In 2019, there was a 25.82% increase in the number of individuals with peptic ulcer disease from 1990 globally, i.e., 8.09 million people worldwide suffered from peptic ulcers in 2019 [1]. An imbalance of gastroprotective and aggressive factors causes peptic ulcer disease. The two most frequent etiological causes of bleeding in peptic ulcer disease include nonsteroidal anti-inflammatory drugs (NSAIDs) use and Helicobacter pylori infections [2]. Mucus layers with their battery of substances that prevent mucosal damage and promote mucosal regeneration are the most important protective factor [3]. Several herbal medications that exert antioxidative effects can prevent oxidative stress that causes mucosal damage. For example, Zingiber officinale Roscoe, Butea frondosa Roxb. L., Glycyrrhiza glabra L., Centella asiatica, and other herbs containing flavonoid substances have been studied for the treatment of peptic ulcers [4,5].

Quercetin is a polyphenol belonging to flavonoid compounds (flavonol subclass) [6]. It is a crucial bioflavonoid pigment found in several plant species including berries, onions, red grapes, kale, broccoli, and citrus fruits [7,8]. It has been investigated in vivo for the treatment of gastric ulcers [[9], [10], [11]]. Abdel-Tawab et al. [9] found that in a rat model with indomethacin-induced stomach ulcers, rats treated with quercetin had lower gastric ulcer index, stomach acid volume, stress, inflammatory, and apoptotic markers (p < 0.05) than the positive controls. Furthermore, these outcomes were comparable to the effects of omeprazole, which is known to reduce stomach acidity [12]. However, the use of quercetin is limited by its low bioavailability (<10%) because of its poor solubility in water (0.09 μg/mL, 5.5 μg/mL in simulated gastric fluid, and 28.9 μg/mL in simulated intestinal fluid [13]) and extensive metabolism [14]. Nanoemulsion [15], phytosome [16], complexation [17], and solid dispersion are examples of methods used to enhance quercetin water solubility.

Solid dispersion is an attractive strategy to enhance the aqueous solubility of the drug. Several investigations have demonstrated that solid dispersions produced from different hydrophilic polymers can improve the solubility of quercetin. These polymer matrices include polyvinylpyrrolidone (PVP) [[18], [19], [20], [21]], polyethylene glycol (PEG) [22], and cellulose derivatives [20,23,24]. Many techniques have been employed to prepare quercetin solid dispersion such as solvent evaporation [21,25], co-precipitation [24], spray drying [20,23], evaporative precipitation of nanosuspension [19], and fusion methods [22]. The successful enhancement of the solubility of quercetin in different types of media according to its specific purpose has been reported. Most of the media used for solubility and dissolution studies are pH 6.8 phosphate buffer and water. There have been only a few reports of the solubility of quercetin solid dispersions in simulated gastric fluid (pH 1.2) which is useful information for application in stomach-specific delivery systems [18].

PVPs are widely employed as carriers for solid dispersions due to their amorphous nature, high solubility in water, nontoxicity and biocompatibility [26]. PVP K-12 to K-30 (molecular weight from 2500 to 50,000) are particularly suitable carriers, since their high molecular size enables the formation of solid solutions [27]. In this study, PVP K30 was selected as a carrier based on the result of previous study. Solid dispersions formulated using PVP K30 was found to be the most effective carrier to employ in solid dispersions to increase the quercetin solubility and release behavior. By contrast, solid dispersions formulated using PVP K 90 showed lower quercetin release due to the increased viscosity of the diffusion ‘pathway’ through the high molecular weight polymer [18].

Recently, we have introduced the expandable films based on starch and chitosan as gastro-retentive carriers for some bioactive compounds including curcumin [28], resveratrol [29], and 6-gingerol [25]. Different types of starch have been employed in the formulations for example, rice starch, glutinous rice starch, corn starch, banana, and green bean starch. The physicochemical properties of films were found to be dependent on the type and concentration of starch. Boontawee et al. [29] reported that resveratrol-loaded expandable films prepared using pregelatinized starch demonstrate a suitable formulation for prolonging drug release in the stomach. On the other hand, expandable films based on pregelatinized starch exhibited high burst release of curcumin in the first hour, which is a disadvantage for gastroretentive, sustained-release applications [28]. In another study, the ginger extract-loaded film formulation prepared from glutinous rice starch exhibited good tensile strength and high expansion in simulated gastric fluid [25].

In this study, rice starch, glutinous rice starch and pregelatized maize starch have been selected to prepare gastroretentive film due to their unique properties and different amylose content. The amylose content of each type of starch is 33.8% (rice), 27.0% (pregelatinized maize), and 0.6% (glutinous rice), respectively. Previous reports suggested that the amylose to amylopectin ratio of starch is an important factor in determining different characteristics of films such as water absorption, expansion and rate of drug release [25].

The formulation of oral dosage forms containing drugs solid dispersion had been successfully fabricated into several preparations including raft-forming liquid and chewable tablets [18], superporous hydrogel [30], and expandable film [25,28,29]. Oral drug administration is the most preferred route due to its ease of administration, flexibility in formulation, and patient acceptance [31,32]. However, conventional oral dosage forms often contain several limitations e.g., poor bioavailability, short half-life, and limited targeting. The most recent patents and scientific literature showed an upward trend in formulating new medication systems that are maintained in the gastrointestinal (GI) tract for a predictable and extended period. Various strategies are currently used including floating systems, swelling and expandable systems, bioadhesive systems, and other slow-emptying devices.

Expandable film loaded with drug solid dispersion is a delayed gastric emptying system that may overcome the low solubility of the drug and demonstrate prolonged drug release. Expandable films are one type of device that can prevent the stomach from emptying prematurely through the pyloric sphincter. These films are created to respond to gastric fluids by expanding or unfolding shape [33]. The aim of this study was to investigate a suitable expandable device based on starch and chitosan, for localized and prolonged release of quercetin in the stomach. Firstly, the quercetin solid dispersions was prepared to improve the solubility of the compounds, and subsequently incorporated into expandable film formulations. The properties of solid dispersion and expandable film were evaluated, and the anti-inflammatory properties of quercetin were assessed in RAW 264.7 cells.