Development and Optimization of a Biphasic-Release Acetazolamide Tablet-in-Tablet Formulation.

IF 2.5 4区医学 Q3 PHARMACOLOGY & PHARMACY

Drugs in Research & Development Pub Date : 2026-06-01 Epub Date: 2026-06-09 DOI:10.1007/s40268-026-00546-9

Si-Kai Wang, Wei Li, Miao-Miao Guo, Man Han, Ze-Chun Long, Jin-Hui He, Xiang-Yang Xie, Yuan Zeng, Hui Liu

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引用次数: 0

Abstract

Background and objective: High-altitude illness (HAI) poses health risks to individuals at high altitudes, and acetazolamide (ACZ) is the only Food and Drug Administration (FDA)-approved prophylactic drug. Conventional immediate-release (IR) tablets and extended-release (ER) capsules do not simultaneously provide early drug availability and prolonged coverage. This study aimed to develop a biphasic-release ACZ tablet-in-tablet (ACZ-TIT) formulation as a proof-of-concept oral dosage form integrating IR and ER.

Methods: ACZ-excipient compatibility was assessed using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and solubility was evaluated in physiologically relevant media. Formulation optimization was performed via single-factor studies and response surface methodology (RSM). Quality control included weight, hardness, friability, content, and related substances. In vitro dissolution studies were conducted, and drug release kinetics were analyzed using multiple models.

Results: No new incompatibility signals were observed between ACZ and the selected excipients, and only small solubility differences were found across the tested media. ACZ-TIT showed a biphasic-release profile, with 25.3% drug release at 0.5 h and 86.5% at 10 h. Physical properties were within pharmacopeial limits (weight variation ≤ 2.65%, hardness 112.0 ± 21.2 N, friability 0.18%, and assay relative standard deviation < 1.2%), and the related substances were found to be within the specified limits. Release kinetics were best described by the Ritger-Peppas model (R² = 0.993), supporting diffusion-dominated ER.

Conclusion: ACZ-TIT may provide rapid initial release followed by sustained exposure, which could help address limitations of currently available ACZ dosage forms. In vivo pharmacokinetic and clinical studies are still required to establish clinical applicability.

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乙酰唑胺片中片双相释放制剂的研制与优化。

背景与目的：高原病（HAI）对高海拔地区的个体构成健康风险，乙酰唑胺（ACZ）是唯一获得美国食品药品监督管理局（FDA）批准的预防药物。传统的速释（IR）片剂和缓释（ER）胶囊不能同时提供早期药物可用性和延长覆盖范围。本研究旨在开发一种双相释放的ACZ片剂（ACZ- tit）制剂，作为一种整合IR和ER的概念验证口服剂型。方法：采用傅里叶变换红外光谱（FTIR）、差示扫描量热法（DSC）和粉末x射线衍射（PXRD）评价acz与辅料的配型，并评价其在生理相关介质中的溶解度。通过单因素试验和响应面法（RSM）对配方进行优化。质量控制包括重量、硬度、脆性、含量及相关物质。进行了体外溶出研究，并使用多种模型分析了药物释放动力学。结果：ACZ与所选辅料之间没有发现新的不相容信号，在不同的介质中溶解度差异很小。ACZ-TIT呈双相释放，0.5 h释药25.3%，10 h释药86.5%，物性在药典规定范围内（重量变化≤2.65%，硬度112.0±21.2 N，脆度0.18%，相对标准偏差< 1.2%），相关物质均在规定范围内。释放动力学用Ritger-Peppas模型描述（R2 = 0.993），支持扩散为主的内质网。结论：ACZ- tit具有快速初释后持续暴露的特点，有助于解决目前ACZ剂型的局限性。体内药代动力学和临床研究仍需建立临床适用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drugs in Research & Development Pharmacology, Toxicology and Pharmaceutics-Pharmacology

CiteScore

5.10

自引率

0.00%

发文量

审稿时长

8 weeks

期刊介绍： Drugs in R&D is an international, peer reviewed, open access, online only journal, and provides timely information from all phases of drug research and development that will inform clinical practice. Healthcare decision makers are thus provided with knowledge about the developing place of a drug in therapy. The Journal includes: Clinical research on new and established drugs; Preclinical research of direct relevance to clinical drug development; Short communications and case study reports that meet the above criteria will also be considered; Reviews may also be considered.