TWI742004B - 矽酸鋯組合物的延伸用途與其使用方法 - Google Patents
矽酸鋯組合物的延伸用途與其使用方法 Download PDFInfo
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- TWI742004B TWI742004B TW105132645A TW105132645A TWI742004B TW I742004 B TWI742004 B TW I742004B TW 105132645 A TW105132645 A TW 105132645A TW 105132645 A TW105132645 A TW 105132645A TW I742004 B TWI742004 B TW I742004B
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Abstract
本發明係關於具有0.6 ppm以下之鉛含量之矽酸鋯組合物以及在容積為200L以上之反應器中製備具有1.1 ppm以下之鉛含量之矽酸鋯之方法。本發明之矽酸鋯的鉛含量在被認為適用於長期使用地給予所需劑量之矽酸鋯之程度的範圍內。
Description
本發明係一種配製以提升之速率從腸胃道移除毒素(例如，鉀離子或銨離子)而不引發不期望的副作用之新型微孔矽酸鋯組合物。此組合物被製備成呈現用於長期給予以治療或預防某些病症(高血鉀)的復發或發生之所需的特性。
急性高血鉀症是血鉀濃度升高所導致之具有嚴重生命威脅的病症。鉀離子為參與人體中許多機制之普遍存在的離子。鉀離子係含量最多的人體細胞內陽離子，且對於包含維持細胞膜電位、平衡細胞體積以及傳輸動作電之許多生理機制而言至關重要。主要的膳食來源為蔬菜(番茄和馬鈴薯)、水果(橘子、香蕉)以及肉類。血漿中正常的鉀離子濃度在3.5-5.0mmol/l之間，以腎臟為鉀離子濃度的主要調節器官。腎臟排泄鉀離子係被動的(透過腎小球)，且在近端小管及亨利氏環的上升肢中主動再吸收。鉀離子在原端小管及集尿管中主動排泄，此二機制皆由醛固酮控制。
細胞外鉀離子濃度的增加導致細胞膜電位的去極化反應。去極化反應會開啟電壓依賴型鈉離子通道，但不足以產生動作電位。經過一小段時間
後，開啟之鈉離子通道失去活性且變得不反應，增加閥值以產生動作電位。此將造成神經肌肉系統、心臟系統、腸胃道器官系統的損壞，且這些損壞將導致在高血鉀症患者身上看到的症狀。最令人擔憂的是對心臟系統的影響，其中對心臟傳導的損壞可造成致命性的心律不整，像是心搏停止或心室纖維顫動。由於高血鉀症有造成致命性的心律不整的可能，高血鉀症表示需要立刻救治的急性代謝性急症。
在血鉀過度產生時(口服攝、組織分解)會發展成高血鉀症。最常見導致高血鉀症的排泄功能失去效用的可為荷爾蒙(像是醛固酮分泌不足)、藥理上的(以ACE-抑制劑或血管張力素受體阻滯劑(angiotensin receptor blockers)治療)或更常見的是腎功能降低及重度心臟衰竭。最常見造成高血鉀症之原因為腎功能不全，且腎衰竭的程度與血鉀濃度(S-K level)間有高度相關性。此外，許多不同的常用藥也會導致高血鉀症，像是ACE抑制劑、血管張力素受體阻滯劑、保鉀利尿劑(如：阿米洛利(amiloride)、螺內酯(spironolactone))、NSAIDs(如：布洛芬(ibuprofen)、萘普生(naproxen)、希樂葆(celecoxib))、肝素及細胞毒性藥及/或抗生素藥物(如：環孢素(cyclosporin)及甲氧芐啶(trimethoprim))。最後，β受體阻斷劑、地高辛(digoxin)或琥珀膽鹼(succinylcholine)的使用亦為常見造成高血鉀症的原因。此外，與代謝性酸中毒(其最常見為糖尿病造成的酮酸中毒的一部分)相同，重度的鬱血性心臟衰竭或是大量的外傷、燒傷或是血管內溶血可造成高血鉀症。
高血鉀症的症狀有些不具體且一般而言包含不適、心悸、肌肉無力、或是心律不整徵兆，像是心悸、心搏過速過緩或是頭暈/昏厥。然而，通常
高血鉀症會在醫療疾病的常態性血液篩查期間或在已發展為像是心律不整或猝死之嚴重的併發症之後被發現。診斷係由S-K測量明確的判定。
治療取決於S-K濃度。在輕微的情況下(S-K在5-6.5mmol/l之間)會以使用鉀離子結合樹脂凱鉀力寧散(Kayexalate®)配合飲食建議(低鉀飲食)，以及可能對藥物治療進行調整(如果有以會導致高血鉀症的藥物進行治療)的急性治療作為護理標準；如果S-K高於6.5mmol/l，或是出現心律不整，則須強制緊急降低鉀離子濃度並在醫院環境下緊密監控。以下為常用治療：
凱鉀力寧散，為結合腸道內鉀離子，並因此促進糞便排泄，從而降低S-K濃度的樹脂。然而，凱鉀力寧散已被證實會導致腸梗阻和潛在的腸破裂。另外，需要與治療同步地誘導腹瀉。此些因素降低了以凱鉀力寧散治療的適口性。
胰島素IV(加入葡萄糖以避免低血糖)，其鉀離子移進細胞並將鉀離子自血液移除。
補充鈣離子。鈣離子不會降低S-K濃度，但鈣離子會降低心肌興奮性從而穩定心肌，降低心律不整的風險。
碳酸氫鹽(Bicarbonate)。碳酸氫根離子將刺激K+與Na+的交換，從而導致鈉-鉀ATP酶的刺激，在嚴重情況下透析。
唯一以藥理學之方式實際促進體內鉀離子含量減少的為凱鉀力寧散，然而，因為有誘導腹瀉之需求，因此凱鉀力寧散不能長期給藥，且即使在急性情況下，誘導腹瀉之需求加上僅具有邊際效益和惡臭和味道，降低其有用性。
在全部內容皆整合於本文中之美國專利號6,579,460、6,099,737、6,332,985以及2004/0105895中揭露矽酸鋯或矽酸鈦微孔離子交換劑用於自血液或透析液以移除毒性陰離子及陽離子之用途。微孔離子交換劑的其他實例可在全部內容皆整合於本文中之美國專利號6,814,871、5,891,417以及5,888,472中找到。
發明人發現已知的矽酸鋯組合物在用於體內以於高血鉀症的治療中移除鉀離子時，可能呈現不想要的效果。具體而言，發明人發現矽酸鋯分子篩組合物的施予與混合性白血球炎症、輕度的急性膀胱炎症(minimal acute urinary bladder inflammation)和在動物研究中觀察到在腎盂和尿中的不明晶體的發生率，以及尿液pH的增加相關。發明人藉由控制矽酸鋯組合物的粒子大小以及鈉含量來處理上述問題。參考全部內容皆整合於本文中之美國專利號8,802,152及8,808,750。
另外，已知矽酸鋯組合物具有結晶雜質及不理想的低陽離子交換量的問題。更多可溶性形式的矽酸鋯的減少對於減少或消除鋯以及矽酸鋯的全身吸收而言是重要的。發明人藉由以從組合物實質上消除ZS-8(導致無法測得程度的ZS-8)的方式控制生產條件來處理此些問題。請參照美國專利號8,877,255。
發明人已發現幾種矽酸鋯組合物可用於長期治療，如用於與血鉀濃度升高相關病症的治療。在長期醫療方案中使用矽酸鋯時須注意控制組合物中的雜質，尤其是鉛。食品藥物管理署規定長期使用的組合物中鉛的攝取標準為每日5微克。發明人已發現使用習知的方式產出之工業量的矽酸鋯含有約1-1.1ppm或更多的鉛。即使以少量、高純度製備的矽酸鋯(使用可購自Sigma-Aldrich之試驗級起始材料)仍發現鉛的含量為0.6ppm或更多。由於矽酸鋯治療使用劑量
為每日5至45克，因此需要降低鉛含量。本發明關於具有一種矽酸鋯組合物，其具有矽酸鋯的每日劑量所需的可接受範圍內的鉛含量。
本發明係關於一種陽離子交換組合物，其包含式(I)之矽酸鋯：ApMxZr1-xSinGeyOm (I)
A為鉀離子、鈉離子、銣離子、銫離子、鈣離子、鎂離子、水合氫離子或其混合物。
M為至少一骨架金屬，其中骨架金屬可為鉿(4+)、錫(4+)、鈮(5+)、鈦(4+)、鈰(4+)、鍺(4+)、鐠(4+)、鋱(4+)或其混合物。
“p”具有約1至約20的值。
“x”具有0至小於1的值。
“n”具有約0至約12的值。
“y”具有0至約12的值。
“m”具有約3至約36的值，且1
n+y
12。
其中組合物呈現低於0.6ppm之鉛含量。較佳地，鉛含量在0.1至0.6ppm之範圍內，更佳地，鉛含量在0.3至0.5ppm之範圍內，最佳地，鉛含量在0.3至0.45ppm之範圍內。在一個實施例中，鉛含量為0.38ppm。本發明亦關於在容積為200L或超過200L之反應器中製備鉛含量低於1.1ppm之矽酸鋯之方法。在此實施例中，鉛含量的範圍在0.1至1.1ppm，較佳地在0.3至0.5ppm，更佳地在0.3至0.45ppm。
除了具有理想程度之鉛雜質以外，組合物可呈現使其合乎作為口服攝入離子阱(orally ingested ion trap)之需求的一或多種特性。在一態樣中，此矽
酸鋯組合物可具有超過2.3meq/g的鉀離子交換量，較佳地，在2.3至3.5meq/g範圍內的鉀離子交換量，更佳地，在3.05至3.35meq/g範圍內的鉀離子交換量，且最佳地，為約3.2meq/g的鉀離子交換量。在一個實施例中，組合物中少於7%的顆粒具有小於3微米的直徑。在另一個實施例中，組合物中少於0.5%的顆粒具有小於1微米的直徑。較佳地，含鈉含量低12wt%，且更佳地低於9wt%或更少。較佳地，所述之矽酸鋯呈現具有在約15.5及28.9處產生兩個最高峰的XRD衍射圖，其中最高峰在28.9處產生。較佳地，材料為ZS-9或主要為ZS-9，具有在7至9之範圍內之pH值，且鉀離子承載量在2.7至3.7mEq/g之間，最佳地，鉀離子承載量為約3.5mEq/g。
本發明亦關於給予上述矽酸鋯組合物之方法。在一較佳的實施例中，在多於5天的連續天數的週期期間給予矽酸鋯組合物。
200:反應器
201:攪拌器
204:檔板
第1圖係顯示矽酸鋯Na2.19ZrSi3.01O9.11*2.71H2O(分子量420.71)之結構的多面體圖。
第2圖係顯示用於製備矽酸鋯之具有檔板之反應容器的示意圖。
第3圖係顯示用於製備矽酸鋯之加工設備的圖。
第4圖係顯示根據實例3製備之矽酸鋯之粒徑分布之圖。
第5圖係顯示根據實例3製備之矽酸鋯之XRD圖。
發明人發現處理長期使用組合物之需求的新式矽酸鋯分子篩吸收劑具有低雜質分布。所述之矽酸鋯組合物符合前述矽酸鋯組合物的性能標準，亦呈現減少之雜質(特別是鉛)，使組合物適於長期使用。
發明人設計用於大量生產高純度、高KEC的ZS-9結晶的反應器。參考美國專利號8,802,152；8,808,750；及8,877,255。反應器200在其側壁上具有檔板結構204，檔板結構204與攪拌器201結合以在反應期間提供結晶的拉伸(lift)及懸浮並產生高濃度、高KEC ZS-9結晶。第2圖，除了檔板結構204以外該改良之反應器亦設有控制結晶期間的反應溫度之冷卻或加熱套。較佳地，該反應器具有至少20L的容積，更佳地至少200L、500L、2000L或5000L，且介於200L至30,000L的範圍內。
第3圖顯示生產矽酸鋯的製備流程。於反應器中加入矽酸鹽來源(silicate source)。習知製程能夠使用矽酸鈉作為矽酸鹽來源而生產用於口服之具有所需特性之矽酸鋯。製程亦使用加入如第3圖所示之反應器之50% NaOH溶液、水以及醋酸鋯。亦顯示其中進料原始之矽酸鋯產物之乾燥器。將矽酸鋯進行清洗、質子化及在乾燥器中乾燥以產生所需的矽酸鋯以及廢液。
如以下實施例二中之討論，矽酸鹽來源為膠體二氧化矽(Ludox®)而非矽酸鈉。發明人發現替換習知製程中之矽酸鈉無法有效地生產更高品質的矽酸鋯。本發明係以發明人對於反應器中不應該先填入膠體二氧化矽，而應該加入預先混合之氫氧化鈉及水的發現為基礎。此外，攪拌速率需在加入膠體二氧化矽後增加至少20分鐘來打斷二氧化矽的鍵結並獲得攪拌良好的溶液。本發明製程的其他態樣可透過參照以下實施例二來理解。
根據本發明之矽酸鋯呈現低於1ppm的鉛含量。優選地鉛含量介於0.1至0.8ppm，更優選地介於0.3至0.6ppm，最優選地介於0.3至0.45ppm的範圍內。在一個實施例中，鉛含量為0.38ppm。
比較例1
高容量ZS-9結晶係根據以下具代表性的實施例製備。
反應物準備如下：22L之Morton燒瓶裝有頂部攪拌器、熱電偶和平衡加料漏斗。於燒瓶中注入去離子水(8,600g，477.37莫耳)。一開始以約145-150rpm攪拌並加入氫氧化鈉(661.0g，16.53莫耳NaOH，8.26莫耳Na2O)於燒瓶中。燒瓶內物質在氫氧化鈉溶解時於3分鐘期間由24℃放熱至40℃。將溶液攪拌一小時以使一開始的放熱消退。加入矽酸鈉溶液(5,017g，22.53莫耳SO2，8.67莫耳Na2O)。矽酸鈉可自Sigma-Aldrich購入。透過加料漏斗之手段於30分鐘期間加入醋酸鋯溶液(2,080g，3.76莫耳ZrO2)於溶液中。所得之懸浮液再攪拌30分鐘。
將混合物移到5-G Parr壓力容器4555型(5-G Parr pressure vessel Model 4555)中並加入去離子水(500g，27.75莫耳)。反應器裝上具有蛇形結構的冷卻盤管以相鄰於攪拌器提供反應器內之類檔板結構。當冷卻盤管在此反應中僅用以提供相鄰於攪拌器之類檔板結構時並未填充熱交換液體。
容器被密封，且反應混合物以約230至235rpm攪拌，並於7.5小時期間從21℃升溫到140至145℃，並將溫度在140至150℃維持10.5小時，接著在6.5小時期間升溫到210至215℃，其中獲得295至300psi的最大壓力，接著在210至215℃維持41.5小時。隨後在4.5小時期間將反應器降溫到45℃。將所得之白色固體藉由添加去離子水(1.0KG)來過濾。固體以去離子水(40L)沖洗到洗脫濾液的pH值低於11(10.54)。濕濾餅的代表性部分(representative portion)在真空(25英吋汞柱)中以100℃乾燥隔夜，以為得到白色固體之1,376g(87.1%)的ZS-9。
如美國專利號8,802,152中所討論的，此比較例的特定反應器結構及製程條件證實可達成較高容量之矽酸鋯。舉例而言，相較於進達成1.7至2.3meq/g範圍內之容量之習知製程，本發明可達成3.8至3.9meq/g範圍內之容量。
然而，發明人發現根據此比較例產生之材料呈現0.6ppm的含鉛量。含鉛量以感應耦合電漿-質譜儀(Inductively Coupled Plasma-Mass Spectrometry,ICP-MS)測定。此樣品以含0.1g稱重部分混合0.5mL氫氟酸、2mL硝酸、1mL鹽酸及1mL純水。將樣品使用封閉容器微波系統在最高200℃下浸煮(digested)至材料出現溶解。冷卻後加入內標準液並以純水稀釋到50g以產生供ICP-MS檢測的溶液。
矽酸鋯產物中主要的鉛來源係來自反應物醋酸鋯及矽酸鈉。此比較例說明就算以試劑級材料(矽酸鹽、醋酸鋯)為原料，鉛含量依然超出可接受量。
實例2
本實例說明以矽酸鈉及醋酸鋯於500L之反應器生產矽酸鋯。加入矽酸鈉(148.8kg)及水(100.1kg)到500L之反應器中，並以200rpm攪拌。加入氫氧化鈉(37.7kg)及剩餘的水(100.2kg)。將攪拌速率降到80rpm並加入醋酸鋯(62.0kg)及水(49.4kg)，並使反應器混合25至35分鐘。將反應器加熱以於140rpm在210±5℃反應材料48小時以上。將所得材料質子化到pH 4.75至5.25，並乾燥到含水率
5.0%。
組合物具有21.8微米之體積加權平均及13.56微米之表面加權平均。1微米以下者低於材料體積的0.05%，而3微米以下者低於1.41%。所得材料呈現出ZS-9之特徵XRD圖。5至10之2θ範圍內不存在峰值表示沒有可測得濃度的ZS-8。如發明人過往專利中所述，具有減少量之顆粒細粉以及缺乏可溶形式之矽酸鋯(ZS-8)之本材料，適用於口服給藥，例如用於治療高血鉀症中之口服給藥。
然而，發明人發現根據此實例產生之材料呈現高於給予藥物所需劑量適合含量之鉛含量。參考以下表2。具體而言，發現所得產物具有1.0ppm之鉛含量。矽酸鋯產物中鉛的主要來源係來自於反應物醋酸鋯(0.28ppm)及矽酸鈉(0.38ppm)。無法商業規模地得到具有更低鉛含量之醋酸鋯形式。雖然發現其他
形式之矽酸鹽，膠體二氧化矽，具有無法測出之濃度的鉛，但膠體二氧化矽不適用於與醋酸鋯反應以形成矽酸鋯之上述製程中。發明人發現當不控制試劑中之鉛含量時(可能在大量供應這些試劑的情況下)，最終產物傾向具有較高之鉛含量。當反應在反應器容積為200L及500L的規模下進行時，觀察到在1至1.1ppm數量級的類似之鉛含量。
實例3
本實例說明自醋酸鋯及膠體二氧化矽於500L反應器中反應製備矽酸鋯之方式。發明人發現為使膠體二氧化矽與醋酸鋯反應，製呈需要包含額外的步驟以及不同的攪拌速率。舉例來說，使用膠體二氧化矽之製程需要增加攪拌(200rpm)20分鐘以上的步驟來打斷二氧化矽的鍵結並得到混合良好的溶液。發明人發現透過此製程可將鉛含量減低至低於1ppm，且如下述在500L反應器中可低至0.38ppm。
氫氧化鈉(97.2kg)與84.5kg的水混合並以150rpm攪拌，同時加入108.8kg的膠體二氧化矽(Ludox®)。以相同之速率持續攪拌，同時以10.5kg的水從加料管線(charge line)將膠體二氧化矽洗入反應器中。當膠體二氧化矽加入反應器後，將攪拌速率提升到200rpm至少20分鐘以打斷二氧化矽的鍵結並得到混合良好的溶液。將攪拌速率降到100rpm同時加入52.9kg的水，隨後再將攪拌速率提升到200rpm至少五分鐘。
接著將攪拌速率降到150rpm，同時在約30分鐘的週期期間加入81.0kg的醋酸鋯。加入水(62.8kg)並在加熱前持續攪拌30分鐘。
盡快將反應器升溫到210℃，同時以150rpm混合。將反應器於210±5℃維持至少36小時。完成後，將材料質子化兩次至pH值介於4.75至5.25的範圍之間。藉由以160℃加熱30分鐘將材料乾燥至含水率低於5%。
根據本實例製備所得之矽酸鋯之粒徑分布示於第4圖。組合物呈現約2%低於3微米的粒徑分布。XRD圖顯示ZS-9之特徵，其包含在約15.5及28.9產生兩個最高峰，其中在28.9產生最高峰。5至10之2θ範圍內不存在峰值表示沒有可測得濃度的ZS-8。參見第5圖。所得之矽酸鋯為基本上無碎片及細項(particulars)之白色流動性粉末(free flowing powder)。FTIR光譜在約799與917cm-1處顯示有吸收帶(band)，其與先前可接受之批次一致。適合之FTIR光譜顯示於發明人過往專利中。所得材料之pH值為9。測得之鉀離子承載量(potassium loading capacity)為3.5mEq/g。其中鋯含量為約21.7%、矽含量為約17%、鈉含量約為7.3%。最終產物之含水率為5%。
透過上述製程利用膠體二氧化矽產生之最終產物中之含鉛量為0.38ppm，此為用於長期給予此組合物之適合的含量。
藉由參考本說明書及實踐本文中所揭露之發明，本發明的其他實施例及其用途對於領域中具有通常知識者而言為顯而易見的。本文引用之所有參考文獻，包含美國及其他國家之專利及專利申請，藉由參照完整且明確整合於本文中。說明書及所揭露之實例僅為示例，本發明實際之精神及範疇由所附之申請專利範圍表明。
Claims (20)
- 一種陽離子交換組合物，其包含式(I)之矽酸鋯：ApMxZr1-xSinGeyOm (I)其中A為鉀離子、鈉離子、銣離子、銫離子、鈣離子、鎂離子、水合氫離子或其混合物，M為至少一骨架金屬，其中該骨架金屬為鉿(4+)、錫(4+)、鈮(5+)、鈦(4+)、鈰(4+)、鍺(4+)、鐠(4+)、鋱(4+)或其混合物，“p”具有1至20的值，“x”具有0至小於1的值，“n”具有0至12的值，“y”具有0至12的值，“m”具有3至36的值，且1n+y
12，其中該矽酸鋯呈現低於0.6ppm的鉛含量，且其中鉀離子承載量在2.7及3.7mEq/g之間。
- 如申請專利範圍第1項所述之組合物，其中該鉛含量在0.1至0.5ppm之範圍內。
- 如申請專利範圍第1項所述之組合物，其中該鉛含量在0.3至0.5ppm之範圍內。
- 如申請專利範圍第1項所述之組合物，其中該鉛含量在0.3至0.45ppm之範圍內。
- 如申請專利範圍第1項所述之組合物，其中該組合物包含少於 7%之直徑小於3微米的顆粒。
- 如申請專利範圍第5項所述之組合物，其中在該組合物中少於0.5%的顆粒具有小於1微米的直徑。
- 如申請專利範圍第1項所述之組合物，其中該組合物包含少於7%之直徑小於3微米的顆粒，且鈉含量低於12%。
- 如申請專利範圍第1項所述之組合物，其中該組合物包含少於7%之直徑小於3微米的顆粒，且鈉含量為9%或更低。
- 如申請專利範圍第1項所述之組合物，其中該矽酸鋯之pH值在7至9之範圍內。
- 如申請專利範圍第1項所述之組合物，其中該鉀離子承載量為3.5mEq/g。
- 如申請專利範圍第1項所述之組合物，其中該組合物包含約2%之直徑小於3微米的顆粒。
- 如申請專利範圍第1項所述之組合物，其中該矽酸鋯主要為ZS-9。
- 一種治療高血鉀症的藥劑，其包含如申請專利範圍第1項所述之組合物。
- 一種陽離子交換組合物，其包含式(I)之矽酸鋯：ApMxZr1-xSinGeyOm (I)其中A為鉀離子、鈉離子、銣離子、銫離子、鈣離子、鎂離子、水合氫離子或其混合物，M為至少一骨架金屬，其中該骨架金屬為鉿(4+)、錫(4+)、鈮 (5+)、鈦(4+)、鈰(4+)、鍺(4+)、鐠(4+)、鋱(4+)或其混合物，“p”具有1至20的值，“x”具有0至小於1的值，“n”具有0至12的值，“y”具有0至12的值，“m”具有3至36的值，且1n+y
12，其中該矽酸鋯主要為ZS-9且呈現在0.1至低於0.6ppm之範圍內的鉛含量，且具有在2.7及3.7mEq/g之間的鉀離子承載量。
- 如申請專利範圍第14項所述之組合物，其中該鉛含量在0.3至0.45ppm之範圍內。
- 如申請專利範圍第14項所述之組合物，其中該組合物包含少於7%之直徑小於3微米的顆粒。
- 如申請專利範圍第16項所述之組合物，其中在該組合物中少於0.5%的顆粒具有小於1微米的直徑。
- 如申請專利範圍第14項所述之組合物，其中該組合物包含少於7%之直徑小於3微米的顆粒，且鈉含量低於12%。
- 如申請專利範圍第14項所述之組合物，其中該組合物包含少於7%之直徑小於3微米的顆粒，且鈉含量為9%或更低。
- 如申請專利範圍第14項所述之組合物，其中該矽酸鋯之pH值在7至9之範圍內。
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