貫施例1同樣地，縱使在冷 來乾燥前之試料為非溶解妝能 b 狀態（在其中為懸浮狀態）且很易 政集成幾何學之平均粒徑為 1 14认未之粒子，亦可藉由空氣 速度約35m/sec及空氣流量約 夏匀4〇ml/sec之空氣所產生之衝 擊而衰變，形成為空氣力學之伞 一 之平均粒徑為5微米以下之適 於經肺投與之微粒狀乾燥粉末製劑。 以上之實施例2至6之4士婁gs - .. &lt;、、·。果顯不’與貫施例1同樣地， 縱使在冷凍乾燥前之試料為非 、竹馬非洛解狀態（在其中為懸浮狀 態)，藉由在本發明中所規定之特定空氣衝擊，可以提供能 調製成適於經肺投與之微粒化乾燥粉末之冷凌乾燥組成 物，亦即顯示縱使添加成分對溶媒而言係不溶性或難溶 性，在本發明之經肺投與用乾㈣末吸人“中亦適用\ 且可有效地經肺投與。 實施例7至8 分別調製胰島素（重組人類胰島素結晶，比利時 Biobras公司製’比活性：％·4 u/mg)(在實施例7中為〇 2 mg，在實施例8中為丨mg)溶於鹽酸水溶液所得之水溶液 以及表5所示各種載體溶於精製水所得之溶液，若將 315314 96 丄 W/U73 ^、5所不之添加比率混合，可以得到各個懸浮狀態之懸 射 Λ :心浮液所包含之粒子之幾何學平均粒徑用雷射折 掣散^射式粒度分佈測定裝置（SALD_3〇〇〇J，島津製作所 接下來，將該懸浮液充填於容器（筒徑0 1 8 mm)中，用 =狀冷來乾燥機（LY〇VAC GT_4 ’ LEYB0LD公司製）進行 换K乾〃燥對於得到之非粉末狀冷凍乾燥組成物（冷凍乾燥 成：异Λ衰變指數。接下來，將充填非粉末狀冷凍乾燥組 1?之谷斋（筒徑0 18 mm)安裝在被設計成空氣導入流路 之之孔技為01.99mm•且吸引流路16之孔徑為01.99mm 自己吸入型乾燥粉末吸入裝置(參照實施形 圖）。使用其並蕤讲斗、曲 弟3 製）（對於冷康乾定器则CQpley公司 約295ml/ &amp;塊賦與空氣速度約95m/SeC及空氣流量 叫將 Γ空氣所產生之衝擊），計算出有效粒子比率 均以非’谷解狀態存在於各懸浮液中之粒子之幾何學平 立k各冷凍乾燥組成物之衰變指數及粒 不於表5中。 c牛（/〇 315314 97 1327073 &lt;表5&gt; 組成‘ 平均粒徑指數比例（〇/〇) -—__ (μηι)315314 92 1327073 &lt;Table 3&gt; Cold-bundled dryness * I composition---------------------------------- 〇-RNA+ leucine 4) Superfect + pEGF 3.74 P-C2+ leucine MMAD) 0.225 1.578±1,403 0.189 1.646±1.420 5)Superfect + pEGF 3.74 P-C2 +Lactose 0.080 2.848 Soil 1.837 Comparative Example 2) Superfect+01ig 〇11.12 -RNA+ dextran 40 0-003 Can not be measured completely without dispersing ''The number of shackles is 〇.08〇 to 〇225 (that is, the decay index is more than 0.080% non-motorized ~ not like the frozen free-drying block) In the same manner as in the first embodiment, 'even if the sample before the cold drying is in a non-dissolved state, and it is easy to coagulate and hit the 'Τ ^, it can also be 7 pieces by air (4) 11 μm. The impact generated by the air of the granules collapses m 4 about - 5 micrometers or less suitable for fine lungs ~ the average particle diameter of aerodynamics is relative to this, showing a decaying granular dry powder preparation. - 借 ... 冲 冲 冲 冲 成为 成为 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥The m gas impact specified in the above can be adjusted to supply energy. (4) Cold-rolling drying of the micronized dry powder administered by the lung:: 'π ie' is applied to the dry powder inhalation system for transpulmonary administration of the present invention. It can be effectively administered through the lungs. In addition, it can be replaced by the use of the cancer inhibitor gene Ρ53 (for lung cancer) and the cystic fibrosis membrane-regulated protein (:R) gene (for cystic fibrosis). The greedy body (pEGFP_C2) used in the present embodiment can introduce a therapeutically effective gene or an antisense molecule into the body by pulmonary administration. Further, 〇Ug〇_RNA is RNAi (RNA dry (4)) The double-strand RNA of the canned heart can be introduced into the short double-stranded rna corresponding to the target gene, which can specifically inhibit the function of the target gene, and can also be applied to the treatment of lung cancer. Therefore, the dry powder inhalation system for transpulmonary administration of the present invention is considered to be a gene It can be used effectively in the treatment. • Example 6 Superactive (manufactured by Qiagen) 3 60 /^ and 〇丨4〇_111^ (made by Otsuka Pharmaceutical Co., Ltd.) 5# layer for the introduction of the active dendrimer for gene introduction , in the presence of MEM MEM I 12〇〇# kgacobrl company), the suspension is suspended, and the composite is opened. The geometric mean particle size of the far complex is measured by a laser refracting and scattering particle size distribution device (SALD_3〇) 〇〇J, Shimadzu Manufacturing Co., Ltd.. Next, each of the suspensions containing these complexes was added to each of the previously prepared L-proline acid solution (2.5 mg/ml). 〇//1 container (caliber diameter must be 18 mm) (10), prepared to freeze-dried 315314 94 1327073 sample. After that, use shed-like freeze dryer (LY〇VAC G Ding _4, LEYBOLD company The system was subjected to freeze-drying, and the obtained non-powder freeze-dried composition (freeze-dried cake) was subjected to calculation of a decay index. Next, a container containing the obtained non-powder-like freeze-dried composition (freeze-dried cake) was installed. The hole diameter designed to be the air jet flow path 3 is 0 1.2 Mm, a spray-type dry powder inhalation device having a hole diameter of 0 丨 8 mm in the discharge flow path 4 (having a bellows body that can supply an air amount of about 2 〇ml, refer to the first embodiment and the first embodiment). With respect to the freeze-dried composition of Example 6, it was confirmed that the amount of air was about 2 〇ml from the inhalation device into the container (given by air having an air velocity of about 35 m/SeC and an air flow rate of about 4 〇ml/sec). In the impact), the non-powder-shaped freeze-dried cake in the trough can be atomized and instantaneously ejected from the container through the particle discharge flow path 4. In the same manner as in Example ,, a particle size distribution meter (gas gel analysis) using an air breathing apparatus (manufactured by Amherst Prence Instrument Co., Ltd.) (measurement conditions, respiration rate: 60 L/min; respiratory volume: 1 L; acceleration: 19) was used. (aer〇sizer): manufactured by Amherest Process InStrument, USA)), which is used to measure the particle size distribution of the micronized particles, and calculate the aerodynamic mean particle size (V m ± SD) from the 〇 will be in a non-dissolved state. The geometric mean diameter of the granules present in each suspension, and the decay index of each lyophilized composition, and the aerodynamic mean particle size of the particles sprayed from the apparatus are shown in Table 4. 95 315314 1327073 <Table 4> Cold composition ~~ Department--- Average grain index index aerodynamic flat ____μ } Average particle size (μηι土 SD, 6) Sniper fect+Olig 13 9 ' ~--- MAD)_\RNA +proline acid 0.275 1.589 ± 1.553 As shown in Table 4, a non-powder freeze-dried composition (freeze-dried cake) with a known number of 0.275 is shown, and the same applies to Example 1 Even if the sample before cold drying is in the non-dissolving makeup b state (in which it is in suspension) and the average particle size of the easy-to-governance integrated geometry is 1 14, the air velocity can also be about 35 m. /sec and the air flow rate decays due to the impact of the air of 4〇ml/sec in the summer, forming an aerodynamic umbrella with an average particle size of 5 μm or less suitable for the pulmonary dry powder preparation . The above examples 2 to 6 of 4 gs gs - .. &lt;,, ·. In the same manner as in the first embodiment, even if the sample before the freeze-drying is in a non-lost state (in which it is in a suspended state), it can be provided by the specific air impact specified in the present invention. It can be prepared into a cold-bloomed dry composition suitable for pulmonary-administered micronized dry powder, that is, even if the added component is insoluble or poorly soluble to the solvent, in the lung of the present invention, the dry (four) end is absorbed. It is also applicable to humans and can be effectively administered via the lungs. Examples 7 to 8 respectively modulate insulin (recombinant human insulin crystal, specific activity: %·4 u/mg, manufactured by Biobras, Belgium) (in Example 7 It is 〇2 mg, in Example 8, it is 水溶液mg) an aqueous solution obtained by dissolving in an aqueous solution of hydrochloric acid, and a solution obtained by dissolving various carriers shown in Table 5 in purified water, if 315314 96 丄W/U73 ^, 5 By adding the ratio mixing, it is possible to obtain the suspension 各个 in each suspension state: the geometric mean particle diameter of the particles contained in the heart floating liquid is measured by a laser 掣 ^ ^ 粒度 粒度 粒度 ( ( ( ( ( ( , , , , , , , , , , The suspension Filled in a container (bottle diameter 0 1 8 mm), and dried in a non-powdered freeze-dried composition (freeze-dried by a dry-type dryer (LY〇VAC GT_4 'LEYB0LD)) : Λ Λ Λ 。 。 。 。 。 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来16 hole diameter is 01.99mm self-inhalation type dry powder inhalation device (refer to the implementation of the figure). Use it to talk about the bucket, the song brother 3 system) (for the cold Kang dryer, CQpley company about 295ml / &block; The air velocity is about 95m/SeC and the air flow is called the impact generated by the air. The geometrical ratio of the particles in the non-glutinous state in each suspension is calculated. The decay index and grain are not shown in Table 5. c cattle (/〇315314 97 1327073 &lt;Table 5&gt; Composition 'Average particle size index ratio (〇/〇) -___ (μηι)

7)胰島素 0.2mg+ 白 f 酸 0.52~~0.292 9TI 0‘lmg+ 精胺酸 0.042 mg · (PH6.5) 57.9 8)胰島素lmg+苯基丙胺酸 0.63 0.238 〇.6mg+精胺酸 0.11mg(pH6.4)7) Insulin 0.2mg + white f acid 0.52~~0.292 9TI 0'lmg + arginine 0.042 mg · (PH6.5) 57.9 8) Insulin lmg + phenylalanine 0.63 0.238 〇.6mg + arginine 0.11mg (pH6.4 )

如表5所示，顯示衰變指數至少（j ug之非粉末狀冷 凍乾燥組成物（冷凍乾燥塊），縱使冷凍乾燥前之試料包含 非溶解狀態之有效成份（胰島素），但藉由上述空氣衝擊， 在容器中易於微粒化，而可調製成適於經肺投與之乾燥粉 末製劑。 實施你丨9 $ 1 1 分別調製胰島素（重組人類胰島素結晶，比利時 Bi〇bras公司製，比活性：26 4 u/mg)1 mg溶於鹽酸水溶液 所得之溶液以及苯基丙胺酸〇·5 mg溶於精製水所得之溶 液’將彼等混合’若藉由氫氧化鈉調整各種pH值，可以 于丨各種跑浮狀悲之懸浮液。該該懸浮液所包含之粒子之 幾何學平均粒徑用雷射折射及散射式粒度分佈測定裝置 (SALD· 30〇〇J，島津製作所製）測定。 接下來，將該懸浮液充填於容器（筒徑0 1 8 mm)中，用 棚狀冷凍乾燥機（LYOVAC GT-4，LEYBOLD公司製）進行 315314 98 1327073 冷凍乾燥。對於得到之非粉末狀冷凍乾燥組成物（冷凍乾燥 鬼）十算出衰變指數。接下來，將充填非粉末狀冷凍乾燥組 成物之谷益（筒徑必18 mm)安裝在被設計成空氣喷射流路 之孔杈為0丨·2 mm且流出流路之孔徑為0 1.8 mm之噴射 型乾燥粉末吸入裝置(具有可供給空氣量約心丨之風箱體) =。使用其並藉由二段式塵埃測定器（英國c〇piey公司 製）（對於冷康乾燥塊賦與空氣速度約35* :40 一空氣所產生之衝擊)，計算出有效粒：：： ()。將以非溶解狀態存在於各懸浮液中之粒子之幾何學平 均粒徑，各冷;東乾燥組成物之衰變指數及有效粒子比率 示於表6中。 &lt;表6&gt; 冷凍乾燥組成物 + 苯基丙 酸 〇.5mg (pH6.0) . i〇)胰島素lmg +苯基丙 〇 胺酸 0.5mg (ΡΗ6·4) ' η)胰島素lmg +苯基丙 〇 6 〇.5mg (pH6_6) . 指數上b例（％) 〇_39 69.3 75.1 72.0 0.39 0.36 如表6所示，顯示衰-— 乾紐組成物（冷束乾燥塊），縱使 東 ^ . 术罕0岛别之試料包含非 浴解狀態之有效成份（胰島素） .卜 容器中易於微粒化，可調製成適 /、.封袋在 劑。 、於經肺投與之乾燥粉束製 复及例12至13 315314 99 1327073 比利時 分別調製胰島素（重組人類胰島素結晶As shown in Table 5, a non-powdered freeze-dried composition (freeze-dried cake) having a decay index of at least (j ug) was used, even though the sample before freeze-drying contained an active ingredient (insulin) in a non-dissolved state, but by the above air impact It is easy to micronize in the container, and can be made into a dry powder preparation suitable for pulmonary administration. Implementing your 丨9 $ 1 1 separately modulating insulin (recombinant human insulin crystal, made by Bi〇bras, Belgium, specific activity: 26 4 u / mg) 1 mg of the solution obtained by dissolving in hydrochloric acid aqueous solution and phenyl phenylalaninate · 5 mg of the solution obtained by dissolving in purified water 'mix them'. If the pH is adjusted by sodium hydroxide, it can be used in 丨Each of the suspensions of the floating sorrows was measured by a laser refracting and scattering particle size distribution measuring apparatus (SALD·30〇〇J, manufactured by Shimadzu Corporation). The suspension was filled in a container (both diameter: 0 18 mm), and lyophilized by a shed-type freeze dryer (LYOVAC GT-4, manufactured by LEYBOLD Co., Ltd.) at 315314 98 1327073. The lyophilized composition (freeze-dried ghost) is used to calculate the decay index. Next, the gluten (the diameter of the cylinder must be 18 mm) filled with the non-powder lyophilized composition is installed in the hole designed as the air jet flow path. Spray dry powder inhalation device with 0 丨 · 2 mm and an outflow flow path with a hole diameter of 0 1.8 mm (with a bellows capable of supplying air to the heart) = use it with a two-stage dust detector ( British c〇piey company) (for the impact of the air speed of about 35*:40 on the cold block), calculate the effective particles::: (). will be present in the non-dissolved state in each suspension The geometric mean particle diameter of the particles in each, cold; the decay index and effective particle ratio of the eastern dry composition are shown in Table 6. &lt;Table 6&gt; Freeze-dried composition + phenyl phenylpropionate. 5 mg (pH 6. 0) . i〇) Insulin 1mg + phenylpropionine 0.5mg (ΡΗ6·4) ' η) Insulin 1mg + Phenylpropanoid 6 〇.5mg (pH6_6) . Index b (%) 〇 _39 69.3 75.1 72.0 0.39 0.36 As shown in Table 6, the fading-dry composition (cold bundle drying block) is shown, even Active ingredient (insulin) ^. 0 Island Hampshire surgery Bie sample comprises a non-state solution of the bath. Bu easily micronized vessel, adjustable made fitness / ,. agent in the envelope. Preparation of dry powder bundles administered by the lungs and Examples 12 to 13 315314 99 1327073 Belgium Preparation of insulin (recombinant human insulin crystals)

Biobras公司製 比活性：26.4 U/mg)〇.lmg溶於鹽酸水溶 液所得之水溶液以及表7所示各種載體溶於精製水所得之 溶液’將彼等混合並用氫氧化鈉調整pH值，可以得到各 個懸浮狀態之懸浮液。該懸浮液所包含之粒子之幾何學平 均粒徑用雷射折射及散射式粒度分佈測定裝置（sald_ 3〇〇OJ，島津製作所製）測定。 接下來，將該懸浮液充填於容器（筒徑0 i 8 mm)中，用 棚狀冷凍乾燥機（LYOVAC GT-4，LEYBOLD公司製）進行 冷凍乾燥。對於得到之非粉末狀冷凍乾燥組成物（冷凍乾燥 塊）計算出衰變指數。接下來，將充填非粉末狀冷凍乾燥組 成物之容器（筒徑018 mm)安裝在被設計成空氣導入流路 17之孔徑為0 1.99 mm且吸引流路16之孔徑為必丨99爪爪 之自己吸入型乾燥粉末吸入裝置（參照實施形態例3及第3 =)。使用其並藉由二段式塵埃測定器（英國c〇pley公司 氣）（對於冷/東乾燥塊賦與空氣速度約9 5 m / s e c及空氣流量 7 295 ml/sec之空氣所產生之衝擊），計算出有效粒子比率 (0)將以非溶解狀態存在於各懸浮液中之粒子之幾何學平 句粒徑，各冷凍乾燥組成物之衰變指數及有效粒子比率（％) 示於表7中。 315314 100 1327073 〈表7 &gt; 冷凍乾燥組成物 幾1可學之&quot;平 基鑛胺酸 〇.5mg(pH6.4) 68.7 1 3)胰島素0_ lmg+白胺醯 〇 67 基結負胺酸1.5mg(pH6.5) 0.051 58.9 如表7所不，顯不衰變指數至少〇 〇5 i之非粉末狀冷 凍乾燥組成物（冷凍乾燥塊），縱使冷凍乾燥前之^料包| 非2解狀態之有效成份（胰島素），但藉由上述空氣衝擊， 在容器中易於微粒化，而可調製成適於經肺投與之乾燥粉 末製劑。 ’ 實施你| 1 4 V， 分別調製胰島素（重組人類胰島 頰趿馬索結晶，比利時 B1〇bras公司製，比活性：26 4 /mg)〇.l mg浴於鹽酸水溶 液所得之水溶液以及纈胺酸〇 s 5 溶於精製水所得之溶 液，將彼等混合並用氫氧化鈉調整 n正PH值至6.5，可以得到 懸浮狀態之懸浮液。該懸浮液所 G 3之粒子之幾何學平均 粒徑用雷射折射及散射式粒 ΛΛ 度分佈測定裝置（SALD- 3000J ’島津製作所製）測定。拯 接下來，將該懸浮液充填於 谷态（筒徑0 1 8 mm)中，用棚肤 '入、击 、 狀冷/東乾燥機（LYOVAC GT 4，LEYBOLD公司製）進行冷凌獻 果乾梃。對於得到之非粉太 狀冷凍乾燥組成物（冷凍乾燥塊 尼）叶异出衰變指數。 接下來，將充填非粉末狀冷凍仏β ν /果乾燥組成物之容器（筒 必1 8 mm)安裝在被設計成空氣邋 ^ 導入流路17之孔徑為0 315314 101 1327073 1.99 mm且吸引流路1 6之孔徑為0 1.99 mm之自己吸入型 乾煉粉末吸入裝置（參照實施形態例3及第3圖）中。 用其對於容器中之非粉末狀冷凍乾燥組成物（冷凍乾 燥塊）賦與空氣速度約1 m/sec及空氣流量約17 ml/sec之 空乳所產生之衝擊’將生成之粒子從裝置直接喷射於安裝 肺&amp;工氣乎吸器（美國Amherst Process Instrument公 司製）（測定條件，呼吸速率：！ L/min ;呼吸體積：〇 1L) 氣膠刀析儀（aer〇sizer)(美國 Amherest Process Instrument公司製）中，並測定微粒之粒度分佈。然後從該 結果算出該微粒之空氣力學平均粒徑（μ 土 SD)。將各冷凍 乾燥組成物之衰變指數及從裝置噴射之粒子之空氣力學平 均粒徑示於表8中。 &lt;表8&gt; 冷凍乾燥組成物幾何， 均粒徑（μΐΏ)指數粒徑（_±SD,二 纈胺酸 0.5mg U75士1·384 如表8所示，顯示衰變 凍乾燥組成物（冷凍乾燥塊）’縱使冷凍乾燥前之試料 非溶解狀態之有效成份（胰島素），但藉由上述空氣衝 在容器中易於微粒化，且可調製成適於經肺投與之^ 末製劑。 315314 102 1327073 參考例1至5 將胰島素（重組人類胰島素結晶，比利時Biobras公司 製，比活性：26.4U/mg)(l mg，2mg)或胰島素與表9所示 各種載體分別溶於包含鹽酸之注射蒸餾水中並調製成〇.2 ml，將其充填於容器（筒徑0】8 mm)中，用棚狀冷凍乾燥 機（LYOVAC GT-4 ’ LEYBOLD公司製）進行冷;東乾燥。對 於知·到之非粉末狀冷凍乾燥組成物（冷凍乾燥塊）計算出衰 &amp;指數。接下來，將充填非粉末狀冷凍乾燥組成物之容器 (筒徑0 1 8 mm)安裝在被設計成空氣導入流路1 7之孔徑為 0 1.99 mm且吸引流路μ之孔徑為0 ! .99 mm之自己吸入 型乾燥粉末吸入裝置（參照實施形態例3及第3圖）。使用 其並藉由—段式塵埃測定器（英國Copley公司製）（對於冷 東乾燥塊賦與空氣速度約95m/sec及空氣流量約295 ml/sec之空氣所產生之衝擊），計算出有效粒子比率（％)。 將各冷凍乾燥塊之衰變指數及有效粒子比率（％)示於表9 中。 . … &lt;表9&gt; -X—_ 指數 參 〇胰島素 lmg 0.1 59 75.0 參2)胰島素img+白胺酸1.4mg 0.145 80.7 f&quot; 3)胰島素 lmg +纈胺酸 l.〇mg 0.1 10 79:4 參 4)胰島素 2mg 0.177 42.4 島素 2mg+ 白胺酸 1.4mg 0.137 65.1 如表9所示’顯示衰變指數至少〇. 11 〇之非粉末狀冷 4乾燥組成物（冷凍乾燥塊），在容器中易被上述空氣衝擊 315314 103 丄 J厶/VJ/：) 微粒化， 且可调製成適於經肺投與 之乾燥粉末製劑。 奎考 分別將胰島素（重組人 制，》_L、&lt; ,· 人^員姨島素結晶，比利時Bi〇brasBiobras specific activity: 26.4 U / mg) l.lmg of the aqueous solution obtained by dissolving the aqueous solution of hydrochloric acid and the solution of the various carriers shown in Table 7 dissolved in purified water 'mixing them and adjusting the pH with sodium hydroxide, can be obtained Suspensions in each suspension state. The geometrical average particle diameter of the particles contained in the suspension was measured by a laser refracting and scattering type particle size distribution measuring apparatus (sald_3〇〇OJ, manufactured by Shimadzu Corporation). Next, the suspension was filled in a container (bottle diameter 0 i 8 mm), and lyophilized by a shed-type freeze dryer (LYOVAC GT-4, manufactured by LEYBOLD Co., Ltd.). The decay index was calculated for the obtained non-powder freeze-dried composition (freeze-dried block). Next, a container filled with a non-powder-like freeze-dried composition (bottle diameter: 018 mm) was attached to a hole having a diameter of 0 1.99 mm designed to be an air introduction flow path 17 and a suction hole 16 was required to be a claw of 99. Self-inhalation type dry powder inhalation device (see Example 3 and 3 =). Use it and use a two-stage dust tester (C〇pley, UK) (for cold/east dry blocks with air velocity of about 9 5 m / sec and air flow of 7 295 ml / sec) ), the effective particle ratio (0) is calculated as the geometric flat particle diameter of the particles present in each suspension in an insoluble state, and the decay index and effective particle ratio (%) of each freeze-dried composition are shown in Table 7. in. 315314 100 1327073 <Table 7 &gt; Freeze-dried composition 1 can be learned &quot;Platinyl bismuth citrate. 5mg (pH6.4) 68.7 1 3) Insulin 0_ lmg + leucine 醯〇 67 nucleoside nucleoside 1.5 Mg(pH6.5) 0.051 58.9 Non-powdered freeze-dried composition (freeze-dried cake) with a non-decay index of at least i5 i, as shown in Table 7, even before freeze-drying The active ingredient (insulin), but which is easily micronized in the container by the above-mentioned air impact, can be adjusted to a dry powder preparation suitable for pulmonary administration. ' Implementing you | 1 4 V, respectively, to modulate insulin (recombinant human islet cheek sputum horse crystallization, made by Belgian B1〇bras, specific activity: 26 4 /mg) 〇.l mg bath in aqueous solution of hydrochloric acid and guanamine The solution obtained by dissolving the acid s s 5 in purified water, mixing them and adjusting n positive pH to 6.5 with sodium hydroxide, can obtain a suspension in suspension. The geometric mean particle diameter of the particles of the suspension G 3 was measured by a laser refracting and scattering type particle size distribution measuring apparatus (SALD-3000J's manufactured by Shimadzu Corporation). Next, the suspension was filled in a trough state (bottle diameter 0 18 mm), and the cold skin was sacrificed by the shed skin 'in, shot, cold/east dryer (LYOVAC GT 4, manufactured by LEYBOLD) Dry up. The leaf heterogeneous decay index was obtained for the non-powdered lyophilized composition (freeze-dried mer). Next, a container filled with a non-powder-like frozen 仏βν/fruit dried composition (cylinder must be 18 mm) is installed in an air 邋^ introduction flow path 17 having a pore diameter of 0 315314 101 1327073 1.99 mm and attracting flow The self-inhalation type dry powder inhalation device (see the third embodiment and the third embodiment) having a hole diameter of 0 1.99 mm. Using the non-powdered freeze-dried composition (freeze-dried block) in the container to impart an impact on the air at a speed of about 1 m/sec and an air flow of about 17 ml/sec, the resulting particles are directly from the device. Sprayed in the installation of lung & gas suction device (manufactured by Amherst Process Instrument, USA) (measurement conditions, respiration rate: ! L / min; respiratory volume: 〇 1L) aer〇sizer (Amherst Process, USA) In the instrument company, the particle size distribution of the particles was measured. Then, the aerodynamic mean particle diameter (μ soil SD) of the fine particles was calculated from the results. The decay index of each freeze-dried composition and the aerodynamic average particle diameter of the particles sprayed from the apparatus are shown in Table 8. &lt;Table 8&gt; Freeze-dried composition geometry, average particle size (μΐΏ) exponential particle size (_±SD, bis-amino acid 0.5 mg U75 ±1·384 as shown in Table 8, showing decay freeze-dried composition (freezing The dry block) 'even the active ingredient (insulin) in the non-dissolved state of the sample before freeze-drying, but is easily micronized by the above-mentioned air flushing in the container, and can be adjusted into a preparation suitable for pulmonary administration. 315314 102 1327073 Reference Examples 1 to 5 Insulin (recombinant human insulin crystal, specific activity: 26.4 U/mg, manufactured by Belgian Biobras Co., Ltd.) (l mg, 2 mg) or insulin and various carriers shown in Table 9 were respectively dissolved in distilled water containing hydrochloric acid. 2 ml was prepared and filled in a container (bottle diameter 0) 8 mm), and cooled by a shed-type freeze dryer (LYOVAC GT-4 'LEYBOLD company); The non-powdered freeze-dried composition (freeze-dried cake) was calculated for the fading &amp; index. Next, a container filled with a non-powder-like freeze-dried composition (bottle diameter 0 18 mm) was installed in the air-introduced flow. Road 1 7 has a hole diameter of 0 1.99 mm and sucks A self-inhalation type dry powder inhalation device having a pore diameter of 0 to .99 mm (refer to the third and third embodiments of the embodiment), and using the same type of dust measuring device (manufactured by Copley, UK) (for The cold east drying block is given an impact of air with an air velocity of about 95 m/sec and an air flow of about 295 ml/sec, and the effective particle ratio (%) is calculated. The decay index and effective particle ratio of each freeze-dried block ( %) is shown in Table 9. . . . &lt;Table 9&gt; -X-_ Index Insulin Insulin lmg 0.1 59 75.0 Reference 2) Insulin img + leucine 1.4 mg 0.145 80.7 f&quot; 3) Insulin 1 mg + proline 1 〇mg 0.1 10 79:4 参4)Insulin 2mg 0.177 42.4 Island 2mg+ lysine 1.4mg 0.137 65.1 As shown in Table 9, 'shows a decay index of at least 〇. 11 〇 non-powdered cold 4 dry composition (freezing The dry block) is easily micronized in the container by the above-mentioned air impact 315314 103 丄J厶/VJ/:), and can be made into a dry powder preparation suitable for pulmonary administration. Kui Keo will separately insulin (recombinant system, "_L, &lt;, · people ^ 姨 素 素 结晶, Belgium Bi〇bras

籲（LYOVAC GT-4，LEYBOLD 公司製）進行冷凍乾燥。對於 =到之非粉末狀冷凍乾燥組成物（冷凍乾燥塊），計算出衰 變^數。接下來，將充填得到之非粉末狀冷床乾燥組成物 之谷器（筒徑0 1 8 mm)安裝在被設計成空氣喷射流路3之 孔徑為4 1.2 mm且流出流路4之孔徑為0丨8 mm之嘴射 型乾燥粉末吸入裝置（具有可供給空氣量約20 ml之風箱 體.參照實施形態例1及第1圖）。使用其對於容器中之非 粉末狀冷束乾燥組成物（冷凍乾燥塊）賦與空氣速度約 籲3 5m/sec及空氣流量約40 ml/sec之空氣衝擊，將生成之粒 子從裝置直接噴射於安裝人工肺型空氣呼吸器（美國 Amh:erst Process Instrument公司製；測定條件，呼吸速率： 60 L/min ;呼吸體積·· 1L)之粒度分佈計（氣膠分析儀 (aerosizer):美國 Amlierest Process Instrument 公司製；r ψ Niven: Pharmaceutical Technology, 72-78 (1993))中，並測 定微粒之粒度分佈。然後從該結果算出該微粒之空氣力學 平均粒徑（# m± SD)。 將充填非粉末狀冷凍乾燥組成物之容器（筒徑0 ! 8 104 315314 1327073 叫安裝在被設計成空氣導人流路17之孔徑為^99 且吸引流路之孔徑為0丨99 mm之自？叨λ别± mm 入裝置(參照實施形態例3及第3圖)。使用其二：：： 定器(英國Copley公司製)(對於冷凌㈣塊：： 工虱速度約95m/SeC及空氣流量約295 mi/sec之空#吝、 生之衝擊），計算出有效粒子比率（％)。 一乳·，二 將各冷凍乾燥塊之衰變指數，以及從裝置噴射之粒子 之空氣力學平均粒徑U m± SD)及有效粒子比率㈧）示於 表10中。 、 :表 10&gt;Yu (LYOVAC GT-4, manufactured by LEYBOLD) is freeze-dried. For the non-powder freeze-dried composition (freeze-dried block) of =, the decay number was calculated. Next, the barn (tube diameter 0 18 mm) of the non-powdered cold-bed drying composition obtained by charging is installed in a hole diameter of 4 1.2 mm designed as the air jet flow path 3 and the flow path of the outflow flow path 4 is A nozzle-type dry powder inhalation device of 0 丨 8 mm (having a bellows capable of supplying about 20 ml of air. Refer to the first embodiment and the first embodiment). Using the non-powdered cold-dried composition (freeze-dried block) in the container, an air impact of about 35 m/sec and an air flow of about 40 ml/sec is applied to spray the generated particles directly from the device. Installation of artificial lung air breathing apparatus (made by Amh: erst Process Instrument, USA; measurement conditions, respiration rate: 60 L/min; respiratory volume · 1 L). Particle size distribution analyzer (aerosizer: Amlierest Process, USA) Instrumentation, r ψ Niven: Pharmaceutical Technology, 72-78 (1993)), and determining the particle size distribution of the particles. Then, the aerodynamic mean particle diameter (# m ± SD) of the fine particles was calculated from the results. A container filled with a non-powdered lyophilized composition (both diameter 0! 8 104 315314 1327073 is attached to a hole designed to be an air guiding passage 17 with a hole diameter of ^99 and a suction flow path of 0 丨 99 mm.叨λ±± mm into the device (refer to the third and third embodiments). Use the second::: device (manufactured by Copley, UK) (for cold (four) block:: work speed of about 95m/SeC and air The flow rate is about 295 mi/sec (吝, the impact of the birth), and the effective particle ratio (%) is calculated. One milk·, two will be the decay index of each freeze-dried block, and the aerodynamic average of the particles sprayed from the device. The diameter U m ± SD) and the effective particle ratio (eight) are shown in Table 10. , :Table 10&gt;

空氣5學之平均有效粒子 粒徑（μ®士SD，比例（％) MMAD、_ 17759±7^425~~~ 7ΤΤ 1.954±1.454 74:1 2.007 士. 1.438 72 1 1.872±1.477 62.0 2.239±1.435 61.2 L124 0.250 0.124 參6)胰島素+異白胺酸 參7)胰島素+白胺酸 ^ 8)胰島素+纈胺酸 υ ιζ4 务9)胰島素+苯基丙胺酸 0.204 jlJJ))騰島素+D-甘露:醇0.160 ------------------------ v ▲•知 如表10所示，顯示衰變指數至少0124之非粉末狀冷 凍乾燥組成物（冷凍乾燥塊），藉由空氣速度約35m/sec及 空氣流量約40ml/Sec生成之空氣衝擊或者空氣速度約. 95m/sec及空氣流量約295 ml/sec生成之空氣衝擊，在容 器中易被微粒化。而且藉由空氣速度約95rn/sec及空氣流 里約295 ml/sec生成之空氣衝擊而微粒化之粒子之平均粒 仏為5微米以下’可調製成適於經肺投與之乾燥粉末製 劑。 315314 105 若藉由本發明之經肺投與用乾 ^ A、去i/· 展卷末吸入系統，可將 ▽凍乾燥組成物經微粒化成送達肺所* . ==入投與至肺，，若依照本發明之經肺投* 來二=:系統’使用(投與)調製成非粉末狀態之； 此1==，：將其微粒化之同時，可吸入投與1 :而為了製劑之微粒化而進行特别之操作。因 本發明之經肺投與 右依 不會有……系統(製劑系統)，將 成之損失）、於佯存中^ 不活性化及充填操作造 性化等)以及粒狀保存造成之藥物不活 陧化寻）以及在製造過程中混入 投與期望之-定量。i在时^雜物之虞’而可以安定地 活性物質為有效成分之製胃及胜肽等-般高價藥理 ο负政成刀之製劑上特別有用。 之有二發明之經肺投與用乾燥粉末吸入系統中得到 =1率至少為1。%以上，再者，若依照本發明」 Ί、用乾燥粉末吸入系統 20。/。以上，25%以上，3〇 于比羊了k冋至 v 上以及35%以上。而若依昭美 國專利公報第6153224號之β ^ …、 多數中，附著於肺下部之右 在先如乾粉吸入裝置之 效成分之10%。又，在 八韦 一 特開2001-151 673號公報中記载， 身又及入用粉末製劑到；查曰 中排出之筚#^ &amp; 達肺之罝（肺到達率），為從該製劑 T排出之枭物之約丨〇%。 粉末吸入系統，從可以^本舍明之經肺投與用乾燥 有效粒子比率之觀點^成比先前之吸入用粉末製劑高之 斗分 ...5之，可謂極有用的投與系統。The average effective particle size of air 5 (μ®士SD, ratio (%) MMAD, _ 17759±7^425~~~ 7ΤΤ 1.954±1.454 74:1 2.007 士. 1.438 72 1 1.872±1.477 62.0 2.239±1.435 61.2 L124 0.250 0.124 Reference 6) Insulin + Isoleucine 7) Insulin + leucine ^ 8) Insulin + guanidinium ζ ζ 4 9) Insulin + Phenylalanine 0.204 jlJJ)) Tengdaosu + D- Manna: alcohol 0.160 ------------------------ v ▲• Know as shown in Table 10, showing a non-powdered freeze-dried composition with a decay index of at least 0124 (freeze-dried block), an air impact generated by an air velocity of about 35 m/sec and an air flow of about 40 ml/sec, or an air velocity of about 95 m/sec and an air flow of about 295 ml/sec, in a container Easy to be micronized. Further, the average particle size of the microparticulated particles is 5 micrometers or less by an air impact of about 95 rn/sec at an air velocity of about 295 cc/sec in an air flow, and the dry powder preparation suitable for pulmonary administration can be adjusted. 315314 105 The lyophilized composition of the lyophilized composition can be micronized into the lungs by the transpulmonary administration of the sputum-injection system of the present invention, and the lyophilized composition can be delivered to the lungs. If the lung is administered according to the present invention, the system is 'used (administered) to be in a non-powder state; this 1 ==,: while it is micronized, it can be inhaled and administered for 1: Special operations are carried out by micronization. According to the present invention, there is no such thing as a systemic (preparation system), a loss (in the case of inactivation) and a filling operation, and a drug caused by granular preservation. Do not live and seek) and mix in the manufacturing process with the expectation - quantitative. i can be stable in the case of 杂 杂 而 而 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 制 制 制 制 制 制 负 负 负 负 负 负 负 负 负 负 负 负 负 负 负 负 负In the case of the invention, the transpulmonary administration uses a dry powder inhalation system to obtain a =1 rate of at least 1. More than or equal to, in addition, according to the present invention, the system 20 is sucked into the system with a dry powder. /. Above, 25% or more, 3〇 is more than the sheep and k冋 to v and more than 35%. And in the β ^ ... of most of the US Patent Publication No. 6153224, the right part attached to the lower part of the lung is 10% of the effective ingredient of the dry powder inhalation device. In addition, it is described in the publication No. 2001-151 673 of the Japanese Unexamined Patent Publication No. 2001-151673, which is incorporated in the sputum, and the sputum of the lungs (the lung arrival rate) is About 丨〇% of the waste discharged from Formulation T. The powder inhalation system is a very useful administration system from the viewpoint of the ratio of the ratio of the dry active particles to the lungs which can be used in the present invention, which is higher than the previous powder preparation for inhalation.

右·依照本發明之A 7 /果乾燥組成物及噴射型乾燥粉末吸 315314 106 1327073 入裝置，僅藉由空氣屋送手段將空氣從空氣喷射流路喷射 至容器内並將空氣衝擊賦與冷凌乾燥組成物，就可將該冷 東乾知組成物微粒化。基於此，利用簡單構造之吸入裝置 及用時進行簡單的操作，就可以微粒化。又該吸入裝置由 於具有平易之構造，可以低成本生產，結果可以大量擴張。 又，若依照噴射型之乾燥粉末吸入裝置，#由調整風 =體等空氣壓送手段之壓縮速度，可以調整氣化噴霧劑（粉 末製劑)之吸引量以符合使用者之呼吸能力。又藉由將針部 $集成根’針部扎入容器之口栓之作業將變得容易。 再者，若依照自己吸入型之乾燥粉末吸入裴置，藉由 使用者之吸氣壓產生空氣衝擊’可以將冷凌乾燥組成㈣ :(微粒化)’且可於使用者吸氣之同時’將冷凌乾燥組成 $經微粒化並投與至肺，藉此可以期待獲得無損失且安定 量之藥物投與。又’由於無需霧化(微粒化)以外之特別操 作’操作容h又，與喷射型同#，藉由將針部匯集成： 根，扎入容器之口栓背部之作業將變得容易。 依照本發明之乾燥粉末吸入裝置 ^ 、洽 衣直將具有吸引流路及 二乳v入流路之針部扎入容器之口栓，萨 1日思者之吸氣 壓，可將上述容器内之空氣從吸引口吸入，友以 π之空氣導入流路流入容器内以將空氣衝擊賦與上述冷凍 乾燥組成物，並可從容器中吸引出已粉末 =μ 7 / 成物。 心東㈣、組 又，尤其是在實施形態例4中記載之本發明 吸入裝置之情況，可以發揮下述效果。 l呆&amp;禾 315314 107 1327073 在對於冷凍乾燥組成物賦與有效的空氣衝擊，並從容 器吸引出經微粒化之粉末狀冷凍乾燥組成物之情況，必= 將吸弓丨流路及空氣導入流路之戴面積增*，目*匕針部之： 徑必須增大。 但是，要將口徑大之針部札入口检，必須將容器確實 保持，以不偏離針部之軸線之方式靠近針尖，並用 二 針尖壓入口栓。 等 所以，本發明之乾燥粉末吸入裝置藉由具備保持容器 之保持部、保持部之引導部、以及有機構部及操作該機構 部之操作體之保持部運轉部，可以將容器用保持部保持， 並=著引導部在針部之軸線上移動並靠近針尖，又藉由操 作操作體：可用比較小的力使針部扎入容器之口栓。 像這樣，若依照本發明之乾燥粉末吸入裝置可容 且破實地將針部扎入容器之口栓。 又，若構成為「上述外殼形成筒狀，在該外殼之前部 :成上述吸引口部’在上述外殼内形成上述容器之收二 +將上述針以針尖朝向上i收納室之彳式配設在上述 外Λ又内’將與上述針部之空氣導人流路連通並供導入外氣 之導入口設置在上述外殼之壁部，藉由上述保持部運轉部 將上述保持部在上述收納室巾，以上述外殼之軸方向前進 及後退」’可以形成鉛筆形之乾燥粉末吸入裝置，其容易 用且携帶方便。 置 於 , 、 边外冗又’若藉由在上述保持部後退之 形成有上述容哭夕山x 。。之出入口之外殼本體’以及用絞鏈連 108 315314 1327073 ^述外殼本體之上述出入口之蓋子所形成之保持部運轉 邛具備在蓋上上述蓋子使上述出入口關閉之 持部前進，且在拉起上述蓋子使上述出入口打開之時= ^保持部後退之上述機構部，且上述蓋子兼做為上述機構 :之刼作體，將可使保持部運轉部之機構部簡略化，在製 造成本方面有利。x，由於在容器之口栓被針尖札 = 時，可以蓋住容器之出入口，所以變得易於使用。 [圖式簡單說明] 圖為顯示實施形態例丨記載之本發明乾燥粉末吸 、（嘴射型1)之剖面圖。又’圖中箭頭表示 流動（在下文之第2圖及第3圖中亦同）。 4之 2圖為顯示實施形態例2記載之本發明乾燥 裝置（自己吸入型1)之剖面圖。 第3圖為顯示實施形態例3記載之 入裝置（自己吸人型2)之剖面圖。 ^如末吸 入二4自圖己為广貫施形態例4記载之本發明乾燥粉末吸 入哀置(自己吸入型3)之透視圖。冬及 面圖^圖為上述乾燥粉末吸入裝置（自己吸入型3)之剖 第6圖之(a)為上述乾燥粉末吸入裝置(自 之部分剖面圖；我 入i 3) 圖。 ）為该乾燥粉末吸入裝置之針部之側面 別胃7 i 1 ^ ^ ^ ^ i $乾燥粉末吸人裝置(自己明 型3)之動作之剖面圖。 K自己吸入 315314 109 1327073 第 π圖係為本發明之其他實施形態之乾燥粉末吸入 裝置（自己吸入型4)之透視圖。 第1 2圖係為本發明之其他實施形態之乾燥粉末吸入 裝置（自己吸入型5)之透視圖。 第1 3圖係為本發明之其他實施形態之乾燥粉末吸入 裝置（自己吸入型5)之透視圖。Right · A 7 / dried fruit composition and spray-type dry powder according to the present invention 315314 106 1327073 into the device, only by air to send air from the air jet flow path into the container and the air impact cold By cooling the composition, the composition of the cold east can be micronized. Based on this, it is possible to atomize by using a simple structure of the inhalation device and a simple operation at the time of use. Further, since the inhalation device has a structure which is easy to manufacture, it can be produced at a low cost, and as a result, it can be expanded in a large amount. Further, according to the dry type powder inhalation device of the spray type, the suction amount of the vaporized spray (powder preparation) can be adjusted by adjusting the compression speed of the air pressure feed means such as the air type to conform to the breathing ability of the user. It is also easy to work by inserting the needle portion into the mouth of the container. Furthermore, if the dry powder is inhaled according to the inhalation type of the inhalation type, the air impact can be generated by the user's suction pressure, and the cold can be dried to form (4): (micronized) and can be inhaled by the user. The cold-blooming composition is micronized and administered to the lungs, whereby it is expected to obtain a drug-free drug with no loss and safety. Further, since there is no need for special operation other than atomization (micronization), the operation volume h is the same as that of the ejection type, and by assembling the needles into the roots, the operation of inserting the back of the mouth of the container becomes easy. According to the dry powder inhaling device of the present invention, the needle having the suction flow path and the second milk v inflow path is inserted into the container, and the air pressure in the container can be used. Inhaled from the suction port, the friend introduces a flow path into the container by the air of π to impart an air impact to the freeze-dried composition, and can suck out the powder = μ 7 / product from the container. In the case of the inhalation device of the present invention described in the fourth embodiment, the following effects can be exhibited. l Stay &amp; 315314 107 1327073 In the case of imparting an effective air impact on the freeze-dried composition and attracting the micronized powdery freeze-dried composition from the container, it is necessary to introduce the suction flow path and air The wearing area of the flow path is increased by *, and the diameter of the needle is: the diameter must be increased. However, in order to check the entrance of the needle with a large diameter, the container must be held securely, close to the tip of the needle so as not to deviate from the axis of the needle, and the inlet plug is pressed with the tip of the needle. In the dry powder inhalation device of the present invention, the container holding portion can be held by the holding portion for holding the holding portion of the container, the holding portion, and the holding portion operating portion of the mechanism portion and the operation body for operating the mechanism portion. And = the guide moves on the axis of the needle and close to the tip of the needle, and by operating the operating body: the needle can be inserted into the mouth of the container with a relatively small force. As such, the dry powder inhalation device according to the present invention can accommodate the needle of the container into the container. Further, in the case where the outer casing is formed in a tubular shape, the front portion of the outer casing is formed as the suction opening portion, and the container is formed in the outer casing, and the needle is placed in the cymbal type with the needle tip facing the upper storage chamber. In the outer casing, an inlet port for communicating with the air guiding passage of the needle portion and for introducing the outside air is provided in a wall portion of the outer casing, and the holding portion is in the storage chamber by the holding portion operating portion The pencil-shaped dry powder inhalation device can be formed to advance and retreat in the axial direction of the outer casing, which is easy to use and convenient to carry. It is placed at , and is redundant. If the above-mentioned holding portion is retreated, the above-mentioned Rong Chou Xi Shan x is formed. . The housing body of the inlet and outlet and the holding portion formed by the lid of the above-mentioned inlet and outlet of the housing body of the hinge body 108 are provided with a lid that covers the lid to close the holder, and pulls up the above When the cover is opened, the mechanism is retracted by the above-mentioned mechanism, and the above-mentioned mechanism is used as the above-mentioned mechanism, and the mechanism of the holding portion operation portion can be simplified, which is advantageous in terms of manufacturing cost. x, since it can cover the entrance and exit of the container when the tip of the container is pinned, it becomes easy to use. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a cross-sectional view showing a dry powder suction (nozzle type 1) of the present invention described in an embodiment. In the figure, the arrows indicate the flow (the same applies to Figures 2 and 3 below). Fig. 4 is a cross-sectional view showing the drying apparatus (self-inhalation type 1) of the present invention described in the second embodiment. Fig. 3 is a cross-sectional view showing the device (self-inhalation type 2) described in the third embodiment. ^ If the end is taken in 2, the self-image of the present invention is a perspective view of the dry powder of the present invention as described in Example 4 (self-inhalation type 3). Fig. 6 is a cross-sectional view of the above dry powder inhaling device (self-inhalation type 3). Fig. 6(a) is the above-mentioned dry powder inhaling device (from a partial sectional view; I enter i 3). Is the cross-sectional view of the action of the dry powder inhalation device (self-type 3) on the side of the needle portion of the dry powder inhalation device. K Inhalation 315314 109 1327073 The πth diagram is a perspective view of a dry powder inhalation device (self-inhalation type 4) according to another embodiment of the present invention. Fig. 1 is a perspective view showing a dry powder inhaling device (self-inhalation type 5) according to another embodiment of the present invention. Fig. 1 is a perspective view showing a dry powder inhaling device (self-inhalation type 5) according to another embodiment of the present invention.

1 容器 1 a 口栓 2 冷凍乾燥組成物 3 空氣喷射流路 4 排出流.路 5 針部 6 吸入口 7 吸氣構件 8 筒狀安全罩 9 空氣壓送手段 10 風箱體 11 吸進閥 12 吸進口 13 吐出閥 14 吐出口 15 接續口 16a 吸引流路1 6之前端 口 17a 空氣導入流路1 7之 前端口 18 吸入口 19 吸氣構件 20 收容室 21 外殼 21A 鉸鏈 22 保持部 23 引導部 24 保持部運轉部 26 外殼本體 27 蓋子 28 窗子 29 導入口 30 逆止間 31 吸引口 110 315314 1327073 32 咬嘴 32a 咬嘴之蓋子 33 隔壁部 34 周壁部 35 取出體 36 控制桿 37 機構部 39 連結體 40 鉸-鏈 41 鉸鏈 42 第2導入路 42a 隔壁部33之導入溝 42b 周壁部34之導入溝 43 間隙 44 第2導入路42之一 端 45 第2導入路42之另 一端 46 通氣孔 47 壁 48 操作體 49 操作體 111 3153141 Container 1 a Port 2 Freeze-dried composition 3 Air jet flow path 4 Discharge flow. Road 5 Needle 6 Intake port 7 Suction member 8 Cylindrical safety cover 9 Air pressure transmission means 10 Wind box body 11 Suction valve 12 Suction inlet 13 Discharge valve 14 Discharge port 15 Connection port 16a Suction flow path 16 Front port 17a Air introduction flow path 17 Front port 18 Suction port 19 Suction member 20 Containment chamber 21 Housing 21A Hinge 22 Holding portion 23 Guide portion 24 Hold Part operation unit 26 Case body 27 Cover 28 Window 29 Guide inlet 30 Backstop 31 Suction port 110 315314 1327073 32 Mouthpiece 32a Mouthpiece cover 33 Partition portion 34 Peripheral wall portion 35 Extraction body 36 Control lever 37 Mechanism portion 39 Linking body 40 Hinge-chain 41 Hinge 42 Second introduction path 42a Leading groove 42b of partition wall portion 33 Leading groove 43 of peripheral wall portion 34 Clearance 44 One end of second introduction path 42 45 The other end of second introduction path 42 46 Vent hole 47 Wall 48 Operation Body 49 operating body 111 315314

Claims (1)

13270731327073 公告本 拾、申請專利範圍 第92135122號尊？牵 (99年1月^日) .:種經肺投與用之冷凍乾燥組成物，係將包含非溶解狀 態之添加成分之組成液經冷凍乾燥而調製成，且具有下 述⑴至（iii)之特性： (0具有非粉末之塊狀形態； (11)衰變指數為〇 〇5以上；以及 φ (111)藉由承受具有至少lm/sec之空氣速度及至少17ml/ sec之空氣流量之空氣衝擊，可成為平均粒徑（空氣力學 之粒徨）在1 〇微米以下或有效粒子比率在丨〇%以上之微 粒0 2. 如申請專利範圍第1項之冷凍乾燥組成物，纟中，包含 做為有效成分之高分子藥物。 3. :種經肺投與用乾燥粉末製劑之製造方法，係包含在收 谷下述冷凍乾燥組成物之容器中，使用可將下述空氣衝 擊賦與該容器内之冷凍乾燥組成物之裝置，導入具備該 二氣衝擊能力之空氣，藉此使得上述冷凍乾燥組成物形 成平均粒徑在10微米以下或有效粒子比率在1〇%以上 之微粒；其中該冷凍乾燥組成物藉由將包含非溶解狀態 之添加成分之組成液經冷凍乾燥而調製成，且具有下述 (i) 至（iii)之特性： (0具有非粉末之塊狀形態， (ii) 衰變指數為〇.〇5以上，以及 (iii) 藉由承受具有至少lm/sec之空氣速度及至少 17ml/Sec之空氣流量之空氣衝擊，可成為平均粒徑在 112 315314修正版 ΐ32Ί〇Ίό 第92135122號專利申請案 (99年1月27曰) 微米以下或有效粒 4, 申請專利範圍第3項之二在1〇/°以上之微粒。 造方法，其中，兮二 =肺投與用乾燥粉末製劑之製 高分子藥物。…東乾無组成物包含做為有效成份之 5. 如申請專利範圍第 、、、坐肺投與用乾燥粉末製劑之製 句万决其中’使用在 吸入裝置做為裝置，將a、^a)或（B)中記載之乾燥粉末 7凍乾燥組成物微粒化： (Α)經肺投與用乾燥粉 收容於容器中之…：係將以非粉末狀態 7凍乾刼組成物微粒化並使被驗者 及所仵微粒用之裝置，其具備： =有空氣喷射流路之針部’具有排出流路之針部， 送=針部之空氣噴射流路中輸送空氣用之空氣壓 又以及與上述針部之排出流路連通之吸入口； 且構成為： 使上述針部扎入供密封上述容器之口栓以將空氣喷 射流路及排出流路與上述容器内部連通，並用上述 空氣麼送手段使空氣經由上述空氣喷射流路喷射於 上边容器内，藉由該喷射空氣之衝擊使上述冷康乾 餘组成物微粒化’且得到之微粒經由上述排出流路 從吸入口排出；或者 ⑻經料與用乾燥粉末吸人裝置，制以非粉末狀態 收谷於容器中之冷滚乾燥組成物微粒化並使被驗者 吸入得到之微粒用之裝置，其具備： 具有吸引流路之針部，且右处名播 ^ 八百工虱導入流路之針部以 315314修正版 113 1327073 第92135122號專利申請案 (99年1月27曰） 及與上述吸引流路連通之吸入口； 且構成為： 在上述針部扎入供密封上述容器之口栓之狀態，藉 由使用者之吸氣壓從上述吸入口吸入上述容器内之 空氣’同時使空氣經由上述空氣導入流路流入已成 為負壓之容器内’藉由流入之空氣衝擊將上述冷凍 乾燥組成物微粒化，且得到之微粒經由上述吸引流 路從吸入口排出。 6. —種經肺投與用乾燥粉末吸入系統，係包含： (1) 收谷具有冷凍乾燥組成物之容器，該冷凍乾燥組成 物係將包含非溶解狀態之添加成分之組成液經冷床 乾燥而調製成’且具有下述⑴至（iii)之特性： ⑴具有非粉末之塊狀形態， (ii) 衰變指數為0.05以上，以及 (iii) 藉由承受具有至少lm/sec之空氣速度及至少 17ml/SeC之空氣流量之空氣衝擊，可成為平均粒徑在 10微米以下或有效粒子比率在10%以上之微粒； (2) 具備可將上述空氣衝擊賦與於上述容器内之冷東乾 燥組成物之手段以及排出經微粒化之粉末狀冷凍乾 燥組成物之手段之袭置。 7. 如申請專利範圍第6項之經肺投與用乾燥粉末吸入系 統，其中，在吸入時將上述容器與上述裴置組合使用。 8. 如申請專利範圍第6項之經肺投與用乾燦粉末吸入系 統’其中’該冷康乾燥組成物係包含做為有效成份之高 315314修正版 114 1327073 分子藥物。 第92135122號專利申請案 (99年1月27曰） 9· rm圍第6項之經肺投與用乾燥粉末吸入系 統，、中’包含下述（A)或（B)做為裝置： ⑷㈣末吸μ置，其係將《非粉末狀 --於容&quot;之冷凍乾燥組成物經微粒化並使使 用者吸入所得微粒用之裝置，其具備： '、有工虱喷射流路之針部，具有排出流路之針部， 在上述針部^氣喷射料巾輸^氣用之空氣塵 送手段，以及與上述針部之排出流路連通之吸入口； 且構成為： 使上述針部扎入供密封上述容器之口栓以將空氣喷 射^路及W祕與上述容H㈣連通，並用上述 空氣壓送手段使空氣經由上述空氣喷射流路噴射於 上述容器内，藉由該喷射空氣之衝擊使上述冷凍乾 燥組成物經微粒化，且得到之微粒經由上述排出流 路從吸入口排出；或者 (Β)經肺投與用乾燥粉末吸入裝置，其係將以非粉末狀 態收容於容器中之冷凍乾燥組成物經微粒化並使被 驗者吸入得到之微粒用之裝置，其具備： 具有吸引流路之針部，具有空氣導入流路之針部以 及與上述吸引流路連通之吸入口； 且構成為： 在上述針部扎入供密封上述容器之口栓之狀態，藉 由被驗者之吸氣塵從上述吸入口吸入上述容器内之 115 315314修正版 1327073 第92135122號專利申請案 (99年1月27日） 空氣’同時使空氣經由上述空氣導人流路流入已成 為負壓之容器内，藉由流入之空氣衝擊將上述冷凍 乾燥組成物經微粒化，且得到之微粒經由上述吸引 流路從吸入口排出。 !〇.一種冷柬乾燥k成物在製造吸入式經肺投與用之乾燥 、末製劑之使用，其中，該冷凍乾燥組成物具有下述特 • 性： (I) 將包3非/谷解狀態之添加成分之組成液經冷凍乾燥 而§周製成， (II) 具有非粉末之塊狀形態， (ill)衰變指數為0.05以上，以及 (1V)藉由承受具有至少lm/sec之空氣速度及至少. 17ml/sec之空氣流量之空氣衝擊，可成為平均粒徑在 10微米以下或有效粒子比率在10%以上之微粒；並且 % 於使用時，將該冷凍乾燥組成物經微粒化使成為具有上 述平均粒徑或上述有效粒子比率。 1 1.如申晴專利範圍第1〇項之冷凍乾燥組成物在製造經肺 投與用乾燥粉末製劑之使用，其中，該冷凍乾燥組成物 係包含做為有效成份之高分子藥物。 12 Jfn 由-* 主 '甲請專利範圍第1 〇項之冷凍乾燥組成物在製造經肺 才又與用乾燥粉末製劑之使用’其中’該冷凍乾燥組成物 被收谷於容器内，以及該經微粒化之粉末係用具備可將 上述空氣衝擊賦與該容器内之冷凍乾燥組成物之手段 以及可從容器中排出經微粒化之粉末狀冷凍乾燥組成 116 315314修正版 ιυ/ό 第92135122號專利申請案 (99年1月27曰） 物之手段之裝置調製而成。 種。3非办解狀態之添加成分之組成液之使用，其用 於製造供調製經肺投與用乾燥粉末製劑用之冷柬乾燥 組成物，該冷凍乾燥組成物具有下述特性： (0具有非粉末之塊狀形態， (ii)衰變指數為0.05以上，以及 (in)藉由承受具有至少im/sec之空氣速度及至少 Hml/sec之空氣流量之空氣之衝擊，可成為平均粒徑在 10微米以下或有效粒子比率在10%以上之微粒； 並且於使用時經微粒化為上述平均粒徑或上述有效粒 子比率。 H，如申請專利範圍第.項之包含非溶解狀態之添加成分 之紐成液之使用，其中’該冷凍乾燥組成物係包含做為 有效成份之高分子藥物。 15.如申請專利範圍帛13項之包含非溶解狀態之添加成分 之組成液之使用，其中，該冷凍乾燥組成物係收容於容 Is内，以及該經微粒化之粉末係用具備可將上述空氣衝 擊賦與該容器内之冷康乾燥組成物之手段以及可從容 器中排出經微粒化之粉末狀冷凍乾燥組成物之手段之 裝置調製而成。 315314修正版 117Announcement, picking up the scope of patent application No. 92135122? The lyophilized composition for the administration of the lungs is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state, and has the following (1) to (iii). Characteristics: (0 has a non-powder block form; (11) a decay index of 〇〇5 or more; and φ (111) by withstanding an air velocity of at least lm/sec and an air flow of at least 17 ml/sec Air impact, which can be a particle having an average particle diameter (aerodynamic enthalpy) of less than 1 〇 micron or an effective particle ratio of 丨〇% or more. 2. The freeze-dried composition of claim 1 of the patent scope, A polymer drug as an active ingredient is contained. 3. A method for producing a dry powder preparation for pulmonary administration, which is contained in a container of the following freeze-dried composition, which can be used to impart the following air impact. a device for freeze-drying the composition in the container, introducing air having the two-gas impact capability, whereby the freeze-dried composition forms particles having an average particle diameter of 10 μm or less or an effective particle ratio of 1% or more; The The freeze-dried composition is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state, and has the following characteristics (i) to (iii): (0 has a non-powdered bulk form, (ii) The decay index is 〇.5 or more, and (iii) by subjecting to an air impact having an air velocity of at least lm/sec and an air flow of at least 17 ml/sec, the average particle size can be corrected at 112 315314 ΐ32Ί〇Ίό Patent application No. 92,135,122 (January 27, 1999) Micron or below or effective granule 4, the third bisth of the patent application is in the range of 1 〇 / ° or more. The method, wherein, 兮 2 = lung investment A high-molecular-weight drug for dry powder preparations....Donggan no-form composition contains as an active ingredient. 5. If the scope of the patent application is the first, and the lung is administered with a dry powder preparation, the phrase is used in the inhalation device. As a device, the dry-dried composition of the dry powder 7 described in a, ^a) or (B) is micronized: (Α) is placed in a container by a dry powder for use in a lung; 7 lyophilized hydrazine composition is micronized and The device for the subject and the particles to be used has: a needle portion having an air jet flow path having a needle portion for discharging the flow path, and an air pressure for conveying air in the air jet flow path for sending the needle portion and a suction port that communicates with the discharge flow path of the needle portion; and configured to: insert the needle portion into a port plug for sealing the container to communicate the air injection flow path and the discharge flow path with the inside of the container, and use the air Sending means that air is ejected into the upper container through the air jet flow path, and the cold-drying composition is atomized by the impact of the jet air and the obtained fine particles are discharged from the suction port through the discharge flow path; or (8) A device for pulverizing and drying a cold-rolled dry composition in a container in a non-powder state by using a dry powder inhaling device, and allowing the subject to inhale the obtained microparticles, comprising: a needle having a suction flow path Department, and the right place name broadcast ^ 800 workers into the flow path of the needle part to 315314 revised version 113 1327073 Patent No. 92135122 (January 27, 1999) and with the above suction a suction port through which the flow path communicates; and a state in which the needle is inserted into the port plug for sealing the container, and the air in the container is sucked from the suction port by the suction pressure of the user while the air is passed through The air introduction flow path flows into the container which has become a negative pressure. The freeze-dried composition is atomized by the inflowing air impact, and the obtained fine particles are discharged from the suction port through the suction flow path. 6. A dry powder inhalation system for transpulmonary administration, comprising: (1) a container having a freeze-dried composition, the freeze-dried composition is a composition comprising a non-dissolved additive component through a cooling bed Dry to be prepared as 'and having the following characteristics (1) to (iii): (1) having a non-powdered bulk morphology, (ii) having a decay index of 0.05 or more, and (iii) by withstanding an air velocity of at least lm/sec And an air impact of an air flow of at least 17 ml/SeC may be a particle having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; (2) having cold air capable of imparting the above air impact to the container Means for drying the composition and means for discharging the micronized powdery freeze-dried composition. 7. The dry powder inhalation system for transpulmonary administration according to claim 6 of the patent application, wherein the container is used in combination with the above-mentioned device during inhalation. 8. The dry-powder inhalation system for transpulmonary administration according to claim 6 of the patent application 'where' is the high-temperature 315314 revision 114 1327073 molecular drug as an active ingredient. Patent Application No. 92135122 (January 27, 1999) 9· rm circumference of the lungs for dry administration of a dry powder inhalation system, containing 'the following (A) or (B) as a device: (4) (4) A device for pulverizing a freeze-dried composition of "non-powder--Yu Rong" and allowing the user to inhale the obtained particles, which has: ', a needle having a jet flow path a needle portion having a discharge flow path, an air dust supply means for discharging the gas to the needle portion, and a suction port communicating with the discharge flow path of the needle portion; and configured to: Inserting a port plug for sealing the container to connect the air jet and the door to the above-mentioned capacity H (4), and using the air pressure feeding means to spray air into the container through the air jet flow path, by the jet air The lyophilized composition is micronized, and the obtained fine particles are discharged from the suction port through the discharge passage; or the dry powder inhalation device for pulmonary administration is contained in the container in a non-powder state. Freeze-dried composition The apparatus for microparticles and inhaling the microparticles obtained by the subject, comprising: a needle portion having a suction flow path; a needle portion having an air introduction flow path; and a suction port communicating with the suction flow path; and configured to: In the state in which the needle portion is inserted into the mouth plug for sealing the container, the inhalation dust of the subject is sucked into the container from the suction port. 115 315314 Rev. 13207073 Patent Application No. 92135122 (January 99) 27th) The air 'at the same time, the air is introduced into the container which has become a negative pressure through the air guiding flow path, and the freeze-dried composition is atomized by the inflowing air impact, and the obtained fine particles are sucked from the suction flow path. The mouth is discharged. 〇. A cold-dried dry k-form is used in the manufacture of a dry, terminal preparation for inhaled transpulmonary administration, wherein the freeze-dried composition has the following characteristics: (I) The composition of the added component of the solution state is freeze-dried and made § week, (II) has a non-powder block form, (ill) has a decay index of 0.05 or more, and (1V) is subjected to an air velocity of at least lm/sec. And an air impact of at least a flow rate of 17 ml/sec, which may be a particle having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; and % of the freeze-dried composition is micronized at the time of use. It has the above average particle diameter or the above effective particle ratio. 1 1. The use of the freeze-dried composition of the first aspect of the Shenqing patent scope in the manufacture of a dry powder preparation for transpulmonary administration, wherein the freeze-dried composition comprises a polymer drug as an active ingredient. 12 Jfn by -* main 'A, please freeze-dry composition of the first aspect of the patent, in the manufacture of transpulmonary and in the use of a dry powder preparation, wherein the freeze-dried composition is collected in a container, and The micronized powder is composed of a means for imparting the above-mentioned air impingement to the freeze-dried composition in the container, and a micronized powdery freeze-dried composition can be discharged from the container. 116 315314 Revised version ιυ/ό No. 92135122 Patent application (January 27, 1999) The device of the means of modulation is modulated. Kind. (3) Use of a component liquid of an additive component in a non-dissociated state, which is used for producing a cold-dried composition for preparing a dry powder preparation for pulmonary administration, the freeze-dried composition having the following characteristics: a bulk morphology of the powder, (ii) a decay index of 0.05 or more, and (in) an average particle size of 10 by subjecting to an impact of air having an air velocity of at least im/sec and an air flow of at least Hml/sec. Microparticles having a ratio of micron or less or an effective particle ratio of 10% or more; and micronized to the above average particle diameter or the above-mentioned effective particle ratio at the time of use. H, as the additive component containing the non-dissolved state in the scope of the patent application The use of the liquid, wherein the freeze-dried composition comprises a polymer drug as an active ingredient. 15. The use of a component liquid comprising an additive component in an insoluble state as claimed in claim 13 wherein the freezing The dry composition is contained in the volume Is, and the micronized powder is provided with means for imparting the above-mentioned air impact to the cold-drying composition in the container and It can be prepared by a means for discharging the micronized powdery freeze-dried composition from the container. 315314 Rev. 117