Page 60 - 2019年9月第30卷第18期

Design and Optimization of the Formulation and Technology of Theophylline Gel Matrix Sustained-release
Tablets Based on QbD Concept
JIANG Xiwei，FEI Yunyang，LIAN Guiyu，XIANG Rongwu，ZHAI Fei，JIANG Yukun，CHE Xin（College of
Pharmacy，Shenyang Pharmaceutical University，Shenyang 110016，China）

ABSTRACT OBJECTIVE：To design and optimize the formulation and technology of Theophylline hydrophilic gel matrix
sustained-release tablets （self-made sustained-release tablets for short） based on the concept of“Quality by Design”（QbD）.
METHODS：Diluent type，tablet diameter，the property of adhesive（ratio of different adhesive types），the amount of adhesive
were regarded as critical process parameters （CPPs）. Similarity factor of dissolution curves of self-made Theophylline
sustained-release tablets and reference preparation and its accumulative release rate at different time points were regarded as critical
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quality attributes（CQAs）. L18 （3）orthogonal tablet was adopted for design and trial，and secondary polynomial regression model
was established. By using Modde 12.0 software，the design space and its acceptable range（PAR）were calculated through the
optimal model. The optimal formulation and technology of Theophylline sustained-release tablets was determined，and validation
test and Monte Carlo simulation verification were conducted. RESULTS：The optimal model with good coincidence，accuracy，
validity and reproducibility was obtained，which could better fit the relationship between CQAs and CPPs. The design space and
PAR value were obtained by further calculation（The optimum value of diluent was lactose；tablet diameter was 9.07-9.33 mm，and
the optimal value was 9.20 mm；ratio of HPMC K4M to HPMC was 0.50-0.83，and the optimal value was 0.80；total amount of
HPMC was 0.036 0-0.041 3 g per tablet，and the optimal value was 0.038 g per tablet）. The optimal formulation and technology
included that ratio of theophylline，HPMC K4M and HPMC K100M were 50％，15.48％ and 3.87％，respectively；the rest was
filled with lactose and the diameter of the tablet was 9.20 mm. The results of validation confirmed that self-made Theophylline
sustained-release tablets had similar in vitro release behavior compared with reference preparation. CONCLUSIONS：Based on the
concept of QbD，the formulation and technology of Theophylline sustained-release tablets can meet the requirements of design，and
the CPPs can be adjusted within the PAR range to meet the requirements of CQAs. This shows that the QbD concept is scientific
and effective in the design and optimization of the formulation and technology of sustained and controlled release preparations.
KEYWORDS Theophylline；Hydrophilic gel matrix sustained-release tablets；Quality by design；Critical quality attributes；
Critical process parameters；Orthogonal test；Design space；Formulation；Technology；Optimization

[6]
“质量源于设计”（Quality by Design，QbD）理念最 带来的不良反应，提高患者服药依从性 。缓控释骨架
早于 2004 年由美国 FDA 提出，其旨在通过处方工艺设 片剂是市售口服缓控释剂型的重要组成，其处方组成相
计生产，从而确定影响产品关键质量属性（Critical quali- 对简单且易生产，常采用亲水凝胶骨架作为释放载体。
ty attributes，CQAs）的关键工艺参数（Critical process pa- 为此，本研究以市售茶碱缓释片为参比制剂，运用 QbD
rameters，CPPs），并通过控制 CPPs 的范围，使生产出来 理念设计并制备其仿制制剂——茶碱凝胶骨架缓释片
[1]
的药品达到预定的质量标准 。QbD强调产品质量来源 （以下简称“自制缓释片”），为基于QbD理念的处方工艺
于其生产前设计，而非对已有产品的检测。在传统的产 优化和仿制药研发提供方法学参考。本研究通过风险
品设计生产理念下，产品质量极度依赖产品的检测把 评估确定稀释剂类型、片径、黏合剂性质及用量为CPPs，
[2]
控，而 QbD 的理念则很好地克服了上述问题 。目前， 以自制缓释片与参比制剂释放曲线的相似因子以及其
QbD 理念在一些传统剂型的工艺筛选和处方优化中已 在不同时间点的药物释放度为 CQAs，采用正交试验设
有应用，但将其用于对释放性能要求较严格的缓控释制 计进行处方工艺筛选，并采用二项式回归分析和设计空
剂生产罕见报道。 间确定最优处方工艺，最终制备获得与参比制剂体外溶
茶碱（Theophylline）是一种甲基嘌呤类药物，在治疗 出行为相似的自制缓释片，旨在进一步探究QbD理念用
支气管扩张、抗炎、调节免疫等方面具有确切的效果 。 于缓控释制剂处方工艺设计的科学性和有效性。
[3]
临床常用的剂型为氨茶碱片（100 mg/片），每日需服用3 1 材料
次，频繁给药常导致患者体内血药浓度波动大、疗效不 1.1 仪器
稳定等现象 ；而且，当茶碱的血药浓度超过 20 μg/mL FA2004B 型电子天平[奥豪斯仪器（常州）有限公
[4]
[5]
时，还会引起如恶心、心悸、心律失常等不良反应 ，因此 司]；LSP50 型单冲压片机（扬州市诺亚机械有限公司）；
有必要采用缓控释剂型给药。将传统药物设计成缓控 UV-1000型紫外-可见分光光度计[翱艺仪器（上海）有限
释制剂可延长有效血药浓度的持续时间，减轻药物突释 公司]；RC806D 型溶出试验仪（天津市天大天发科技有

中国药房 2019年第30卷第18期 China Pharmacy 2019 Vol. 30 No. 18 ·2503 ·