Möschwitzer Jan, Müller Rainer H
Department of Pharmaceutical Technology, Biotechnology, and Quality Management, Free University of Berlin, Berlin, Germany.
J Nanosci Nanotechnol. 2006 Sep-Oct;6(9-10):3145-53. doi: 10.1166/jnn.2006.480.
Particle size reduction, particularly nanonization, is a non-specific, universal approach to improve the bioavailability of poorly soluble drugs. The decreased particle size of drug nanocrystals leads to a distinct increase in surface area. Due to the increased surface area the rate of dissolution will be proportionally raised, leading to a better absorption of the poorly soluble drug. Various technologies for the production of drug nanocrystals are known, e.g., pearl milling (Nanocrystal technology, elan/Nanosystems), high pressure homogenization in water (DissoCubes, SkyePharma) or alternatively in non-aqueous media or water-reduced media (Nanopure, PharmaSol Berlin). A first combinative technology (precipitation followed by high pressure homogenization) is known as NANOEDGETM technology (Baxter). Relatively long milling times, high numbers of homogenization cycles or solvent residues are typical drawbacks of the existing technologies. In order to overcome the limitations of the existing technologies a new combination method was developed for the production of ultra-fine submicron suspensions. The method involves an evaporation step to provide a solvent-free modified starting material followed by high pressure homogenization to produce ultrafine drug nanocrystals. In this study it could be shown that modified hydrocortisone acetate was particularly suitable to be further processed by high pressure homogenization. In comparison to jet-milled hydrocortisone acetate powder the high pressure homogenization of spray-dried hydrocortisone acetate powder resulted in much more homogeneously dispersed nanosuspensions. By using co-processed, spray-dried material (9:1 drug/poloxamer 188 ratio) the required number of homogenization cycles to obtain nanosuspensions was distinctly reduced. In case of the modified material only 1 homogenization cycle at 1500 bar was sufficient to obtain a particle size smaller than that after 20 homogenization cycles using the jet-milled drug powder. The obtained nanosuspensions have shown excellent long-term storage stability.
减小粒径，尤其是纳米化，是提高难溶性药物生物利用度的一种非特异性通用方法。药物纳米晶体粒径的减小会导致表面积显著增加。由于表面积增加，溶解速率将成比例提高，从而使难溶性药物的吸收更好。已知多种制备药物纳米晶体的技术，例如珠磨法（纳米晶体技术，伊兰/纳米系统公司）、在水中进行高压均质化（DissoCubes，斯凯制药公司），或者在非水介质或低水介质中进行（Nanopure，柏林制药溶胶公司）。第一种组合技术（沉淀后进行高压均质化）被称为NANOEDGETM技术（百特公司）。现有技术的典型缺点是研磨时间相对较长、均质化循环次数多或有溶剂残留。为了克服现有技术的局限性，开发了一种用于生产超细亚微米混悬液的新组合方法。该方法包括一个蒸发步骤以提供无溶剂的改性起始材料，随后进行高压均质化以生产超细药物纳米晶体。在本研究中可以表明，改性醋酸氢化可的松特别适合通过高压均质化进一步加工。与气流粉碎的醋酸氢化可的松粉末相比，喷雾干燥的醋酸氢化可的松粉末进行高压均质化可得到分散更均匀的纳米混悬液。通过使用共处理的喷雾干燥材料（药物/泊洛沙姆188比例为9:1），获得纳米混悬液所需的均质化循环次数明显减少。对于改性材料，在1500巴压力下仅进行1次均质化循环就足以获得比使用气流粉碎药物粉末进行20次均质化循环后更小的粒径。所获得的纳米混悬液显示出优异的长期储存稳定性。
