Insomnia represents the most prevalent clinical sleep disorder, manifesting as either a primary condition or secondary symptom [1]. Characterized by persistent difficulties in sleep initiation or maintenance, it is classified by ICSD-3 into chronic, short-term, and other subtypes [2]. The sleep-wake cycle is primarily regulated by the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) [3], with diagnosis typically following DSM-IV-TR, ICSD-2, or ICD-10[4] criteria. Epidemiological data reveal China's insomnia prevalence significantly exceeds global averages, particularly among elderly populations (35–50 % incidence), with growing prevalence in younger demographics (10–20 %). Anxiety disorders, characterized by excessive worry, autonomic dysfunction, and motor restlessness, encompass generalized anxiety disorder, social phobia, and related conditions. Global prevalence ranges from 7.3-28.0 % [4,5], with lifetime rates reaching 7.6 % in China and 30 % worldwide. WHO ranks anxiety disorders as the sixth leading cause of global disability [6]. Contemporary socioeconomic stressors have significantly increased the prevalence of comorbid insomnia and anxiety disorders [7]. These conditions demonstrate a complex bidirectional relationship at the pathophysiological level: heightened cortical excitability secondary to anxiety disrupts sleep onset mechanisms [8], while prolonged sleep insufficiency impairs prefrontal cortical regulation of emotional processing, thereby exacerbating anxiety symptoms [9,10].Scheme 1..

Current insomnia treatments include benzodiazepines, sedative antidepressants, and non-prescription alternatives, yet their efficacy is limited by adverse effects [[11], [12], [13]]. Similarly, anxiety treatments (GABA/5-HT receptor agonists, H1 blockers) may adversely affect brain function [14]. In contrast, melatonin demonstrates multifaceted benefits: regulating circadian rhythms (1–3 mg dose, 5 mg max), enhancing immunity [15], inhibiting tumorigenesis [16], and improving sleep quality without significant side effects [17,18]. Despite being marketed only as supplements, melatonin products generate $200 million annually in various oral formulations. Buspirone hydrochloride offers distinct advantages for anxiety treatment: non-addictive properties, minimal withdrawal effects, and mild transient side effects. Currently available only in tablet form, its safety profile makes it ideal for novel formulations [[19], [20], [21]]. Preclinical and clinical evidence suggests that melatonin, through MT1/MT2 receptor agonism, promotes sleep initiation and regulates circadian rhythms [22,23]. Buspirone hydrochloride, as a 5-HT1A receptor partial agonist, exerts anxiolytic effects, which can address the anxiety component that often co-exists with and exacerbates sleep disorders [24,25]. It is plausible that the rapid anxiolysis induced by sublingual buspirone hydrochloride may create a calmer mental state, thereby potentiating the sleep-promoting effects of concurrently administered melatonin. This proposed sequential dual action—rapid anxiety reduction followed by sleep induction—provides a strong theoretical foundation for synergy.

While oral administration remains the preferred drug delivery route due to its convenience [26], we propose an innovative approach for insomnia with comorbid anxiety. Compared to conventional tablets or capsules, oral fast-dissolving films provide superior advantages for our target indication. Their water-free administration eliminates the need for nighttime water intake, preventing further sleep disruption [27,28]. Recognizing the vicious cycle between anxiety and insomnia, we designed a synergistic dual-drug therapy. Melatonin, an endogenous hormone [29,30], combined with buspirone hydrochloride (which has a short half-life), creates an ideal combination for oral fast-dissolving films formulation due to their favorable safety profiles. This study aims to develop a compound melatonin/buspirone hydrochloride oral fast-dissolving films for sublingual administration. This delivery method enables direct drug absorption through the sublingual venous plexus, ensuring rapid onset to simultaneously alleviate anxiety and promote sleep initiation [31,32]. In addition, the oral film does not need to be swallowed with water, making it easy to take and suitable for children, the elderly, and patients with swallowing difficulties.