Ozon Emma Adriana, Mati Erand, Karampelas Oana, Anuta Valentina, Sarbu Iulian, Musuc Adina Magdalena, Mitran Raul-Augustin, Culita Daniela C, Atkinson Irina, Anastasescu Mihai, Lupuliasa Dumitru, Mitu Mirela Adriana
Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 020945, Bucharest, Romania.
"Titu Maiorescu" University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 16 Sincai Boulevard, 040314, Bucharest, Romania.
Heliyon. 2024 Jun 15;10(12):e33162. doi: 10.1016/j.heliyon.2024.e33162. eCollection 2024 Jun 30.
Recent advancements in the formulation of solid dosage forms involving active ingredient-cyclodextrin complexes have garnered considerable attention in pharmaceutical research. While previous studies predominantly focused on incorporating these complexes into solid states, issues regarding incomplete inclusion prompted the exploration of novel methods. In this study, we aimed to develop an innovative approach to integrate liquid-state drug-cyclodextrin inclusion complexes into solid dosage forms. Our investigation centered on rivaroxaban, a hydrophobic compound practically insoluble in water, included in hydroxypropyl-β-cyclodextrin at a 1:1 M ratio, and maintained in a liquid state. To enhance viscosity, hydroxypropyl-cellulose (2 % w/w) was introduced, and the resulting dispersion was sprayed onto the surface of cellulose pellets (CELLETS®780) using a Caleva Mini Coater. The process parameters were meticulously controlled, with atomization air pressure set at 1.1 atm and a fluidizing airflow maintained at 35-45 m/h. Characterization of the coated cellets, alongside raw materials, was conducted using Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) analyses. Physicochemical evaluations affirmed the successful incorporation of rivaroxaban into hydroxypropyl-β-cyclodextrin, with the final cellets demonstrating excellent flowability, compressibility, and adequate hardness. Quantitative analysis the HPLC-DAD method confirmed a drug loading of 10 mg rivaroxaban/750 mg coated cellets. dissolution studies were performed in two distinct media: 0.022 M sodium acetate buffer pH 4.5 with 0.2 % sodium dodecyl sulfate (mirroring compendial conditions for 10 mg rivaroxaban tablets), and 0.05 M phosphate buffer pH 6.8 without surfactants, compared to reference capsules and conventional tablet formulations. The experimental capsules exhibited similar release profiles to the commercial product, Xarelto® 10 mg, with enhanced dissolution rates observed within the initial 10 min. This research presents a significant advancement in the development of solid dosage forms incorporating liquid-state drug-cyclodextrin inclusion complexes, offering a promising avenue for improving drug delivery and bioavailability.
涉及活性成分 - 环糊精复合物的固体剂型配方的最新进展在药物研究中引起了广泛关注。虽然先前的研究主要集中于将这些复合物纳入固态，但不完全包合的问题促使人们探索新方法。在本研究中，我们旨在开发一种创新方法，将液态药物 - 环糊精包合物整合到固体剂型中。我们的研究聚焦于利伐沙班，一种几乎不溶于水的疏水化合物，以1:1摩尔比包含在羟丙基 - β - 环糊精中，并保持液态。为提高粘度，引入了羟丙基纤维素（2% w/w），然后使用Caleva Mini包衣机将所得分散体喷雾到纤维素微丸（CELLETS®780）表面。工艺参数得到精心控制，雾化气压设定为1.1大气压，流化气流保持在35 - 45米/小时。使用傅里叶变换红外光谱（FTIR）、X射线衍射（XRD）、扫描电子显微镜（SEM）和差示扫描量热法（DSC）分析对包衣微丸以及原材料进行表征。物理化学评估证实利伐沙班成功纳入羟丙基 - β - 环糊精，最终微丸表现出优异的流动性、可压缩性和足够的硬度。采用HPLC - DAD方法进行的定量分析证实药物载量为10毫克利伐沙班/750毫克包衣微丸。在两种不同介质中进行了溶出度研究：含有0.2%十二烷基硫酸钠的0.022 M醋酸钠缓冲液pH 4.5（模拟10毫克利伐沙班片剂的药典条件），以及不含表面活性剂的0.05 M磷酸盐缓冲液pH 6.8，并与参比胶囊和传统片剂剂型进行比较。实验胶囊表现出与市售产品Xarelto® 10毫克相似的释放曲线，在最初10分钟内观察到溶出速率提高。本研究在包含液态药物 - 环糊精包合物的固体剂型开发方面取得了重大进展，为改善药物递送和生物利用度提供了一条有前景的途径。
