TWI486178B - 含有羧基乙烯基聚合物之奈米粒子懸浮液 - Google Patents
含有羧基乙烯基聚合物之奈米粒子懸浮液 Download PDFInfo
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Description
本案依美國專利法第119節請求提申於2009年12月3日之美國臨時申請案第61/266,368號的優先權,其全部內容併入本文作為參考。
本發明係關於用於眼科藥物輸送之組成物,且更特別地係關於包含羧基乙烯基聚合物、半乳甘露聚糖及硼酸鹽之奈米粒子懸浮液。
用於眼科適應症之醫藥品的局部投藥一般係以容易使用及病患順從性為較佳。具有生理上互溶的pH及滲透壓之水性溶液係此類輸送系統之代表。然而,許多藥劑係相對地不溶於水性載劑且必須以懸浮液輸送。通常,如此之藥劑無法好好地穿過角膜組織。在藥劑能夠以足夠的濃度進入角膜組織前,懸浮液可能會藉由淚液膜而稀釋或自眼睛沖洗出。
據此,各種技術已被使用以改善微溶性藥劑之整體生物可用性及增加此藥劑於標的組織中之濃度。增加局部施用的溶液之黏度以增加溶液在角膜上之停留時間並無法總是達成生物可用性的增加,且可能實際上延遲藥劑穿過進入角膜。見,例如2006年5月8日提申之美國專利申請案第11/429,736號且標題為「奈帕芬胺(Nepafenac)之懸浮液組配物及用於眼科病症之局部治療的其他眼科藥物」。
利用半乳甘露聚糖-硼酸鹽凝膠系統之眼科組成物已在先前被描述。授與Asgharian且題為「含有半乳甘露聚糖聚合物及硼酸鹽之眼科組成物」之美國專利案第6,403,609號描述如此之系統且其全文係併入本文作為參考。
促進諸如奈帕芬胺之微溶性藥劑穿過角膜的眼科組成物已揭露於2006年5月8日提申、題為「奈帕芬胺懸浮液組配物及其他用於眼科病症之局部治療的眼科藥物」之美國專利申請案第11/430239號中。該‘239號申請案描述泊洛沙姆(poloxamer)或美羅沙波(meroxapol)界面活性劑及乙二醇張力調節劑於具有該活性醫藥品良好的角膜穿透性的組成物中之用途。這些組成物不包含羧基乙烯基聚合物。
美國專利案第5,188,826號揭露用於治療乾眼症之眼科凝膠懸浮液。該懸浮液組成物在眼中維持為凝膠歷一段延長的時間,且釋放出水及一或多種眼科緩和劑或血管收縮劑。該懸浮液組成物含有一水不溶性、輕度交聯且含羧基之聚合物,該聚合物在等效球體直徑中具有不大於50微米之粒子大小。緩和劑較佳係羧甲基纖維素鈉鹽、羥乙基纖維素、羥丙基甲基纖維素、甲基纖維素、葡萄聚糖70、明膠、甘油、聚乙二醇、聚山梨醇酯80、丙二醇、聚乙烯醇或聚乙烯吡咯啶酮之至少一者。特別較佳之含羧基聚合物係976。該懸浮液組成物不含有處方藥物。
美國專利案第5,192,535號揭露眼科藥物之懸浮液組成物,其具有適當地低黏度以容許容易於滴劑形式投藥,但其在眼中快速地凝膠化以提供持續藥物釋放。懸浮液組成物係調配成pH由約3至約6.5且含有水不溶性、含羧基之聚合物,其係藉由聚合一或多種含羧基之單乙烯不飽和單體與少於約5重量%之交聯劑而製得。976及聚卡波非(polycarbophil)係鑑定為適當的含羧基聚合物之示例。由於該聚合物之熱凝膠性質,該等組配物在眼中會形成凝膠。離子交換樹脂可包括為懸浮物組成物中的一種佐劑。緩和劑係鑑定為適合用於懸浮液組成物之許多種藥劑的一種。
本發明一般地係關於局部水性眼科奈米粒子懸浮液,其包含微溶性微粒化合物(例如藥劑)、羧基乙烯基聚合物、半乳甘露聚糖及硼酸鹽。本發明之較佳組成物係奈帕芬胺懸浮液,其包含丙烯酸與烯丙基蔗糖或烯丙基季戊四醇交聯之羧基乙烯基聚合物、瓜爾及硼酸。
本發明之組成物係生理上互溶的且對於微溶性微粒化合物,諸如奈帕芬胺,提供良好的生物可用性,即使在不頻繁的給藥間隔,諸如一天一次或一天兩次下。維持羧基乙烯基聚合物溶液之黏度一般係相當困難的,因羧基乙烯基聚合物所給與的黏度係對鹽濃度非常敏感;據此,這類溶液通常不包含氯化鈉。然而,一旦局部施用至眼睛,因淚液膜包含相對高濃度之氯化鈉,羧基乙烯基聚合物溶液之黏度典型地會降低。本案發明人發現若溶液亦含有半乳甘露聚糖及硼酸鹽,羧基乙烯基聚合物溶液之黏度可被維持。本發明之羧基乙烯基聚合物、半乳甘露聚糖及硼酸鹽組成物當施用至眼睛時具有穩定的黏度,且提供微溶性微粒化合物良好的生物可用性。本案發明人亦發現50至700奈米之減少的粒子大小可改善這類化合物在使用局部眼科懸浮液的標的組織中之生物可用性。
前述簡短概要廣泛地描述本發明特定實施例的特徵及技術優點。額外的特徵及技術優點將在隨後的發明詳細說明中描述。
本發明及其優點之更完整瞭解可藉由參考下列描述、結合其中相同元件編號表示相同特徵的隨附圖式之圖樣而獲得,且其中:第1圖係顯示在投與局部奈帕芬胺組配物後氨芬酸(amfenac)(一種奈帕芬胺代謝物)在兔子虹膜睫狀體中之濃度的圖表;第2a及2b圖係顯示投與局部奈帕芬胺組配物後,在不同時間點時氨芬酸在兔子水樣液及虹膜睫狀體中之濃度的圖表;第3a及3b圖係顯示在施用局部奈帕芬胺組配物後奈帕芬胺及氨芬酸在兔子水樣液及虹膜睫狀體中濃度對時間作圖之曲線下面積的柱狀圖。
本發明之組成物包含羧基乙烯基聚合物。羧基乙烯基聚合物具有大約自約50,000至約6百萬道爾吞之分子量。該等聚合物之特徵在於具有羧酸性官能基。較佳之羧基乙烯基聚合物包括水溶性及水膨脹性卡波姆(carbomer)。許多這類卡波姆係以商標名而可得自路博潤公司(Lubrizol Corporation)。卡波姆聚合物係經交聯、以丙烯酸為主之聚合物。其係與烯丙基蔗糖或烯丙基季戊四醇交聯。卡波姆共聚物係丙烯酸之聚合物、以C10-30
烷基丙烯酸酯改質、及與烯丙基季戊四醇交聯。供用於本發明組成物中之較佳卡波姆係丙烯酸與烯丙基蔗糖或烯丙基季戊四醇交聯之聚合物,其係商業上可得之974P。本發明懸浮液組成物中羧基乙烯基聚合物存在之量係自約0.1至1.0 w/v%之範圍,較佳為0.1至0.5 w/v%,且最佳為0.4 w/v%。
除了羧基乙烯基聚合物,本發明之組成物利用一於水性溶液中之半乳甘露聚糖-硼酸鹽系統。硼酸鹽陰離子會縮合至半乳甘露聚糖分子的順式二醇基上,且可與第二半乳甘露聚糖分子交聯。硼酸鹽與半乳甘露聚糖之交聯係受到諸如,尤其是pH之因素影響,且如此之交聯會進而影響溶液之黏度。
可用於本發明的半乳甘露聚糖類別典型地係衍生自瓜爾、刺槐豆膠與塔拉膠。如本文所使用,該用語「半乳甘露聚糖」代表衍生自上述天然膠或含有甘露糖或半乳糖部分,或該兩基團,作為主要結構組份的類似天然或合成膠之多醣。本發明較佳的半乳甘露聚糖係由直鏈(1-4)-β-D-甘露吡喃糖單元與α-D-半乳吡喃糖單元以(1-6)鍵結附接所構成。
就較佳的半乳甘露聚糖,D-半乳糖對D-甘露糖的比例會改變,但一般會在自約1:2至1:4。具有D-半乳糖:D-甘露糖的比例在約1:2之半乳甘露聚糖為最佳。此外,該等多醣之其他化學改質變異亦包括在「半乳甘露聚糖」之定義中。例如,羥乙基、羥丙基與羧甲基羥丙基取代可加諸至本發明的半乳甘露聚糖。當軟凝膠係所欲的時,對半乳甘露聚糖之非離子性變異,諸如含有烷氧基與烷基(C1-C6)者係特別較佳的(例如羥丙基取代)。非順式羥基位置中的取代係最佳的。本發明半乳甘露聚糖非離子性取代的示例係羥丙基瓜爾,其具約0.4之莫耳取代。陰離子性取代亦可加諸至半乳甘露聚糖。陰離子性取代係特別較佳當強回應性凝膠係所欲的時。半乳甘露聚糖典型地係存在於本發明之組配物中於約0.01至約10 w/v%之濃度,較佳於約0.1至約2.0 w/v%,且最佳於約0.1至約0.4 w/v%。本發明之較佳半乳甘露聚糖係瓜爾、天然瓜爾及羥丙基瓜爾。於本發明之一較佳實施例中,天然瓜爾係存在於約0.2 w/v之濃度。天然瓜爾係特別較佳的,例如USP或獲自TIC膠品公司(TIC Gums,Inc)之一般等級天然瓜爾粉。用於生產特別較佳的天然瓜爾之方法係揭露於2010年2月5日提申之共同申請案美國專利申請號第12/701,339號,題為「用於純化瓜爾之方法」。
可使用於本發明之組成物的硼酸鹽化合物包括,但不限於,硼酸及其他藥學上可接受鹽類,諸如硼酸鈉(硼砂)及硼酸鉀。硼酸鹽典型地係存在於0.2至2.0 w/v%之濃度,較佳於0.4至0.6 w/v%之濃度,且最佳於約0.5 w/v%。如本文所使用,該用語「硼酸鹽」代表硼酸鹽所有藥學上適合的形式,包括但不限於硼酸,以及鹼金屬硼酸鹽諸如硼酸鈉與硼酸鉀。硼酸係與本發明之實施例使用之較佳硼酸鹽。
本發明之某些水性組成物含有藥學上有效量之奈帕芬胺或其他微溶性微粒化合物。如本文所使用,「微溶於水」或「微溶性微粒化合物」意指在25 ℃之水中具有於0.001至0.1 w/v%範圍之溶解度極限的化合物或藥劑。奈帕芬胺係已知的非固醇類抗發炎化合物,且可以已知的方法製得。見,例如美國專利第5,475,034及4,313,949號,其整體內容係併入本文以為參考。奈帕芬胺亦已知為2-胺基-3-苯甲醯基苯乙酸。奈帕芬胺及3-苯甲醯基苯乙酸之其他醯胺與酯類衍生物之局部使用以治療眼部發炎及疼痛係揭露於美國專利第5,475,034號。本發明之奈帕芬胺組成物將一般地含有0.1至1.0 w/v%,較佳地0.25至0.35 w/v%且最佳地約0.3 w/v%之奈帕芬胺。
本案發明人發現降低本發明特定組成物中奈帕芬胺的粒子大小可增進奈帕芬胺的生物可用性。較佳的組成物據此具有50至700奈米之平均粒子大小,更加為100至600奈米之平均粒子大小,且最佳為400奈米之平均粒子大小。生產藥物之奈米及次微米粒子的方法係已知,包括但不限於,碾磨、高壓均質化或自溶液形成小型結晶。
可使用於本發明的實施例之其他微溶性微粒化合物包括,但不限於,非固醇類抗發炎化合物、碳酸脫氫酶抑制劑、抗真菌劑、磷酸二酯酶IV抑制劑、受體酪胺酸激酶抑制劑、rho激酶抑制劑、緩激肽促效劑、CNP促效劑、Hl/syk激酶抑制劑、VEGF抑制劑、抗體及其片段、TNF-α抑制劑、鹵化化合物諸如鹵化胺基酸、及固醇類。
本發明之組成物係眼科上適合用於施用至一個體之眼睛。該等滴劑可自單一劑量安瓿輸送,其可較佳地為無菌且因此使得組配物之制菌組份不必要。或者,該等滴劑可自多劑量瓶輸送,其可較佳地包含一當該組配物係輸送時自該組配物提取任何防腐劑之裝置,如此之裝置係該技藝中所熟知。
本發明之組成物可選擇性地包含一或多種額外的賦形劑及/或一或多種額外的活性成分(例如藥劑)。普遍使用於藥學組成物的賦形劑包括,但不限於,緩和劑、張力劑、防腐劑、助防腐劑(preservative aid)、螯合劑,緩衝劑及界面活性劑。其他賦形劑包含助溶劑、黏度調整劑、安定劑、舒適促進劑、聚合物、軟化劑、pH調整劑及/或潤滑劑。
本發明之組成物選擇性地含有金屬氯化物鹽(諸如氯化鈉)或非離子性張力調整劑(諸如丙二醇或羥基化合物)作為額外的張力調整劑。適當的緩衝劑包括,但不限於,磷酸鹽、醋酸鹽及類似者、及胺基醇諸如2-胺基-2-甲基-1-丙醇(AMP)。於一較佳組成物中,金屬氯化物諸如氯化鈉係存在於0.15至0.5 w/v%之濃度,且最佳於0.4 w/v%。
本文所述之組成物可包含一或多種防腐劑。許多眼科上可接受的防腐劑係已知且包括,但不限於,鹵化苄二甲烴銨及聚季銨-1。最佳之防腐劑係氯化苄二甲烴銨(BAC)與聚季銨-1。在氯化苄二甲烴銨的情況下,防腐劑較佳係存在於自0.001至0.02%之量,且最佳係0.005%。
本發明之組成物較佳係等張,或輕微低張,以對抗任何由蒸發作用及/或疾病所引起的淚液高張。這可能需要張力劑以將組配物之滲透壓帶至或接近每公斤250-350毫滲透莫耳濃度(mOsm/kg)之程度。本發明之組成物一般具有於250至350毫滲透莫耳濃度範圍之滲透壓。該眼科組成物一般將會被組配成無菌水性溶液。該用語「水性」典型地表示一水性組配物,其中該組配物>50%,更加>75%且特別>90%重量係水。
本發明之水性組成物選擇性地包含一或多種緩衝劑,諸如磷酸鹽緩衝劑(例如磷酸氫二鈉與磷酸二氫鈉)與檸檬酸緩衝劑。該緩衝劑係基於用於該組成物之目標pH而選用,其一般係自pH 5.0至8.5之範圍。用於組成物之目標pH係依照所選用的眼科藥物。眼科上可接受的pH調整劑係已知且包括,但不限於,氫氯酸(HCl)及氫氧化鈉(NaOH)。於一特別較佳的實施例中,該組成物之pH係5.8至6.8。
非離子性縮溶劑(milling agent)諸如泰洛沙泊(tyloxapol)、聚山梨醇酯80及羧甲基纖維素鈉鹽可包括於本發明之某些實施例中。若有存在,則此等縮溶劑在本發明組成物中具有0.005至0.1 w/v%之濃度。
適當的螯合劑包括乙二胺四乙基二鈉、乙二胺四乙基三鈉、乙二胺四乙基四鈉、及二乙胺五乙酸酯(diethyleneamine pentaacetate)。最佳係乙二胺四乙基二鈉。若有包括,則該螯合劑典型地將會存在於自0.001至0.1 w/v%之量。在乙二胺四乙基二鈉的情況下,螯合劑較佳係以0.01%之濃度存在。
本發明之組成物可使用以治療許多眼科病症。該等病症包括,但不侷限於,眼表面及視網膜病症、青光眼、乾眼症、眼表面疼痛、葡萄膜炎、鞏膜炎、上鞏膜炎、角膜炎、手術引起的發炎、眼內炎、虹膜炎、萎縮性黃斑部病變、色素性視網膜炎、醫原性視網膜病變、視網膜撕裂與破洞、黃斑部水腫(例如黃斑部囊樣水腫)、糖尿病性黃斑部水腫、糖尿病性視網膜病變、鐮形細胞視網膜病變、視網膜靜脈與動脈阻塞、視神經病變、滲出性黃斑部病變、新生血管型青光眼、角膜新生血管、睫狀體炎、鐮形細胞視網膜病變及眼翳。
於較佳實施例中,本發明之組成物係每日投與一次。本發明某些組成物之增強的生物可用性能夠讓含奈帕芬胺的組成物每日投藥一次。此給藥療法改善病患順從性與成功治療的機率。然而,此等組成物亦可組配為用於在任何投藥頻率下投藥,包括每週一次、每5天一次、每3天一次、每2天一次、一天兩次、一天三次、一天四次、一天五次、一天六次、一天八次、每小時投藥或更高的頻率。依治療療法的不同,此等給藥頻率係亦維持在不同的持續時間。特定治療療法的持續時間可自一次給藥變化至延伸數月或數年之療法。該技藝中具有通常知識者將會對決定用於特定適應症之治療療法熟悉。
本發明之某些方面具有許多優點。凝膠組成物形成澄清與無色的凝膠且不會干擾視線。當施用至眼睛時,該等凝膠係藉由微小的pH改變而活化。此外,當高壓蒸氣滅菌時,瓜爾及卡波姆聚合物不具有濁點,且因而提供容易的滅菌處理。該等聚合物亦與許多常用的賦形劑互溶。
下列實施例係呈現以進一步說明本發明所選擇的實施例。
第1圖係顯示在一劑量之商業0.1 w/v%奈帕芬胺()懸浮液後,相較於0.3 w/v%之奈帕芬胺於卡波姆(carbopol)(FID114971)中及於卡波姆/瓜爾/硼酸鹽(FID114949)中之組配物,兔子虹膜睫狀體(ICB)中氨芬酸(amfenac)(一種奈帕芬胺代謝物)之濃度的圖表。該圖表顯示卡波姆/瓜爾/硼酸鹽組配物較僅包含卡波姆的類似組配物提供較佳之生物可用性。NEVANAC組配物相較於卡波姆/瓜爾/硼酸鹽組配物在ICB中具有較低量之氨芬酸。
奈帕芬胺及其代謝物氨芬酸之分布係在紐西蘭白兔中研究。兔子係兩側給藥、犧牲,且水樣液(AH)及虹膜睫狀體(ICB)組織係使用LC/MS/MS分析。第2a與2b圖中顯示的各個時間點資料係由6個兔子眼睛所測得的平均濃度。以TID給藥的動物接受以8小時分開的三次給藥歷4天,並在第5天早晨給藥一次。以QD給藥的動物接受一次給藥歷5天。.
第2a與2b圖係顯示在奈帕芬胺組配物投藥後在不同時間點兔子水樣液及虹膜睫狀體中氨芬酸之濃度的圖表。第3a與3b圖係顯示在施用局部奈帕芬胺組配物後奈帕芬胺與氨芬酸在兔子水樣液與虹膜睫狀體中濃度對時間作圖之曲線下面積的柱狀圖。該等圖表指出所測試的卡波姆/瓜爾奈帕芬胺組配物較現今銷售的奈帕芬胺組配物及僅具有卡波姆的組配物一致地產生較高的生物可用性。在局部眼部投藥時,卡波姆/瓜爾奈帕芬胺組配物(FID 114949)較僅有卡波姆的組配物(FID 104045)顯示較高的生物可用性。當奈帕芬胺粒子大小降低至大約400奈米時,該奈米粒子卡波姆/瓜爾組配物(FID 115535)比具有較大粒子大小的組配物顯示出增加的生物可用性。如第2a與2b圖所示,所有的卡波姆/瓜爾組配物在所有時間點皆產生較高的水樣液與虹膜睫狀體氨芬酸濃度。
奈帕芬胺之卡波姆/瓜爾奈米懸浮液係依下列方式製得。在2000毫升玻璃罐中,係取出200克之2%974P儲備溶液。接著加入5克硼酸、4克氯化鈉及約200克純水至其。充分攪拌至溶解且pH係調整至7.0。加入400克之0.5%瓜爾儲備溶液至此且完全混合。加入5克丙二醇、5克之1%氯化苄二甲烴銨儲備溶液及10克之1% EDTA二鈉儲備溶液至此溶液。溶液pH係被檢查且藉由加入純水,溶液重量被調整至950克。此溶液係在121℃高壓蒸氣滅菌35分鐘。在冷卻時,加入60克之奈帕芬胺於CMC溶液中之5%儲備漿料。所得的溶液係充分攪拌且藉純水適量至100%批次大小。
奈帕芬胺漿料係依下列方式製得。在1000毫升玻璃罐中,讓10克之羧甲基纖維素鈉鹽(CMC)7LF PH水合2小時,而後在121℃高壓蒸氣滅菌35分鐘。一3-5%奈帕芬胺漿料係在上述CMC溶液中無菌地製得。該懸浮液係使用手持均質機於5000-10000RPM均質10分鐘。該漿料而後係在乾淨空間中使用140毫升之0.2毫米Zr顆粒以那茲克研磨器高能碾磨機(Netszch Minicer High Energy Mill)(HEM)在3000RPM無菌地碾磨30分鐘,以達成目標粒子大小。所得的漿料係被檢查粒子大小。
本發明及其實施例已詳細地描述。然而,本發明之範圍並非意欲限制於說明書中所描述的任何製程、製造、物質之組成物、化合物、手段、方法及/或步驟之特定實施例。各種修飾、取代及變異可加諸於所揭露的材料而不會偏離本發明之精神及/或必要特徵。因此,下列申請專利範圍係意欲將對本文所揭露的製程、製造、物質之組成物、化合物、手段、方法及/或步驟之修飾、取代及變異包含於其範圍中。說明書中所提及的所有的專利與出版品係併入本文,就像各個出版品係特定地且個別地指出要被併入作為參考般,作為相同程度的參考。
第1圖係顯示在投與局部奈帕芬胺組配物後氨芬酸(amfenac)(一種奈帕芬胺代謝物)在兔子虹膜睫狀體中之濃度的圖表;
第2a及2b圖係顯示投與局部奈帕芬胺組配物後,在不同時間點時氨芬酸在兔子水樣液及虹膜睫狀體中之濃度的圖表;
第3a及3b圖係顯示在施用局部奈帕芬胺組配物後奈帕芬胺及氨芬酸在兔子水樣液及虹膜睫狀體中濃度對時間作圖之曲線下面積的柱狀圖。
Claims (15)
- 一種可局部投藥的水性眼科懸浮液組成物,其包含:卡波姆(carbomer),為0.1至0.5w/v%之濃度;瓜爾,為0.1至0.4w/v%之濃度;硼酸鹽,為0.4至2.0w/v%之濃度;及微溶性微粒化合物,該化合物具有在25℃的水中0.001至0.1w/v%之溶解度及50至700奈米之粒子大小,以及其中該微溶性微粒化合物係0.25至0.35w/v%之濃度的奈帕芬胺(nepafenac)。
- 如申請專利範圍第1項之組成物,進一步包含足以造成該組成物具有5.0至7.2之pH的量之pH調整劑。
- 如申請專利範圍第1項之組成物,進一步包含足以造成該組成物具有250至350毫滲透莫耳濃度(mOsm/kg)之滲透壓的量之張力調整劑。
- 如申請專利範圍第1項之組成物,其中該卡波姆為0.4w/v%之濃度。
- 如申請專利範圍第1項之組成物,進一步包含為0.005至0.1w/v%之濃度的縮溶劑(milling agent)。
- 如申請專利範圍第5項之組成物,其中該縮溶劑係界面活性劑或聚合物。
- 如申請專利範圍第6項之組成物,其中該縮溶劑係羧甲基纖維素鈉鹽。
- 如申請專利範圍第1項之組成物,進一步包含金屬氯化物鹽張力調整劑。
- 如申請專利範圍第8項之組成物,其中該金屬氯化物鹽係0.4w/v%之濃度的氯化鈉。
- 如申請專利範圍第1項之組成物,進一步包含非離子性羥基化合物作為張力調整劑。
- 如申請專利範圍第1項之組成物,進一步包含防腐劑與螯合劑兩者。
- 如申請專利範圍第11項之組成物,其中該防腐劑係0.005w/v%之濃度的氯化苄二甲烴銨且該螯合劑係0.01w/v%之濃度的乙二胺四乙基二鈉。
- 如申請專利範圍第1項之組成物,包含0.4w/v%卡波姆、0.2w/v%瓜爾、0.5w/v%硼酸及0.3w/v%奈帕芬胺。
- 如申請專利範圍第13項之組成物,其中該奈帕芬胺具有400奈米之平均粒子大小。
- 一種可局部投藥的眼科懸浮液組成物,其基本上由下列所組成:a1)0.3w/v%奈帕芬胺,其具有50至700奈米之粒子大小;b)0.4w/v%卡波姆;c)0.2w/v%瓜爾;d)0.5w/v%硼酸;e)0.06w/v%羧甲基纖維素鈉鹽;f)0.4w/v%氯化鈉;g)0.5w/v%丙二醇;h)pH調整劑,其係足以造成該組成物具有7.0之pH的 量;i)0.005%(w/v)氯化苄二甲烴銨;j)0.01%乙二胺四乙基二鈉;及k)純水。
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