口服硝苯地平有机-无机复合缓释材料的研制

doi:10.5246/jcps.2025.07.045

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (7): 605-621.DOI: 10.5246/jcps.2025.07.045

• 【研究论文】 • 下一篇

口服硝苯地平有机-无机复合缓释材料的研制

闫嘉¹^,², 梁艳琴³^,^*(), 吴翠栓¹^,⁴, 张强¹^,²^,^*()

^1. 内蒙古医科大学药学院, 内蒙古呼和浩特 010110
^2. 北京大学医学部药学院, 北京 100191
^3. 天津中医药大学药学院, 天津 301617
^4. 北京德立福瑞医药科技有限公司, 北京 102100

收稿日期:2025-02-20 修回日期:2025-04-11 接受日期:2025-04-24 出版日期:2025-07-31 发布日期:2025-07-31
通讯作者: 梁艳琴, 张强

Development of an oral organic-inorganic hybrid nanocomposite for prolonged sustained release of nifedipine

Jia Yan¹^,², Yanqin Liang³^,^*(), Cuishuan Wu¹^,⁴, Qiang Zhang¹^,²^,^*()

¹ College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, Inner Mongolia, China
² School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
³ School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
⁴ Beijing Delivery Pharm. Technology Co, Ltd, Beijing 102100, China

Received:2025-02-20 Revised:2025-04-11 Accepted:2025-04-24 Online:2025-07-31 Published:2025-07-31
Contact: Yanqin Liang, Qiang Zhang
Supported by:
The National Natural Science Foundation of China (Grant Nos. U20A20412, 81821004, U22A20384, 82225044, 52273136), the National Key R&D Program of China (Grant Nos. 2022YFC3501900, 2023YFC2605004), the Beijing Natural Science Foundation (Grant Nos. L222127, L212013), and the AI+ Health Collaborative Innovation Cultivation Project (Grant No. Z211100003521002).

摘要/Abstract

摘要：

硝苯地平是一种用于治疗高血压的药物, 需要长期使用。虽然其渗透泵制剂(如拜耳的Adalat^®)因零级药物释放特性而广受认可, 但它对生产设备的严格要求使其成本高昂。本研究利用介孔二氧化硅作为硝苯地平的载体, 将其与有机聚合物结合, 形成有机-无机杂化纳米复合材料(OIN)。结果表明, OIN在体外和体内均表现出良好的缓释效果, 体外释放曲线呈现典型的一级药物释放特征。然后, 我们进一步将OIN与传统的片剂制备技术相结合, 开发出具有理想零级释放特性的口服纳米复合体系(ONS)。与拜耳公司的硝苯地平渗透泵制剂(Adalat^®)相比, 不同时间点的累积释放度均显著相似。此外, 从理论上探讨了OIN和ONS的体外释放机制, 为缓释药物的研究提供了新的思路。

关键词: 硝苯地平, 有机-无机杂化纳米复合材料, 零级释放, 二氧化硅, Eudragit? RSPO

Abstract:

Nifedipine (NF), a widely prescribed antihypertensive agent, necessitates long-term administration to maintain therapeutic efficacy. Although osmotic pump formulations, such as Bayer’s Adalat^®, are well-established for achieving zero-order drug release, their complex manufacturing requirements significantly elevate production costs. In this study, we employed mesoporous silica as a drug carrier for nifedipine and incorporated it with an organic polymer matrix to construct an organic-inorganic hybrid nanocomposite (OIN). This nanostructured system demonstrated robust sustained-release properties in both in vitro and in vivo evaluations, with the in vitro release profile exhibiting classical first-order kinetics. To further optimize the release behavior, we combined OIN with conventional tablet-forming techniques to create an oral nanocomposite system (ONS) capable of achieving near-zero-order release. Remarkably, the cumulative release profiles of ONS closely mirrored those of the commercially available Adalat^® osmotic formulation across multiple time points. Moreover, we conducted a theoretical analysis of the release mechanisms underlying both OIN and ONS systems, offering novel mechanistic insights that could inform the future design of advanced sustained-release drug delivery platforms.

Key words: Nifedipine, Organic-inorganic hybrid nanocomposite, Zero-order release, Silica, Eudragit? RSPO

Supporting:

闫嘉, 梁艳琴, 吴翠栓, 张强. 口服硝苯地平有机-无机复合缓释材料的研制[J]. 中国药学(英文版), 2025, 34(7): 605-621.

Jia Yan, Yanqin Liang, Cuishuan Wu, Qiang Zhang. Development of an oral organic-inorganic hybrid nanocomposite for prolonged sustained release of nifedipine[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(7): 605-621.

图/表 16

Table 1. Orthogonal experimental design based on the types and ratios of silica and sustained-release materials.

Table 2. Preparation of different OINs.

Table 3. Fitting results of in vitro drug release curves for various OINs.

Figure 1. In vitro dissolution results of orthogonal experimental design.

Figure 2. In vitro dissolution of various OINs in 1% SDS phosphate–citrate buffer (pH 6.8) at 37 °C over a 24-hour period.

Figure 3. TEM of (A) S350 and (B) NF-S350-RS13 (P.S. Scale bar: 1 cm = 50 nm).

Figure 4. SEM of (A) S350 and (B) NF-S350-RS13.

Figure 5. Nitrogen adsorption-desorption isotherms and pore size distribution curves (blue) of (A) S350 and (B) NF-S350-RS13.

Figure 6. DSC and PXRD characterization of S350, NF, and NF-S350-RS13.

Figure 7. In vivo pharmacodynamic evaluation of NF and NF-S350-RS13 in SD rats. The results provided clear and intuitive evidence of the enhanced therapeutic efficacy achieved by our formulation in vivo.

Table 4. Several formulations for the production of tablets.

Figure 8. In vitro dissolution profiles of various tablet formulations. (A) Comparison of dissolution results for three formulations containing different amounts of disintegrating agent; (B) Dissolution profiles of seven formulations incorporating the same dose of different sustained-release excipients; (C) Comparative analysis of Tablet A and Tablet B, both coated with identical coating materials; the data show that Tablet A with Coating 1 exhibits superior dissolution performance; (D) Comparison of the final selected formulation (ONS) with a commercially available reference product (Adalat®) in terms of in vitro dissolution behavior.

Table 5. Formulation design for sustained-release materials added in equal amounts based on Formula 3 in Table 4 (The names of the formulations were designated based on the names of the sustained-release materials added).

Table 6. The formulation design for Tablet A and Tablet B coated with two different coatings (Coating 1= Opadry®, Coating 2= Acryl-EZE®).

Table 7. Fitting results of in vitro drug release curves of ONS and Adalat®.

Scheme 1. Schematic illustration of the in vitro drug release mechanisms of the OIN and the ONS based on the final tablet formulation. α (red) represents the porous membrane formed by the swelling and partial dissolution of Eudragit® RSPO in the medium, while β (blue) denotes the gel layer generated by HPMC 1.5W upon hydration.

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口服硝苯地平有机-无机复合缓释材料的研制

Development of an oral organic-inorganic hybrid nanocomposite for prolonged sustained release of nifedipine

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