Owing to tremendous curative benefits of the oral controlled release dosage forms are being preferred as the interesting topic in pharmaceutical field to achieved improved therapeutics advantages. Gastroretentive drug delivery system is novel drug delivery systems which has an upper hand owing to its ability of prolonged retaining ability in the stomach and thereby increase gastric residence time of drugs and also improves bioavailability of drugs. Attempt has been made to summarize important factors controlling gastroretentive drug delivery systems. This review covers the advantages, disadvantages, marketed preparation and some patents of gastroretentive drug delivery system and represents the floating and non-floating gastroretentive system and also highlights some of the current gastroretentive approaches. Recent approaches to increase the gastric residence time of drug delivery systems include bioadhesive systems, floating systems low density systems , non-floating systems high density systems , magnetic systems, swelling systems, unfoldable and expandable systems, raft forming systems and superporous systems, biodegradable hydrogel systems.
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In recent years, many attempts have been made to enhance the drug bioavailability and therapeutic effectiveness of oral dosage forms. In this context, various gastroretentive drug delivery systems GRDDS have been used to improve the therapeutic efficacy of drugs that have a narrow absorption window, are unstable at alkaline pH, are soluble in acidic conditions, and are active locally in the stomach.
In this review, we discuss the physiological state of the stomach and various factors that affect GRDDS. The significance of in vitro and in vivo evaluation parameters of various GRDDS is summarized along with their applications.
Moreover, future perspectives on this technology are discussed to minimize the gastric emptying rate in both the fasted and fed states. Oral drug delivery systems have dominated other drug delivery systems for human administration due to their various advantages including ease of administration, flexibility in formulation, cost-effectiveness, easy storage and transport, and high patient compliance.
However, oral drug delivery systems face challenges such as low bioavailability due to the heterogeneity of the gastrointestinal system, pH of the commensal flora, gastric retention time of the dosage form, surface area, and enzymatic activity [ 1 ].
Conventional drug delivery systems may not overcome the issues imposed by the gastrointestinal tract GIT such as incomplete release of drugs, decrease in dose effectiveness, and frequent dose requirement. Therefore, the failure of conventional drug delivery systems to retain drugs in the stomach may lead to the development of GRDDS.
These systems offer several benefits such as prolonged gastric residence time GRT of dosage forms in the stomach up to several hours, increased therapeutic efficacy of drugs by improving drug absorption, and suitability for targeted delivery in the stomach. In addition, GRDDS can enhance the controlled delivery of drugs by continuously releasing the drug for an extended period at the desired rate and to the desired absorption site until the drug is completely released from the dosage form [ 1 , 2 ].
GRDDS are feasible for drugs that have low absorption in the lower part of the GIT, are unstable and poorly soluble at alkaline pH, have a short half-life, and show local activity at the upper part of the intestine for eradication of Helicobacter pylori [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].
Various formulation-related factors such as polymer types nonionic, cationic, and anionic polymers , polymer composition in dosage form, viscosity grade, molecular weight of the polymer, and drug solubility can affect the quality of the gastroretentive dosage form [ 9 ].
For instance, density of excipients and composition of effervescent agents are critical factors in effervescent floating systems. In the case of superporous hydrogel systems, high swelling excipients such as crospovidone and sodium carboxymethylcellulose are required to form a superporous hydrogel [ 9 , 16 ].
Likewise, process variables can also influence the quality of the gastroretentive dosage form, as the density of a tablet can be altered by the compression pressure during tableting [ 9 ]. In the GRDDS, the stomach has a crucial role; therefore, a good understanding of the anatomy and physiology of the stomach is a prerequisite for successful development of the gastroretentive dosage form. Anatomically, the stomach is divided into two parts: the proximal stomach, which consists of the fundus and body; and the distal stomach, which consists of the antrum and the pylorus as shown in Figure 1.
The main role of the stomach is to store the food temporarily, grind it, and then slowly release it into the duodenum [ 17 ]. The fundus and body primarily act as reservoirs for undigested food, whereas the antrum acts as a pump to assist in gastric emptying by a propelling action [ 17 , 18 ]. The mobility pattern of the stomach is termed as the migrating myoelectric complex MMC ; the different phases of the MMC are presented in Table 1.
Gastric emptying occurs in both the fed and fasted states, but the pattern of gastric emptying drastically varies between both states. In the fasted state, an interdigestive sequence of electrical events follows in a cyclic manner through both the stomach and the small intestine every 90— min [ 17 ].
During the interdigestive phase, the diameter of the pylorus increases up to approximately 19 mm [ 1 , 19 ]. As a result, particles smaller than the diameter of pyloric sphincter can easily evacuate from the pylorus to the duodenum during the interdigestive phase [ 19 , 20 ].
However, in the fed state, motor activity is generated 5—10 min after ingestion of a meal and continues as long as the food remains in the stomach, which can delay the gastric emptying rate. Four phases of the migrating myoelectric complex [ 17 , 18 ]. Even though various types of GRDDS are reported in the literature, floating and mucoadhesive systems are the most popular gastroretentive dosage forms in pharmaceutical companies and contribute the most to the market.
Table 3 presents the commercially available gastroretentive dosage forms. Various gastroretentive products available in the market [ 1 , 18 , 19 , 36 , 37 ].
There are various factors that affect the performance of gastroretentive dosage forms. These factors are mainly categorized into pharmaceutical factors, physiological factors, and patient-related factors. For instance, in the mucoadhesive system, polymers with high mucoadhesion strength, such as carbopol and hydroxypropyl methylcellulose HPMC may be required for successful design of the mucoadhesive dosage form. Likewise, with the expandable system, polymers with high swelling properties are more desirable.
Moreover, the molecular weight, viscosity, and physiochemical properties of polymers can also affect the dosage form. Other formulation components such as gas generating agents in an effervescent floating tablet, high swelling excipients of sodium croscarmellose, and crospovidone for superporous hydrogels may be required.
Moreover, the shape and size of the dosage unit is also important [ 38 ]. Garg and Sharma reported that ring shape and tetrahedron-shape dosage forms have a longer GRT compared to other shapes [ 39 ].
In most cases, the GRT of the dosage form is proportionately dependent on the size. An increase in the size of the dosage form could prevent its passage through the pyloric antrum in the intestine due to the size of the dosage form being larger than the pyloric sphincter diameter mean, Similarly, the density of the dosage form is also an important factor for low- and high-density systems.
In low-density systems, the density of the dosage forms should be lower than that of the gastric fluid 1. Increasing the floating capacity can improve the GRT of the low-density system; however, this effect is decreased in the presence of food. Moreover, the floating force of the dosage form decreases as a function of time, which could be due to the hydrodynamic equilibrium [ 43 ].
On the other hand, in high-density systems, the density of the dosage form should be greater than that of the gastric fluid so that it can sink in the bottom of the stomach and prevent gastric emptying. An increase in density of the dosage form greater than 2. Several studies have reported that various extrinsic factors including the nature of meal, caloric content caloric density and nature of the calories , frequency of ingestion, posture, sleep, and physical activity can affect the GRTs of drugs in the stomach [ 1 , 38 , 45 , 46 ].
In fasting states, gastrointestinal motility is represented by the MMC that occurs every 90— min [ 17 ]. During this period, motor activity sweeps undigested material from the stomach. However, in the presence of food in the stomach, the MMC is interrupted and housekeeper waves are not generated leading to a prolonged GRT [ 17 , 47 ]. Likewise, the gastric emptying rate is also affected by the caloric density and nature of the calories of the ingested food [ 45 ].
In general, an increase in the caloric density significantly increases the GRT whereas the nature of calories only have a minor effect in the GRT [ 48 ]. In addition, high food viscosity may also increase the GRT [ 49 , 50 ]. Furthermore, the GRT is influenced by posture, and the effect is different for floating and non-floating dosage forms [ 1 ].
In the upright position, the floating system floats in the gastric fluid for a prolonged amount of time which can eventually increase the GRT. However, in similar conditions, the non-floating system remains in the lower part of the stomach and the gastric emptying rate is faster as a result of peristaltic contractions [ 1 ]. In contrast, in the supine position, the non-floating system has a longer GRT compared to the floating system [ 51 , 52 ].
A recent study reported that gender affected the gastric emptying time and intraluminal pH [ 53 ]. The authors demonstrated that females had slower gastric emptying times than males [ 53 ]. Hormonal influences could explain the longer GRT in females than in males. Another study showed that males secreted more gastric acid compared to females [ 54 ]. Likewise, the age of the patient also affects the GRT.
Elderly patients have a longer GRT compared to younger patients [ 55 ]. It was reported that a decrease in gastric emptying rate was observed in patients suffering from depression, whereas an increased rate was observed in patients experiencing anxiety [ 38 , 47 ].
In this section, we describe currently used gastroretentive drug delivery approaches. The main mechanism of GRDDS includes floating, sinking, swelling, effervescence, mucoadhesion, and magnetic properties. A brief description for each system is summarized in Table 4.
The floating system was first introduced by Davis in In this system, the bulk density of the dosage form is lower than that of the gastric fluid 1. This property allows the system to remain buoyant in the stomach for a prolonged period of time while the drug is released at the desired rate from the system during the GRT [ 1 , 17 , 60 ]. Figure 2 a illustrates the concept of low-density systems. These systems are classified into two subtypes based on the mechanism of buoyancy: non-effervescent floating and effervescent floating systems.
GRDDS based on a low-density systems and b high-density systems. In non-effervescent systems, highly swellable cellulose derivatives or gel-forming polymers are used [ 5 ]. The formulation technique of non-effervescent systems involves mixing the drug with a gel-forming polymer.
It is a single unit dosage form composed of one or more gel-forming hydrophilic polymers. HPMC, hydroxy propyl cellulose HPC , hydroxyethylcellulose, sodium carboxymethylcellulose, carrageenan, agar, and alginic acid are some of the polymers that are used to design the HBS system [ 17 , 66 ].
In this system, the drug is mixed with the polymer and filled in the gelatin capsule. Thus, the low-density systems float on the gastric fluid and prolong the GRT. Wei et al. The immediate-release layer contained a disintegrating agent, which aided the prompt release of drug, whereas the sustained release layer contained a hydrophilic polymer to control the drug release rate and also provided the tablet buoyancy. Polycarbonate, cellulose acetate, calcium alginate, Eudragit S, agar, and low-methoxylated pectin are commonly used polymers to design microballons.
Various formulation variables such as the amount of polymer, ratio of plasticizer and polymer, and solvent can affect the floating behavior and drug release of these kinds of dosage forms [ 69 ]. One drawback of the HBS is that this system, being a matrix formulation, consists of a blend of drug and low-density polymers.
The release kinetics of the drug cannot be changed without changing the floating properties of the dosage form and vice versa. Effervescent floating systems include a gas-generating agent and volatile liquids.
This approach has been applied for single- and multiple-unit systems. In the gas-generating floating system, effervescent agents such as sodium bicarbonate, calcium carbonate, tartaric acid, and citric acid are used in combination with hydrophilic polymers [ 9 , 70 ].
When this system comes into contact with gastric fluid, CO 2 is liberated due to the reaction of the effervescent agent with gastric fluid. The liberated CO 2 gas is entrapped in the hydrocolloid matrix, which provides the tablet buoyancy and influences the drug release properties [ 71 ].
In volatile liquid systems, volatile liquids such as ether and cyclopentane are introduced into an inflatable chamber, which volatilize at body temperature allowing inflation of the chamber in the stomach [ 38 ]. Hydrophilic polymers are often used to control the drug release rate in this system. Effervescent floating systems can be categorized into single- and double-layer effervescent floating tablets and multiple-unit effervescent floating systems [ 14 , 17 ]. Single-layer effervescent tablets are formulated by intimately mixing effervescent agent, polymer, drug, and excipients.
However, in bilayer effervescent floating tablets, one layer comprises the drug, polymer, and CO 2 gas-generating agent, whereas the other layer constitutes an immediate-release drug and excipients without CO 2 and polymer. In a recent study, sodium bicarbonate in HPMC matrix formulation was used to improve the GRT by increasing the hydration volume of dosage form and increasing the surface area of drug diffusion [ 14 ].
In addition, an increase in the amount of sodium bicarbonate decreased the drug release rate from the matrix, which could be due to obstruction of the diffusion path by CO 2 gas bubbles [ 14 ]. Another study also utilized this approach to evaluate the in vitro and in vivo behaviors of ciprofloxacin hydrochloride effervescent floating tablets [ 72 ].
The optimized formulation was selected based on the GRT in humans i.
Overview on Gastroretentive Drug Delivery Systems for Improving Drug Bioavailability
Current State and Future Perspectives on Gastroretentive Drug Delivery Systems