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使用納米顆粒的藥物遞送

 更新時(shí)間:2023-07-27  點(diǎn)擊量:1463

1.引言

 

ISO/TS 276871和ASTM E24562都將納米粒子定義為100nm及以下的粒徑,使其成為使用廣泛的分類(lèi)。由于科學(xué)和其他原因,不太嚴(yán)格的解釋擴(kuò)大了上限范圍?,F(xiàn)在許多大于100nm的納米材料通常被稱(chēng)為納米顆粒。開(kāi)發(fā)這種尺寸范圍的藥物產(chǎn)品的動(dòng)機(jī)在于改善其溶出度/生物利用度、靶向性、系統(tǒng)中的循環(huán)時(shí)間和藥代動(dòng)力學(xué)。

 

這些藥物的研究許多是為了增強(qiáng)靶向性而開(kāi)發(fā)的。被動(dòng)靶向方法通過(guò)減小尺寸并用諸如聚乙二醇(PEG)的涂層掩蓋納米顆粒來(lái)增加循環(huán)時(shí)間。主動(dòng)靶向方法改變納米顆粒的表面以尋找并粘附于身體的特定部位,同時(shí)避免健康組織,例如癌癥腫瘤??梢蕴砑蛹{米顆粒表面上的細(xì)胞特異性配體以特異性結(jié)合互補(bǔ)受體。

 

Nicomp 3000系列納米粒度儀(圖1)是用于測(cè)量藥物遞送的納米顆粒粒徑和zeta電位(表面電荷)的儀器。

 

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圖1. Nicomp 3000系列納米粒度儀

 

 

2.  納米粒子的類(lèi)型

 

納米晶

 

活性藥物成分(API)通常是結(jié)晶的。疏水性晶體可能難以配制成以親水性載體機(jī)制遞送。通過(guò)將尺寸減小到納米晶體范圍,納米膨脹可以提高藥物的生物利用度,其中溶解速度是限速步驟,例如水溶性差的藥物3。這些納米晶體通常需要使用表面活性劑或聚合物來(lái)穩(wěn)定,包括在加工過(guò)程中。粒徑的減小通過(guò)增加表面積A(圖2)和飽和溶解度Cs來(lái)增加溶解速率。

 

 

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圖2. 表面積擴(kuò)大,粒徑減小

 

Noyes-Whitney方程(方程1)顯示了A和Cs的增加將如何影響溶解速率dC/dt。

 

dC/dt=DA/Vh(Cs - Cx).......(方程1)

? dC/dt=溶出速率

? D=擴(kuò)散系數(shù)

? A=表面積

? Cs=邊界層的濃度

? Cx=濃度API@給定時(shí)間

? V=體積溶解介質(zhì)

? h=邊界層的高度

 

基于脂質(zhì)的液晶納米顆粒(LCNP)是另一種能夠提高疏水性和親水性藥物的生物利用度的遞送系統(tǒng)。這些是通過(guò)將非層狀液晶基質(zhì)進(jìn)行高剪切能量分散到水相中制備的自組裝結(jié)構(gòu)。LCNP的粒徑是需要適當(dāng)分析和控制的重要物理化學(xué)性質(zhì)。Nicomp3000系列納米粒度儀已成功用于確定LCNP分散體中的平均大小和聚集體的存在。4將紫杉醇加入LCNP分散體中并通過(guò)Nicomp3000系列納米粒度儀和TEM分析,參見(jiàn)圖3。

 

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圖3. LCNP分散體的Nicomp和TEM結(jié)果,版權(quán)復(fù)制自4

 

TEM圖像表示較小的近25nm顆粒和100nm范圍內(nèi)的較大顆粒的雙峰粒度分布 。較高的Nicomp結(jié)果是高斯強(qiáng)度分布平均值迫使整個(gè)分布成為一個(gè)峰值。較低的Nicomp結(jié)果利用專(zhuān)有的Nicomp非負(fù)最小二乘算法來(lái)報(bào)告更高的分辨率和更準(zhǔn)確地描述實(shí)際粒度分布的雙峰性質(zhì)。突出了Nicomp3000系列納米粒度儀的一個(gè)主要優(yōu)點(diǎn)?即使在濃度低至0.2mg/mL時(shí)也能解析多峰分布。

 

膠束

 

另一種增加疏水性藥物增溶作用的潛在藥物遞送系統(tǒng)是聚合物膠束。6當(dāng)溶液中聚合物的濃度超過(guò)一定的臨界膠束濃度(CMC)時(shí),就會(huì)形成膠束。聚合物膠束是由兩親性嵌段共聚物合成的核殼納米結(jié)構(gòu)。膠束具有尺寸非常?。?0?100 nm)的優(yōu)點(diǎn),可以改善對(duì)實(shí)體瘤的被動(dòng)靶向。通過(guò)用配體修飾表面,聚合物膠束能夠進(jìn)行位點(diǎn)特異的藥物遞送。

 

Nicomp3000系列納米粒度儀已被用于許多基于膠束的研究項(xiàng)目中的顆粒尺寸測(cè)量。7-12在一項(xiàng)研究中,12聚合物膠束是使用聚己內(nèi)酯(PCL)和聚乙二醇(PEG)共聚物形成的。以多西他賽(DTX)為模型藥物,用前列腺特異性膜抗原(SMLP)小分子配體修飾表面。圖4顯示了膠束的自組裝和藥物負(fù)載的最終結(jié)構(gòu)的內(nèi)吞過(guò)程。 

 

 

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圖4. 靶向PSMA的DTX負(fù)載聚合物膠束的制備和內(nèi)吞作用12


本研究中使用的兩個(gè)樣品通過(guò)Nicomp3000系列納米粒度儀和TEM測(cè)試的粒度如圖5所示。非靶向膠束的數(shù)據(jù)顯示在左邊,靶向膠束顯示在右邊。DLS數(shù)據(jù)看起來(lái)略大于TEM圖像,這可能是由于在TEM分析之前水蒸發(fā)引起的PEG殼的收縮。

 

image.png

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圖5. DLS和TEM測(cè)定的非靶向(上)和靶向(下)聚合物膠束的尺寸12

 

脂質(zhì)體

 

脂質(zhì)體是一種雙層囊泡,通常在制藥工業(yè)中用作將化療藥物輸送到腫瘤區(qū)域的藥物輸送系統(tǒng)。它們由磷脂組成,磷脂的極性末端連接到非極性鏈上,自組裝成雙層囊泡,極性末端面向水介質(zhì),非極性末端形成雙層。在藥物應(yīng)用中,活性藥物成分(API)通常被摻入脂質(zhì)體,或者被摻入親水口袋,或者被夾在雙層之間,這取決于API的親水性,見(jiàn)圖6。表面改性對(duì)于靶向遞送是常見(jiàn)的。

 

 

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圖6. 復(fù)雜的脂質(zhì)體結(jié)構(gòu)

 

在處理脂質(zhì)體時(shí)監(jiān)測(cè)粒徑至關(guān)重要,Nicomp3000系列納米粒度儀經(jīng)常用于此應(yīng)用。13-20在Entegris的一項(xiàng)內(nèi)部研究中,脂質(zhì)體是使用3:1:1的HSPC、膽固醇和mPEG-DSP的配方制成的。樣品首先通過(guò)轉(zhuǎn)速7200rpm混合10分鐘,然后使用微射流均質(zhì)機(jī)21搭配Y型腔采用25000psi的壓力制成脂質(zhì)體。對(duì)樣品進(jìn)行均質(zhì)處理1次、3次、5次和10次,使其通過(guò)微流器。預(yù)混物和處理過(guò)的樣品的圖像(從左到右)如圖7所示。

 

 

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圖7. 預(yù)混合,均質(zhì)1次、3次、5次和10次

 

脂質(zhì)體樣品在Nicomp3000系列納米粒度儀和AccuSizer®系列液體顆粒計(jì)數(shù)器上進(jìn)行分析。Nicomp用于確定加工過(guò)程中強(qiáng)度平均尺寸的減小,而AccuSizer(LE傳感器范圍0.5?400μm)用于量化分布中較大粒子尾部的存在。Nicomp檢測(cè)結(jié)果如圖8所示,AccuSizer檢測(cè)結(jié)果如圖9所示。

 

 

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圖8. Nicomp 檢測(cè)結(jié)果從右到左;預(yù)混合,均質(zhì)1次、3次、5次和10次

 

 

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圖9. AccuSizer 檢測(cè)結(jié)果從右到左;預(yù)混合,均質(zhì)1次、3次、5次和10次

 

使用DLS來(lái)確定平均尺寸,使用SPOS來(lái)量化尾部的存在和濃度,這個(gè)搭配在許多行業(yè)中都能見(jiàn)到,是USP<729>脂質(zhì)注射乳劑中球粒徑分布的一個(gè)組成部分。

 

用于過(guò)程監(jiān)控的DLS

 

雖然絕大多數(shù)DLS檢測(cè)都是在實(shí)驗(yàn)室進(jìn)行的,但Entegris在客戶(hù)生產(chǎn)操作中安裝了多個(gè)設(shè)備,在生產(chǎn)工藝期間定期檢測(cè)顆粒尺寸。23這些設(shè)備已用于監(jiān)測(cè)藥物輸送的納米顆粒制造過(guò)程中使用的高壓均質(zhì)過(guò)程、稀釋樣品以避免造成多重散射效應(yīng)、檢測(cè)樣品,然后重復(fù)該程序(見(jiàn)圖10)。整個(gè)測(cè)量周期約為兩分鐘,為監(jiān)控生產(chǎn)工藝操作的工程師提供實(shí)時(shí)的粒度信息。

 

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圖10. 在線DLS系統(tǒng)示意圖

 

圖11顯示了作為高壓均質(zhì)器下游壓力函數(shù)的在線DLS結(jié)果。目標(biāo)是確定將顆粒尺寸保持在非常接近100nm尺寸的最佳壓力。在確定最佳壓力(~10000 psi)后,使用在線DLS系統(tǒng)來(lái)確保整個(gè)批次的生產(chǎn)符合規(guī)范。

 

 

第4頁(yè)-12.PNG

圖11. DLS實(shí)時(shí)檢測(cè)結(jié)果中的壓力與顆粒尺寸對(duì)比 

 

3.  結(jié)論

 

Nicomp納米粒度儀廣泛用于研究、24-39質(zhì)量釋放測(cè)試和過(guò)程監(jiān)測(cè)中納米級(jí)藥物遞送系統(tǒng)的粒度和zeta電位分析。AccuSizer液體顆粒計(jì)數(shù)器提供了一種補(bǔ)充技術(shù),用于確定較大顆粒的濃度,用于表明不穩(wěn)定或未優(yōu)化的配方或工藝條件。 




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