TWI324518B - Pulmonary delivery of aminoglycosides - Google Patents
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Description
1324518 A7 B7 五、發明説明(1 ) 本發明係關於投用胺基糖苷。特定言之,本發明係關 於在肺部投用胺基糖苷之組成物及方法。依據較佳的具體 實施例,本發明提供局部治療呼吸感染之乾燥胺基糖苷粉 末組成物及投用彼之方法。 發明背景 胺基糖苷是一種有效的殺菌劑。其主要的機制是作用 在細菌的核糖體上抑制蛋白質之合成。彼可有效的對抗寬 廣範圍之革蘭氏陽性及革蘭氏陰性菌與分枝桿菌。在一些 嚴重的革蘭氏陰性菌感染之下,胺基糖苷或胺基糖苷與其 它抗菌劑結合可作爲治療假單胞菌及其它感染之藥物。 下呼吸道感染綠膿假單胞菌(Psa)是囊胞性纖維症(CF) 以及非CF支氣管擴張的病人之中發病及死亡的主要原因。 一旦被感染後,即使是積極性的抗生素處理也僅能暫時降 低呼吸道中Psa生物體之數目。結果,許多CF病人會有持 續性的Psa感染,須要頻繁的住院進行靜脈內的化學治療 〇 支氣管擴張之病症特徵是感染後其呼吸道防衛系統無 法維持下呼吸道及肺臟薄壁細胞滅菌之環境,因而感染性 分泌造成呼吸道壁進行性的破壞及擴張。由於大量的感染 性分泌須要在開始感染時即進行積極性的抗生素治療,因 此有效治療的主要障礙是細菌對一般及常用的抗生素已有 明顯抗性》支氣管擴張最有效的治療方法仍是抗生素治療 ’通常是口服或靜脈注射全身投用。 本纸伕尺度適用中國國家標準(CNS ) A4規格(210X25·7公犮) (請先聞讀背面之注意事項再填寫本頁) -裝-
經濟部智慧財產局員工消費合作社印K -5- 1324518 經濟部智慧財產局員工消費合作社印% A7 B7 五.、發明説明(2) 胺基糖苷是治療Psa感染最適用的抗生素群。然而, 用抗生素治療各種呼吸感染(尤其是支氣管擴張)仍是醫學上 主要的挑戰。 胺基糖苷的主要缺點是會引發相當嚴重的副作用。一 般而言,胺基糖苷的口服吸收性不佳,爲此緣故必須以靜 脈內或肌肉內的投用。使用胺基糖苷穿過多痰區對抗Psa 的活性不佳,因此必須使用大靜脈內全身性劑量以便在肺 部之感染位點最適化的穿透多痰虛。該高劑量可產生腎毒 性及耳毒性效應,經常造成永久性的腎臟官能不足以及聽 神經損害,造成耳聾、頭暈目眩、及不平衡感》 同時,抗生素投服不足及不完全是造成治療無效的問 題之一部份。呼吸道感染時投服不足可能產生的後果包括 :未充分的根除病原菌、發展抗生物抗性以及延長根除時 間、與由於增加肺臟損傷可能產生的持續性臨床症狀、支 氣管擴張、結疤、及早發性死亡。 過度使用抗生素治療呼吸感染是一個重大的問題且日 益受到醫學界及藥物界的重視。疾病防治中心(CDC)視抗生 物抗性之問題爲目前公眾衛生上重要的挑戰。CDC視過度 使用抗生素是抗生物抗性成長方面的問題之主要元兇。 基於上述抗生素療法之問題,硏究的焦點是著重在發 現可提供可能解決方案之新分子上。此外,已開始硏究使 用新藥物遞送技藝,例如吸氣氣溶膠,投用胺基糖苷治療 呼吸道感染可能產生的療效。特定言之,係以超音波或空 氣壓縮驅動之小體積噴霧器(SVN)投用氣溶膠化抗生素。 本紙張尺度適用中.國國家標準(CNS ) A4坑格(210X 297公釐) I I H - - I .....J!s n H 1^1 I --^- n u m n 丁 In _ I___ U3-56I n I n (請先閱讀背面之注意事項再填寫本頁) -6- 1324518 A7 ____B7_ 五、發明説明(3) 二十年來,已使用吸入性抗生素有效改善慢性肺部感 染的症狀,例如囊胞性纖維症以及非CF支氣管擴張。目前 美國食品及藥物管理局(FDA)僅核准一種氣溶膠化抗傳染劑 :TOBI®(Chiron Corporation,Seattle,WA)。TOBI 是經霧 化吸入的妥布黴素溶液。妥布黴素(0-3-胺基去氧-a -D-哌喃葡萄糖基·(1-4)-0-[2,6-二胺基-2,3,6-三去氧-£^-0-核糖 哌喃己糖基-(1 _6)]-2去氧基-L-鏈黴胺)是水溶性的胺基糖苷 抗生素,其分子量是46 7.52克/莫耳。妥布黴素可有效的對 抗革蘭氐陰性病原體,尤其是CF病患的關鍵性感染源綠膿 假單胞菌。 調製的Τ0ΒΙ產物是經滅菌 '澄淸的、微黃色的、非熱 原性、及調整過酸鹼度和鹽濃度之水溶液。彼包含300毫 克妥布黴素自由鹽基之5毫升氯化鈉(2.25毫克/毫升),酸 鹼度6.0以及可在2-8 °C下保存二年,或在室溫下保存28 天。該溶液在強光下會變黑。在酸鹼度6.0下,大約2.2/5 之妥布黴素胺基會轉換成硫酸鹽鹽類。一個劑量是單一的 3〇〇毫克安瓿(每日二次,相隔12小時)。 病人接受2 8天之"投用"治療接著2 8天之"停藥"期,以 降低可能產生的抗性細菌品系。吸入3 0 0毫克,僅大約 10%或30毫克可運送至肺。全身性的IV注射投用妥布黴素 會有嚴重的不.良副作用,包括腎臟及耳毒性。由於藥物通 過肺臟內皮以及進入多痰區的穿透性差,所以一般係投用 高IV劑量。T0BI的臨床硏究展示吸入的妥布黴素可導致 耳鳴及聲音改變。 -—1--5---- 裝 — I (請先閱讀背面之注意事項再填寫本頁)
、1T 經濟部智慧財產局8工消費合作社印製 本紙張尺度適用中.國國家標準(〇^)六4規格(2〗0\ 297公楚) 1324518 A7 _B7___ 五.、發明説明(4) (請先閱讀背面之注意事項再填寫本頁) 霧化有許多缺點,包括延伸投藥時間、高成本、效率 以及重現性差、細菌污染風險、以及須要笨重的壓縮機或 氣瓶。此類缺點會對病患之順服性產生影響。 經氣溶膠吸氣的肺部遞送法由於不需要注射器及針頭 所以比靜脈內的、肌肉內的、以及皮下的注射更有吸引力 。肺部的遞送因爲不須要鼻腔的及皮膚穿透增強劑(鼻腔內 及經皮系統的代表性成份,經常引起皮膚過敏/皮膚炎)亦對 皮膚及身體黏膜只有少量之刺激(此爲經皮地、離子透入地 、及鼻內地運送藥物共同的副作用),因此在經濟上有吸引 力、病患能自行投藥、以及比起其它另一投藥模式彼經常 較爲病人所樂用。已試圖投用胺基糖苷乾燥粉末氣溶膠至 肺臓,但低效率的遞送裝置及/或不良分散的乳糖調配物限 制了此類硏究。 經濟部智慧財產局員工消費合作社印" 乾燥粉末吸入器爲習知的技藝,如揭示於美國專利第 5,458,135 ; 5,740,794 ; 5,775,320 ;以及 5,785,049 號,以 及共同申請中之美國申請案第09/0 04,558號,申請曰期 1 998年1月8曰;09/3 1 2,434,申請曰期1999年6月4日 ;60/ 1 3 6,5 1 8,申請日期1999年 5月 28日;以及 60/141,793,申請日期1 999年6月30日;所有文獻全部在 此并入參考文獻》 此外’美國專利第5,S75,776號揭示乾燥粉末吸入器並 揭示大批適用此裝置投藥之抗生素,例如:硫酸慶大霉素 、硫酸丁胺卡那霉素、硫酸及妥布黴素。該專利並無揭示 調配物之實施例。WO 00/3 546 ]進一步的揭示治療支氣管 本纸張尺度適用中國國家標率(CNS ) Αί規格(2iOX 297公釐) -8- 1324518 A7 ._B7_ .五、發明説明(5) 擴張之方法,其係包含投用胺基糖苷氣溶膠。 (請先Μ讀背面之注意事項再填寫本頁} 最近的臨床硏究已製造出中空多孔的妥布黴素乾燥粉 末調配物,並使用Turbospin(PH&T, Italy)乾燥粉末吸入器 運送。臨床硏究發現負載25毫克粉末之膠囊中,僅4.6毫 克(18.4%)的活性原料藥被運送至肺。此藥物荷載及效率下 ,大約須要6個膠囊(約27.6毫克)才相當於霧化的TOBI產 物運送至肺臟的劑量。在該治療中至少需要投用6個膠囊 會產生病患之順服性問題。 經濟部智慧財產局員工消費合作社印製 除非在廣泛的抗生素以及藥物遞送技藝上有重大的新 發現之外,否則仍須要改良抗生素例如胺基糖苷投用之方 法。特定言之,依據現行的療法投用胺基糖苷之極大安全 全身性劑量所提供之劑量遠低於要使在肺臟組織及分泌中 之藥物量超過最小抑制量(即能排除或顯著降低造成氣道及 肺臟組織感染之細菌濃度)所需之充分劑量。因此,該治療 並非適當的治療方法,不但易於產生抗性生物體,且易發 展不良副作用。因此須要另一種易於對病患投用胺基糖苷 之方法,其能在病人呼吸道分泌及相鄰的肺臓組織提供較 高的藥物濃度,卻無顯著的全身性副作用的風險。在理想 的情況下,該投藥方法必須使用有病患順服性之裝置。本 發明則是符合了此類以及其它的須求。 術語定義 本文術語之"胺基糖苷"意指合成的及分離自鏈黴菌及 小單孢菌之技藝上已知的天然抗生素,包括(但並非限制於) 本紙尜尺度適用中國國家標準(CNS ) Α4規格(210X297公左) -9- 1324518
經濟部智慈財產局員工消費合作社印K A7 B7 五、發明説明(7) 本文術語之"質量中位數氣動粒徑"或"MMAD"是計量分 散粒子之氣動大小。氣動粒徑係用以描述氣溶膠化粉末之 沈降行爲,一般而言是與空氣粒子有相同的沈降速度之單 位密度球體的直徑。氣動粒徑包含粒子形狀 '密度以及粒 子之物理大小。本文術語之MMAD意指經Anderson串聯反 應衝擊測定之氣溶膠化粉末的氣動粒子粒度分佈之中點或 中位數* 本文術語之"醫藥學上可接受的賦形劑或載體"意指可 將胺基糖苷帶入肺部而對患者(尤其是患者的肺)無顯著毒性 的相關賦形劑。 本文術語之"藥理上有效量"或"生理上有效量"是胺基糖 苷之用量,其係存在於在此描述之乾燥粉末組成物’當對 肺投用該組成物時其係在分泌及氣道組織、以及肺或此外 在治療的患者血流中提供可生成預期生理的反應所必須的 藥物量。精確的量將取決於許多的因子,例如:特定的胺 基糖苷、組成物比活性、使用之遞送裝置、粉末之物理特 性、預期的用途、以及生物體之抗性與病患,例如:疾病 狀態之嚴重性、病患之合作等,以及熟悉此技藝的專業人 士可基於本文提供之資料立即加以測定。 本文術語之"呼吸感染"包括(但並非限制於):上呼吸道 感染,例如:鼻寶炎、咽頭炎、以及流行性感冒、及下呼 吸道感染,例如:結核病、支氣管擴張(囊胞性纖維症以及 非囊胞性纖維症適應症)、支氣管炎(急性支氣管炎以及急性 惡化的慢性支氣管炎)、以及肺炎(包括來自病毒及細菌感染 本纸張尺度適用中國國家標準(CNS ) A4规格(210X29·?公犮) (請先閲讀背面之注意事項再填寫本頁)
-11 - 1324518 A7 B7 五、發明説明(8) 症,包括醫院的及社群感染的各種型態之倂發症)。 (請先閲讀背面之注意事項再填寫本頁) 本文術語之"胺基糖苷治療相關的副作用11意指病患經 歷之不令人滿意的效應,包括(但非限於):耳毒性和腎毒性 及進一步的預期包括對胺基糖苷治療所發展之抗性。 本文術語之"有效治療量"係指當在此描述之乾燥粉末 組成物運送至患者肺部以及肺部氣道時可提供所要求的生 物效應的胺基糖苷用量》 圖形簡述 \圖1描述需要之膠囊數目與總體密度之函數圖。 圖2描述妥布黴素調配物之發出劑量與膠囊充塡質量 之函數圖。 圖3描述依據本發明之妥布黴素調配物在Anderson串 聯反應衝擊器中之粒子粒度分佈(繞流)圖。 圖4描述妥布黴素自由鹽基與硫酸之滴定曲線》右軸 爲90%W/w調配物理論上的粉末藥效。
經濟部智慧財產局Μ工消費合作社印K 本發明槪要 本發明一般的特色是提供肺部投用的胺基糖苷乾燥粉 末組成物及方法。本發明方法一般而言對肺提供較高濃度 的胺基糖苷以治療呼吸感染而無不利的全身效應。 因此,本發明特色是提供肺部投用的胺基糖苷組成物 及方法。 本發明另一特色是對肺提供治療呼吸感染之肢基糖苷 本紙張尺度適用中g國家標车(CMS ) A4規格(;M〇X 297公釐) -12- 1324518 A7 B7 五、發明説明(9) 組成物及方法。 (請先聞讀背面之注意事項再填寫本頁) 本發明另一特色是提供對肺部遞送胺基糖苷的組成物 及方法以治療呼吸感染並降低副作用。 本發明另一特色係關於投用胺基糖苷之方法,彼可降 低胺基糖苷可能產生的抗性。 本發明另一特色係關於投用妥布黴素之乾燥粉末氣溶 膠,其中經由投用少於5個膠囊、較佳者少於4個膠囊, 其中該膠囊較佳者爲2號膠囊,妥布黴素調配物可有效的 提供治療上有效的治療。 本發明另一特色係經由增加粉末密度、藥效、及調配 物效率以降低單位劑量須要的膠囊之數目。 本發明此類以及其它特色因下列詳細描述及實施例而 更明顯。 發明之詳細描述 經濟部智慈財產局員工消費合作钍印製 依據本發明,提供對肺部投用胺基糖苷以治療呼吸感 染之組成物及方法。肺部的投藥路徑有許多優點,包括在 呼吸分泌產生商抗生素濃度’而只有有限的全身毒性。本 發明粉末展現優異的氣溶膠特性而不須要混和內含藥物之 粉末與較大的載體顆粒’其可使本發明調配物符合降低治 療膠囊之數目而有高劑量胺基糖苷之需求。 由於在治療上有效的治療須要相對大劑量的胺基糖昔 ’本發明乾媒粉末組成物較佳者係用肺部的運送裝置以發 出較高劑量遞送。依據本發明’該乾燥粉末組成物包含至 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -13- 1324518 A7 B7 五 '發明説明( (讀先聞讀背面之注意事項再填寫本頁) 少50%之發出劑量,更佳者至少70%,以及最佳之發出劑 量大於90%。該高發出劑量可降低藥物成本,達成胺基糖 苷更高的投藥效率,以及亦可改良病患的順服性,使有效 的治療須要較少之裝置內驅動噴灑量。依據本發明具體實 施例之組成物及方法,顯著的改進肺部藥物遞送的技藝, 使大藥物劑量的能投用至肺部以提供治療上有效的治療。 該治療在24小時之投藥期間提供有效治療量之胺基糖苷, 爲了提供治療上有效的治療,其投用量少於5個單位劑量 ,較佳者少於4個單位劑量。 依據本發明另一具體實施例,投藥方法可直接的降低 相關於胺基糖苷治療的副作用》此類方法包括投藥劑量高 於現行的療法(例如大於MIC 8倍)。依據此具體實施例, 可降低以上討論的與投服相關之問題(例如胺基糖苷抗性之 發展)。經肺部投用本發明之乾燥粉末組成物可使胺基糖苷 在肺臓之高局部濃度而無相關於胺基糖苷治療之不良副作 用。 依據直接的降低胺基糖苷抗性發展之另一具體實施例 經濟部智慧財產局3工消費合作社印 ’可輪流吸入投用二種(或許更多)不同作用機制之不同類的 抗生素。 依據較佳的具體實施例,其係經乾燥粉末吸入器吸氣 投用胺基糖苷乾燥粉末組成物以最適化劑量之便利性及投 藥速度。 一般而言本發明胺基糖苷乾燥粉末組成物包含胺基糖 音與一種或多種適用於呼吸及肺部投藥的醫藥學賦形劑^ 本纸張尺度適用中國國家標準(CNS ) A4双_格(2丨οχ2?7公釐) -14 - 1324518 A7 __B7 ___ 五、發明説明(ιί (请先閱讀背面之注意事項再填寫本頁) 當要求降低運送至病患之粉末中的活性劑濃度時’該賦形 劑可僅作爲膨脹劑β該賦形劑亦可改良粉末分散裝置內粉 末之分散性以使活性劑的遞送更高效率及再現性,並改良 活性劑之操作特性(例如,流動能力及堅硬度)以增進製造及 粉末充塡。特定言之,賦形劑材料經常可改良胺基糖苷的 物理及化學穩定性、使殘餘的含水率減到最少及避免攝入 濕氣、以及增進粒度、凝集之程度、表面性質(即粗糙)、易 於吸入、以及將顆粒導向肺部深處。此外,胺基糖苷可用 本質上純淨的形式調製,其中組成物在需要的大小範圍含 有胺基糖苷顆粒以及實質上不含其它生物活性成份、醫藥 學的賦形劑等。 經DPI投藥比噴霧器快約十倍,從經濟及順服性的觀 點而言’經DPI投藥將可極有利的降低有效治療所須要提 供的膠囊總數至6至4或更低,較佳者2或3。 下列之討論經£>PI以降低有效的胺基糖苷治療之膠囊 數目’將專注於直接投用妥布黴素的較佳的具體實施例。 經濟部智慧財度局g (工消費合作社印,¾ 須要運送某些藥物質量至肺臟(miung)膠囊之數目 (ncapsule)可得自以下之遞送效率關係式: (1) n = 肺)/(m 其中是膠囊中粉末之質量,ρ是藥物產品(妥布黴素自 由鹽基)之藥物藥效,7? R是氣溶膠遞送至肺的效率。 從此關保式可知經以下方式可降低膠褒總數之須求: (紙張尺度中關家斜(CNS ) AAim ( -15- 1324518 A7 _ B7_ 五、發明説明(4 (1) 增加膠囊之粉末荷載; (2) 增加粉末中之藥物藥效;以及 (請先聞讀背面之注意事項再填寫本頁) (3) 增加氣溶膠遞送效率(發出劑量以及細微粒子劑量) 例如,充塡35毫克、70%藥效、以及40%氣溶膠效率 ’須要2.8個膠囊運送27.6毫克之目標肺臟劑量。充塡40 毫克,80%藥效、及50%效率,只須要1.7個膠囊。依據本 發明較佳的充塡質量爲20-50毫克/膠囊。最佳者爲25-40 毫克/膠囊。 增加膠囊之充塡質量,係可充塡較大的膠囊體積百分 比’或增加粉末之總體密度。依據本發明調配物之總體密 度大於0.08克/公分3。依據本發明較佳的粉末總體密度爲 0.10克/公分3或更大。 經濟部智慧財產局員工消費合作社印製 理論上,與上述臨床硏究的妥布黴素調配物藥效及氣 溶膠效能相當的調配物,只要50毫克之荷載即可將膠囊之 需求降至3。爲了在2號膠囊達成該大的充塡質量,須要增 加粉末密度而對氣溶膠無不利影響之特性。妥布黴素調配 物開始顯示降低氣溶膠效能時,一般熟悉此技藝的專業人 士可依據本文之教示測定其總體密度。例如,總體密度在 膠囊總數須要上的效應描述於圖1。圖1是估計運送3 〇毫 克自由鹽基至肺臓,膠囊須要之數目與總體密度及酸鹼度 之函數。該圖假定膠囊裝入2/3體積之粉末,殘餘的含水率 爲5°/。’殘餘的溶劑(pf0B)含量爲〇.1%,以及4〇%之給定 劑量儲存於肺。 妥布黴素之藥效因許多因素而定,包括調配物之藥物 本纸張尺度適用中國國家標準(CNS ) Λ4規格(:丨〇><297公犮) •16- 1324518 A7 B7 .五、發明説明(θ (請先閲讀背面之注意事項再填寫本頁} 荷載、在自由鹽基上之一級胺基團與酸反應形成鹽之百分 比、反離子(氯化物或硫酸鹽)分子量、以及調配物中吸取之 殘餘水及發泡劑。上述臨床的妥布黴素調配物之自由鹽基 的理論藥效爲6:3 %。質量之平衡係歸因於硫酸鹽,每五個 一級胺中平均大約三個被硫酸化。由於調配物中殘餘的濕 氣(5.3%w/w)及氟碳(約4.6%w/w)之滯留,故妥布黴素臨床 的調配物之實際的藥效數値爲53%。 在TOBI噴霧器產物中,酸鹼度被滴定至6.0。酸鹼度 調整至6_0允許產物在不加入防腐劑(例如酚)之下延長穩定 的時間。由於在溶液中的時間短暫,粉末調配物不須要有 相同的穩定性負擔。因此,滴定自由鹽基至較高的酸鹼度 比起使用現行的TOBI產物可減低終產物之硫酸鹽含量。依 據圖4,藥效可從60%增加至約80%。 用於臨床硏究的妥布黴素調配物包含90%w/w之硫酸 妥布黴素。硫酸妥布黴素中在自由鹽基上平均每5個一級 胺基團約有3個硫酸鹽。此硫酸妥布黴素之分子量可作如 下的估計: 經濟部智慈財產局8工消費合作社印製 分子量(硫酸妥布黴素)Μ67·54(自由鹽基)+ 3.1(96) = 765克/莫耳 可用相同的方式計算氯化鹽,假設每分子之氯化鹽之 數目相等: 分子星(氯化妥布黴素)= 467,54 + 3.1(35.5) = 578克/莫耳 本紙張尺度適用巾國國家標A4規格(2iOX 297公及) -17- 1324518 經濟部智慈財產局員工消費合作社卬" A7 B7_五、發明説明(14 轉換成氯化鹽可能降低之膠囊數目爲; (578/765)x 6膠囊=4.5膠囊(即,省下1.5個膠囊) 使用之酸;硫酸 '氯化氫、或磷酸,其本.質不僅取決 於須要降低之膠囊數目,且亦在改變酸造成之調控上的影 響,以及固態之變異及氣溶膠之效能。增進氣溶膠之特性 亦可降低有效治療須要的膠囊之數目。 組成物中使用之醫藥學的賦形劑及添加劑包括(但非限 於):單一或結合之蛋白質、肽類、胺基酸、脂質、聚合物 、及碳水化合物(例如糖類,包括:單糖、二-、三-、四-' 及寡糖類;衍生的糖例如醣醇、糖酸、酯化的糖及其類似 者;以及多糖或糖聚合物)。典型的蛋白質賦形劑包括: 血淸白蛋白,例如:人血白蛋白(HSA)、重組人類白蛋白 (rHA)、明膠、酪蛋白等。代表性的胺基酸/多肽成份(亦可 具有緩衝容量功能)包括:丙胺酸、甘胺酸、精胺酸、甜菜 鹼、組織胺酸、麩胺酸、天門冬胺酸、半胱胺酸、離胺酸 、白胺酸、脯胺酸、異白胺酸、纈胺酸、甲硫胺酸、苯丙 胺酸、阿斯巴甜等。代表性的聚胺基酸例如:二·白胺酸以 及三白胺酸亦適用於本發明。較佳的胺基酸是白胺酸。 適用於本發明中之碳水化合物賦形劑包括,例如單糖 例如:果糖、麥芽糖' 半乳糖、葡萄糖、D_甘露糖、山梨 糖、及其類似者;雙糖類,例如:乳糖、蔗糖、海藻糖' 纖維一糖、及其類似者;多糖例如:蜜三糖、松三糖、麥 牙糊精、聚葡萄糖、澱粉、及其類似者;以及醣醇例如: 本纸張尺度ϊί用中國國家標準(CNS ) A4规格(2丨公釐) —--- -18- (請先聞讀背面之注意事項再填寫本頁)
*1T 1324518 A7 B7 經濟部智慧財產局8工消費合作社卬装 五、發明説明(3 甘露糖醇、木糖醇、麥芽糖醇、乳糖醇、木糖醇、山梨糖 醇(glucitol)、肌纖維醇等。 乾燥粉末組成物亦可包括緩衝劑或酸鹼度調整劑;典 型緩衝劑是有機酸或鹼製備的鹽類。代表性的緩衝溶液包 括有機酸鹽類。例如檸檬酸鹽、抗壞血酸鹽、葡萄糖酸鹽 、碳酸鹽、酒石酸鹽、琥珀酸鹽、乙酸、或肽酸鹽;三羥 甲基胺基甲烷、鹽酸緩血酸胺、或磷酸鹽緩衝劑 此外。本發明之胺基糖苷乾燥粉末可包括:聚合的賦 形劑/添加劑,例如:聚乙烯基吡咯烷酮、羥基丙基甲基纖 維素 '甲基纖維素、乙基纖維素、Fi colls(聚合的糖)、右旋 聚醣、聚葡萄糖酯(dextrates)(例如環糊精,例如:2-羥基 丙基-鄰環糊精、羥乙基淀粉)、聚乙二醇、果膠、調味劑、 鹽類(例如氯化鈉)、抗菌劑、甜劑 '抗氧化劑、抗靜電劑、 表面活性劑(例如聚山梨酸酯,例如:"TWEEN 20"及 "TWEEN 8 0”、卵磷脂、油酸、氯化苄烷銨、及山梨糖醇酐 酯類)、脂質(例如磷脂、脂肪酸)、類固醇(例如膽固醇)、 及螯合劑(例如乙二氨四醋酸)。其它適用於用於依據本發明 胺基糖苷組成物之醫藥學的賦形劑及/或添加劑列於 "Remington.The Science & Practice of Pharmacy", 19'h ed, Williams & Williams,( 1 995),and in the "Physician's Desk Reference", 5 2' d ed., Medical Economics, Montvale, Nl(l 998) ’該揭示全文在此倂入參考文獻e 依據本發明’可加入改進內在胺基糖苷粉末分散性質 之分散劑》適當的藥劑已揭示於pCT申請案WO 95/3 1 479 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家樣準(〇^^)六4規格(210'乂 297公犮) -19- 1324518
五、發明説明(17) 整胺基糖苷的特定劑量。 製備胺基糖苷之乾燥粉末 (請先閱讀背面之注意事項再填寫本頁) 可在形成上述實質上爲非結晶形玻璃狀或實質上爲結 晶的生物活性粉末之噴霧乾燥條件下製備胺基糖苷乾燥粉 末之調配物。噴霧乾燥胺基糖苷-溶液調配物,一般而言係 依例如"Spray Drying Handbook", 5th ed.,K. Masters, John Wiley & Sons, Inc.,NY,NY(1991)以及 WO 97/4 1 833 所述 方法進行,該文全文在此倂入參考文獻。 經濟部智慧財產局員工消費合作社印". 爲了製備依據本發明具體實施例之噴灑-乾燥的胺基糖 苷溶液,一般而言其係將胺基糖苷溶於生理上可接受的溶 劑例如水。噴灑-乾燥之溶液的酸鹼度範圍一般係介於約3 至1 Q,較佳者爲5至8,以接近中性酸鹼度較佳,因爲此 酸鹼度有助於維持粉末溶解之後在肺部之生理相容性.。水 溶性調配物可視需要含有其他互溶性溶劑,例如醇類、丙 酮等。代表性的醇類爲較低碳數的醇類,例如:甲醇、乙 醇、丙醇、.異丙醇等。一般而言胺基糖苷溶液含有胺基糖 苷,溶解濃度爲〇.〇 5 %(重量/體積)至約20%(重量/體積), 通常爲0.4%至5.0%(重量/體積)。 然後將內含胺基糖苷之溶液用習見的噴灑乾燥器,例 如商購之例如.Niro A/S(丹麥)、Buchi (瑞士)及其類似者噴 灑乾燥’以造成穩定的胺基糖苷乾燥粉末。胺基糖苷溶液 之最理想的噴霧乾燥條件取決於調配物之成份而定,一般 而言由實驗測定。用以噴灑乾燥材料的氣體一般爲空氣, 本紙張尺度適用中國國家搮準(CNS ) A4規格(2)0X所公犮) 1324518 經濟部智怂財產局員工消費合作社印製 A7 B7 五、發明説明(1δ) 雖然惰性氣體例如氮或氬亦爲適當。此外,用以乾燥噴灑 材料之氣體入口和出口溫度不會引起噴灑材料中胺基糖苷 之去活化作用,該溫度一般是以實驗測定,雖然一般而言 入口溫度介於約50°C至約200°C,而出口溫度介於約30°C 至約1 5 0 °C。 此外,可用冷凍乾燥法、真空乾燥、噴灑冷凍乾燥、 超臨界流體加工、或其它形式之蒸發乾燥或混合、硏磨或 噴射硏磨調配物成份形成乾燥粉末以製備胺基糖苷乾燥粉 末。在一些實例中,可令人滿意的提供胺基糖苷乾燥粉末 調配物,其形式爲具有改良操作/加工特性,例如·_降低靜 電、較佳流動能力、低結塊、及其類似者,其係由細微粒 子聚集物製備之組成物,即上述胺基糖苷粉末顆粒的聚集 物或結塊,其中遞送至肺部後聚集物可立即破碎成細微粉 末成份,如描述於例如美國專利第5,6 54,007號,全文在此 倂入參考文獻》此外,製備胺基糖苷粉末時可將粉末成份 結塊、篩選材料取得凝聚物、球狀化處理以提供更具球形 的凝聚物、以及依大小分級取得均勻之篩選產物,如描述 於例如 WO 95/096 1 6,全文在此倂入參考文獻。於生產、 加工、及貯藏期間,胺基糖苷乾燥粉末較佳者係維持在乾 燥(較低的溼度)的條件下。 依據較佳的具體實施例,胺基糖苷粉末係依據乳化/噴 霧乾燥方法製作,如揭示於上述之WO 99/1 64 19及WO 01/85136。依據該較佳具體實施例的乾燥粉末微粒調配物係 包含至少7 5 % w Λν,較佳者至少8 5 % w / w之妥布黴素’ 2 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(2i〇X 297公茇) ----------------------„---IT------ (請先閱讀背面之注意事項再填寫本頁) 22- 1324518 A7 __B7_ 五.、發明説明(22) 硫酸慶大霉素(H&A(Canada)Industrial) 硫酸奈替米星(Scientific Instruments And Technology) (請先聞讀背面之注意事項再填寫本頁) 妥布黴素(Chiron, Berkeley, CA) L-白胺酸(Aldrich) 鹽酸(J. T. Baker) 0.1N氫氧化鈉體積溶液(J. T. Baker) 乙醇,200 度(USP/NF,Spectrum Chemical Mfg. Corp.) 甲醇(HPLC 級,EM Industries) 實施例1 A. 調配物 內含慶大黴素之乾燥粉末組成物,其係以攪拌硫酸慶 大黴素與賦形劑(若使用的話)和液體介質以形成溶液而製備 成。溶液之酸鹼度經過適當調整以提高溶解度及/或穩定溶 液中之成份。定量的調配物如以下之表1。 B. 噴霧乾燥 將慶大黴素溶液用Buchi 190 Mini Spray Dryers噴灑 經濟部智慧財產局員工消費合作社印製 乾燥,其噴嘴及氣旋之設計係用以產生及捕獲非常細微之 顆粒。用於以有機溶劑調配之調配物時,其係使用經修飾 之Buchi 190 Mini Spray Dryer,以氮作氣體來源,裝有氧 感應器及其它安全設備以使發生爆炸之可能性減到最少。 溶液進料速率爲5毫升/分鐘,溶液維持於室溫,入口溫度 範圍爲]20-13Γ(:,出口溫度調至大約80°C,乾燥氣體流 -26- 本纸張尺度適用中國國家標準(CMS ) A4規格(21〇Χ297公犮) 1324518 A7 ____B7___ 五、發明説明(1 速約18SCFM,噴霧空氣爲0.5至1.5SCFM,壓力通常在約 1 00 PSI » (請先閱讀背面之注意事項再填寫本頁) C.鑑定 各粉末之特徵在於含水率、發出劑量(ED)、及質量中 位數氣動粒徑(MMAD),ED是計量粉末包裝/裝置組合之效 率。MMAD是計量氣溶膠化粉末之粒度。 含水率係用卡耳費雪(Karl-Fischer)試劑滴定方法或熱 重分析測定,如下表》 形態學係用掃描電子顯微鏡術(SEM)測定。 經濟部智慧財產局8工消費合作社印製 爲了測定ED,先將噴灑乾燥粉末充塡入發泡包裝。將 真空系統與上述美國專利第5,740,794號所述之吸入器裝置 的吹口連結進行測試。真空系統之設定與人類吸氣之體積 及流速(總體積1.2公升,30公升/分鐘)相似。將待評估之 內含5毫克調配物之發泡包裝裝入裝置中,其係用測試固 定架稱住。此裝置開始抽吸並發射,真空"吸氣"開關打開 。用真空從裝置室吸出氣溶膠霧,並用置於吹口和真空來 源之間的濾器收集粉末。測定濾器上所收集的粉末重量。 此重量乘以〗00除以發泡裝置充塡重量’計算發出劑量。 數目越高其結果越佳。 用Andersen串聯反應衝擊器測定MMAD。在串聯的反 應衝擊器中使粉末霧化(使用吸入器裝置霧化,如美國專利 第5,74 0,794號),隨空氣液流進入衝擊器中,並依顆粒之 氣動直徑而分成數個等級(最小顆粒最快通過衝擊器)。各階 -27- 本纸张尺度適用中國國家標準(CNS ) A4^格(2】0χ 297公釐) 1324518
經濟部智慧財產局員工消費合作社印" 五、發明説明( 段收集之粉末量用比重計測定,然後計算質量中位數氣動 力直徑。 表1顯示慶大黴素調配物定量的組成物,粒子形態學 之描述、含水率、MMAD、以及慶大黴素粉末發出劑量之 結果。 表1慶大黴素乾燥粉末組成物 批號 定量的組成物 粒子形態學 濕氣含 量 MMAD( 微米) 發出劑量 1326-31 硫酸慶大霉素2076毫克 DI水200毫升 鹽酸QS至酸鹼度=5 光滑的球體上有日寺 有一或二個大凹痕 4.1%1 3.0 37%(RSD3 =6) 1326-32 硫酸慶大霉素2053毫克 DI水200毫升 氫氧化鈉QS至酸鹼度=10 略有凹痕的球體 1.1%1 2.4 40%(RSD= 14) 1300- MG-11 硫酸慶大霉素2012毫克 乙醇40毫升 DI水160毫升 光滑的球體上有時 有一或二個大的凹 痕 4.8%2 3.0 45%(RSD= 10) 1300- MG-12 硫酸慶大霉素2006毫克 L-白胺酸205毫克 DI水220毫升 有多個凹痕的球體 6.2%2 2.6 61%(RSD= 7) 1300- MG-18 硫酸慶大霉素1500毫克 L-白胺酸510毫克 DI水200毫升 葡萄千狀 4.3%2 2.4 80%(RSD= 6) 用卡耳費雪(Karl-Fischer)試劑滴定法測定 用熱重分析測定。 相對標準差 本紙張尺度適用中國國家標準(CNS ) A4規格(ΙΠΟΧ297公釐) (請先閱讀背面之注意事項再填寫本頁)
-28 1324518 A7 B7 五、發明説明(9 實施例2 (請先閱讀背面之注意事項再填寫本頁) 內含奈替米星之調配物係依據實施例1之步驟製備。 將其特徵如實施例1之奈替米星調配物噴灑乾燥。結果如 以下之表2。 表2奈替米星乾燥粉末組成物 批號 定量的組成物 粒子形態學 濕氣含 量 MMAD*( 微米) 發出劑量 1300-MG-9 硫酸奈替米星1626毫克 DI水163毫升 不規則的以及鋸齒 狀的 4.2% 3.2 47%(RSD =8) 1300-MG-14 硫酸奈替米星1512毫克 乙醇30毫升 DI水120毫升 光滑的球體有時有 —或數個关的凹痕 5.1% 2.9 39%(RSD =7) 1300-MG-15 硫酸奈替米星1202毫克 L-白胺酸393毫克 DI水160毫升 葡萄干狀 4.1% 2.3 78%(RSD =10) 1300-MG-19 硫酸奈替米星1426毫克 L-白胺酸77毫克 DI水150毫升 有凹痕的球體 5.3% 2.6 75%(RSD =6) 用熱重分析測定。 經濟部智慧財產局®工消費合作社印製 實施例3 重覆實施例1製作胺基糖苷妥布黴素之步驟。結果示 於以下之表3。 -29- 本紙乐尺度適用中國國家標準(CNS ) A4規格(2i〇X 297公釐) 1324518 A7 ____B7_ 五 、發明説明(27) 长大小範圍之液滴。然後將硫酸妥布黴素溶於乳劑連續相 ,將產生的分散液用於噴霧乾燥之供料。 然後供料經使用表5之設備及條件噴灑乾燥。 硫酸妥布黴素 9 0.0 4 % w / w DSPC 9 5 6% w/w CaC12 0.40%w/w PFOB, ψ 0.198 v/v PFOB/殘渣總量 6.3 7% w/w 進料濃度 5.92%w/v 表4.硫酸妥布黴素調配物 (請先閱讀背面之注f項再填寫本頁) 5. 噴灑乾燥設備及條件 批樣杜 2715-08 2792-11 2792-12 噴灑乾燥器 Buchi NIRO NIRO 乾燥氣體 CDA Room空氣 Room空氣 規度計條件: 總空氣流動(SCFM) 12 70 70 入口溫度(°C ) 85 140 1 1 2 出口溫度(°C ) 62 76 54 泵速率(毫升/分鐘) 2.1 3 5 35 噴霧器壓力(psi) 11 1 00 100 噴霧器流速(SCFM) 2.8 1 2 ]2 經濟部智慈財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CMS ) A4規格UlOX297公& ) 1324518 A7 ____B7 __ 五、發明説明(9 (請先閱讀背面之注意事項再填寫本頁) 手工充塡:氣溶膠測試係將粉末用手塡入#2 HPMC膠 囊。膠囊在<5%RH下平衡過夜》將粉末置於相對濕度10至 15%之膠囊充塡台並在操作之前平衡1〇分鐘。所探索之 充塡重量介於20毫克至40毫克,代表充塡體積約1/2至 7/8。使用Turbospin ®(PH&T,義大利)膠囊型的被動遞送 裝置進行氣溶膠測試。裝入的膠囊在充塡當日進行測試。 使用雷射繞射進行粒度分析:粉末之幾何粒度分析係 使用裝有RODOS之T4.1型振動槽的Sympatec雷射繞射分 析器(HEIRS H1 006,Clausthal-Zellerfe!d,德國)測定。將大 約2毫克散裝的粉末傾倒入R0D0S振動槽,接著經由雷射 光束霧化,使用1巴氣壓'53毫巴(bar)真空、70%進料速 率、1.30毫米漏斗間隙,R2鏡頭設定。每隔0.4秒收集數 據,】75微米焦距,在0.1 %視障下觸發。使用FraUnhofer 模式測定粒子粒度分佈。 殘餘濕氣:用卡耳費雪滴定法測定散裝粉末的殘餘濕 氣。 經濟部智慧財產局員工消費合作社印製 發出劑量測試:使用中等抗性之Turbo spin裝置在最理 想的抽樣流速60 L ·分鐘u下進行測量'各充塡質量總共 測定I 〇次。結果描述於圖2,其顯示發出劑量與40毫克充 塡質量之調配物的結果相同。ED無顯著減低或RSD無顯著 增加。粉末負荷增加25%至3 5%(相等於氣溶膠效能)可省下 約2個膠騷,使膠囊之需要從6下降至4。 氣動粒子粒度分佈:使用 Andersen串聯反應衝擊器 (AC1)決定重力測定氣動粒度分佈。在流速50.6 L .分鐘」 -32- 本纸張尺度適用中國國家標準(CNS ) A4規格(210x;!97公釐) 1324518 A7 B7 五、發明説明(2巧 下(即強力的吸氣施力)使用Turbo spin DPI裝置測定粒子粒 度分佈。結果描述於圖3,其顯示氣溶膠粒子粒度分佈與膝 囊充塡質量之函數圖。結果淸楚顯示可顯著增加膠囊充塡 質量而不會顯著的改變異氣動粒子粒度分佈。 (請先聞讀背面之注意事項再填寫本頁) 經濟部智慈財產局員工消費合作社印製 -33- 本紙張尺度適用中國國家標準(CNS ) A4规格(2!〇Χ297公釐)
Claims (1)
1324518 A8 B8 C8 D8 六、申請專利範圍 1 第91 1 36704號專利申請案 中文申請專利範圍替換本‘ S 跨L 民國|9卑每2a^V·^修正 補充 1. 一種局部遞送至病人肺臟的可分散乾燥粉末組成物 ,該組成物爲單位劑量之形式,且包含細微分散固體顆粒 ,其中 (i) 該粒子包含具有磷脂、金屬離子及藥理上有效量 之胺基糖苷之固態基質, (ii) 該組成物之總體密度大於0.10克/公分3, (iii )該組成物提供每單位劑量至少70%之發出劑 , ^-------II (請先聞脅背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 (iv )該組成物包含至少75重量%之胺基糖苷,2· 25%w/w之磷脂,及〇-5%w/w之金屬離子, (v) —單位劑量之該組成物包含10-60毫克之胺基 糖苷, (vi) 該胺基糖苷爲妥布黴素或其藥學上可接受之鹽 類,且 (vii) 藉由乾燥粉末吸入裝置投用少於6個該單位劑 量,可遞送至少2 7.6毫克妥布黴素至病人之肺臟。 2. 如申請專利範圔第1項之組成物,其中胺基糖苷之 存在量至少爲8 0重量%。 3. 如申請專利範圍第1項之組成物,其殘餘含水率少 於1 5重量%。 本纸張尺度逋用中國國家楼準(CNS > Λ4规格(210X297公釐) 1324518 A8 B8 C8 D8 六、申請專利範圍 2 4.如申請專利範圍第〗項之組成物,其殘餘含水率低 於8重量%。 ----------— (請先聞讀背面之注意事項再填寫本頁) 5 .如申請專利範圍第1項之組成物,其中該組成物包 含之顆粒之幾何直徑爲0.5-5微米。 6.如申請專利範圍第1項之組成物,其中該組成物包 含之顆粒之質量中位數氣動粒徑小於5微米。 7 ·如申請專利範圔第1項之組成物,其中該質量中位 數氣動粒徑小於4 · 0微米。 8 ·如申請專利範圍第1項之組成物,其中發出劑量至 少爲8 0 % » 9.如申請專利範圍第1項之組成物,其中包含至少 8 5% w/w之妥布黴素或其藥學上可接受之鹽類。 1 0 ·如申請專利範圍第9項之組成物,其總體密度大 於0.12克/公分3。 線- 1 1.如申請專利範圍第9項之組成物,其中該顆粒具 有中空及多孔的形態。 經濟部智慧對產局員工消费合作社印製 12.如申請專利範圍第7項之組成物,其妥布黴素之 藥效大於6 0 %。 1 3 · ~種如申請專利範圍第1 -1 2項中任一項之組成物 ’其中該顆粒係經噴灑乾燥而製成。 1 4.如申請專利範圍第1 4項之組成物,其中該顆粒係 經使用乳化/噴灑乾燥方法而製成。 1 5 ·如申請專利範圍第1項之組成物,其中該金屬離 子包含鈣。 ③ 本纸張尺度逋用中國國家操準(CNS) A4规格(210x297公釐) 1324518 A8 B8 C8 D8 六、申請專利範圍 3 16·如申請專利範圍第1項之組成物,其中少於4個單 位劑量可提供至少27.6毫克胺基糖苷至病人之肺臟。 17. 如申請專利範圍第1項之組成物,其中,該乾燥粉 末組成物包含氯化鈣* 18. 如申請專利範圍第1項之組成物,其中,該乾燥粉 末組成物之玻璃轉移溫度高於約35°C。 1 9.如申請專利範圍第1項之組成物,其中在單位劑量 膠囊中組成物之塡充質量爲每膠囊2 0-50毫克之範圍內》 2 0 ·如申請專利範圍第1項之組成物,其中在單位劑量 膠囊中組成物之塡充質量爲每膠囊25-40毫克之範圍內。 2 1 ·如申請專利範圍第1項之組成物,其中一單位劑 量之該組成物可塡充大小對應於#3膠囊或更小之膠囊。 22.—種單位劑量膠囊,包含一種可藉由乾燥粉末吸入 裝置之吸入遞送至病患肺臟之可分散乾燥粉末組成物,該 組成物包含細微分散顆粒,其中 (i)該顆粒包含具有磷脂及胺基糖苷之固態基質, (ii )該顆粒之幾何直徑低於5微米, (iii)顆粒之總體密度大於0.10克/公分3, (iv )該組成物提供每單位劑量至少70%之發出劑量 (v )該組成物包含至少75重量%之胺基糖苷,2· 2 5%w/w之鱗脂,及〇-5%w/w之金屬離子, (vi)該胺基糖苷爲妥布黴素或其藥學上可接受之鹽 類, 本纸張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) ,:, ! (請先閲讀背面之注^^項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 1324518 8888 ABCD 六、申請專利範圍 4 (vii )該膠囊大小係對應於#3膠囊或更小,及 (Viii)該膠囊包含丨0_60毫克胺基糖苷。 23. 如申請專利範圍第22項之膠囊,其包含大小#2膠 囊。 24. 如申請專利範圍第22項之膠囊,其中該顆粒更包含 氯化鈣。 25. 如申請專利範圍第21項之膠囊,其中該顆粒之玻璃 轉移溫度高於約35°C。 26. 如申請專利範圍第21項之膠囊,其中該顆粒爲經噴 霧乾燥顆粒。 :----^-- (請先閲讀背面之注$項再填寫本頁> 訂 線 經濟‘部智慧產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐) -4- ⑤
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- 2002-12-19 TW TW091136704A patent/TWI324518B/zh not_active IP Right Cessation
- 2002-12-19 CA CA2468958A patent/CA2468958C/en not_active Expired - Lifetime
- 2002-12-19 EP EP02797527A patent/EP1458360B1/en not_active Expired - Lifetime
- 2002-12-19 US US10/327,510 patent/US7368102B2/en not_active Expired - Lifetime
- 2002-12-19 PT PT02797527T patent/PT1458360E/pt unknown
- 2002-12-19 AT AT02797527T patent/ATE508735T1/de active
- 2002-12-19 JP JP2003554170A patent/JP2005514393A/ja not_active Withdrawn
- 2002-12-19 SI SI200230951T patent/SI1458360T1/sl unknown
- 2002-12-19 ES ES02797527T patent/ES2364636T3/es not_active Expired - Lifetime
- 2002-12-19 MX MXPA04005865A patent/MXPA04005865A/es active IP Right Grant
- 2002-12-19 DK DK02797527.5T patent/DK1458360T3/da active
- 2002-12-19 KR KR1020047009770A patent/KR100958235B1/ko active IP Right Grant
- 2002-12-19 WO PCT/US2002/041733 patent/WO2003053411A1/en active Application Filing
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Also Published As
Publication number | Publication date |
---|---|
EP1458360A1 (en) | 2004-09-22 |
US8715623B2 (en) | 2014-05-06 |
CA2468958A1 (en) | 2003-07-03 |
US20080063606A1 (en) | 2008-03-13 |
EP1458360B1 (en) | 2011-05-11 |
MXPA04005865A (es) | 2004-09-13 |
KR100958235B1 (ko) | 2010-05-17 |
ES2364636T3 (es) | 2011-09-08 |
WO2003053411A1 (en) | 2003-07-03 |
AU2002361897A1 (en) | 2003-07-09 |
US9421166B2 (en) | 2016-08-23 |
CY1112560T1 (el) | 2016-02-10 |
TW200301131A (en) | 2003-07-01 |
PT1458360E (pt) | 2011-07-13 |
JP5351120B2 (ja) | 2013-11-27 |
ATE508735T1 (de) | 2011-05-15 |
JP2011001389A (ja) | 2011-01-06 |
JP2005514393A (ja) | 2005-05-19 |
KR20040075897A (ko) | 2004-08-30 |
CA2468958C (en) | 2012-07-03 |
DK1458360T3 (da) | 2011-08-29 |
US20030129140A1 (en) | 2003-07-10 |
US20140206638A1 (en) | 2014-07-24 |
US7368102B2 (en) | 2008-05-06 |
SI1458360T1 (sl) | 2011-08-31 |
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