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Circadian-guided asthma therapy: compressed-coated chronotherapeutic tablets for precision early-morning drug delivery
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DOI：10.1007/s40199-026-00626-w.png)
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Abstract
En 中文
Early-morning worsening of asthma, most often observed between 03:00 and 06:00 am, arises from circadian regulation of airway smooth muscle tone, enhanced nocturnal release of inflammatory mediators, and the physiological nadir of endogenous cortisol levels. During this vulnerable interval, patients experience marked airway narrowing; however, conventional oral and inhaled therapies frequently fail to maintain adequate drug concentrations, highlighting the need for delivery systems capable of chronologically programmed pulsatile release. This review aims to critically evaluate recent advances in compressed-coated chronotherapeutic tablets (CCCTs) for early-morning asthma, with emphasis on polymer selection, hydration swelling-rupture mechanisms, and material characteristics governing lag-time precision, and to explore the interplay between circadian pathophysiology and pharmacokinetic-pharmacodynamic alignment in optimizing pulsatile oral drug delivery. An extensive and systematic literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar, covering publications from January 2000 to November 2025, using terms including chronotherapy, pulsatile drug delivery, compressed-coated tablets, press-coated tablets, lag-time systems, circadian asthma, and oral chronotherapeutic formulations. Preclinical, clinical, formulation, mechanistic, and translational reports published in English were critically analysed to synthesise advances in formulation design, material engineering, biopharmaceutical performance, and clinical relevance of CCCTs for early-morning asthma. Compressed-coated chronotherapeutic tablets (CCCTs) offer a robust oral pulsatile platform that can be designed to provide a defined lag phase followed by rapid drug release after bedtime administration, with lag-time precision governed predominantly by polymer hydration, swelling, and rupture behaviour. Appropriately timed drug exposure aligned with circadian pathophysiology was found to enhance bronchodilation and anti-inflammatory efficacy while minimizing unnecessary nocturnal exposure. Preclinical findings and emerging clinical evidence supporting circadian-aligned delivery are summarized, together with key translational considerations including biorelevant dissolution testing, in vitro-in vivo correlation, scale-up challenges, and regulatory expectations for pulsatile oral systems. By integrating chronobiology with formulation engineering and quality-by-design principles, CCCTs represent a rational and adaptable strategy for synchronizing oral asthma therapy with endogenous biological rhythms. This review positions CCCT-based chronotherapy as a promising approach to improve early-morning symptom control and underlines the critical challenges that must be addressed to enable successful clinical translation. The graphical abstract depicts a chronotherapeutic tablet intended for administration at bedtime. Its protective compressed coating keeps the core intact during early gastrointestinal transit. After the intended delay, the coating softens, allowing the drug to be released quickly. The formulation is designed to deliver the dose in the early morning, when circadian variation often produces greater airway narrowing and bronchial sensitivity in asthma, supporting better overnight control and reducing symptoms on waking. Early-morning asthma defines a circadian period of increased airway vulnerability that calls for drug delivery strategies capable of precise temporal control. Compressed-coated chronotherapeutic tablets provide a practical oral platform for achieving reproducible lag times and pulsatile drug release following bedtime administration. The onset of release and in vivo lag-time precision are primarily governed by polymer hydration, swelling behavior, and subsequent rupture of the coating layer. Alignment of pharmacokinetic exposure with circadian pharmacodynamic demand can enhance therapeutic efficacy while avoiding unnecessary drug exposure during the night. Successful clinical translation relies on the use of biorelevant dissolution methods, robust in vitro-in vivo correlation, and quality-by-design–driven formulation development.
Keywords:
Chronotherapy
Pulsatile drug delivery
Compressed-coated chronotherapeutic tablets
Early-morning asthma
Circadian rhythms
Lag-time control
Oral drug delivery
Pharmacokinetic-pharmacodynamic alignment
Journal
D
IF:
2.1
Papers:
68
Citations:
0