Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA; Pii Center for Pharmaceutical Technology, The University of Mississippi, University, MS 38677, USA.
Eur J Pharm Biopharm. 2024 Jul;200:114335. doi: 10.1016/j.ejpb.2024.114335. Epub 2024 May 19.
The study endeavors the fabrication of extended-release adipic acid (APA) buccal films employing a quality by design (QbD) approach. The films intended for the treatment of xerostomia were developed utilizing hot-melt extrusion technology. The patient-centered quality target product profile was created, and the critical quality attributes were identified accordingly. Three early-stage formulation development trials, complemented by risk assessment aligned the formulation and process parameters with the product quality standards. Employing a D-optimal mixture design, the formulations were systematically optimized by evaluating three formulation variables: amount of the release-controlling polymer Eudragit® (E RSPO), bioadhesive agent Carbopol® (CBP 971P), and pore forming agent polyethylene glycol (PEG 1500) as independent variables, and % APA release in 1, 4 and 8 h as responses. Using design of experiment software (Design-Expert®), a total of 16 experimental runs were computed and extruded using a Thermofisher Scientific twin screw extruder. All films exhibited acceptable content uniformity and extended-release profiles with the potential for releasing APA for at least 8 h. Films containing 30% E RSPO, 10% CBP 971P, and 20% PEG 1500 released 88.6% APA in 8 h. Increasing the CBP concentration enhanced adhesiveness and swelling capacities while decreasing E RSPO concentration yielded films with higher mechanical strength. The release kinetics fitted well into Higuchi and Krosmeyer-Peppas models indicating a Fickian diffusion release mechanism.
本研究致力于采用质量源于设计（QbD）方法制备用于治疗口干症的缓控释己二酸（APA）颊膜。采用热熔挤出技术开发了以患者为中心的质量目标产品概况，并据此确定了关键质量属性。通过进行三个早期制剂开发试验和风险评估，使制剂和工艺参数与产品质量标准保持一致。采用 D-最优混合设计，通过评估三个制剂变量（控释聚合物 Eudragit®（E RSPO）的用量、生物黏附剂 Carbopol®（CBP 971P）和致孔剂聚乙二醇（PEG 1500））以及 1、4 和 8 h 的%APA 释放作为响应，对制剂进行了系统优化。使用实验设计软件（Design-Expert®）计算并共挤出了 16 个实验运行，采用 Thermofisher Scientific 双螺杆挤出机。所有膜均表现出良好的含量均匀性和缓控释性能，有望至少在 8 h 内释放 APA。含有 30% E RSPO、10% CBP 971P 和 20% PEG 1500 的膜在 8 h 内释放了 88.6%的 APA。增加 CBP 浓度可提高黏附性和溶胀能力，而降低 E RSPO 浓度则可使膜具有更高的机械强度。释放动力学符合 Higuchi 和 Krosmeyer-Peppas 模型，表明为 Fickian 扩散释放机制。
