First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
Eur J Pharm Sci. 2019 Feb 1;128:222-231. doi: 10.1016/j.ejps.2018.12.005. Epub 2018 Dec 13.
The ability to increase the bioavailability and dissolution of poorly soluble hydrophobic drugs has been a major challenge for pharmaceutical development. This study shows that the dissolution rate, apparent solubility and oral bioavailability of tadalafil (Td) can be improved by nano-sized amorphous particles prepared by using antisolvent precipitation. Acetone and an acetone-water solution (v:v, 9:1) were selected as solvents, with deionized water as the antisolvent. The antisolvent precipitation process was conducted at a constant drug concentration of 10 mg/ml, at temperatures of 5, 10 and 15 °C and at volume ratios of antisolvent to solvent (AS/S) of 5, 8 and 10. Solid dispersion was achieved by dissolving the polymer in the antisolvent prior to the precipitation and by spray drying the suspension after the antisolvent precipitation process. The selected polymers were HPMC, VA64, and PVPK30 at concentrations of 33, 100 and 300 mg per 100 ml of water (equivalent to weight ratios of drug-to-polymer of 1:3, 1:1 and 3:1, respectively). The solid dispersions were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FT-IR). The improvements in the dissolution rate, equilibrium solubility, apparent solubility and bioavailability were tested and compared with unprocessed Td. Td particles in the suspension (before spray drying) were 200 nm, and the obtained Td solid dispersion had a size of approximately 5-10 μm. The XRPD, DSC and FT-IR analyses confirmed that the prepared Td particles in the solid dispersions were amorphous. The solid dispersion obtained using the optimized process conditions exhibited 8.5 times faster dissolution rates in the first minute of dissolution, 22 times greater apparent solubility at 10 min and a 3.67-fold increase in oral bioavailability than the as-received Td. The present work demonstrated that low temperature antisolvent precipitation technique has excellent potential to prepare nano-sized amorphous particles with a faster release and a higher bioavailability.
提高疏水性差的难溶性药物的生物利用度和溶解度一直是药物开发的主要挑战。本研究表明,通过使用抗溶剂沉淀法制备的纳米无定形颗粒可以提高他达拉非(Td)的溶解速率、表观溶解度和口服生物利用度。选择丙酮和丙酮-水(v:v,9:1)作为溶剂,去离子水作为抗溶剂。抗溶剂沉淀过程在药物浓度为 10mg/ml、温度为 5、10 和 15°C 以及抗溶剂与溶剂(AS/S)体积比为 5、8 和 10 的条件下进行。通过在沉淀前将聚合物溶解在抗溶剂中,并在抗溶剂沉淀过程后将悬浮液喷雾干燥,实现固体分散。选择的聚合物为 HPMC、VA64 和 PVPK30,浓度分别为 33、100 和 300mg/100ml 水(相当于药物-聚合物的重量比分别为 1:3、1:1 和 3:1)。通过扫描电子显微镜(SEM)、X 射线粉末衍射(XRPD)、差示扫描量热法(DSC)和傅里叶变换红外光谱(FT-IR)对固体分散体进行了表征。测试并比较了未加工 Td 的溶解速率、平衡溶解度、表观溶解度和生物利用度的提高。悬浮液(喷雾干燥前)中的 Td 颗粒为 200nm,所得 Td 固体分散体的粒径约为 5-10μm。XRPD、DSC 和 FT-IR 分析证实,制备的固体分散体中的 Td 颗粒为无定形。在优化的工艺条件下得到的固体分散体在溶解的前 1 分钟内具有 8.5 倍更快的溶解速率,在 10 分钟时具有 22 倍更大的表观溶解度,口服生物利用度提高了 3.67 倍。本工作表明,低温抗溶剂沉淀技术具有制备具有更快释放和更高生物利用度的纳米级无定形颗粒的巨大潜力。