Current technological advancements have made feasible dose alternatives available through a variety of administration methods. Nowadays, there are many other ways that can be employed, such as oral, parentral, topical, nasal, rectal, vaginal, ophthalmic, etc. out of these delivery methods the oral route is said to be the most popular and commonly used approach for the reasons that follow ^[1,2]

• Simple to administer
• Greater adaptability when designing
• Production simplicity
• Inexpensive

The term GRDD refers to dosage forms that are capable of being kept in the stomach. These dosage forms allow a medication to be released gradually over a long duration until it reaches its absorption site under controlled circumstances. Several factors, including as the feed's volume and content, temperature and viscidity, stomach pH, posture, emotional state of the individual, illness, and the use of medicines that change gastric motility, can affect how fast a given dosage form passes through the stomach ^[3,4]

       
           
       
Figure 2: Rationale for the use of GRDDS

In general, appropriated candidate for GRDDS are molecules that have poor colonic absorption but are characterizes by better absorption properties at upper part of GIT:

Table 1: Suitable drug candidates for GRDDS

Table 2: Unsuitable drug candidates for GRDDS

5. ---

   Factors Affecting GRDDS ^[7,8]:

The following are some of the several methods that have been explored for creating dosage forms that results in sufficient gastric retention and release inside the stomach region ^[1,2,11]:

Gastric contents have an analogous viscosity as water (1.004 g/ cm3). Sedimentation has been used as a retention medium. A viscosity lesser than 2.5 g/ cm3 is needed to significantly extend GIT. Excipients that are generally employed include barium sulfate, zinc oxide, titanium dioxide, iron, and so on ^[12,13].

Low-density devices known as floating drug delivery systems (FDDS) can float above stomach contents and stay in the stomach for extended periods of time without slowing down the rate at which the stomach empties. While the system floats above the gastric contents, the medicine is gently released at the desired rate. This leads to enhanced gastric retention time and greater control of changes in plasma medication concentrations ^[14,15].

These systems are often made up of hydrophilic gel-forming polymers such as HPMC, hydroxy ethyl cellulose, hydroxy propyl cellulose and alginic acid, and are intended for single-unit administration. Hygroscopic gelatin rapidly dissolves in stomach juice, exposing the hydrophilic polymer and medication contents to the bodily fluids. The polymer fraction existing on the surface is then hydrated and swollen, resulting in a floating mass ^[7,16].

Carbonate/bicarbonate salts and citric/tartaric acid react effervescently to release CO2 in buoyant delivery methods. The CO2 is then trapped in the jellified hydrocolloid layer, lowering its specific gravity and causing it to float above stomach fluid. The dosage forms are designed to create C02 when in contact with acidic gastric contents, which is then encapsulated in swelling hydrocolloids to offer floating properties ^[17,18].

5. Raft Forming System:

Antacids and drugs for gastrointestinal diseases and infections have been administered using raft-forming systems, which have attracted a lot of interest. This type of GRDDS is induced by the production of a viscous gel in contact with gastric fluids, which forms a continuous layer known as RAFT on top of the fluids due to low bulk density brought on by CO2 formation. Alkaline bicarbonates or carbonates that produce CO2 are typically included in this system's composition, along with a gel-forming substance (such as alginic acid) to help the system float on the stomach juices and become less dense ^[19-21].

The time lag before floating on the stomach contents is a major drawback of the effervescent delivery mechanism. Prior to floating and medication release, it is likely that the delivery system will be purged during this time. Hence, low density systems (less than 1000 mg/cm³) that demonstrate instantaneous drug floating and release on the stomach content surface have been created to get around this restriction. The system is essentially made up of low density materials that trap air or oil ^[11].

3. Expandable System:  

These systems can be mechanically expanded in size in relation to their initial dimensions. They are composed of biodegradable polymers. They come in a variety of geometric shapes, such as tetrahedron, ring, or planner membrane made of bio-erodible polymer that is squeezed inside a stomach-extending capsule. If a dosage form in the stomach is larger than the pyloric sphincter, it will not pass through the stomach ^[22-24].

Conventional hydrogel absorbs water relatively slowly; it may take several hours   to achieve an equilibrium condition. Super porous hydrogels (SPH) are porous hydrophilic materials that can absorb aqueous fluids up to a hundred times their own weight. They have a three-dimensional cross-linked, network-like structure. Due to rapid water uptake through multiple linked open pores (average pores of 200 µm), maximum swelling is typically obtained in a fraction of a minute ^[25,26].

5. Bio-Adhesive System:

By sticking to the gastric mucous membrane of bio-adhesive system, the gastric retention time has increased. The adherence of the delivery system to the stomach wall increases bioavailability by extending residence duration. Nevertheless, the propulsion force of the stomach wall cannot be resisted by the gastric mucoadhesive force alone ^[25,26].

Using this procedure, a tiny magnet is incorporated into the dose form, and a second magnet is positioned on the abdomen above the stomach. Precise setting of the external magnet may result in less patient cooperation ^[25].

5. Stomach Specific Floating In-Situ Gel:

An applicable system of delivering regulated drug delivery within the stomach has been made possible by gastro-forgetful in- situ gel forming systems, in which an environment-specific gel forming solution floats on the top of the gastric fluids (owing to its lower viscosity than the gastric contents) once it has gelated. This system uses a low density solution, when in contact with the stomach fluids, changes the polymeric conformation to produce a viscid gel with a viscosity that's lower than the gastric fluids. This low density gel conformation produces the continual and phased drug release in addition to the significant desired gastro retention to extend the contact period^[6].

5. ADVANTAGES:

• In-situ gel offers a greater effective surface area than tablets because it creates a low-density viscous layer on the stomach contents. This increases the drug's release and boosts its bioavailability.
• Compared to floating tablets, floating obtained is faster.

5. Limitations

• In-situ gel forming systems are essentially solutions that are more prone to stability issues as a result of microbiological or chemical deterioration (hydrolysis, oxidation, etc.).
• If such a system is not stored correctly, it may experience instability issues as a result of the system's pH changing over time or when it is kept at an improper temperature. Certain polymers may also develop gel inside the packaging in which they are stored if they are exposed to radiations (such as UV, visible, electromagnetic, etc.).

5. Approaches To Produce In-Situ Gel:

Various mechanisms have been reported to underlie the formation of in-situ gel:

• Swelling: Swelling occurs when a polymer in the system, such as glycerol mono-oleate, absorbs water from the surroundings and swells to produce a viscous gel.
• Diffusion: Diffusion occurs when a solvent, such as N-methyl pyrrolidone, dissolves or disperses a drug and polymer into the surrounding tissues, precipitating the polymer to form gel.

5. Chemical Changes: Gel formation may result from alterations in the systems chemical environment that create polymeric cross linking.

• Ionic cross-linking: When different ions, such as Na⁺, K⁺, Ca²⁺, Fe²⁺, etc., are present in body fluids, ion-sensitive polysaccharides like carrageenan, gellan gum, pectin, etc., experience phase transitions because the polymer cross-linking develop ^[28].
• Enzymatic cross-linking: The most practical method of gel production is thought to be cross-linking, which creates a polymer network through the presence of enzymes in body fluids ^[27].
• Photo polymerization: When a gel producing system is injected into tissues, it can generate gels such as ethyl eosin, 2, 2 dimethoxy-2-phenyl acetophenone, and others within the tissues when exposed to microwave, UV, or electromagnetic radiation ^[27,29].

5. Physiological Stimuli:

The following physiological triggers can result in the development of gel:

• Change in temperature: This method shows a temperature-dependent phase transition from a relatively high viscosity gel to a less viscous solution. A sudden change in temperature causes the solubility of the polymer within the system to alter, and this interaction between the polymers results in the formation of a hydrophobic solvated macromolecule ^[27,29].

• Change in pH: Polymers with different ionizable groups in their chemical      structure, such as polymethacrylate, polyacrylic acid, and its derivative carbopol, undergo gel formation in response to pH changes. When the pH rises, polymers containing anionic groups cause swelling to increase, whereas polymers containing cationic groups exhibit decreasing swelling ^[6].
• Dilution sensitive: In the presence of more water, a polymer found in this kind of hydrogel goes through a phase transition. More polymer can be utilized if the system is going through a phase change as a result of being diluted with water. Example, Lutrol F68 ^[51].
• Light sensitive: Light-sensitive hydrogels can be employed as in-situ forming gels for cartilage tissue engineering or in the creation of photo-responsive artificial muscle. In order to create a gel by enzymatic processes, polymerizable functional groups and their initiators, such as ethyl eosin and camphorquinone, can be injected into tissue and electromagnetic radiation applied ^[51].
• Glucose sensitive: Insulin-releasing hydrogels have been used is intelligent stimuli-responsive delivery devices. In reaction to blood glucose levels, cationic pH-sensitive polymers that contain glucose oxidase and immobilized insulin can swell, pulsatively release the trapped insulin ^[51].

Ideal Characteristics of Polymer ^[50]:

• Gellan gum: Gellan gum is a chemically anionic deacetylated polysaccharide that is secreted by the pseudomonas elodea (Sphingomonas elodea). A change in temperature or the presence of cations (such as Na⁺, K⁺, or Ca²⁺) causes gellan gum to develop ^[28,29].

• Pectin: These are anionic polysaccharides of plant origin. Gel formation occurs in pectin when divalent ions, such as Ca²⁺, are present. This results in ionic cross linking, which links the galacturonic acid units, and pH dependent gelling, which occurs when H ions are present ^[27].
• Xyloglucan: It is a polysaccharide derived from plants that is extracted from tamarind seeds. While xyloglucan itself does not produce gels, diluted solutions that have been partially broken down by galactosidase when heated up to a certain temperature ^[27].
• Xanthan Gum: Extracting a high molecular weight extracellular polymer, xanthan gum is generated by the bacterium xanthomonas campestris. A powerful gel can be created by combining positively charged polymers with xanthan gum ^[31].

• Chitosan: By alkaline deacetylating chitin, a natural and adaptable polycationic polymer known as chitosan is produced. It is non-toxic, thermosensitive, and biodegradable. Up to a pH of 6.2, chitosan, a biocompatible pH-dependent cationic polymer, stays dissolved in aqueous solutions ^[32].

• Carbopol: The pH-dependent polymer carbopol remains in solution at an acidic pH but forms a low viscosity gel at an alkaline pH. When used in conjunction with carbapol, HPMC gives the carbopol solution viscosity while lowering its acidity ^[33].

5. Evaluation Of Stomach Specific In -Situ Gel System:

• Appearance: Particulate matter should not be present, and in-situ solutions should be transparent. The amount of time needed for a solution to become a gel in a buffer with a pH of 1.2 is monitored, and the gel's visual consistency is examined ^[34].
• Viscosity: Viscosity of solution is measured with a Brookfield viscometer or a cone and plate viscometer at an appropriate temperature (25±1⁰ C) using 1 or 2 milliliters of sample aliquots before and after gelling ^[30,34].
• pH of in-situ gel: A calibrated pH meter is used to measure the pH of the gel-forming solution at 27⁰C ^[34].
• In -vitro gelation time: Using a USP (Type II) dissolution device with 500 mL of 0.1N HCl (pH 1.2) at 37±0.5?C, the in-vitro gelation time was ascertained. As the formulation came into contact with 0.1N HCl and the time was recorded, it changed from a sol to a gel. The amount of time needed for an in-situ gelling system to gel initially is known as the gelling time. The gel was found to float on the buffer solution in a matter of seconds ^[33].
• Buoyant time: The floating lag time, also known as the buoyant time, is the amount of time it takes the gel to rise to the top from the bottom of the dissolution flask. Visual examination was used to determine the floating lag time of the gel in a USP type II dissolution test device holding 500 ml of 0.1 N HCl (pH 1.2) at 37±0.5?C ^[33].
• Strength of gel: The gel is made from the sol form in a beaker. A rheometer probe is little by little pushed through the gel by raising the beaker containing the gel at a specific rate. It can be determined by monitoring variations in the probe's loading as a function of the probe's depth of immersion below the gel surface^[33].
• In-vitro drug release study: Using a USP dissolving equipment (type II) at 50 rpm in 900 ml of 0.1N HCl at pH 1.2 at 37 C, in-vitro drug release is measured. A Petri plate containing 10 milliliters of the formulation is placed in a dissolving vessel. Subsequently, the dissolve medium is silently added to the dissolution vessel. At every predetermined period, an appropriate sample is taken and replaced with new medium. A minimum of eight hours should be spent conducting the dissolution study ^[30].

5. Applications ^[50]:

Table 2: Recent research activities on in-situ gel

Marketed Formulations Available as GRDDS ^[52]:

5. In-Situ Gelling System Available in Market ^[31,51]:

Table 4: In-situ formulations in market

5. Some Us Patents for In-Situ Gel Drug Delivery System ^[51]:

Table 5: Patentable formulations

5. Comparison Between Conventional and Gasro-Retentive Drug Delivery System ^[49]:

Table 6: Comparison between conventional and GRDDS