Institute of Nano Science and Technology (INST), Habitat Centre, Phase- 10, Sector- 64, Mohali, Punjab, 160062, India.
National Institute of Pharmaceutical Education and Research (Rae Bareli), Lucknow, India.
AAPS PharmSciTech. 2020 Sep 17;21(7):260. doi: 10.1208/s12249-020-01803-z.
Niclosamide (NIC), an anthelminthic drug, is found to be promising in overcoming the problem of various types of drug-resistant cancer. In spite of strong anti-proliferative effect, NIC shows low aqueous solubility, leading to poor bioavailability. To overcome this limitation, and enhance its physicochemical properties and pharmacokinetic profile, we used co-crystallization technique as a promising strategy. In this work, we brought together the crystal and particle engineering at a time using spray drying to enhance physicochemical and aerodynamic properties of co-crystal particle for inhalation purpose. We investigated the formation and evaluation of pharmaceutical co-crystals of niclosamide-nicotinamide (NIC-NCT) prepared by rapid, continuous and scalable spray drying method and compared with conventional solvent evaporation technique. The newly formed co-crystal was evaluated by XRPD, FTIR, Raman spectroscopy and DSC, which showed an indication of formation of H bonds between drug (NIC) and co-former (NCT) as a major binding force in co-crystal development. The particle geometry of co-crystals including spherical shape, size 1-5 μm and aerodynamic properties (ED, 97.1 ± 8.9%; MMAD, 3.61 ± 0.87 μm; FPF, 71.74 ± 6.9% and GSD 1.46) attributes suitable for inhalation. For spray-dried co-crystal systems, an improvement in solubility characteristics (≥ 14.8-fold) was observed, relative to pure drug. To investigate the anti-proliferative activity, NIC-NCT co-crystals were investigated on A549 human lung adenomas cells, which showed a superior cytotoxic activity compared with pure drug. Mechanistically, NIC-NCT co-crystals enhanced autophagic flux in cancer cell which demonstrates autophagy-mediated cell death as shown by confocal microscopy. This technique could help in improving bioavailability of drug, hence reducing the need for high dosages and signifying a novel paradigm for future clinical applications.
硝氯酚（NIC）是一种驱虫药物，被发现有望克服各种类型的耐药性癌症问题。尽管具有很强的抗增殖作用，但 NIC 的水溶性很差，导致生物利用度低。为了克服这一限制，提高其物理化学性质和药代动力学特性，我们使用共结晶技术作为一种有前途的策略。在这项工作中，我们同时将晶体和颗粒工程结合起来，使用喷雾干燥技术来增强共晶颗粒的物理化学和空气动力学性质，以用于吸入。我们研究了通过快速、连续和规模化的喷雾干燥方法制备的硝氯酚-烟酰胺（NIC-NCT）共晶的形成和评价，并与传统的溶剂蒸发技术进行了比较。新形成的共晶通过 X 射线粉末衍射（XRPD）、傅里叶变换红外光谱（FTIR）、拉曼光谱和差示扫描量热法（DSC）进行了评估，这表明药物（NIC）和共晶形成剂（NCT）之间形成了氢键，这是共晶形成的主要结合力。共晶的颗粒几何形状包括球形、1-5μm 的尺寸和空气动力学特性（ED，97.1±8.9%；MMAD，3.61±0.87μm；FPF，71.74±6.9%和 GSD 1.46）适合吸入。对于喷雾干燥共晶系统，与纯药物相比，观察到溶解度特性（≥14.8 倍）的提高。为了研究抗增殖活性，我们研究了 NIC-NCT 共晶在 A549 人肺腺癌细胞中的作用，结果表明其比纯药物具有更好的细胞毒性活性。从机制上讲，NIC-NCT 共晶增强了癌细胞中的自噬通量，这表明自噬介导的细胞死亡如共聚焦显微镜所示。该技术有助于提高药物的生物利用度，从而减少对高剂量的需求，并为未来的临床应用提供新的范例。
