Floating In Situ Gel Systems: A Novel Approach for Prolonged Gastric Retention

Given how simple it is to administer, the oral route is seen to be the best option. Since many traditional oral medication administration methods have some drawbacks related to stomach emptying time, gastric retention has drawn interest in the latter years by remaining in the stomach region for a few hours, a The GRDDS, or gastro retentive drug delivery system, can prolong the duration of a medication's gastric occupancy. Prolonged stomach retention improves solubility, enhances bioavailability, and minimises medication waste for medications that are less soluble at high pH levels settings. A systems that float, bio adhesive, high-density, swell, and expand etc., are some of the methods used to accomplish gastric retention. Has been created. ^[1] The floating drug delivery system (FDDS) works well for prolonging the stomach residence duration and improve the bioavailability of the medications. In 1968, Davis gave the first description of FDDS. Low-density devices known as FDDS are buoyant enough to float over the contents of the stomach and stay there for an extended amount of time. Mechanisms for floating medicine delivery were intended. They float atop the stomach's contents for gastric retention due to their low density, and by exhibiting a regulated release, they produce a long-lasting action.  Pharmaceuticals that are absorbed from the upper portion of the stomach benefit greatly from this kind of delivery method. It is also beneficial for pharmaceuticals that are administered at an alkaline pH of the stomach and are either not absorbed or have negative side effects due to their insoluble nature. For medications that must possess a stomach local action, the FDDS are very helpful. ^[2] Gastro-retentive floating systems are used to manufacture a wide range of dosage forms, like tablets, capsules, films, microspheres, microbeads, and more. One recent development in floating DDS is the in-situ gelling technique. A variety of delivery routes, including oral, nasal, ocular, peroral, rectal, vaginal, and parenteral, can be used with an in-situ gelling system. ^[2] In recent years, in situ gelling methods have attracted good attention. The use of in situ gel-forming devices in a range of medical applications, such as medication delivery, has been the subject of many published patents in recent years. The rising interest in these delivery systems may be due to the several Benefits of in situ forming polymers include increased patient compliance, comfort, decreased frequency of administration, and case of administration. ^[3] One the "in-situ gel" technology is one of the most cutting-edge drug delivery techniques. The "sol to gel" transition's special properties mean that the in-situ gelling helps to enhance patient compliance, comfort, and the regulated and prolonged release of the drug. A formulation known as an in-situ gelling system is one that is a solution before it enters the body, but under one or more of many physiological circumstances, it transforms into a gel. Numerous factors, including pH, temperature variations, solvent exchange, ionic cross-linking, etc., affect the the transition from sol to gel. The "system for in-situ gelling" system" offers several benefits, such as simpler dosage delivery and fewer doses ^[1] other names for oral in situ gel forming systems include stomach-specific or raft forming systems. Improved gastro-retention and controlled drug distribution in the stomach. Despite being more stable than liquids, floating dose forms like tablets and capsules have the drawback of having to be swallowed whole. These are likewise designed for controlled release, and because the size of the tablet affects its capacity to float, they cannot be split in two if the dosage is changed. It becomes challenging for older patients, youngsters, and patients with certain diseases (such as dysphasia) to swallow tablet or capsule dose forms. ^[4] Verbal Drug distribution that is regulated and maintained can be achieved with in situ gel-forming technologies. An appropriate technique of regulated medication administration within the stomach is provided by the conversion of an environment-specific gel-forming solution into gel, which, because of its lower density than the gastric acid, floats on the surface of the stomach fluids contents. Using a low-viscosity solution, this technique that changes its polymeric structure when the stomach contents and a viscous gel with a density less than the stomach contents come into touch. This gel formation with a low density not only creates a continuous and progressive release of the medicine but also provides the required gastro retention and extends the contact duration. The gel's capacity to float can also be improved by adding substances that produce effervescence, like carbonates or bicarbonates, both with and without tartaric or citric acid The gel will become significantly lighter due to the carbon dioxide release, which will aid in its ability to float. By adding viscosity enhancers, such as HPMC (Hydroxy propyl methyl cellulose), the gel's ability to generate a more controlled and extended release can also be improved. ^[5] Drug delivery techniques that are in sol form prior to body administration but gel in-situ to form a gel after injection are known as floating in-situ forming polymeric formulations. The variables that affect the gels from which the drug is extracted include temperature control, pH variations, the presence of ions and UV light, electrical sensitivity, and enzyme sensitivity. Released under control and gradually. Due to a great deal of research being done to improve the performance, dependability, and safety of pharmaceutical goods, regulated and extended drug administration has recently become more common in modern pharmaceutical design. The In-situ gel-forming

Polymeric formulations have numerous benefits over traditional drug immunisation methods, such as strong patient compliance and prolonged and prolonged action and excellent biocompatibility and durability qualities, which make in situ gel dosage forms very reliable. The biodegradable polymers used to create in situ gels include gellan gum, sodium alginate, HPMC (hydroxypropyl methylcellulose), xyloglucan, pectin, chitosan, poly (DI, lactic acid), poly (DI-lactide-co-glycolide), and poly caprolactone. ^[6]

GASTRORETENTIVE DRUG DELIVERY SYSTEM BENEFITS (GRDDS)

The GRDDS approach could be applied to analyze a wide range of drugs or pharmacological classes. Among the primary advantages are:

• Targeted Absorption: GRDDS is particularly useful for drugs that are intended to act locally, such as antacids used to treat peptic ulcers or that are absorbed in the stomach, like ferrous salts.
• Sustained Release: By enabling sustained drug release, GRDDS can increase the efficacy of medications.
• Better Absorption during Rapid Transit: GRDDS ensures better stomach retention and absorption, which is crucial in circumstances like diarrhea or excessive intestinal motility when rapid transit may hinder medication absorption.
• Optimized Drug Delivery for Limited Absorption Windows: GRDDS effectively disperses drugs with a small intestine absorption window that is restricted.
• Versatility Beyond Stomach-Absorbed Drugs: GRDDS is effective with drugs that are absorbed in the intestine, such as chlorpheniramine maleate.
• Increased Bioavailability: For instance, furosemide, which is exclusively accessible in the upper gastrointestinal tract, had a 42.9% bioavailability when taken in a floating dosage form, compared to 33.4% when taken as a regular tablet and 27.5% when taken as an enteric-coated tablet.
• Reduced changes in Plasma Level: By postponing stomach emptying, GRDDS reduces changes in plasma levels. For example, the bioavailability of regular madopar varied between 60% and 70% when compared to HBS formulations; the differences were attributed to insufficient absorption.
• Uniform Transit Performance: By reducing transit time variations, tacrine and other floating, sustained-release formulations help Alzheimer's patients have fewer gastrointestinal side effects.
• Less Dosage Needed: When manufactured as a floating system, which avoids plasma changes, ranitidine, which is typically given at 300 mg once a day or 150 mg twice a day. Showed longer-lasting benefits and a lower frequency of doses.
• Better Therapeutic Effectiveness: Floating systems improve the absorption and therapeutic efficacy of drugs that are intestinally unstable or acid-soluble, such as the Parkinson's disease treatment bromocriptine.
• Effective Helicobacter Pylori Eradication: Floating systems help achieve high localized medicine concentrations in the stomach mucosa, which is necessary to eradicate Helicobacter pylori, which is linked to peptic ulcers and chronic gastritis. ^[7]

FACTORS AFFECTING GASTRIC RETENTION

Numerous factors influence the gastrointestinal residence time, which in turn influences the gastroretentive system's bioavailability and effectiveness.

1. Density: The buoyancy of the dosage form, which depends on density, determines GRT. The density of the dose form should be less than the density of the contents of the stomach (1.004 gm/ml).
2. Dosage form shape: Tetrahedron and ring-shaped devices are considered to have a superior GRT when their flexural modulus is 48 and 22.5 kg/sq in (KSI) than others, with 90% to 100% retention at 24 hours.
3. Size: The GRT is higher for dosage form units larger than 7.5 mm in diameter as opposed to those that are 9.9 mm in diameter.
4. Single or multiple-unit formulation: Due to their more consistent release profile, multiple-unit formulations provide a higher margin of safety against dosage form failure than single-unit dosage forms.
5. Meal type: The stomach's motility pattern can alter how Fatty acid salts or indigestible polymers are fed. This results in a longer release of the medication and a slower rate of stomach emptying.
6. Fed or unfed state: Gl motility during fasting is characterised by bursts of intense motor activity or the migrating myoelectric complex (MMC), which occurs every 1.5–2 hours. When the formulation is administered concurrently with the MMC, the unit's GRT should be relatively brief because the MMC removes undigested material from the stomach. But MMC is delayed, and GRT is much longer in the fed state.
7. Caloric content: A meal heavy in lipids and proteins might raise GRT by 4 to 10 hours.
8. Feed frequency: When consecutive meals are provided instead of a single meal, the GRT might increase by more than 400 minutes because of the low frequency of MMC.
9. Gender: Regardless of body surface, height, or weight, men's mean ambulatory GRT It is less than that of their female counterparts of the same age and race (3.4±0.6 hours) (4.6±1.2 hours).
10. Age: The GRT is noticeably longer in older adults, particularly those over 70.
11. Posture: Depending on whether the patient is standing and walking or lying down, GRT may vary.
12. Concurrent administration of medications: The floating time may be impacted by prokinetic medications like metoclopramide, anticholinergics such as atropine, propantheline, and cisapride, as well as opiates like codeine.
13. A biological component: The floating time may also be impacted by diabetes and Crohn's illness. ^[8]

THE SIGNIFICANCE OF THE IN SITU GELLING SYSTEM

1. The ability to provide precise and repeatable amounts is crucial when compared to gels that have already formed.
2. The in-situ forming polymeric delivery method has the advantages of being simple to use and requiring less frequent administration.
3. Buoyancy causes a prolonged time of stomach retention.
4. Lowers the frequency of dosages, improving patient adherence.
5. Because continuous drug release minimizes Maintains a desired level of plasma drug concentration despite variations in it, bioavailability increases even in the face of the first-pass effect.
6. Long-term, controlled drug release.
7. Site-specific drug distribution may occur in the stomach.
8. Because there is no possibility of dose dumping and the medication is released equally, floating in-situ dosage forms are better than single-unit floating dosage forms.
9. It works with a variety of solutes and medications that are hydrophilic or hydrophobic.
10. Therapeutic agent release can be managed by regulating cross-linking density and water swelling. ^[6]

ADVANTAGES OF IN SITU GELS

• Long-Term Drug Release: In situ gels have the potential to prolong the duration of drug release. Enhance therapeutic effectiveness and reduce dosage frequency.
• Increased Patient Compliance: In situ gels are more convenient for patients due to their facile administration and lower frequency of dosage, particularly in ocular or injectable applications.
• Reduced Systemic Negative Effects: In situ gels can lessen systemic exposure and related negative effects by delivering the medication straight to the location.
• Better Medicine Bioavailability: They enable more efficient absorption and retention of medications at the target site. Boosting bioavailability. The drug's
• Non-Invasive or Minimally Invasive: In ophthalmic and nasal applications, in situ gels can be applied without needles, providing a non-invasive approach to drug delivery Because of their formulation flexibility, they may be customized to satisfy a range of delivery needs by responding to different environmental signals, including ions, pH, and temperature. ^[7]

DISADVANTAGES OF IN SITU GELS

It can be challenging to create a stable in situ gel formulation that gels in the ideal setting, at the ideal moment, and in the ideal circumstances.

• Potential for Incomplete Gelation: Ineffective medication release or leakage might arise from incomplete gelation.
• Variability in Drug Release: A patient's physiology and the environment can have an impact on gel formation and, in turn, drug release rates.
• Low Drug Loading Capacity: In situ gels frequently have a low drug loading capacity, particularly for poorly soluble medicines. Restricting their use for medications with large dosages. Short Shelf Life: To preserve their effectiveness, certain in situ gel compositions may need certain storage settings due to stability concerns.
• Potential Irritation: The gel's ingredients have the potential to irritate sensitive areas, such as the eyes or nasal passages. ^[7]

PRINCIPLE OF IN-SITU GEL FORMATION

A gelling agent that may create a stable sol with other excipients and the medication being administered are utilised in the creation of the gastroretentive in situ gel system. Ionic complexation brought on by a pH shift is what causes this sol system to gel in a stomach environment. The formulation used is a sodium alginate solution that contains sodium citrate and calcium carbonate (as a source of Ca2+); it complexes the free Ca2+ ions and releases them only into the stomach's acidic environment. Sodium alginate is the gelling agent. Sodium alginate polymeric chains cross-link to form a macrostructure when free Ca2+ ions are trapped within them. This gelation process produces double helical junction zones, after which the double helical segments reaggregate to form a three-dimensional network through hydrogen bonding with water and complexation with cations. ^[9]

Sodium citrate + Ca-Carbonate (Ca2+)→ Ca-Citrate complex--------------> Ca²+COO

Until the formulation reaches the stomach, where sodium alginate gels instantly, it stays in liquid form. Together with the cross-linking agent, the gelling agent acts as a dispersion medium in the form of an aqueous solution to hold the medication in a dispersed state. ^[10

Figure 1: Floating in situ gelling system ^[11]

FLOATING DRUG DELIVERY SYSTEM CLASSIFICATION

The buoyancy principle has led to the development of floating drug delivery systems using two completely distinct methods.

1. Effervescent systems

The matrices used in these buoyant delivery methods include polysaccharides like chitosan, swellable polymers like Methocel, effervescent chemicals like sodium bicarbonate and citric or tartaric acid, and liquid chambers that gasify at body temperature. Either organic solvents (such as ether or cyclopentane) or carbon dioxide generated by an effervescent reaction between organic acids and carbonate-bicarbonate salts can volatilise and release gas into the floating chamber. Since the stomach's contents are acidic, the matrices are designed to ensure that carbon dioxide is released and retained in the gellified hydroonilloid when it reaches the stomach. The dosage form rises and keeps its buoyancy as a result. Recently, a floating tablet that contains multiple carbon dioxide gas-emitting components was created.

2. Non-effervescent systems

Gel-forming or highly swellable polysaccharides or matrix-forming polymers such as polyacrylate, polycarbonate, polystyrene, and polymethacrylate are typically used to create non-effervescent floating drug delivery systems. In the stomach environment, it retains its relative shape and bulk density below unity. The medicine can come into contact with the stomach fluid after oral administration when it is intimately mixed with a gel-forming hydrocolloid. These dosage forms are buoyant because the expanded polymer traps air. Polyacrylates, calcium chloride, sodium alginate, carbopol, polyethylene oxide, and polycarbonates, polyvinyl acetate, and hydroxyl propyl methylcellulose (HPMC) are the excipients most frequently used in these systems. ^[2]

Figure 2: Classification of floating drug delivery systems ^[1]

THE STOMACH-SPECIFIC FIOTATION IN SITU GEL AND ITS APPLICATIONS

1. Enhanced absorption

For medications that are primarily absorbed from the upper part of the stomach, a longer contact time at the site of maximum absorption increases the degree of absorption.

2. Enhancement of bioavailability

Improved bioavailability is the outcome of increased medicine absorption in the stomach. As the stomach transit time increases, so does the medication's bioavailability.

3. Less negative medication effects

As the medication stays in the stomach until it is fully released, the frequency of the negative effect on the colon reduces.

4. Site-specific medication administration

The absorption rate of drugs that are absorbed from the stomach increases because they have enough residence time for absorption. Additionally, the medication's local action in the stomach is maintained, necessitating a reduced dosage. ^[1]

SUITABLE CHARACTERISTICS OF POLYMERS

Any gel's manufacturing requires the use of a polymer. The following are some essential polymer properties for in situ gels:

• It should be compatible.
• It should affect tear behavior and not have any harmful effects.
• It should be optically transparent, have appropriate tolerance, and exhibit pseudo-plastic behavior.
• As the shear rate rises, it ought to be able to adhere to the mucosal membrane and reduce viscosity. ^[12]

CLASSIFICATION OF IN SITU GEL POLYMERS

The origin or gelation method is used to classify polymers. According to an in situ source, gelling systems fall into two categories:

1. Natural polymers, such as sodium hyaluronate, xanthan gum, xyloglucan, chitosan, guar gum, gellan gum, pectin, alginic acid, and carrageenan
2. Synthetic or semi-synthetic polymers (E. G., hydroxypropyl methylcellulose, methylcellulose, polyacrylic acid, cellulose acetate phthalate, poly (lactic-co-glycolic acid, poloxamers). ^[12]

APPROACHES TO PRODUCE IN SITU GEL

The following are some of the different techniques and procedures used to create the in-situ gel formation:

• Predicated on causing physical modifications
• Predicated on creating chemical transformations
• Predicated on physiological cues

Gel Creation through Physical Modifications

This technique uses either the swelling or diffusion phenomena. The polymer in the system swells and produces a viscous gel, such as glycerol mono-oleate, as it absorbs water from the environment. is used to dissolve or distribute the medication and the polymer seeps into the surrounding tissues, the polymer (such as N-methyl pyrrolidone) precipitates and gels.

Based on Stimuli or Chemical Changes, In Situ Gel Formation

Changes to the chemical environment of the system that produce polymeric cross-linking might lead to gel formation:

Ionic cross connecting

Some examples of ion-sensitive polysaccharides are sodium alginate, pectin, carrageenan, and Gellan gum (Gelrite®).  that experience phase transitions when exposed to different ions like K+, Ca+2, Mg+2, and Na+. For example, divalent cations, particularly Ca2+, can cause the low methoxypectins to gel. When divalent or polyvalent cations, such as Ca2+, are present, alginic acid gels because of its interaction in alginate chai with the guluronic acid block.

Catalysed cross-linking

It is believed to be the most feasible way to produce gels when a network of polymers is created by cross-linking caused by enzymes present in body fluids.

Photo polymerization 

When tissues containing such a gel forming system are exposed to microwave, ultraviolet, or electromagnetic radiation, gels such as 2, 2 dimethoxy-2-phenyl acetophenone, ethyl eosin, etc., form inside the tissues.

Physiological Stimuli-Induced Gel Formation in Situ:

Changes in the system's pH and temperature are two physiological triggers that might cause gel formation.

pH-Dependent Gelling

A different method of in-situ gel production relies on pH changes. When the pH changes, several polymers, like Polyvinylacetal diethylaminoacetate (AEA), PAA (Carbopol, carbomer) or its derivatives, and blends of poly (ethylene glycol) (PEG) and poly (methacrylic acid) (PMA), shift from sol to gel. As the external pH rises, the hydrogel's swelling decreases when weakly basic (cationic) groups are present, and increases when weakly acidic (anionic) groups are present.

Temperature-Dependent in Situ Gelling 

At room temperature (between 200 and 250 degrees Celsius), these hydro gels are liquid; however, when they come into contact with body fluids (between 350 and 370 degrees Celsius), the temperature rise causes them to gel. This technique exploits the temperature-induced phase change. An abrupt change in temperature causes a polymer to become soluble in the system, and interactions between polymers produce a hydrophobic solvated macromolecule. The most researched family of polymers for creating in-situ gel properties are temperature-sensitive polymers, such as polyacrylic acid and polyacrylamide. ^[5]

Figure 3: Technique for Floating in Sit Gel Preparation ^[13]

MECHANISM OF FLOATING IN-SITU GEL

As the drug floats on the stomach, it is progressively released from the sestem at the proper rate. The stomach empties the residual system after the drug is released. In addition to the small quantity of stomach content needed to allow the proper A small amount of floating force (F) is also required to keep the dosage form continuously buoyant on the surface of the meal in order to realise the buoyancy retention principle. In order to measure the kinetics of the floating force, a novel method for computing the resulting weight has been published in the literature. The apparatus measures the force equal to F continuously (in relation to time) required to submerge the primary object. The item floats more readily if F is on the upper positive side. (Figure 2). This device helps to improve FDDS in terms of stability and endurance of floating forces generated, thereby avoiding the drawbacks of unpredictable intragastric buoyancy capability fluctuations.

 F = F buoyancy – F gravity 

     = (Df – Ds) gv

where v is the volume, g is the acceleration caused by gravity, Df is the fluid density, Ds is the object density, and F is the total vertical force. ^[14]

Figure 4: The floating system's mechanism, where GF stands for gastric fluid ^[1]