Giri Bhupendra Raj, Kim Jung Suk, Park Jong Hyuck, Jin Sung Giu, Kim Kyeong Soo, Din Fakhar Ud, Choi Han Gon, Kim Dong Wuk
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Kyungpook National University, Daegu 41566, Korea.
College of Pharmacy, Hanyang University, Ansan 15588, Korea.
Pharmaceutics. 2021 Jan 16;13(1):111. doi: 10.3390/pharmaceutics13010111.
Low aqueous solubility and poor bioavailability are major concerns in the development of oral solid-dosage drug forms. In this study, we fabricated surface-attached solid dispersion (SASD) to enhance the solubility, bioavailability, and photostability of methotrexate (MTX), a highly lipophilic and photo-unstable drug. Several MTX-loaded SASD formulations were developed for spray-drying using water as the solvent, and were investigated for their aqueous solubility and dissolution kinetics. An optimized ternary SASD formulation composed of MTX/ sodium carboxymethyl cellulose (Na-CMC)/sodium lauryl sulfate (SLS) at 3/0.5/0.5 (/) had 31.78-fold and 1.88-fold higher solubility and dissolution, respectively, than MTX powder. For SASD, the in vivo pharmacokinetic parameters AUC and C were 2.90- and 3.41-fold higher, respectively, than for the MTX powder. Solid-state characterizations by differential scanning calorimetry and X-ray diffraction revealed that MTX exists in its crystalline state within the spray-dried SASD. The MTX-loaded SASD formulation showed few physical changes with photostability testing. Overall, the results indicate that the spray-dried MTX-loaded SASD formulation without organic solvents enhances the solubility and oral bioavailability of MTX without a significant deterioration of its photochemical stability.
低水溶性和低生物利用度是口服固体制剂药物研发过程中的主要关注点。在本研究中，我们制备了表面附着型固体分散体（SASD）以提高甲氨蝶呤（MTX）的溶解度、生物利用度和光稳定性，MTX是一种高亲脂性且光不稳定的药物。我们开发了几种以水为溶剂通过喷雾干燥法制备的载MTX的SASD制剂，并对其水溶性和溶解动力学进行了研究。一种优化的三元SASD制剂，其组成为MTX/羧甲基纤维素钠（Na-CMC）/月桂基硫酸钠（SLS），比例为3/0.5/0.5（/），其溶解度和溶出度分别比MTX粉末高31.78倍和1.88倍。对于SASD，其体内药代动力学参数AUC和C分别比MTX粉末高2.90倍和3.41倍。通过差示扫描量热法和X射线衍射进行的固态表征表明，MTX以结晶态存在于喷雾干燥的SASD中。载MTX的SASD制剂在光稳定性测试中几乎没有物理变化。总体而言，结果表明，不含有机溶剂的喷雾干燥载MTX的SASD制剂可提高MTX的溶解度和口服生物利用度，且不会显著降低其光化学稳定性。
