了解納米晶體的納米(mǐ)穩定劑和(hé)納(nà)米(mǐ)生物相(xiāng)互作用
介質(zhì)研(yán)磨(mó)是製藥行(háng)業大規模(mó)生(shēng)產納(nà)米(mǐ)晶(jīng)體的(dí)標準做法，使(shǐ)用攪拌式(shì)球(珠)磨(mó)機，如(rú)在循環模(mó)式下(xià)的臥式珠(球)磨(mó)機。市(shì)場上(shàng)大多數納米(mǐ)晶體產(chǎn)品都是采用(yòng)Perrigo公(gōng)司(sī)的(dí)PLC專利NanoCrystal®技(jì)術(shù)生產的(dí)。該專利(lì)的核(hé)心(xīn)是(shì)采用一種(zhǒng)具(jù)有循(xún)環藥(yào)物(wù)懸(xuán)浮液的臥式珠(zhū)(球(qiú))磨機。在這項工作中使用實驗室型的攪拌(bàn)球(珠)磨(mó)機是臥(wò)式珠(球)磨機Dispermat®(圖(tú)15)。
將由(yóu)粗藥物顆(kē)粒和穩(wěn)定劑溶(róng)液組(zǔ)成的懸浮液(yè)與(yǔ)研磨珠一起保存在(zài)密閉容器中(zhōng)。研磨(mó)後必須將(jiāng)懸浮(fú)液(yè)與(yǔ)研磨(mó)珠(zhū)分離。 因(yīn)此(cǐ)，Dispermat®在研(yán)磨容器和(hé)出(chū)口之(zhī)間(jiān)具(jù)有用於循(xún)環(huán)目(mù)的(dí)的(dí)動(dòng)態(tài)密封技術(shù)。 懸(xuán)浮(fú)顆(kē)粒能夠(gòu)通(tōng)過該密封間隙，同時(shí)研磨珠留在研(yán)磨(mó)腔(qiāng)中。因此，如(rú)果將(jiāng)研(yán)磨(mó)珠分(fēn)離(lí)過程與(yǔ)行星(xīng)研(yán)磨機(jī)(例如(rú)，行(háng)星研磨(mó)機必須(xū)手動(dòng)去(qù)除(chú)珠粒(lì))進(jìn)行(háng)比(bǐ)較(jiào)，就(jiù)更容易實(shí)現(xiàn)珠粒和產品(pǐn)的自(zì)動(dòng)分(fēn)離。在珠與珠，珠與(yǔ)壁(bì)和珠(zhū)與轉子(zǐ)接(jiē)觸(chù)點之間的起始(shǐ)物料(liào)受到(dào)一(yī)定的作用力(lì)，這取(qǔ)決於(yú)接觸點的(dí)性質，因此根據轉子的(dí)轉(zhuǎn)速(sù)，研(yán)磨時(shí)間和研磨珠尺(chǐ)寸，可以(yǐ)產(chǎn)生不同的顆粒粒(lì)徑。
實(shí)現將(jiāng)顆(kē)粒(lì)粒徑(jìng)下(xià)降到納米級(jí),這(zhè)項工(gōng)作采用循環模(mó)式(shì)下(xià)的Dispermat®SL-C 5(德國VMA Getzmann GmbH)。所有實(shí)驗的泵(bèng)速為69mL / min(雙(shuāng)重蒸(zhēng)餾(liù)水(shuǐ))。將外部冷卻液(yè)體冷卻(què)至8℃並在研磨(mó)時(shí)循環(huán)通過(guò)研磨(mó)腔(qiāng)內。 作(zuò)為密(mì)封(fēng)液(yè)，使用正在進行研(yán)磨(mó)的(dí)穩(wěn)定(dìng)劑溶(róng)液(yè)。 轉(zhuǎn)子(zǐ)轉速設(shè)定為(wéi)4,000rpm，並且對於(yú)每個實驗，將(jiāng)10g藥(yào)物用於100g最(zuì)終(zhōng)製(zhì)劑中(zhōng)。
循環模(mó)式(shì)下的臥式珠（球）磨機(jī)方案(àn)
Understanding nano-stabiliser and nano-bio interactions of nanocrystals
3.2.1 Media milling
Media milling is a standard practise for large scale production of nanocrystals in pharmaceutical industry, using agitated ball mills, like horizontal bead mills in recirculation mode [M?schwitzer, 2013]. Most nanocrystal products on the market are produced with the NanoCrystal® technology which is patented by the Perrigo Company PLC [US Patent 5145684]. The core of the patent is a horizontal bead mill with a circulating drug suspension. One example for the construction of an agitated ball mill on laboratory scale is the horizontal bead mill type Dispermat® which was utilised in this work (Figure 15).
The suspension, consisting of coarse drug particles and stabiliser solution, is kept in a closed vessel together with the milling beads. The suspension has to be separated from the beads after milling. Therefore, the Dispermat® has a dynamic gap between milling vessel and outlet for circulation purposes. Particles in suspension are able to pass this gap while milling beads stay in the milling chamber. Hence, an automated separation of beads and product is achieved more easily when comparing the bead separation process to, for example, a planetary mill, where the beads have to be manually removed. Starting material that gets in between bead–bead, bead-wall and bead-rotor contacts is exposed to a certain force, depending on the nature of the contact, so that depending on the rotor speed, milling time and bead size, different particle sizes can be produced.
Figure 15: Scheme of a horizontal media mill in circulating mode.
Particle size reduction to the nano-scale was accomplished, in this work, with the Dispermat® SL-C 5 (VMA Getzmann GmbH, Germany) in a circulation setup. Pump speed for all experiments was at 69 mL/min (set for double-distilled water). External cooling fluid was cooled down to 8 °C and circulated through the casing of the milling chamber while milling. As sealing liquid, the stabiliser solution for the ongoing milling was used. Rotor speed was set to 4,000 rpm and for every experiment 10 g of drug was used in 100 g of final formulation. Before milling, the drug was added to the stabiliser solution and directly homogenised with an Ultra Turrax® (Ultra Turrax® T25 basic, IKA®-Werke GmbH & Co. KG, Germany, rod of 1.7 cm diameter) for 10 seconds at 11,000 min-1 to minimise floating of the drug on the surface.”
