Miracle of Gastroretentive Drug Delivery Systems: Approaches for Treatment of Gastric Disorders and their Future Perspectives

Nearly half of the world’s population suffers from Helicobacter pylori (H. pylori) and gastric disorders. It is the most common pathogenic bacteria that cause gastritis, gastroduodenal ulcer disease, and gastric cancer. Because short residence period, a narrow absorption window in the upper small intestine results in poor bioavailability with standard dosage forms. In addition, combination therapies develop antibiotics, undesirable responses, and poor patient compliance. Therefore, these drawbacks may overcome by Gastro-retentive drug delivery systems (GRDDs). A site-specific drug delivery system comes into force for boosting the therapeutic oral bioavailability, prolonging the residence site, effective medication through a small absorption window of GIT, and stimulating local effect in the stomach and duodenum. This review highlighted anatomy and physiology of gastric barrier, various GRDDS approach, merits, demerits for improving drug delivery, and future perspectives. Finally, this review may benefit researchers and industrialists working in this field.


INTRODUCTION
The oral route is the most popular drug delivery administration due to the ease of administration [1]. In addition, the patient compliance and ease of administration make them readily available in the market and widely used delivery system [2]. However, the bioavailability of drugs in oral dose forms is affected by various circumstances. Although, this route has limitations, such as short gastric residence time (GRT) and requiring time for contents to enter the intestine, and reduced absorption [3]. Further, gastric retention has gotten attention due to quick gastric emptying time. Drugs with a short half-life are rapidly absorbed and easily removed from the bloodstream, thus requiring frequent dosing. Further, the limitation can be overcome by developing oral sustained-controlled-release formulations to modify drug release time; this slowly releases the medication in the Gastro intestinal I tract (GIT) and maintains effective drug concentration in blood [4]. However, such oral drug delivery devices encounter physiological restriction during variable GRT showing the inadequate medicament release from the drug delivery system. Although it is essential to deliver the therapeutic drug at a specific site to maintain drug concentration, due to variable GRT, concentration in the bloodstream is altered.
Innovative drug delivery devices overcome the drawback of poor oral drug delivery as gastroretentive dosage forms. Further, this increases the stay of the drug for an extended period in the stomach and increases the GRT of medicines, improving drug absorption. In addition to this, this further improves drug bioavailability, prolongs the drug release, reduces drug wastage at high pH. The prolonged gastric emptying approach also treats peptic ulcer patients and reduces GI side effects by modifying drug delivery release. In addition to this, it improves the GRT of drugs in the stomach [5].
Gastro-retentive drug delivery systems (GRDDs) effectively delivered weakly acidic drugs like domperidone and papaverine to enhance solubility and reduce the dose. In addition to this, the Gastro-resistant tablet dosage form intentionally delays drug release to allow the tablet to pass after some time from one part to another. Prolong-release delivery systems are modified-release systems that show delayed drug release. Enteric-coated system designed to combat the stomach acidic environment and provide site-specific release of drugs in the intestine. Drugs like Proton pump inhibitors, H-2 blockers, insulin delivery, and NSAIDs are suitable candidates for preparing delayed release dosage forms [6].
GRDDs are fruitful approaches that prolong GRT, targeting site-specific drug release for local and systemic effects. Over the last few decades, GRDD approaches designed and developed and further includes: High density (sinking) systems that show retention in the bottom of the stomach [7], low density (floating) systems [8][9][10], mucoadhesive systems offer adhesion to stomach mucosa [11] and Swellable systems through the pyloric sphincter [12,13], super porous hydrogel systems [14], and magnetic systems [15]. This review highlights various GRRDs approaches and methodologies for site-specific delivery of drugs at controlled release.

NEED FOR GRDDS
• Drugs absorbed at a particular site only require that maximum drug reaches a particular site. • Drugs absorbing from the proximal part of the GIT. • Drugs show low solubility and degradation at basic pH and erratic gastric emptying time (GET). • A local or sustained drug delivery system treats certain conditions [16]. accessibility. • Rapid absorption shows good blood flow rates. • Minimize mucosal irritation due to controlled release, e.g., NSAIDs.

Merits of GRDDS
• Decreased fluctuations in plasma drug concentration prevent adverse effects [17].
Further, a study highlights the importance of several patents reported where the development of GRDDS has shown significant improvements in drug delivery over conventional formulations. The gastro retentive pulsatile pharmaceutical delivery of Valsartan improves solubility and enhances residence time [18].
Another study suggested minocycline enhances bioavailability. In addition to this, this further reduces severe gastrointestinal side effects, such as reflux, vertigo, dizziness, and nausea [19]. Finally, another study highlights that biodegradable, multi-layered controlled release gastro-retentive dosage form of zaleplon provides adequate sleep maintenance and minimizes next-day residual consequences [20].

GRDDS ACTING DRUGS
The gastro retentive drug delivery systems are suitable for the following types of drug therapy that helps in prolonging GRT, depicted in Fig. 1 [21-27], and their impact over conventional delivery, summarized in Table 1 [28].

Gastric Motility and Emptying of Food
Gastric emptying mainly happens during fed and fasted states, but the mortality pattern differs in both states. The inter-digestive cycle occurs every 2-3 hrs in a fasting state via the stomach and small intestine, known as the inter-digestive myoelectric cycle of relocating myoelectric complex (MMC). Further divided into four phases, shown in Fig. 2 [31]. First, the activities occur during gastric emptying, shown in Table 2 [32-60].

FACTORS AFFECTING GASTRIC RETENTION TIME OF THE GRDDS [61]
The following are the factors which affect the stability and performance of GRDDs.
 Density of Dosage form: Good floating property is often exhibited by the dosage forms having a thickness less than that of gastric fluids (~1.004g/ml). In contrast, a density closer to 2.7g/ml is needed for high-density systems to achieve good gastro-retention.  Size of the Dosage form: Due to larger particle size, the dosage form having a diameter of more than 7.5mm, shows more GRT because it does not quickly pass from the pyloric antrum to the intestine.

GASTRIC RETENTION APPROACHES
GRDDs concept was described in early 1962 and shows less bulk density than gastric fluids, so it stays in the stomach longer. Due to the buoyancy effect on the gastric contents, the drug liberated slowly, showing increased GRT and controlled plasma drug concentration. In addition, the device forms a cohesive gel barricade and maintains specific gravity less than gastric contents (1.004-1.010), discussed in (Table 3  and

FUTURE PERSPECTIVES
The rationale for GRDDS and its importance in industries are discussed in Fig. 5 [85][86], along with the list of patents and marketed formulation of GRDDS showing prolonged residence time in Table 4 [87-123] and Table 5.

CONCLUSION
Gastro retentive drug delivery offers potential advantages in delivering drugs at enhanced solubility and bioavailability. On the other hand, the drawbacks of poor solubility, bioavailability, and high first-pass effect promote ideas for designing newer techniques for improving drug delivery at a controlled rate. In recent years, the Gastro retentive drug delivery system has been explored to ensure optimized drug delivery. Newer technologies adopted in GRDD offer swellable, absorbable, floating, and high-density systems, promoting the controlled release. In addition, it offers to improve patient compliance and promote industrial growth. GRDDs will provide newer leads that promote improved efficiencies for various pharmacotherapeutics in the coming future.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.