了解納米晶體的納米穩(wěn)定劑和納米生物相互作用
介質(zhì)研磨是制藥行業(yè)大規(guī)模生產(chǎn)納米晶體的標(biāo)準(zhǔn)做法，使用攪拌式球(珠)磨機(jī)，如在循環(huán)模式下的臥式珠(球)磨機(jī)。市場(chǎng)上大多數(shù)納米晶體產(chǎn)品都是采用Perrigo公司的PLC專(zhuān)利NanoCrystal®技術(shù)生產(chǎn)的。該專(zhuān)利的核心是采用一種具有循環(huán)藥物懸浮液的臥式珠(球)磨機(jī)。在這項(xiàng)工作中使用實(shí)驗(yàn)室型的攪拌球(珠)磨機(jī)是臥式珠(球)磨機(jī)Dispermat®(圖15)。
將由粗藥物顆粒和穩(wěn)定劑溶液組成的懸浮液與研磨珠一起保存在密閉容器中。研磨后必須將懸浮液與研磨珠分離。 因此，Dispermat®在研磨容器和出口之間具有用于循環(huán)目的的動(dòng)態(tài)密封技術(shù)。 懸浮顆粒能夠通過(guò)該密封間隙，同時(shí)研磨珠留在研磨腔中。因此，如果將研磨珠分離過(guò)程與行星研磨機(jī)(例如，行星研磨機(jī)必須手動(dòng)去除珠粒)進(jìn)行比較，就更容易實(shí)現(xiàn)珠粒和產(chǎn)品的自動(dòng)分離。在珠與珠、珠與壁和珠與轉(zhuǎn)子接觸點(diǎn)之間的起始物料受到一定的作用力，這取決于接觸點(diǎn)的性質(zhì)，因此根據(jù)轉(zhuǎn)子的轉(zhuǎn)速、研磨時(shí)間和研磨珠尺寸，可以產(chǎn)生不同的顆粒粒徑。
實(shí)現(xiàn)將顆粒粒徑下降到納米級(jí),這項(xiàng)工作采用循環(huán)模式下的Dispermat®SL-C 5(德國(guó)VMA Getzmann GmbH)。所有實(shí)驗(yàn)的泵速為69mL / min(雙重蒸餾水)。將外部冷卻液體冷卻至8℃并在研磨時(shí)循環(huán)通過(guò)研磨腔內(nèi)。 作為密封液，使用正在進(jìn)行研磨的穩(wěn)定劑溶液。 轉(zhuǎn)子轉(zhuǎn)速設(shè)定為4,000rpm，并且對(duì)于每個(gè)實(shí)驗(yàn)，將10g藥物用于100g最終制劑中。
循環(huán)模式下的臥式珠（球）磨機(jī)方案
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.”
