Mahajan Radhika Rajiv, Ravi Punna Rao, Marathe Riya Kamlesh, Dongare Ajay Gorakh, Prabhu Apoorva Vinayak, Szeleszczuk Łukasz
Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Hyderabad 500078, Telangana, India.
Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-093 Warsaw, Poland.
Pharmaceutics. 2024 Aug 19;16(8):1087. doi: 10.3390/pharmaceutics16081087.
Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. NM is orally administered at a high dose of 290 mg due to its low solubility and poor dissolution rate at pH > 3, as well as gut-wall metabolism limiting its bioavailability. Self-emulsifying drug delivery systems (SEDDSs) of NM were developed in the current study to improve its oral bioavailability. The oily vehicle (clove oil) was selected based on the solubility of NM, while the surfactant and the cosurfactant were selected based on the turbidimetric analysis. Three different sets were screened for surfactant selection in the preparation of SEDDS formulations, the first set containing Cremophor EL alone as the surfactant, the second set containing a mixture of Cremophor EL (surfactant) and Caproyl PGMC (cosurfactant), and the third set containing a mixture of Cremophor EL (surfactant) and Capmul MCM C8 (cosurfactant). Propylene glycol was used as the cosolubilizer in the preparation of SEDDSs. A series of studies, including the construction of ternary phase diagrams to determine the zone of emulsification, thermodynamic stability studies (involving dilution studies, freeze-thaw, and heating-cooling studies), turbidimetric analysis, and physicochemical characterization studies were conducted to identify the two most stable combinations of SEDDSs. The two optimized SEDDS formulations, TP16 and TP25, consisted of clove oil (45% /) and propylene glycol (5% /) in common but differed with respect to the surfactant or surfactant mixture in the formulations. TP16 was prepared using a mixture of Cremophor EL (surfactant) and Caproyl PGMC (cosurfactant) in a 4:1 ratio (50% /), while TP25 contained only Cremophor EL (50% /). The mean globule sizes were 239.8 ± 77.8 nm and 204.8 ± 2.4 nm for TP16 and TP25, respectively, with an emulsification time of <12 s for both formulations. In vitro drug dissolution studies performed at different pH conditions (3.0, 4.5, 6.8) have confirmed the increase in solubility and dissolution rate of the drug by TP16 and TP25 at all pH conditions compared to plain NM. An oral pharmacokinetic study in female Wistar rats showed that the relative bioavailability (Frel) values of TP16 and TP25 over the plain NM were 2.18 ( < 0.05) and 2.24 ( < 0.01), respectively.
马来酸奈拉替尼（NM）是一种酪氨酸激酶抑制剂，用于治疗乳腺癌。由于NM在pH>3时溶解度低、溶出速率差，以及肠壁代谢限制其生物利用度，因此以290mg的高剂量口服给药。在本研究中开发了NM的自乳化药物递送系统（SEDDSs）以提高其口服生物利用度。油性载体（丁香油）根据NM的溶解度选择，而表面活性剂和助表面活性剂根据比浊分析选择。在制备SEDDS制剂时筛选了三组不同的表面活性剂，第一组仅含有聚氧乙烯蓖麻油（Cremophor EL）作为表面活性剂，第二组含有聚氧乙烯蓖麻油（表面活性剂）和己酰聚甘油甲基丙烯酸酯（Caproyl PGMC，助表面活性剂）的混合物，第三组含有聚氧乙烯蓖麻油（表面活性剂）和辛酸癸酸甘油三酯（Capmul MCM C8，助表面活性剂）的混合物。丙二醇用作制备SEDDSs的助溶剂。进行了一系列研究，包括构建三元相图以确定乳化区域、热力学稳定性研究（包括稀释研究、冻融和加热-冷却研究）、比浊分析和物理化学表征研究，以确定SEDDSs的两种最稳定组合。两种优化的SEDDS制剂TP16和TP25共同含有丁香油（45%/）和丙二醇（5%/），但在制剂中的表面活性剂或表面活性剂混合物方面有所不同。TP16使用聚氧乙烯蓖麻油（表面活性剂）和己酰聚甘油甲基丙烯酸酯（助表面活性剂）以4:1的比例（50%/）的混合物制备，而TP25仅含有聚氧乙烯蓖麻油（50%/）。TP16和TP25的平均球粒尺寸分别为239.8±77.8nm和204.8±2.4nm，两种制剂的乳化时间均<12s。在不同pH条件（3.0、4.5、6.8）下进行的体外药物溶出研究证实，与普通NM相比，TP16和TP25在所有pH条件下均提高了药物的溶解度和溶出速率。在雌性Wistar大鼠中进行的口服药代动力学研究表明，TP16和TP25相对于普通NM的相对生物利用度（Frel）值分别为2.18（<0.05）和2.24（<0.01）。
