J Pharm Pharm Sci. 2010;13(4):589-606. doi: 10.18433/j3530j.
Nanoparticle engineering offers promising methods for the formulation of poorly water soluble drug compounds. The aim of the present work was to enhance dissolution and oral bioavailability of poorly water-soluble celecoxib (CXB) by preparing stable CXB nanoparticles using a promising method, meanwhile, investigate the mechanism of increasing dissolution of CXB.
CXB nanoparticles were produced by combining the antisolvent precipitation and high pressure homogenization (HPH) approaches in the presence of HPMC E5 and SDS (2:1, w/w). Then the CXB nanosuspensions were converted into dry powders by spray-drying. The effect of process variables on particle size and physical state of CXB were investigated. The physicochemical properties of raw CXB and CXB nanoparticles were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), X-ray photoelectron spectra (XPS), fourier transform infrared (FT-IR) spectroscopy, diffrential scanning calorimetry (DSC), as well as, measuring the particle size and contact angle. Additionally, the studies of in-vitro drug dissolution and oral bioavailability in beagle dogs of nanoparticles were performed.
The images of SEM revealed spherical CXB nanoparticles. The DSC and XRPD results indicated that the antisolvent precipitation process led to the amorphization of CXB. Under storage, the amorphous CXB nanoparticles showed promising physical stability. The XPS data indicated the amorphous CXB nanoparticles exhibited different surface property compared to raw CXB. Hydrogen bonds were formed between the raw CXB and HPMC E5 as proven by the FT-IR spectra. CXB nanoparticles increased the saturation solubility of CXB fourfold. CXB nanoparticles completely dissolved in the dissolution medium of phosphate buffer (pH 6.8, 0.5% SDS) within 5 min, while there was only 30% of raw CXB dissolved. The C(max) and AUC(0-24h) of CXB nanoparticles were approximately threefold and twofold greater than those of the Celecoxib Capsules, respectively.
The process by combining the antisolvent precipitation under sonication and HPH was a promising method to produce small, uniform and stable CXB nanoparticles with markedly enhanced dissolution rate and oral bioavailability due to an increased solubility that is attributed to a combination of amorphization and nanonization with increased surface area, improved wettability and reduced diffusion pathway.
纳米颗粒工程为制备水溶性差的药物化合物提供了有前途的方法。本研究的目的是通过使用有前途的方法制备稳定的塞来昔布（CXB）纳米颗粒来提高其溶解度和口服生物利用度，同时研究增加 CXB 溶解度的机制。
在 HPMC E5 和 SDS（2:1，w/w）存在下，将抗溶剂沉淀和高压匀质（HPH）方法相结合制备 CXB 纳米颗粒。然后，通过喷雾干燥将 CXB 纳米混悬液转化为干粉。考察了工艺变量对 CXB 粒径和物理状态的影响。通过扫描电子显微镜（SEM）、X 射线粉末衍射（XRPD）、X 射线光电子能谱（XPS）、傅里叶变换红外光谱（FT-IR）、差示扫描量热法（DSC）以及测量粒径和接触角对原料药和 CXB 纳米颗粒的物理化学性质进行了表征。此外，还进行了 CXB 纳米颗粒在犬体内的体外药物溶出度和口服生物利用度研究。
SEM 图像显示 CXB 纳米颗粒呈球形。DSC 和 XRPD 结果表明，抗溶剂沉淀过程导致 CXB 非晶化。在储存过程中，无定形 CXB 纳米颗粒表现出良好的物理稳定性。XPS 数据表明，与原料药相比，无定形 CXB 纳米颗粒具有不同的表面性质。通过 FT-IR 光谱证明，原料药 CXB 与 HPMC E5 之间形成了氢键。CXB 纳米颗粒使 CXB 的饱和溶解度提高了四倍。CXB 纳米颗粒在 5 分钟内完全溶解在磷酸盐缓冲液（pH6.8，0.5%SDS）的溶出介质中，而原料药 CXB 只有 30%溶解。CXB 纳米颗粒的 Cmax 和 AUC（0-24h）分别约为塞来昔布胶囊的三倍和两倍。
通过超声辅助抗溶剂沉淀与 HPH 相结合的工艺是一种很有前途的方法，可以制备出具有小粒径、均匀性和稳定性的 CXB 纳米颗粒，由于溶解度的增加，其溶解速率和口服生物利用度显著提高，这归因于非晶化和纳米化与表面积增加、润湿性提高和扩散途径减少的结合。
