Today, controlling the release of medications at the right dose and period to the target place is one of the most significant challenges facing the medical sciences [1]. Attaining this objective is of significant interest to many researchers [[2], [3], [4], [5]]. Drug delivery systems (DDS) have undergone substantial research in order to distribute medications at the desired location over a predetermined period of time and in a regulated manner [6]. In most cases, the drug is released initially in a burst with low control over the rate of delivery [7]. It is necessary to modify the dosage through dose management to reach and maintain therapeutic plasmatic concentrations [8]. Such a method is necessary to stop significant changes in the molecular structure of the medicine. In fact, DDS can improve the efficiency, specificity, therapeutic index, and tolerance of comparable drugs while lowering costs and toxicity concerns for the patient [9]. Researchers are always coming up with new methods and techniques to ensure that DDS are secure and therapeutically effective. Nanotechnology is crucial for controlling medicine distribution because it not only improves the effectiveness of treatment but also lowers negative effects [10].

Nanoclay is one form of nanomaterial that has grown increasingly popular because of its enhanced therapeutic capabilities [11]. It is composed of stacked tetrahedral layers or octahedral sheets with an identifiable layered structure or inter-lamellar spacing. The layer arrangement distinguished the clay minerals into many groups, including kaolinite, hectorite, halloysite, and montmorillonite [12]. They are potential novel drug carriers with distinctive characteristics that arise from their porous structure and well-developed inner surface. These properties encompass a high sorption capacity, a large specific surface area, an ion exchange capacity, a diverse array of active centers on the surface, and biocompatibility [13].

The polymeric blends can help with a number of drug delivery tasks, including dose profile, optimal drug release, high drug loading in composites, making polymers more biodegradable, and making the drug component that is trapped more resistant to outside stimuli [14]. Another type of DDS that has a three-dimensional network structure is called a hydrogel [15,16]. Have already been used in the past decade in wastewater treatment, tissue engineering, wound healing, oil/water separation, 3D printing, various biomedical applications that require cooperative exchange with dynamic cellular microenvironments, and many other things [17]. For instance, the hydrogel surface has a low interfacial tension with biological fluids, which reduces the likelihood of an immune reaction by closely aligning with the properties of living tissue [18]. Hydrogel designs have facilitated the precise manipulation of mechanical properties, degradation rates, and internal structures. This has significantly enhanced the comprehension of how bio cells respond to these alterations. Recent research has primarily concentrated on hydrogels that can regulate and exhibit responsiveness to the surrounding environment or external stimuli, such as light, temperature, pH, etc., in order to modify cellular interactions [19]. In addition, hydrogels can serve as injectable hydrogel systems due to their flexible nature, which allows them to adjust to environmental conditions without compromising their distinctive properties. This approach avoids the necessity of intricate surgeries and reduces harm to the surrounding healthy tissue [20]. Advances in biomolecular engineering and polymer chemistry have led to the creation of hydrogels [21]. However, these materials are not very biocompatible, which makes it hard to use them widely in the medical field [22].

For the formation of biocompatible hydrogels and enabling the design of materials with enhanced physiological performance and tailored functionality, natural polysaccharides with outstanding biocompatibility are a good choice [23]. CH and Alg are types of polysaccharides that, due to their biodegradability, biocompatibility, and non-toxicity, are commonly utilized in biomedical applications [24,25]. The unique characteristics of these hydrogels, such as self-healing, thermosensitivity, pH sensitivity, etc., significantly support their biomedical use [26]. Another benefit of CH is that they can dissolve in acidic aqueous solutions at normal temperature, but as the temperature reaches body temperature, they start to become gel [27].

AMT is among the most popular tricyclic antidepressants that inhibit monoamine reuptake. It prevents serotonergic and adrenergic neurons from using their membrane pumps to receive norepinephrine and serotonin [28]. The currently marketed AMT product can have negative effects such as extremely low blood pressure, a rapid or irregular heartbeat, an inability to respond or enter a coma, and temporary dry eye that is brief and reversible [29]. When compared to instantaneous release or traditional therapy, clinical investigations have shown that controlled release AMT treatment is more useful clinically to start and maintain the anticholinergic characteristics. As a result, it is necessary to intercalate AMT into nanoclay and hydrogel in order to release in a controlled and safe manner [30].

By co-precipitating the AMT with phyllosilicate C-20A [31], several nanohybrids were synthesized. Regarding the CH hydrogel, the size of the pore was decreased by the addition of formaldehyde as the crosslinker in a double-network hydrogel that included CH and formaldehyde [32]. AMT was used as a mimic drug and was encapsulated in CH to construct the DDS. The effect of both the CH and C-20A on the sustained release of AMT drug were observed in the in vitro release profiles. Also, the pH of the medium could be used to control the release rate, which significantly reduces the drug's side effects. The objective of the current work is to develop the AMT/C-20A and AMT/CH nanohybrids by investigating the drug release from the nanohybrids at a range of different pH (1.2–7.4). AMT/C-20A will further be wrapped inside CH hydrogel (AMT/C-20A/CH) and Alg hydrogel (AMT/C-20A/Alg) to make the release of the intercalated AMT drug more sustained and consequently reduce the frequency of AMT administration. Drug release from nanohybrids will be further investigated, and the dissolution of drugs from them will be at its maximum.