College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea; Department of Medical Management, Chodang University, 380 Muan-ro, Muan-eup, Muan-gun, Jeollanam-do 58530, South Korea.
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.
Int J Pharm. 2019 Jan 30;555:135-145. doi: 10.1016/j.ijpharm.2018.11.050. Epub 2018 Nov 17.
In the present study, a multi-system for solid dispersion (SD) of celecoxib (CXB) was designed to improve its solubility and anti-inflammatory effects in vitro as well as oral absorption in rats. The SD formulations were prepared by a solvent evaporation with a multi-system as the solubilizer; an alkalizer; and fumed silica (Aerosil 200). The physicochemical properties of the SD formulations were evaluated. Polyoxyl 15 hydroxystearate (HS 15) was chosen as the solubilizer based on the apparent solubility test. The optimal SD formulation (SD6, CXB: HS 15: K30: meglumine: Aerosil 200 = 200: 50: 50: 100: 100, weight ratio) improved the dissolution (%) over 2-fold compared to that by the commercial product (Celebrex) at pH 1.2, in distilled water (DW), and in a pH 6.8 buffer (sodium lauryl sulfate [SLS], 0.25% w/v). The SD6 formulation altered physical properties such as crystallinity, thermal stability, and intra-molecular interaction. Moreover, SD6 showed a good stability for 6 months. The anti-inflammatory effect of SD6 significantly improved 2.2-fold compared to that of Celebrex in the cell study. The relative bioavailability (BA) of SD6 was significantly improved to 209.4% compared to that of Celebrex. In conclusion, intra-molecular interactions between CXB and solubilizers in multi-systems increase its solubility, dissolution (%), anti-inflammatory effects in vitro, and the relative BA (%) in rats. Thus, SD6 would be effective for the treatment of inflammation in rats and should be evaluated in detail in future clinical studies.
在本研究中，设计了一种塞来昔布（CXB）的多系统固体分散体（SD）系统，以提高其在体外的溶解度和抗炎效果以及在大鼠体内的口服吸收。SD 配方通过溶剂蒸发法制备，多系统作为增溶剂；碱化剂；和气相法二氧化硅（Aerosil 200）。评估了 SD 配方的物理化学性质。根据表观溶解度试验，选择聚氧乙烯 15 硬脂酸酯（HS 15）作为增溶剂。最佳 SD 配方（SD6，CXB：HS 15：K30：葡甲胺：Aerosil 200=200：50：50：100：100，重量比）在 pH1.2、蒸馏水（DW）和 pH6.8 缓冲液（十二烷基硫酸钠[SLS]，0.25%w/v）中，与商业产品（西乐葆）相比，提高了超过 2 倍的溶出度（%）。SD6 配方改变了物理性质，如结晶度、热稳定性和分子内相互作用。此外，SD6 在 6 个月内表现出良好的稳定性。与西乐葆相比，SD6 在细胞研究中的抗炎效果显著提高了 2.2 倍。SD6 的相对生物利用度（BA）与西乐葆相比显著提高到 209.4%。总之，CXB 与多系统中增溶剂之间的分子内相互作用提高了其溶解度、溶出度（%）、体外抗炎效果和大鼠的相对 BA（%）。因此，SD6 有望有效治疗大鼠炎症，应在未来的临床研究中进行详细评估。
