用于连续制造固体晶体悬浮液的同向旋转双螺杆工艺：提高卡维地洛溶解度、渗透率和口服生物利用度的一种有前景的策略。
Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol.
作者信息
Navti Prerana D, Fernandes Gasper, Soman Soji, Nikam Ajinkya N, Kulkarni Sanjay, Birangal Sumit R, Dhas Namdev, Shenoy Gautham G, Rao Vinay, Koteshwara Kunnatur Balasundara, Mutalik Srinivas
机构信息
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
出版信息
F1000Res. 2024 May 22;12:1438. doi: 10.12688/f1000research.139228.1. eCollection 2023.
BACKGROUND
In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier.
METHODS
molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. permeation studies and pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months.
RESULTS
Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the and pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content.
CONCLUSIONS
TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.
背景
在当前工作中，使用同向旋转双螺杆处理器（TSP），以甘露醇作为亲水性载体，制备卡维地洛（CAR）的固体晶体混悬剂（SCS），以提高其溶解度、溶解速率、渗透性和生物利用度。
方法
进行分子动力学（MD）研究，以模拟在不同捏合区温度（KZT）下CAR与甘露醇的相互作用。基于这些研究，评估用于提高CAR溶解度的最佳CAR：甘露醇比例和捏合区温度。使用Box-Behnken设计的实验设计（DoE）方法对CAR-SCS进行优化。对所有制剂进行饱和溶解度研究和溶解研究。使用差示扫描量热法、傅里叶变换红外光谱、X射线衍射研究和拉曼光谱分析进行物理化学表征。对CAR-SCS进行渗透研究和药代动力学研究。在40℃/75%相对湿度的加速稳定性条件下，对DoE优化的CAR-SCS进行三个月的稳定性研究。
结果
实验上，在100 rpm螺杆速度下使用120℃的KZT制备的CAR：甘露醇比例为20：80的制剂显示出最高的溶解度提高，与普通CAR相比提高了50倍。物理化学表征证实了DoE优化的CAR-SCS的结晶状态。溶解研究表明，与纯CAR相比，优化后的CAR-SCS在pH 1.2 HCl溶液和pH 6.8磷酸盐缓冲液中的溶解速率分别提高了6.03倍和3.40倍。在渗透和药代动力学研究中表明优化后的CAR-SCS疗效增强，其中与普通CAR相比，表观渗透率提高了1.84倍，生物利用度提高了1.50倍。稳定性研究表明药物含量具有良好的稳定性。
结论
TSP技术可用于通过制备SCS来提高难溶性CAR的溶解度、生物利用度和渗透性。
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