TWI547487B - 具限定比表面積之二酮基哌微粒子 - Google Patents

具限定比表面積之二酮基哌微粒子 Download PDF

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TWI547487B
TWI547487B TW099119052A TW99119052A TWI547487B TW I547487 B TWI547487 B TW I547487B TW 099119052 A TW099119052 A TW 099119052A TW 99119052 A TW99119052 A TW 99119052A TW I547487 B TWI547487 B TW I547487B
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馬歇爾Ｌ 葛瑞特
葛瑞森Ｗ 史托威爾
保羅 曼金
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曼凱公司
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Description

具限定比表面積之二酮基哌 微粒子 交叉參考之相關申請案
本申請案根據35 U.S.C. §119(e)主張來自2009年6月12日申請之美國臨時專利申請案序號第61/186,773號之權益，將其內容全部以引用方式納入本文中。
本發明揭示比表面積小於約67平方公尺/公克之二酮基哌微粒子。FDKP微粒子可被用作為治療疾病或病症(例如，內分泌起源者，包括糖尿病和肥胖症)之藥物或活性劑之輸送系統。
藥物輸送多年以來一直是主要的問題，特別在經口服投予個體時，在欲輸送之化合物達到其靶定位置之前於胃腸道中遭遇的條件下不穩定時。例如，在許多情況中，較佳的是經口服投予藥物，尤其在投予容易性、病患順從性及降低成本方面。然而，許多化合物在經口服投予時無效或展現低或易變的效力。據推測此係因為藥物對消化道中的條件不穩定或因為彼等吸收無效。
由於與口服藥物輸送有關聯的問題，已探討向肺部輸送藥物。例如，典型地向肺部輸送藥物係經設計在肺部組織上具有作用，例如用於流行性感冒或其他呼吸性疾病的血管舒張劑、界面活性劑、化學治療劑或疫苗。其他藥物(包括核苷酸藥物)已經輸送至肺部，因為肺部代表特別適合於治療的組織，例如在囊腫纖維化中的基因療法，其中將表現缺損性腺苷去胺酶之反轉錄病毒媒介投予肺部。
亦可以具有全身性作用之藥劑執行向肺部輸送藥物。以肺部用於全身性藥劑輸送的優點包括藉由肺部黏膜表面的大表面積及攝取容易性。一個與所有該等肺部藥物輸送形式有關聯的一個問題為難以輸送藥物至肺部中，其係由於在使得藥物通過所有的天然屏障(諸如內襯氣管的纖毛)及嘗試投予均勻的體積和重量之藥物方面的問題。
據此，肺的藥物輸送有改進的空間。
本發明提供給與對肺部改進之藥物輸送的系統、微粒子及方法。本文所揭示之具體實例係藉由提供比表面積(SSA)介於約35平方公尺/公克與約67平方公尺/公克之間的二酮基哌(DKP)微粒子而達成改進之輸送。比表面積在此範圍內之DKP微粒子展現有利於向肺部輸送藥物的特徵，諸如改進之空氣動力學性能及改進之藥物吸附。
本文所揭示之一個具體實例包含比表面積小於約67平方公尺/公克之二酮基哌微粒子。另一具體實例包括其中比表面積係從約35平方公尺/公克至約67平方公尺/公克之二酮基哌微粒子。另一具體實例包括其中比表面積在沒有活性劑存在下大於約35平方公尺/公克，但是在活性劑吸附至粒子之後小於約62平方公尺/公克之二酮基哌微粒子。
在另一具體實例中，比表面積範圍從約35平方公尺/公克至約67平方公尺/公克之反丁烯二醯基二酮基哌(FDKP)微粒子包含藥物或活性劑，其中所述之SSA係在添加藥物至粒子之前測定。活性劑黏結於粒子上傾向減少SSA。在FDKP微粒子的各種具體實例中，藥物可為例如肽或蛋白質，包括內分泌激素，例如胰島素、類升糖素肽-1(GLP-1)、升糖素、艾生丁(exendin)、副甲狀腺激素、肥胖抑制素(obestatin)、抑鈣素、調酸催素和類似物。比表面積範圍從約35平方公尺/公克至約67平方公尺/公克之FDKP微粒子的另一具體實例可包括可取決於製造微粒子之合成方法的下游條件而改變之藥物/肽含量。在特別的實例中，FDKP微粒子可經製備成具有可取決於欲靶定或欲輸送之劑量而改變之藥物/肽含量。例如，其中藥物為胰島素，胰島素組份於包含微粒子之粉末調配物中可以從約3 U/毫克至約4 U/毫克。在某些具體實例中，藥物吸附至微粒子表面。在此等以藥物裝載之微粒子的更多具體實例中，以藥物裝載之微粒子的SSA小於約62平方公尺/公克。
在本文所揭示之具體實例亦包括包含微粒子之乾粉。在一個具體實例中，乾粉包含比表面積小於約67平方公尺/公克之FDKP微粒子。另一具體實例包括其中比表面積係從約35平方公尺/公克至約67平方公尺/公克之二酮基哌微粒子。另一具體實例包括其中比表面積係從約35平方公尺/公克至約62平方公尺/公克之包含藥物或活性劑之二酮基哌微粒子。
在乾粉的具體實例中，FDKP微粒子包含藥物。在乾粉的另一具體實例中，藥物為各種分子大小或質量之肽，包括：胰島素、類升糖素肽-1、升糖素、艾生丁、副甲狀腺激素、抑鈣素、調酸催素和類似物。在其中藥物為胰島素之乾粉的該等具體實例之一中，FDKP微粒子之胰島素含量係從約3 U/毫克至約4 U/毫克。
另外的具體實例關於包含吸入器、單位劑量乾粉藥劑容器(例如，藥匣)及包含本文所揭示之微粒子與活性劑之粉末調配物的藥物輸送系統。在一個具體實例中，供乾粉使用的藥物輸送系統包括吸入系統，其包含具有空氣通道的高阻抗性吸入器，該通道賦予流經通道的氣流高阻抗性，用於去黏聚及分配粉末調配物。在一個具體實例中，吸入系統具有例如從每分鐘約0.065(√kPa)/公升至每分鐘約0.200(√kPa)/公升之阻抗值。在某些具體實例中，乾粉可藉由以吸入系統吸入而有效地輸送，其中高峰吸入壓力差可從約2 kPa至約20 kPa為範圍，其可產生每分鐘約7與70公升之間的所得高峰流速。在某些具體實例中，吸入系統係經配置以提供單次劑量，其係藉由從吸入器排出呈連續流動或呈一或多個粉末脈衝之粉末輸送至病患。在以此揭示的一些具體實例中，乾粉吸入系統包含在吸入器內預定的質量流量平衡。例如，離開吸入器且進入病患之總流量的約10%至70%之流量平衡係藉由一或多個分配口輸送，其允許氣流通過含有粉末調配物之區域，且其中約30%至90%之氣流係從吸入器的其他通道產生。此外，旁通流量或未進入且離開粉末封阻區域之流量(諸如通過藥匣)可與離開粉末分配口之流量重新組合在吸入器內，使流化粉末在離開吸入器吹嘴之前稀釋、加速及最終去黏聚。在一個具體實例中，範圍從每分鐘約7至70公升之吸入器系統流速造成大於75%之容器粉末含量或藥匣粉末含量以介於1與30毫克之間的充量(fill mass)分配。在某些具體實例中，如上述之吸入系統可以單次吸入發射百分比大於40%，大於50%，大於60%或大於70%之可呼吸部分/充量之粉末劑量。
在特別的具體實例中，提供一種吸入系統，其包含乾粉吸入器、包含反丁烯二醯基二酮基哌微粒子(其中未裝載之FDKP微粒子具有小於約67平方公尺/公克之比表面積)及一種或超過一種活性劑之乾粉調配物。在吸入系統的此具體實例的一些觀點中，乾粉調配物係提供在單位劑量藥匣中。另一選擇地，乾粉調配物可預裝載或預填充於吸入器中。在此具體實例中，吸入系統的結構配置考慮到吸入器的去黏聚機制，以得到大於50%之可呼吸部分；亦即在吸入器(藥匣)內所含有之粉末一半以上係以小於5.8微米之粒子發射。在一個具體實例中，吸入器可在給藥期間排出大於85%在容器內所含有之粉末藥劑。在某些具體實例中，吸入器可排出大於85%在單次吸入所含有之粉末藥劑。在某些具體實例中，吸入器可在介於2 kPa與5 kPa之間的壓力差下以範圍至多30毫克的充量於小於3秒內排出大於90%之藥匣含量或容器含量。
本文所揭示之具體實例亦包括方法。在一個具體實例中，治療內分泌相關疾病或病症之方法包含將乾粉調配物投予需要其之個體，該調配物包含比表面積小於約67平方公尺/公克之FDKP微粒子及適合於治療該疾病或病症之藥物。另一具體實例包括其中比表面積係從約35平方公尺/公克至約67平方公尺/公克之二酮基哌微粒子。另一具體實例包括其中比表面積小於約62平方公尺/公克之包含活性物之二酮基哌微粒子。一個具體實例包括一種治療胰島素相關病症之方法，該方法包含將包含上述之FDKP微粒子之乾粉投予需要其之個體。該方法包含將包含具有以上引述範圍內之SSA之反丁烯二醯基二酮基哌微粒子之乾粉調配物投予個體。在各種具體實例中，胰島素相關病症尤其可包括或排除任何或所有的糖尿病前期(pre-diabetes)、第1型糖尿病(蜜月期、後蜜月期或二者)、第2型糖尿病、妊娠糖尿病、低血糖症、高血糖症、抗胰島素症、分泌功能障礙、受損的胰島素早期釋放、胰臟β-細胞功能喪失、胰臟β-細胞喪失及代謝病症。在一個具體實例中，乾粉包含胰島素。在其他的具體實例中，乾粉包含升糖素、艾生丁或GLP-1。
在本文揭示之其他具體實例包括製造適合於肺部投予之微粒子成為乾粉之方法。在一個具體實例中，該方法包括形成具有在95%之可靠界限內的約35平方公尺/公克至約67平方公尺/公克之比表面積之二酮基哌微粒子，該形成係藉由調整製造條件，以生產具有52平方公尺/公克之比表面積之微粒子為目標。在另一具體實例中，調整製造條件包含增加或降低溫度或在進料溶液中的氨、醋酸及/或二酮基哌濃度。
本文所揭示之另一具體實例包括製造適合於肺部投予之微粒子成為包含二酮基哌(諸如FDKP)之乾粉之方法。在具體實例中，微粒子包含合成FDKP化合物或組成物，其中微粒子具有從約35平方公尺/公克至約67平方公尺/公克之表面積，且使用標準的表面積分析儀測定FDKP微粒子表面積，以評定以平方公尺/公克計之表面積。在其他的具體實例中，比表面積係在活性劑吸附於微粒子之後測定，以代替或除了在添加活性劑之前測定；SSA小於約62平方公尺/公克。在一個具體實例中，FDKP合成包含：a)將FDKP組成物溶解在具有鹼性pH之溶液中，以形成FDKP溶液，b)提供揮發性酸溶液，及c)將FDKP溶液與揮發性酸溶液一起在高剪切混合機中混合，以生產微粒子。
在特別的具體實例中，用於製造表面積範圍從約35平方公尺/公克至約67平方公尺/公克之FDKP微粒子之方法包含皂化反應及再結晶。在一個具體實例中，揭示一種製造適合於肺部投予之微粒子成為乾粉之方法，該方法包含：a)合成FDKP化合物或組成物，b)將步驟b)之FDKP化合物溶解在具有鹼性pH之溶液中，以形成FDKP溶液，d)提供揮發性酸溶液，及e)將FDKP溶液與揮發性酸溶液一起在高剪切混合機中混合，以生產微粒子。該方法可進一步包含在粒子形成之後測定粒子之比表面積。
在特殊的具體實例中，合成比表面積小於約67平方公尺/公克之FDKP微粒子之方法包含：將等質量的約10.5重量%之醋酸及約2.5重量%之FDKP溶液在約14℃至約18 ℃下經由高剪切混合機(諸如雙進料SONOLATORTM)在2000 psi下通過0.001平方英吋噴嘴進料，以形成懸浮液。該方法可進一步包含將微粒子從溶液沉澱及將所形成之微粒子收集在約相等質量和溫度之去離子水儲槽中之步驟。在此具體實例中，懸浮液包含約0.8%固體之微粒子含量。在某些具體實例中，該方法進一步包含藉由在例如去離子水中使用切線流動過濾技術清洗微粒子而濃縮微粒子懸浮液。在此及其他的具體實例中，沉澱物可先濃縮成約4%固體，接著進一步以去離子水清洗。在一些具體實例中，懸浮液典型地可濃縮成以所使用之FDKP組成物初質量為基準計約10%固體。經濃縮之懸浮液可藉由烘箱乾燥法分析固體含量。在本文所揭示之具體實例中，該方法進一步包含在粒子乾燥之後測定粒子之表面積。
在本文所揭示之組成物及方法的特殊具體實例中，比表面積小於約67平方公尺/公克之二酮基哌微粒子利用具有式2,5-二酮基-3,6-雙(N-X-4-胺基丁基)哌之二酮基哌，其中X係選自由反丁烯二醯基、琥珀醯基、順丁烯二醯基及戊二醯基所組成之群組。在例示性具體實例中，二酮基哌具有式(雙-3,6-(N-反丁烯二醯基-4-胺基丁基)-2,5-二酮基哌或2,5-二酮基-3,6-雙(N-反丁烯二醯基-4-胺基丁基)哌。
本文所揭示之另一具體實例包括製造比表面積小於約67平方公尺/公克且包含藥物或活性劑之FDKP微粒子之方法，其中所述之比表面積係在將藥物添加至粒子之前測定。在此具體實例中，該方法包含將包含活性劑(諸如肽，包括胰島素、升糖素、類升糖素肽-1、調酸催素、肽YY和類似物)之溶液添加至微粒子懸浮液中；將氨水添加至懸浮液中，以例如提升懸浮液之pH至pH 4.5；將反應保溫；及將所得懸浮液在液態氮中急凍且將所形成之顆粒凍乾，以生產包含比表面積小於約67平方公尺/公克之FDKP微粒子之乾粉。在此具體實例的觀點中，在活性劑吸附於微粒子上之後，微粒子之比表面積小於約62平方公尺/公克。
在一個具體實例中，揭示將胰島素輸送至需要其之病患之方法，其包含將包含比表面積小於約62平方公尺/公克(以未裝載之微粒子為基準計67平方公尺/公克)之二酮基哌微粒子之乾粉由病患藉由吸入乾粉而投予肺部深處。在此具體實例的觀點中，其具體指定吸入器系統的特別特色。
本文所揭示之另一具體實例包括將藥物(例如，胰島素)輸送至需要其之病患之方法，其包含將乾粉由病患藉由吸入乾粉而投予肺部深處；其中乾粉包含二酮基哌微粒子，其包含胰島素；其中微粒子係由二酮基哌形成且具有範圍從約35平方公尺/公克至約67平方公尺/公克之表面積。在此具體實例的觀點中，在活性劑吸附於微粒子上之後，微粒子之比表面積小於約62平方公尺/公克。在此具體實例的觀點中，其具體指定吸入器系統的特別特色。進一步的具體實例包含治療胰島素相關病症之方法，該方法包含將上述乾粉投予需要其之個體。在各種具體實例中，胰島素相關病症尤其可包括或排除任何或所有的糖尿病前期、第1型糖尿病(蜜月期、後蜜月期或二者)、第2型糖尿病、妊娠糖尿病、低血糖症、高血糖症、抗胰島素症、分泌功能障礙、受損的胰島素早期釋放、胰臟β-細胞功能喪失、胰臟β-細胞喪失及代謝病症。
在一個具體實例中，治療內分泌相關疾病或病症之方法包含將包含比表面積小於約67平方公尺/公克之FDKP微粒子及適合於治療該疾病或病症之藥物之乾粉調配物投予需要其之個體。在此具體實例的觀點中，在活性劑吸附於微粒子上之後，微粒子之比表面積小於約62平方公尺/公克。一個具體實例包括治療胰島素相關病症之方法，該方法包含將包含上述FDKP微粒子之乾粉投予需要其之個體。該方法包含將包含比表面積小於約67平方公尺/公克之FDKP微粒子及胰島素之乾粉調配物投予個體。在此具體實例的觀點中，在活性劑吸附於微粒子上之後，微粒子之比表面積小於約62平方公尺/公克。在各種具體實例中，胰島素相關病症尤其可包括或排除任何或所有的糖尿病前期、第1型糖尿病(蜜月期、後蜜月期或二者)、第2型糖尿病、妊娠糖尿病、低血糖症、高血糖症、抗胰島素症、分泌功能障礙、受損的胰島素早期釋放、胰臟β-細胞功能喪失、胰臟β-細胞喪失及代謝病症。在一個具體實例中，乾粉包含胰島素。在其他的具體實例中，乾粉包含升糖素、艾生丁或GLP-1。
如所陳述，向肺部輸送藥物提供許多優點。然而，由於以均勻的藥物體積和重量將藥物運輸通過身體天然屏障的問題而難以輸送藥物至肺部中。本文所揭示的是作為藥物輸送劑之比表面積小於約67平方公尺/公克之二酮基哌微粒子、製造該微粒子之方法及使用該微粒子之治療方法。
如本文所使用之術語〝微粒子〞係指直徑約0.5微米至約1000微米之粒子，與精確的外部或內部結構無關。直徑介於約0.5微米與約10微米之間的微粒子可到達肺部，成功地通過大多數天然屏障。需要小於約10微米之直徑以飛越過咽喉轉角，且需要約0.5微米或更大的直徑避免被呼出。為了到達肺部深處(或肺泡區)，咸信於此發生最有效率的吸收，較佳的是使〝可呼吸部分〞(RF)所容納之粒子比例達到最大，通常公認為那些具有約0.5微米至約5.7微米之空氣動力學直徑之粒子，雖然一些文獻使用略微不同的範圍，該直徑係使用標準技術所測量，例如以安德遜級聯衝擊器(Andersen Cascade Impactor)。可使用其他的衝擊器測量空氣動力學粒子大小，諸如NEXT GENERATION IMPACTORTM(NGITM，MSP Corporation)，其中可呼吸部分係以類似的空氣動力學大小限定，例如＜6.4微米。在一些具體實例中，雷射繞射裝置被用於測定粒子大小，例如在2010年3月18日申請之美國專利申請案序號第12/727,179號中所揭示之雷射繞射裝置，將其相關教示之全部內容納入本文中，其中測量粒子之體積中值幾何直徑(VMGD)來評定吸入系統的性能。例如，在各種具體實例中，≧80%、85%或90%之藥匣排空率及≦12.5微米、≦7.0微米或≦4.8微米之所發射粒子之VMGD可表明漸進更好的空氣動力學性能。本文所揭示之具體實例顯示比表面積小於約67平方公尺/公克之FDKP微粒子展現有利於向肺部輸送藥物的特徵，諸如改進之空氣動力學性能。
充滿時之可呼吸部分(RF/充量)代表從經填充之劑量以適合於肺部輸送之大小發射之粒子的百分比，其為微粒子空氣動力學性能之量度。如本文所述，40%或大於40%之RF/充量值反映出可接受之空氣動力學性能特徵。在本文所揭示之某些具體實例中，相對於填料之可呼吸部分可大於50%，在例示性具體實例中，充滿時之可呼吸部分可為至多約80%，其中約80%之充量係以按使用標準技術所測量＜5.8微米之粒子大小發射。
如本文所使用之術語〝乾粉〞係指不懸浮或溶解於推進劑、載劑或其他液體中的細微粒組成物。其不意謂必然暗示所有的水分子完全不存在。
應瞭解特定的RF/充量值可取決於輸送粉末所使用的吸入器。粉末通常傾向黏聚且結晶狀DKP微粒子特別會形成黏聚粉末。乾粉吸入器的功能之一係使粉末去黏聚，使得所得粒子包含適合於藉由吸入輸送劑量的可呼吸部分。然而，黏聚粉末的去黏聚典型地不完全，使得在測量以吸入器所輸送之可呼吸部分時所見之粒子大小分布並不吻合原粒子之大小分布，亦即分布形態將向較大粒子移動。吸入器設計在其去黏聚效率上有所不同且因此使用不同的設計所觀察之RF/充量絕對值亦將有所不同。然而，與比表面積為函數關係之最適RF/充量從吸入器至吸入器具有類似性。
如本文所使用之術語〝約〞係用於表明數值包括用於測定該數值之裝置或方法的測量之標準偏差。
二酮基哌
一種已用於克服醫藥技藝中的問題(諸如藥物不穩定性及/或不良吸收性)之藥物輸送劑類別為2,5-二酮基哌。2,5-二酮基哌係以如下所示之通式1化合物代表，其中E1及E2獨立為N或更特別為NH。在其他的具體實例中，E1及/或E2獨立為氧或氮，使得其中E1及E2之取代基中之一為氧及另一者為氮之該式得到取代類似物二酮基嗎啉，或當E1及E2二者為氧時，則該式得到取代類似物二酮基二烷。
該等2,5-二酮基哌經顯示有用於藥物輸送，特別為那些攜有酸性R1及R2基團者，如在例如以”Self Assembling Diketopiperazine Drug Delivery System”為標題之美國專利第5,352,461號；以”Method For Making Self-Assembling Diketopiperazine Drug Delivery System”為標題之美國專利第5,503,852號；以”Microparticles For Lung Delivery Comprising Diketopiperazine”為標題之美國專利第6,071,497號及以”Carbon-Substituted Diketopiperazine Delivery System”為標題之美國專利第6,331,318號中所述，將每一該等專利所有關於二酮基哌及二酮基哌介導之藥物輸送之教示的全部內容以引用方式納入本文中。二酮基哌可形成為併入藥物之微粒子或可使藥物吸附於其上之微粒子。藥物與二酮基哌之組合可賦予改進之藥物穩定性及/或吸收特徵。該等微粒子可藉由各種投予途徑投予。作為乾粉，該等微粒子可以吸入輸送至呼吸系統之特定區域，包括肺部。
此等微粒子典型地藉由以pH-為基準之自由酸(或鹼)沉澱而獲得，造成由聚集之結晶板所組成之自組裝微粒子。粒子的穩定性可藉由在DKP溶液中的少量界面活性劑(諸如聚山梨醇酯-80)而增強，從此沉澱出粒子(參閱例如以”Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents”為標題之美國專利公開案第2007/0059373號，將其所有關於DKP微粒子及其乾粉的形成和裝載之教示的全部內容以引用方式納入本文中)。最終，可移除溶劑獲得乾粉。適當的溶劑移除方法包括凍乾及噴霧乾燥(參見例如以”A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent”之美國專利公開案第2007/0196503號及以”Purification and stabilization of peptide and protein pharmaceutical agent”為標題之美國專利第6,444,226號，將每一該等專利所有關於DKP微粒子及其乾粉的形成和裝載之教示的全部內容以引用方式納入本文中)。本文所揭示之微粒子不同於DKP鹽所組成的微粒子。此等粒子典型地藉由噴霧乾燥而形成(與乾燥對比)，得到球粒狀及/或癟掉的球粒狀之非晶形鹽(與自由酸或鹼對比)，使得彼等在化學、物理及形態上完全不同。本揭示內容提及FDKP應瞭解為自由酸或溶解之陰離子。
用於合成二酮基哌之方法說明於例如Katchalski等人之J. Amer. Chem. Soc. 68,879-880(1946)及Kopple等人之J. Org. Chem. 33(2),862-864(1968)中，將該教示的全部內容以引用方式納入本文中。2,5-二酮基-3,6-二(胺基丁基)哌(Katchalski等人稱此為離胺酸酐)亦可經由N-ε-P-L-離胺酸在熔融酚中的環二聚合，類似於Kopple方法，接著以適當的試劑和條件移除封端(P)基而製備。例如，CBz-保護基可使用4.3 M HBr之醋酸溶液移除。此途徑可能較佳，因為其使用市場上可取得的起始材料，其包含經記述以維持起始材料在產物中的立體化學之反應條件，且所有的步驟可輕易按比例增大而用於製造。用於合成二酮基哌之方法亦說明於以”Catalysis of Diketopiperazine Synthesis”為標題之美國專利第7,709,639號中，亦將其關於上述之教示以引用方式納入本文中。
反丁烯二醯基二酮基哌(雙-3,6-(N-反丁烯二醯基-4-胺基丁基)-2,5-二酮基哌；FDKP)為一種用於肺部施予之較佳的二酮基哌：
FDKP提供有利的微粒子基質，因為其在酸中具有低溶解度，但在中性或鹼性pH下可輕易溶解。該等性質允許FDKP在酸性條件下結晶且晶體自組裝成微粒子。粒子在其中pH為中性之生理條件下可輕易地溶解。如本文所註明，直徑介於約0.5與約10微米之間的微粒子可到達肺部，成功地通過大多數天然屏障。在此大小範圍內的粒子可從FDKP輕易地製得。
如本文所註明，直徑介於約0.5與約10微米之間的微粒子可到達肺部，成功地通過大多數天然屏障。在此大小範圍內的粒子可從具有酸性基團之二酮基哌輕易地製得，諸如在FDKP(以及相關之分子中，諸如2,5-二酮基-3,6-二(4-X-胺基丁基)哌，其中X為琥珀醯基、戊二醯基或順丁烯二醯基)中的羧酸酯基團。在酸沉澱時，即獲得由結晶板聚集物所組成之自組裝粒子。該等結晶板的大小與粒子的比表面積有關，該比表面積依次牽連到粒子之結構、裝載量及空氣動力學性能方面的作用。
DKP微粒子之比表面積為平均晶體大小之量度且可用於估計晶體成核及生長成微粒子特徵之相對貢獻。比表面積係取決於微粒子晶體之大小及微粒子基質之密度(ρ)而定，且與晶體之特徵大小L成反比例。比表面積為粒子群的性質，而沒必要是其中每一個別粒子的特徵。本文所揭示之具體實例顯示比表面積小於約67平方公尺/公克之微粒子展現有利於向肺部輸送藥物的特徵，諸如改進之空氣動力學性能，該輸送係以適度效率之吸入器進行，諸如在以”Unit Dose Cartridge and Dry Powder Inhaler”為標題之美國專利第7,464,706號中所揭示之MEDTONE吸入器，將其關於上述之教示以引用方式納入本文中。比表面積小於約62平方公尺/公克之替換具體實例提供使一批粒子將符合最小的空氣動力學性能標準的較高層級之保證。因為比表面積亦影響藥物裝載/含量能力，所以各種具體實例就改進之藥物吸附能力需要大於或等於約35平方公尺/公克、40平方公尺/公克或45平方公尺/公克之比表面積。另外，當比表面積下落至低於約35平方公尺/公克時，甚至以高效率吸入器都觀察到不一致的藥匣排空，諸如在2009年6月12日申請之以”A Dry Powder Inhaler and System for Drug Delivery”為標題之美國專利申請案第12/484,125號及在2010年3月4日申請之以”Improved Dry Powder Drug Delivery System”為標題之美國專利申請案第12/717,884號中所揭示者，將其揭示內容關於上述之教示以引用方式納入本文中。
比表面積範圍的上限
本文所限定之比表面積範圍的上限受迫於微粒子之空氣動力學性能。本文所述之研究已證實當比表面積值增加至大於約50平方公尺/公克時，則有趨向較低的RF/充量值之傾向。另外，當比表面積增加時，則使RF/充量之分布加寬，且增加所選擇之RF/充量準則失敗的可能性，例如RF/充量＞40%。在一些具體實例中，因此可選擇約67平方公尺/公克之上限。以擬合就大多數製品收集之數據的曲線為基準，該上限值經預測係提供40%之RF/充量。在其他的具體實例中，可選擇約62平方公尺/公克之上限。62平方公尺/公克之上限提供具有在95%之可靠界限內的可接受之RF/充量之微粒子(參閱圖6A)。
將上限強加於微粒子之比表面積的另一理由為具有高比表面積之微粒子懸浮液傾向比具有較低比表面積之微粒子懸浮液有數量級計高的黏性。此現象有可能反映出與較小晶體有關聯的粒子間吸引增加。一經冷凍乾燥時，較強的吸引可能產生聚集物，其並未有效地去黏聚，當懸浮液黏度與RF/充量為負面關係時，有可能減低RF/充量。
微粒子比表面積係從凍乾的散裝粉末測定且無法從微粒子形成條件準確地預測。據此，可能希望以約52平方公尺/公克之比表面積為目標。以約52平方公尺/公克設定為比表面積目標時，可預料僅5%之微粒子超過62平方公尺/公克之更保守上限(圖6B)。在此可能超過62平方公尺/公克的5%之微粒子範圍內，可預料僅再5%(0.25%)展現＜40%之RF/充量。該等製造條件可因此提供具有超越99%可靠界限的＞40%之RF/充量之微粒子。
比表面積範圍的下限
本文所限定之比表面積範圍的下限受迫於藥物裝載需求。微粒子必須具有足以裝載必需藥物量的比表面積。若藥物吸附不足時(亦即留置於溶液中)，則未吸附之藥物可〝橋接〞所形成之微粒子，導致聚集物形成。聚集物可不利地影響空氣動力學特徵。在胰島素的情況中，為了避免在適當的治療劑量下被胰島素橋接，需要約35平方公尺/公克之比表面積下限。橋接亦為上述所註明不良藥匣排空之可能原因，其可由具有較低的比表面積之粉末發生。為了提供可避免該等問題且可使裝載達到最大的更高保證，仍可使用較高的比表面積下限，例如40或45平方公尺/公克。另一選擇地，可將衝擊空氣動力學性能的其他因素維持在更窄的容許度內。圖1A顯示具有高比表面積之微粒子叢。圖1B顯示由具有低比表面積之粉末中的胰島素〝橋接〞粒子。
FDKP微粒子形成
在製造FDKP微粒子的第一步驟係形成微粒子，其係藉由以pH誘發之FDKP結晶及FDKP晶體自組裝成具有大體上球形態之微粒子進行(圖2)。據此，微粒子之製造基本為結晶法。過量溶劑可藉由重複離心、傾析及再結晶來清洗懸浮液而移除，或以蒸餾而移除。
為了形成以胰島素裝載之FDKP微粒子，胰島素可趁懸浮時(亦即在冷凍乾燥之前)藉由添加胰島素貯存溶液至FDKP微粒子懸浮液而直接吸附在微粒子上。在一個具體實例中，pH控制步驟亦可在添加胰島素貯存溶液之後執行。此步驟可促進胰島素在進一步加工之前吸附在懸浮液中的微粒子上。增加懸浮液之pH至約4.5促進胰島素完全吸附在懸浮液中的微粒子上，而沒有FDKP從粒子基質過量溶解，且亦改進胰島素在散裝藥物產品中的穩定性。懸浮液可在液態氮中逐滴急凍(亦即低溫顆粒化)且凍乾，以移除溶劑而獲得乾粉。在替換的具體實例中，可將懸浮液噴霧乾燥，獲得乾粉。圖3提供適當製造方法之示意圖。
在一個具體實例中，提供一種用於製造含有胰島素之本發明FDKP微粒子之製造方法。總而言之，使用高剪切混合機，諸如雙進料SONOLATORTM，或例如在2009年11月2日申請之美國臨時專利申請案序號第61/257,311號中所揭示之高剪切混合機(將其揭示內容全部以引用方式納入本文中)，可將等質量的約10.5重量%之醋酸及約2.5重量%之FDKP溶液在約16℃ ±約2℃下以雙進料SONOLATORTM在2000 psi下通過0.001平方英吋噴嘴進料(表1及2)。可將沉澱物收集在約等質量及等溫度的去離子(DI)水儲槽中。所得懸浮液包含約0.8%固體。沉澱物可藉由切線流動過濾方式濃縮及清洗。沉澱物可先濃縮成約4%固體，接著以去離子水清洗。懸浮液最終可濃縮成以FDKP初質量為基準計約10%固體。經濃縮之懸浮液可藉由烘箱乾燥法來分析固體含量。
在一個具體實例中，濃縮之胰島素貯存溶液可以1份胰島素及9份約2重量%之醋酸製備。胰島素貯存溶液可以重力方式添加至懸浮液中，以獲得約11.4重量%之胰島素裝載量。可將胰島素-FDKP懸浮液混合至少約15分鐘。在一些具體實例中，混合可以較短或較長的時間進行。接著可將胰島素-FDKP懸浮液以約14至約15重量%之氨水從約3.5之初pH滴定至約4.5之pH。懸浮液可在液態氮中急凍，以形成顆粒，且凍乾，得到散裝的含胰島素之FDKP微粒子。空白的FDKP微粒子可以相同方式製造，但是減去胰島素裝載及pH調整步驟。在一個具體例中，包含本文所述之微粒子之FDKP-胰島素散狀粉末的密度係從約0.2公克/立方公分至約0.3公克/立方公分。
表1. 10.5重量%之醋酸溶液
經0.2微米過濾
經0.2微米過濾
控制比表面積
FDKP晶體的大小分布及形狀受新晶體成核與現存晶體生長之間的平衡影響。兩種現象極度取決於溶液中的濃度及超飽和而定。FDKP晶體的特徵大小為成核與生長之相對速率的指標。當成核佔優勢時，則形成許多晶體，但是晶體比較小，因為晶體全部為溶液中的FDKP競爭。當生長佔優勢時，則有較少的競爭晶體且晶體的特徵大小較大。
結晶極度取決於超飽和而定，其依次極度取決於組份在進料流中的濃度。較高的超飽和與許多小晶體的形成有關聯；較低的超飽和產生較少、較大的晶體。就超飽和而言：1)增加FDKP濃度提升超飽和；2)增加氨濃度使系統向較高的pH移動，諸如向約pH 4.5移動，以提升平衡溶解度且減少超飽和；及3)增加醋酸濃度係藉由使終點向較低的pH移動而增加超飽和，其中平衡溶解度較低。降低該等組份的濃度誘發相反的效果。
溫度係經由其對FDKP溶解度及FDKP晶體成核和生長之動力學的作用而影響FDKP微粒子形成。在低溫下，形成具有高比表面積之小晶體。該等粒子之懸浮液展現高黏度，表明強的粒子間吸引。約12℃至約26℃之溫度範圍提供在95%之可靠水平下＞40%之RF/充量。藉由說明溫度與比表面積之間的關係，可使用約13℃至約23℃之略窄但內部一致的溫度範圍。
最後，應理解活性劑吸附於微粒子表面上傾向減少比表面積。活性劑的吸附可填充或以另外方式堵塞一些在組成粒子的結晶板之間較窄的空間，藉此減少比表面積。另外，活性劑的吸附係添加質量至微粒子，而不實質影響微粒子的直徑(大小)。因為比表面積與微粒子質量成相反比例，所以將發生比表面積的減少。
活性劑的選擇及併入
只要本文所述之微粒子保有小於約67平方公尺/公克之必需的比表面積，彼等可採取有利於向肺部輸送及/或藥物吸附之其他額外的特徵。以”Method for Drug Delivery to the Pulmonary System”為標題之美國專利第6,428,771號說明向肺部輸送之DKP粒子且將其關於上述之教示以引用方式納入本文中。以”Purification and Stabilization of Peptide and Protein Pharmaceutical Agents”為標題之美國專利第6,444,226號說明用於吸附藥物於微粒子表面上之有利方法且亦將其關於上述之教示以引用方式納入本文中。微粒子表面性質可經處理以達成所欲特徵，如以”Method of Drug Formulation based on Increasing the Affinity of Crystalline Microparticle Surfaces for Active Agents”為標題之美國專利申請案第11/532,063號中所述，將其關於上述之教示以引用方式納入本文中。以”Method of Drug Formation based on Increasing the Affinity of Active Agents for Crystalline Microparticle Surfaces”為標題之美國專利申請案第11/532,065號說明用於促進活性劑吸附於微粒子上之方法。亦將美國專利申請案第11/532,065號關於上述之教示以引用方式納入本文中。
本文所述之微粒子可包含一或多種活性劑。與〝藥物〞可交換使用的如本文所使用之〝活性劑〞係指醫藥物質，包括小分子醫藥品、生物劑及生物活性劑。活性劑可為天然生成、重組體或合成來源，包括蛋白質、多肽、肽、核酸、有機巨分子、合成有機化合物、多醣和其他糖類、脂肪酸和脂質、及抗體和其片段，包括(但不限於此)用於癌症抗原之人化或嵌合抗體、F(ab)、F(ab)2、單獨或與其他多肽融合之單鏈抗體或治療或診斷的單株抗體。活性劑可落在各種生物活性及種類內，諸如血管活性劑、神經活性劑、激素、抗凝劑、免疫調節劑、胞毒劑、抗生素、抗病毒劑、抗原、感染劑、免疫調節劑、激素及細胞表面抗原。更特別地，活性劑可以非限制方式包括細胞介素、脂質介素(lipokine)、腦啡、炔烴、環孢靈(cyclosporin)、抗-IL-8抗體、包括ABX-IL-8的IL-8拮抗劑、包括PG-12的前列腺素、包括LY29311、BIIL 284和CP105696的LTB受體阻斷劑、特利坦(triptan)(諸如舒馬普坦(sumatriptan)和棕櫚油酸鹽)、胰島素和其類似物、生長激素和其類似物、副甲狀腺激素(PTH)和其類似物、副甲狀腺激素相關肽(PTHrP)、生長激素釋放肽(ghrelin)、肥胖抑制素、腸體制素(enterostatin)、顆粒球巨噬細胞聚落刺激因子(GM-CSF)、澱粉素、澱粉素類似物、類升糖素肽-1(GLP-1)、保栓通(clopidogrel)、PPACK(D-苯基丙胺醯基-L-脯胺醯基-L-精胺酸氯甲基酮)、調酸催素(OXM)、肽YY(3-36)(PYY)、脂泌素(adiponectin)、膽囊收縮素(CCK)、胰液催素、胃泌激素、升糖素、腸動素、體抑素、腦鈉尿肽(brain natriuretic peptide)(BNP)、心房納尿肽(atrial natriuretic peptide)(ANP)、IGF-1、生長激素釋放因子(GHRF)、整合素β-4前驅(IBT4)受體拮抗劑、致痛素(nociceptin)、抑痛素(nocistatin)、孤蛋白(orphanin)FQ2、抑鈣素、CGRP、血管收縮素、物質P、神經激肽(neurokinin)A、胰臟多肽、神經肽Y、δ-誘眠肽及血管活性腸肽。微粒子亦可用於輸送其他劑，例如對比染料，諸如德州紅(Texas Red)。
在從比表面積小於67平方公尺/公克之FDKP所形成之微粒子上輸送之藥物含量典型地大於0.01%。在一個具體實例中，以具有前述比表面積之微粒子輸送之藥物含量範圍可從約0.01%至約20%，其為肽的典型含量，諸如胰島素。例如，若藥物為胰島素，則本發明的微粒子典型地包含3-4 U/毫克(約10至15%)之胰島素。在某些具體實例中，粒子的藥物含量可取決於欲輸送之藥物形式及大小而改變。
只要本文所述之微粒子保有必需的比表面積，彼等可採取有利於向肺部輸送及/或藥物吸附之其他額外的特徵。以”Method for Drug Delivery to the Pulmonary System”為標題之美國專利第6,428,771號說明向肺部輸送之DKP粒子且將其關於上述之教示以引用方式納入本文中。以”Purification and Stabilization of Peptide and Protein Pharmaceutical Agents”為標題之美國專利第6,444,226號說明用於吸附藥物於微粒子表面上之有利方法且亦將其關於上述之教示以引用方式納入本文中。微粒子表面性質可經處理以達成所欲特徵，如以”Method of Drug Formulation based on Increasing the Affinity of Crystalline Microparticle Surfaces for Active Agents”為標題之美國專利申請案義11/532,063號中所述，將其關於上述之教示以引用方式納入本文中。以”Method of Drug Formation based on Increasing the Affinity of Active Agents for Crystalline Microparticle Surfaces”為標題之美國專利申請案第11/532,065號說明用於促進活性劑吸附於微粒子上之方法。亦將美國專利申請案第11/532,065號關於其上述之教示以引用方式納入本文中。
實施例
下列的實施例係以證實所揭示之微粒子之具體實例而予以納入。熟習所屬技術領域者應察知在隨後的實施例中所揭示之技術代表由本發明者發現之技術，在實施本揭示內容時起良好作用，且因此可認為是構成其實施的較佳模式。然而，按照本揭示內容，在所屬技術領域中具有通常知識者應察知可在揭示之特定具體實例中進行許多變化且仍獲得相同或類似結果。
實施例1
I.製造程序
A.用於FDKP/胰島素微粒子生產之通用製造程序
微粒子係從反丁烯二醯基二酮基哌(FDKP)及胰島素製造。將FDKP溶解在NH4OH水溶液中，以形成溶液。將此溶液的進料流與醋酸(HOAc)水溶液的進料流在高剪切混合機中組合，以形成微粒子水性懸浮液。
FDKP進料溶液係以約2.5重量%之FDKP、約1.6重量%之濃NH4OH(約28至約30重量%之NH3)及約0.05重量%之聚山梨醇酯80製備。醋酸進料溶液係以約10.5重量%之冰醋酸及約0.05重量%之聚山梨醇酯80製備。在使用之前，將兩種進料溶液通過約0.2微米薄膜過濾。
圖3描繪用於製造含有胰島素之本發明FDKP的製造方法之示意圖。在此具體實例中，使用高剪切混合機，例如雙進料SONOLATORTM，或如在2009年11月2日申請之美國臨時專利申請案序號第61/257,311號中所揭示之混合機(將其揭示內容全部以引用方式納入本文中)，將等量(以質量計)的每一進料溶液經由配備有#5噴嘴(0.0011平方英吋)的雙進料SONOLATORTM泵送。將較小的幫浦就等流速的每一進料流設定成50%且進料壓力為約2000 psi。接收容器含有等於任一進料溶液質量的去離子水(例如，4公斤FDKP進料溶液及4公斤HOAc進料溶液可經由SONOLATORTM泵送至含有4公斤去離子水的接收容器中)。
將所得懸浮液以使用0.2平方公尺PES(聚醚碸)薄膜之切線流動過濾方式濃縮且清洗。懸浮液先濃縮成約4%固體，接著以去離子水透析過濾及最後濃縮成約16%標稱固體。經清洗之懸浮液的實際固體百分比係以〝乾燥失重〞測定。可使用替換方法測量在懸浮液中的固體百分比，諸如一種在2010年5月7日以〝Determining Percent Solids in Suspension Using Raman Spectroscopy〞為標題之美國臨時專利申請案序號第61/332,292號中所揭示之方法，將該揭示內容就其教示以引用方式納入本文中。
製備含有在包含約2重量%HOAc於去離子水中之溶劑中約10重量%胰島素(按收到狀態)的胰島素貯存溶液，且經無菌過濾。將以懸浮液的固體含量為基準計適當的貯存溶液量添加至經混合之懸浮液中。接著藉由使用氨溶液使懸浮液之pH從約3.6之pH調節至約4.5之pH來調整所得微粒子/胰島素懸浮液。
將包含含有胰島素之FDKP微粒子的懸浮液轉移至低溫粒化器/製顆粒機中，例如在2009年11月2日申請之美國臨時專利申請案序號第61/257,385號中所揭示，將其揭示內容全部以引用方式納入本文中，且藉由在液態氮中急凍而製成顆粒。將冰顆粒凍乾，以生產乾粉。
B.用於在5%及10%研究中所使用之FDKP/胰島素微粒子生產之製造程序
在5%及10%研究中檢查進料濃度對比表面積及粉末空氣動力學之作用。在5%研究中，實驗係經設計以測定三種因素之作用，亦即FDKP、氨及醋酸之濃度，且該該等濃度係在3X3因素分析實驗中檢查，其中高及低層級係從對照條件起5%。在10%研究中，FDKP、氨及醋酸之濃度亦在3X3因素分析實驗中檢查，然而高及低層級係從對照條件起10%。
註：所有的進料溶液含有約0.05重量%之聚山梨醇酯80且維持在約16℃下，除非另有註明。
C.最終測量
散裝粉末的可呼吸部分(RF/充量)為空氣動力學性能及微粒子大小分布之量度且藉由以安德遜級聯衝擊器測試而測定。為了獲得RF/充量值，將藥匣以散裝粉末填充且經由MEDTONE吸入器以約30公升/分鐘排出。將在每一吸入器階段所收集之粉末秤重且將所收集之全部粉末標準化成填充在藥匣中的總量。據此，RF/充量為在那些衝擊器階段所收集之粉末，以可呼吸部分除以裝載於藥匣中的粉末表示。
微粒子之比表面積(SSA)係藉由使用比表面積分析儀(MICROMERITICS TriStar 3000 Surface Area and Porosity Analyzer)以氮的吸附測定且以BET(Brunauer-Emmett-Teller)表面積的方式記述。比表面積係取決於晶體大小及微粒子基質之密度(ρ)而定，且與FDKP晶體之特徵大小L成反比：
II.進料濃度對比表面積之作用
測量在5%及10%研究中所製備之所有粉末的比表面積。比表面積係以線性回歸方程式預測(參閱圖3)。預測值之標準偏差就5%研究而言為±2平方公尺/公克及就10%研究而言為±5.6平方公尺/公克。該等結果與理論預期值一致：較高的FDKP濃度、較高的HOAc濃度或較低的氨濃度係藉由促進晶體成核而增加比表面積(生產較小的晶體)。
III.溫度作用
溫度對粒子性質之作用係以一系列研究予以調查，其中將除了溫度以外的進料濃度特徵設定成對照條件。進料溶液溫度範圍係從4-32℃。同時測定微粒子粉末之比表面積及所得微粒子粉末之RF/充量。
將RF/充量、比表面積及溫度交叉繪製於表5中。(RF/充量係以含有胰島素之微粒子測定；所繪製之比表面積係為就吸附胰島素之前的粒子所測定者)。微粒子粉末之RF/充量係在接近約18℃至約19℃時達到最大(圖5A)。虛曲線為預測值之單側95%之下可靠界限(亦即預料在曲線上的值具有95%之或然率)。約12℃至約26℃之溫度範圍會提供在95%之可靠度下＞40%之RF/充量。當RF/充量係相對於空白(不含藥物)微粒子粉末之比表面積繪製時(圖5B)，則所得曲線類似於就溫度繪製之曲線。然而，點的次序相反。(例如，樣品〝A〞現在出現在軸的右端，而樣品〝B〞係出現在左端。)具有26-67平方公尺/公克之比表面積之微粒子提供在95%之可靠度下＞40%之RF/充量。藉由說明溫度與比表面積之間的關係(圖5C)，確認約13℃至約23℃之略窄但內部一致的溫度範圍用於粒子形成。
I V.比表面積對RF/充量之作用
在比表面積值大於約50平方公尺/公克下有趨向較低RF/充量值之傾向(圖6A)。可使用約62平方公尺/公克之上限，同時仍以適當的RF/充量值(亦即＞40%，圖6B)維持95%之可靠界限。
圖7顯示當比表面積向上限範圍增加時，在RF/充量之分布有加寬，且所選擇之RF/充量＞40%之準則有較高的失敗可能性。圖8a顯示具有高比表面(例如，約67平方公尺/公克)之微粒子懸浮液傾向比具有較低比表面積(例如，約＜14平方公尺/公克)之微粒子懸浮液有數量級計高的黏性，如以Brookfield黏度計(Brookfield Engineering Laboratories,Inc.,Middleboro,MA)所測量。圖8B顯示懸浮液黏度與RF/充量呈負面關係。
V.比表面積及胰島素吸附
調查比表面積與胰島素吸附之間的關係。
微粒子懸浮液係如先前以5%及10%研究批次所述而製備且裝載約11.4%胰島素。另外，亦評估以對照進料濃度但範圍從約4℃至約32℃之進料溶液溫度所形成之微粒子。經滴定之懸浮液係藉由連續添加單滴的14重量%之氨而具有從約pH 3.6上升至約pH 4.5之懸浮液pH。分析經滴定之懸浮液及上澄液之樣品的胰島素濃度。將所有的懸浮液(經滴定和未經滴定)凍乾，以生產乾粉。使用MICROMERITICS TriStar 3000測試粉末之比表面積。
在低比表面積下，在未結合胰島素之量與比表面積之間有線性關係(圖9)。當比表面積大於約35平方公尺/公克時，發生至少95%之胰島素吸附。胰島素吸附程度隨至多約40平方公尺/公克之比表面積而持續增加。大於此比表面積時，微粒子吸附了幾乎全部的胰島素。
該等研究的結果暗示約35平方公尺/公克至約62平方公尺/公克之比表面積為微粒子有利的下限及上限。提供其中大於80%，或大於90%，或大於95%之微粒子具有在此範圍內的比表面積之微粒子，提供具有在95%之可靠界限內有利的RF/充量及藥物吸附特徵之微粒子。
實施例2
藉由體積中值幾何直徑(VMGD)特徵化進行所發射之調配物的幾何粒子大小分析
從乾粉吸入器發射之乾粉調配物的雷射繞射為用於使粉末所經受之去黏聚層級特徵化之常見方法。該方法表明幾何大小而不是如工業標準衝擊方法中所呈現之空氣動力學大小之量度。典型地，所發射之粉末的幾何大小包括以中值粒子大小特徵化之體積分布，VMGD。重要的是，與藉由衝擊方法所提供之空氣動力學大小相比，所發射之粒子的幾何大小係以提高的解析度辨別。較小的大小較佳且造成個別粒子向肺部氣道輸送的較大可能性。因此，吸入器去黏聚與最終性能之差異可更容易以繞射解析。在該等實驗中，吸入器係在類似於實際病患吸入能力之壓力下以雷射繞射測試，以測定吸入系統使粉末調配物去黏聚之功效。具體而言，調配物包括有及沒有以活性胰島素裝載之成份的黏聚性二酮基哌粉末。該等粉末調配物具有特徵表面積、異構物比率及卡爾(Carr)指數。在表4中記述在測試期間之VMGD及容器排空效率。FDKP粉末具有約50之卡爾指數而TI粉末具有約40之卡爾指數。
表4中的數據顯示在以DPI 2識別之吸入器相對於MEDTONE吸入器系統中在粉末去黏聚方面的改進。表面積範圍從14-56平方公尺/公克之二酮基哌調配物證實超過85%之排空效率及小於7微米之VMGD。同樣地，異構物比率範圍從45-66%反式之調配物證實超越指定比對(predicate)裝置之改進性能。然而，值得注意的是，即使以在＜15平方公尺/公克下更有效率之吸入器，在藥匣排空率方面仍有降低，表明空氣動力學性能在反式異構物含量背離本文所揭示之所欲範圍時下降(降低)。最後，以40-50之卡爾指數特徵化之調配物使吸入器系統的性能亦顯示出超越指定比對裝置之改進。在所有情況下，所記述之VMGD值均小於7微米。
除非另有陳述，應瞭解在說明書及申請專利範圍中用以表示成分、性質之量的所有數值，諸如分子量、反應條件等等在所有例子中係以術語〝約〞修飾。據此，除非經表明與此相反，否則在下列的說明書及隨附之申請專利範圍中所陳述之數值參數為近似值，其可取決於以本發明所獲得經探索之所欲性質而改變。在最低限度下且不企圖將等效物之原理應用限制於申請專利範圍之範疇，各數值參數至少應按照經記述之有效數位之數值且藉由應用一般捨入技術予以解釋。儘管陳述本發明之寬廣範疇的數值範圍及參數為近似值，但在特定的實施例中所陳述之數值應儘可能精確地記述。然而，任何數值均與生俱來含有從其各自的測試量度中自然形成之標準偏差必然得到的某些誤差。
在說明本發明的上下文中(尤其在下列申請專利範圍的上下文中)所使用之術語〝一〞及〝該〞及類似指示物係以涵蓋單數與複數兩者予以解釋，除非本文中另有表明或以上下文明確否認。在本文之引述值範圍僅意欲適用為個別提且落於該範圍內之每一個別值之速記方法。除非在本文中另有表明，將每一個別值併入說明書中，猶如在本文中個別引述一般。在本文所述之所有方法可以任何適合的次序執行，除非本文中另有表明或以上下文明確否認。在本文提供之任何及所有實施例或例示性語言(例如〝諸如〞)的使用僅欲更好地闡明本發明且不對以其他方式主張之本發明範疇造成限制。在說明書中沒有任何語言應被解釋為表明實施本發明必要的任何未主張要素。
在申請專利範圍中使用的術語〝或〞係用於意謂〝及/或〞，除非明確地表明係指僅有的替代物或替代物互不相容，雖然本揭示內容支持係指僅有的替代物及〝及/或〞之定義。
本文所揭示之本發明的替代要素或具體實例之分類不應被解釋為限制本發明。每一組成員可個別地或以與該組之其他成員或本文所見之其他要素的任何組合形式提及及主張。基於便利性及/或專利性之原因而預料組中之一或多個成員可包括於組中或自組中刪除。當任何此等包括或刪除發生時，則本說明書在本文被認為含有如此修改之組，因此滿足在隨附之申請專利範圍中所使用之所有馬庫西群組(Markush group)之書寫說明。
本發明的較佳具體實例說明於本文中，包括本發明者已知用於進行本發明的最好模式。當然，針對那些較佳的具體實例之變化將為那些在所屬技術領域中具有通常知識者在一經閱讀前述說明時所明白。本發明者預料那些在所屬技術領域中具有通常知識者在適當時使用此等變化，且本發明者想要使本發明以不同於本文特別說明的方式實施。據此，本發明包括隨附於本文的申請專利範圍中所引述之標的物的所有以適用法允許之修改及等效物。此外，本發明包含上述要素以其所有可能的變化之任何組合，除非本文中另有表明或以上下文明確否認。
本文所揭示之特定的具體實例可在申請專利範圍中使用由...組成或基本上由...組成之語言進一步做限制。當在申請專利範圍中使用時，無論在申請或每次修正增加時，過渡用語〝由...組成〞不包括在申請專利範圍中未指明之任何要素、步驟或成分。過渡用語〝基本上由...組成〞係使申請專利範圍之範疇限制於指明之物質或步驟及不實質影響基本和新穎特徵之物質或步驟。如此主張之本發明的具體實例在本文係固有或明確地說明且得據以實施。
此外，在本說明書中全篇已參考諸多專利及發表之公開案。將每一以上引述之參考文獻及發表之公開案的全部內容以引用方式個別納入本文中。
此外，應瞭解本文所揭示之本發明的具體實例為本發明原理之例證。可使用之其他修改係在本發明的範疇內。因此，可依照本文之教示以實施例方式使用本發明的替代組態，並非限制本發明。據此，本發明不完全受限於經顯示與說明者。
下列的圖式構成本說明書的一部分，且係被包括以進一步證實本文所揭示之實施例的某些觀點。揭示內容可藉由參考一或多個圖式配合本文所呈現之特定具體實例之詳細說明而更為瞭解。
圖1A及1B描繪分別具有高及低比表面積(SSA)之微粒子。
圖2描繪具有大體上球粒形態之反丁烯二醯基二酮基哌(FDKP)微粒子。
圖3提供FDKP製造方法之示意圖。
圖4A及4B描繪根據圖3中所顯示之示意圖製造之微粒子/胰島素粉末之預估和實際的SSA。
圖5A-C描繪在RF/充量、(FDKP微粒子之)SSA與進料溶液溫度之間的關係。
圖6A描述在RF/充量與微粒子/胰島素粉末之間的關係且顯示SSA＞約62平方公尺/公克之粉末具有5%之RF/充量＜40%之或然率。圖6B顯示由於從進料濃度預測SSA的不確定性而以SSA為製造目標。
圖7描繪與微粒子/胰島素粉末之SSA為函數關係之RF/充量。每一點代表不同批次之微粒子/胰島素粉末。
圖8A描繪微粒子/胰島素粉末之SSA對約4%固體之微粒子懸浮液的視黏度之作用。圖8B描繪懸浮液黏度與粉末性能之間的關係。
圖9描繪與FDKP微粒子之SSA為函數關係之上澄液中之胰島素濃度。

Claims (48)

  1. 一種包含二酮基哌之微粒子，其中該微粒子具有從約35平方公尺/公克至約67平方公尺/公克之比表面積。
  2. 根據申請專利範圍第1項之微粒子，其中該微粒子包含藥物或活性劑。
  3. 根據申請專利範圍第2項之微粒子，其中該比表面積小於約62平方公尺/公克。
  4. 根據申請專利範圍第3項之微粒子，其中該藥物或活性劑為肽或蛋白質。
  5. 根據申請專利範圍第4項之微粒子，其中該肽為內分泌激素。
  6. 根據申請專利範圍第5項之微粒子，其中該內分泌激素為胰島素、副甲狀腺激素、抑鈣素、升糖素、類升糖素肽-1、調酸催素及該內分泌激素之類似物或活性片段。
  7. 根據申請專利範圍第6項之微粒子，其中該內分泌激素為胰島素。
  8. 根據申請專利範圍第6項之微粒子，其係呈乾粉形式。
  9. 根據申請專利範圍第6項之微粒子，其中該內分泌激素為胰島素之類似物或活性片段。
  10. 根據申請專利範圍第6項之微粒子，其中該內分泌激素為類升糖素肽-1或其類似物或活性片段。
  11. 根據申請專利範圍第1項之微粒子，其具有從約40平方公尺/公克至約67平方公尺/公克之比表面積。
  12. 根據申請專利範圍第1項之微粒子，其具有從約45平方公尺/公克至約67平方公尺/公克之比表面積。
  13. 根據申請專利範圍第1項之微粒子，其具有從約35平方公尺/公克至約56平方公尺/公克之比表面積。
  14. 根據申請專利範圍第1項之微粒子，其具有從約45平方公尺/公克至約56平方公尺/公克之比表面積。
  15. 根據申請專利範圍第9項之微粒子，其中該內分泌激素為胰島素之類似物。
  16. 根據申請專利範圍第15項之微粒子，其中該微粒子包含約10至15%重量之胰島素。
  17. 根據申請專利範圍第5項之微粒子，其中該內分泌激素為艾生丁(exendin)。
  18. 根據申請專利範圍第7項之微粒子，其中該微粒子包含3-4U/毫克之胰島素。
  19. 根據申請專利範圍第16項之微粒子，其中該微粒子包含約11%之胰島素。
  20. 根據申請專利範圍第2項之微粒子，其中該藥物或活性劑佔微粒子重量的約0.01%至約20%。
  21. 一種乾粉，其包含申請專利範圍第20項之微粒子。
  22. 一種乾粉，其包含申請專利範圍第3項之微粒子。
  23. 一種包含包含二酮基哌之微粒子之組成物，其中該微粒子具有從約40平方公尺/公克至約67平方公尺/公克之比表面積。
  24. 根據申請專利範圍第23項之組成物，其中活性劑存 在於微粒子表面。
  25. 根據申請專利範圍第24項之組成物，其中該活性劑係內分泌激素、血管活性劑、神經活性劑、激素、抗凝劑、免疫調節劑、胞毒劑、抗生素、抗病毒劑、抗原、感染劑、免疫調節劑、激素或細胞表面抗原。
  26. 根據申請專利範圍第24項之組成物，其中該活性劑係胰島素。
  27. 根據申請專利範圍第26項之組成物，其中該微粒子包含約11%重量之胰島素。
  28. 根據申請專利範圍第24項之組成物，其中該活性劑係GLP-1。
  29. 根據申請專利範圍第24項之組成物，其中該活性劑佔微粒子重量的約0.01%至約20%。
  30. 根據申請專利範圍第23項之組成物，其中該微粒子的至少一部份係晶體。
  31. 根據申請專利範圍第24項之組成物，其中該微粒子具有從約40平方公尺/公克至約62平方公尺/公克之比表面積。
  32. 根據申請專利範圍第23項之組成物，其中該微粒子包含在約13℃至約23℃之溫度下藉由自水溶液結晶形成的二酮基哌晶體。
  33. 一種二酮基哌微粒子用於製造藥品的用途，該藥品係藉由病患吸入乾粉而將活性劑輸送至需要其之病患中，該微粒子具有範圍從約40平方公尺/公克至約67平方 公尺/公克之比表面積，且該微粒子以藥物或活性劑裝載。
  34. 根據申請專利範圍第33項之用途，其中該活性劑係內分泌激素，其選自由胰島素、副甲狀腺激素、抑鈣素、升糖素、類升糖素肽-1、調酸催素及該內分泌激素之類似物或活性片段所組成之群。
  35. 根據申請專利範圍第33項之用途，其中該病患經診斷患有糖尿病。
  36. 一種吸入系統，其包含呼吸驅動之吸入器及包含二酮基哌微粒子的乾粉，該微粒子具有範圍從約40平方公尺/公克至約67平方公尺/公克之比表面積。
  37. 根據申請專利範圍第36項之吸入系統，其中該乾粉係提供在單位劑量藥匣中。
  38. 根據申請專利範圍第36項之吸入系統，其中該乾粉係預填充於吸入器中提供。
  39. 根據申請專利範圍第36項之吸入系統，其包含1至30毫克之該乾粉。
  40. 根據申請專利範圍第36項之吸入系統，其中可呼吸部分/充量值大於40%。
  41. 根據申請專利範圍第40項之吸入系統，其中可呼吸部分/充量值大於50%。
  42. 根據申請專利範圍第41項之吸入系統，其中可呼吸部分/充量值大於60%。
  43. 根據申請專利範圍第36項之吸入系統，其另外包含活性劑，其中該活性劑包含內分泌激素，其選自由胰島素、 副甲狀腺激素、抑鈣素、升糖素、類升糖素肽-1、調酸催素及該內分泌激素之類似物或活性片段所組成之群。
  44. 根據申請專利範圍第36項之吸入系統，其另外包含活性劑，其中該活性劑包含胰島素。
  45. 一種申請專利範圍第36項之吸入系統的用途，其用於將活性劑輸送至需要其之病患中，其微粒子以藥物或活性劑裝載。
  46. 根據申請專利範圍第1至20項中任一項之微粒子，其中該微粒子包含2,5-二酮基-3,6-雙(N-琥珀醯基-4-胺基丁基)哌、2,5-二酮基-3,6-雙(N-順丁烯二醯基-4-胺基丁基)哌、2,5-二酮基-3,6-雙(N-戊二醯基-4-胺基丁基)哌、2,5-二酮基-3,6-雙(N-丙二醯基-4-胺基丁基)哌、2,5-二酮基-3,6-雙(N-乙二醯基-4-胺基丁基)哌或2,5-二酮基-3,6-雙(N-反丁烯二醯基-4-胺基丁基)哌。
  47. 根據申請專利範圍第1至20項中任一項之微粒子，其中該微粒子包含2,5-二酮基-3,6-雙(N-反丁烯二醯基-4-胺基丁基)哌。
  48. 一種吸入系統，其包含呼吸驅動之吸入器及包含微粒子的乾粉，該微粒子包含2,5-二酮基-3,6-雙(N-反丁烯二醯基-4-胺基丁基)哌及胰島素，其中該微粒子包含約10%至15%胰島素，其中微粒子的比表面積係從約35平方公尺/公克至約62平方公尺/公克，且其中該乾粉係提供在單位劑量藥匣中。
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