INTRODUCTION:

Oral administration is widely considered the most practical and preferred method for drug delivery into the systemic circulation. In recent years, there has been growing interest in developing oral sustained release drug delivery systems to achieve improved therapeutic benefits, including ease of administration, patient compliance, and formulation flexibility^1,2. These systems enable controlled and predetermined release of drugs, ensuring optimal therapeutic concentrations over an extended period. They offer advantages such as prolonged drug activity for medications with short half-lives, reduced side effects, decreased dosing frequency and wastage, and improved patient adherence³.

One of the key challenges in designing oral controlled release drug delivery systems is modifying the gastrointestinal (GI) transit time.

Gastric emptying of pharmaceuticals can vary significantly based on dosage form and whether the patient is fasting or fed⁴. On average, the residence time in the stomach ranges from 2 to 5 hours. The interdigestive myoelectrical cycle, which regulates electrical activity in the fasting stomach, governs the movement and absorption of dosage forms⁵.

This cycle consists of four phases:

Phase I: The absence of contraction (30-60 minutes)

Phase II: Period of irregular contractions (20-40 minutes)

Phase III: Period of regular contractions occurring at the highest frequency (10-20 minutes)

Phase IV: Between Phase III and Phase I (0-5 minutes) ⁶.

In recent decades, there has been increasing interest and research in developing devices designed to remain in the upper gastrointestinal tract (GIT). These innovations include various systems and devices such as floating systems, raft systems, expanding systems, swelling systems, bio-adhesive systems, and low-density systems⁷. Retaining drugs in the stomach can be advantageous for drugs with limited absorption windows in the small intestine. Additionally, prolonged stomach residence can be beneficial for locally targeted therapies in the upper part of the small intestine, such as the treatment of peptic ulcer disease⁸.

In-situ gel-forming systems can be developed for different routes of administration, including oral, nasal, and ophthalmic⁹. These systems utilize polymers that undergo a sol-to-gel transition based on changes in their physicochemical properties. Natural and synthetic polymers like gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly-lactic acid, poly-lactic-co-glycolide, and poly-caprolactone can be employed in formulating in-situ gel-forming drug delivery systems¹⁰. These in-situ gels are initially applied as solutions and undergo gelation in response to biological fluids. They exhibit "sensor" properties and reversible sol-gel phase transitions, making them "intelligent" or "smart" polymers that can control drug release timing, frequency, and site-specificity, based on environmental signals¹¹.

Overall, the development of oral controlled release drug delivery systems and in-situ gel-forming systems represents a significant advancement in drug delivery technology, offering improved therapeutic outcomes and enhancing patient experiences.

ADVANTAGES:

1. Increased absorption: Gastro-retentive drug delivery systems provide extended contact time in the upper region of the stomach, allowing drugs that primarily absorb in this area to have improved absorption.

2. Improved bioavailability: Longer stomach transit time leads to increased bioavailability of drugs as their absorption is enhanced.

3. Reduced adverse effects: By ensuring the drug remains in the stomach until complete release, the frequency of side effects significantly decreases¹².

4. Site-specific drug delivery: Gastro-retentive systems can be designed to deliver drugs to specific organ sites within the stomach, enabling targeted therapy.

5. Ease of administration: Gastro-retentive systems are formulated to be similar to conventional dosage forms, making them easy to administer.

6. Enhanced patient compliance: The reduced frequency of dose administration in gastro-retentive systems improves patient compliance, as patients need to take fewer doses¹³.

LIMITATIONS:

1. Stability issues: Systems involving in-situ gel formation may be prone to stability problems due to microbial or chemical breakdown, which can affect the performance of the drug delivery system.

2. pH sensitivity: Changes in pH can potentially cause degradation of drugs in the gastro-retentive systems, impacting their effectiveness¹⁴.

3. Unsuitability for gastro-irritant drugs: Gastro-retentive systems are not recommended for delivering medications that can irritate the gastric mucosa, as prolonged contact can exacerbate irritation.

4. Solubility concerns: Drugs that have low solubility in the acidic gastric environment may not be suitable for gastro-retentive systems, as their release and absorption could be compromised¹⁵.

In summary, gastro-retentive drug delivery systems offer several advantages such as increased absorption, improved bioavailability, and enhanced patient compliance. However, limitations related to stability, pH sensitivity, suitability for specific drug types, and solubility need to be considered during formulation and design.

APPROACHES:

There are different approaches used for triggering the in-situ gel formation via¹⁶;

Figure 1: Approaches for in-situ gel

1. IN-SITU FORMATION BASED ON PHYSICAL MECHANISM:

a. Swelling and Diffusion:

Stomach floating in-situ gel systems are designed to maintain their position in the stomach, particularly at the stretched pyloric sphincter. A biodegradable lipid molecule called Myverol (glycerol mono-oleate) is utilized in these systems, which leads to in-situ gel formation through the swelling of polymers upon water absorption. The extent of cross-linking between the polymeric chains determines the degree of swelling when exposed to stomach fluid. The inclusion of physical/chemical cross-linkers within the hydrophilic polymer network facilitates significant swelling of the polymers. In the case of polymers like N-methyl pyrrolidone (NMP), the polymer matrix solidifies as the solvent migrates from the polymer solution into the surrounding tissue, contributing to reduced polymer disintegration¹⁷.

a) b) c)

Figure 2: Mechanism of swelling and diffusion

a) Inhibition of gastric fluid, b) Buoyant and swell c) Gas generating system (CO₂ release)

2. IN-SITU GELLING BASED ON CHEMICAL STIMULI:

a. Ionic crosslinking:

Certain ion-pH sensitive polysaccharides, such as carrageenan, Gellan gum, Pectin, and Sodium Alginate, undergo phase transition in the presence of various ions like Ca²⁺, Mg²⁺, and Na⁺.

One example is alginic acid, which forms a gel when exposed to divalent or polyvalent cations, particularly Ca^2+. This gelation occurs when the guluronic acid blocks in the alginate chain interact with the divalent cations, leading to cross-linking and the formation of a three-dimensional gel network. The presence of Ca²⁺ions promotes the binding and aggregation of the alginate chains, resulting in gel formation.

Similarly, other ion-pH sensitive polysaccharides like carrageenan, Gellan gum, and Pectin exhibit similar behaviour. These polysaccharides can undergo gelation or phase transition in the presence of specific ions, depending on the pH conditions. The interaction between the polysaccharide chains and the ions leads to the formation of a gel structure or a change in viscosity ¹⁸.

b. Enzymatic cross linking:

Figure 3: Mechanism of Ionic crosslinking

Enzymatic cross-linking is a process in which natural enzymes are used to facilitate the formation of cross-links within a polymer system, leading to gel formation. This approach offers a practical and biocompatible method for controlling the rate of gel formation without the need for potentially harmful chemicals like monomers and initiators. The use of enzymes allows for precise control over the gelation process and enables the injection of mixtures before gelation occurs in the desired location.

Examples of enzymes commonly used for enzymatic cross-linking include transglutaminase, tyrosinase, and horseradish peroxidase (HRP).

Transglutaminase is an enzyme that catalyzes the formation of covalent bonds between proteins or peptides. It is used to cross-link protein-based polymers, such as gelatin or collagen, to form stable and biocompatible hydrogels. The enzyme reacts with specific amino acid residues, such as lysine and glutamine, to create cross-links between the polymer chains, resulting in gel formation.

Tyrosinase is an enzyme involved in the formation of melanin and plays a role in the browning of fruits and vegetables. It can also be utilized for cross-linking applications. By introducing tyrosinase and its substrate, such as tyrosine or catechol derivatives, into a polymer system, the enzyme catalyzes the oxidation of these substrates, leading to the formation of cross-links and subsequent gelation.

Horseradish peroxidase (HRP) is another commonly used enzyme for cross-linking. HRP can oxidize phenolic compounds in the presence of hydrogen peroxide, resulting in the formation of radicals that initiate polymerization and cross-linking reactions. This enzymatic process can be applied to various polymers, including natural polymers like chitosan or synthetic polymers, to create hydrogels or other cross-linked structures.

The enzymatic cross-linking provides a versatile and biocompatible method for controlling gel formation without the use of harmful chemicals. By utilizing specific enzymes and their respective substrates, the rate and extent of cross-linking can be precisely controlled, allowing for in-situ gel formation and injectability of polymer mixtures for targeted applications in biomedical and pharmaceutical fields¹⁹.

3. IN SITU GEL FORMATION BASED ON PHYSIOLOGICAL STIMULI:

a. pH triggered systems:

Physiological stimuli-based in-situ gels are another type of in-situ gel that undergo gel formation in response to changes in pH. These gels utilize fully pH-sensitive polymers, which contain functional groups that either gain or lose protons in response to changes in the surrounding pH.

Polymer systems with a wide range of ionizable species are known as polyelectrolytes. These polymers typically consist of simple groups that exhibit pH-dependent protonation or deprotonation. For example, polymers with weakly acidic (anionic) groups exhibit increased hydrogel swelling as the pH increases. Conversely, polymers with weakly basic (cationic) groups show decreased hydrogel swelling with increasing pH.

An example of an anionic pH-sensitive polymer is polyacrylic acid (PAA) derivatives. These polymers can form hydrogels that exhibit pH-dependent swelling behavior. On the other hand, hydrogel formation can be achieved using low viscosity polyvinyl alcohol and acetal diethyl amino acetate (AEA) at neutral pH, and the gelation process is triggered by solutions with specific pH values¹⁹.

In summary, physiological stimuli-based in-situ gels rely on pH-sensitive polymers that undergo gel formation in response to changes in pH. The presence of functional groups that can gain or lose protons allows these polymers to exhibit pH-dependent swelling behavior and facilitate the formation of hydrogels with controllable properties.

Figure 4: Mechanism of pH-triggered systems

b. Temperature dependent in situ gelling:

The temperature-sensitive in-situ gel formation method involves a phase transition from a less viscous solution to a gel with higher viscosity. This transition is facilitated by polymer-polymer interactions that result in the formation of a solvated polymer network. Temperature-sensitive polymers, such as polyacrylic acid (PAA) and polyacrylamide, have been extensively studied and utilized for this purpose.

These polymers, which are hydrophobic macromolecules, exhibit a sudden change in solubility in response to temperature variations. Specifically, they undergo a phase change when exposed to body temperature, transforming from a liquid state at room temperature (20°C–25°C) to a gel state at physiological temperature (35°C–37°C). This transition takes advantage of the lower critical solution temperature (LCST) behaviour of certain polymers.

At temperatures below the LCST, the polymer-water interactions are characterized by strong hydrogen bonding, resulting in good solubility of the polymer. However, as the temperature increases beyond the LCST, the hydrogen bonding between the polymer and water decreases dramatically. This leads to dehydration of the solvated polymer, causing it to adopt a more hydrophobic conformation and resulting in gelation.

Conversely, some polymers exhibit an upper critical solution temperature (UCST) behavior, contracting and undergoing gelation when cooled below a certain temperature. However, the temperature-sensitive in-situ gels discussed here primarily utilize the LCST behaviour.

Polymer networks based on polyacrylic acid (PAA), polyacrylamide (PAAm), or copolymers such as poly (acrylamide-co-butyl methacrylate), demonstrate a positive temperature dependency of swelling. This means that these polymers exhibit increased swelling and gelation at higher temperatures²⁰.

we can conclude temperature-sensitive in-situ gels rely on polymers with LCST behavior, where the polymer solution transitions from a liquid state to a gel state when exposed to body temperature. This phase transition is driven by changes in polymer-water interactions and the hydrophobic-hydrophilic balance of the polymer, resulting in the formation of a gel network with increased viscosity.

EVALUATION OF STOMACH SPECIFIC FLOATING IN-SITU GEL SYSTEM:

Evaluation of stomach-specific floating in-situ gel systems involves assessing various parameters to ensure their quality and performance. The following parameters should be considered:

1. Determination of drug content:

The amount of drug present in the formulation is determined by dissolving a specific weight of the formulation in a suitable medium, filtering it, and analyzing the drug content²⁸.

2. Physical appearance:

The in-situ solution should be visually clear and free of any particulate matter. The time required for the solution to convert into a gel in a buffer at pH 1.2 is measured, and the consistency of the formed gel is checked visually.

3. pH of the system:

The pH of the gel-forming solution is measured using a calibrated pH meter at a specified temperature (e.g., 27°C)²⁹.

4. Viscosity of the in-situ gelling system:

The viscosity of the solution is measured before and after gelation using techniques such as a Brookfield viscometer or a cone and plate viscometer at a suitable temperature (e.g., 25±1°C).

5. In-vitro gelling capacity:

The gelling capacity of the in-situ gel-forming system can be determined by preparing a colored solution and visually observing the time taken for gel formation, the stiffness of the formed gel, and the duration for which the gel remains intact³⁰.

6. In-vitro buoyancy studies:

The floating behaviour of the system is evaluated by adding a fixed volume of the in-situ gel-forming formulation to a medium simulating gastric fluid. Parameters such as floating lag time (time taken for the system to float) and floating time (duration of constant floating) are measured.

7. In-vitro drug release studies:

The release rate of the drug from the in-situ gel is determined using appropriate dissolution testing apparatus, such as USP dissolution rate testing apparatus I. The drug release is measured at different time points, and the cumulative release profile is analyzed using UV-Visible spectrophotometry or other suitable methods³¹.

8. Water uptake study:

After gel formation, the gel is collected from the medium, excess medium is removed, and the weight of the gel is noted. The gel is then exposed to the medium or distilled water, and the weight gain due to water uptake is measured at specific time intervals³².

9. Gel strength:

The strength of the gel is evaluated using a rheometer by measuring the change in load on the probe as it penetrates through the gel. This provides information about the gel's mechanical properties³³.

By evaluating these parameters, the performance and characteristics of stomach-specific floating in-situ gel systems can be assessed, ensuring their quality and suitability for drug delivery applications

Table 2: Commercial Formulation of In-situ Floating Gel:

S. No	Name	Drug	Brand
1	Topalkan	Alminium-Magnesium antacid	Pierre Fabre drug, France
2	Liquid Gaviscone	Aluminium hydroxide, Magnesium carbonate	Claxo Smith Kline India
3	Conviron	Folic acid, Ascorbic acid, Dried ferrous sulphate	Ranbaxy, India
4	Almagate flot coat	Aluminium-Magnesium antacid	Ranbaxy, India

RECENT ADVANCES:

The pharmaceutical industry is facing challenges in finding effective treatment alternatives that are accepted by both doctors and patients. In order to provide viable alternatives to current medication delivery methods, new delivery approaches should also contribute to improved therapeutic outcomes. One such approach is the development of in situ gels, which can be challenging due to fabrication issues, complex processing requirements, the use of organic solvents (particularly for synthetic polymer-based systems), burst effects, and unpredictable drug release kinetics. While natural polymers possess ideal characteristics, such as biodegradability, batch-to-batch repeatability can be challenging, leading to the utilization of synthetic polymers instead³⁴.

Antonino et al. utilized a thermo-reversible polymer, Poloxamer P127, to create an in-situ gelling formulation containing budesonide, a potent corticosteroid used in the treatment of gastrointestinal inflammatory conditions. In vivo tests conducted on a mouse model of intestinal mucositis demonstrated the formulation's effectiveness in treating inflammatory damage to the intestinal mucosa³⁵.

Daia et al. combined an in situ gelling vehicle represented by Cremophor with a Class III drug/permeation enhancer complex. The aim was to reduce the dilution effect in the gastrointestinal lumen and synchronize the diffusion of both the drug and permeation enhancer to the absorption site in the duodenum. The researchers found that compared to non-gelling PEG 400-based vehicles, the in situ gelling formulations significantly increased the bioavailability of the studied drug when administered orally to rats³⁶.

Maghraby et al. developed a modified in situ gelling alginate (ALG) formulation for sustained release of dextromethorphan (DX) in the gastrointestinal system. They dispersed a solid matrix composed of micronized DX and Eudragit S 100 in a 2% w/w ALG solution. The presence of gastric medium induced gel formation in the ALG vehicle, enabling sustained release of DX³⁷.

Tenci et al. developed an in-situ gelling system for the local treatment of inflammatory bowel disease using the extract of Maqui berry (Aristotelia chilensis) as an antioxidant and anti-inflammatory agent. They utilized gellan gum, methylcellulose, and hydroxyl propyl cellulose as polymers in the formulation³⁸.

The mentioned above studies highlight the potential of in situ gels as a promising drug delivery approach for various therapeutic applications. These studies have addressed challenges related to fabrication, drug release, and bioavailability, showcasing the effectiveness of in situ gels in overcoming these hurdles. By utilizing different polymers and formulation techniques, researchers have successfully demonstrated the ability of in situ gels to improve the targeted delivery of drugs, enhance therapeutic outcomes, and provide sustained release profiles. These findings contribute to the advancement of drug delivery systems and pave the way for the development of innovative and effective treatment options in the pharmaceutical field.

CONCLUSION:

Creating dosage forms that can effectively remain in the stomach and provide sustained drug release has been a challenge in the field of drug delivery. However, floating in-situ drug delivery systems have emerged as a promising solution to address this difficulty. These systems undergo a transition from a solution (sol) to a gel state in the acidic environment of the stomach. This gel formation allows the dosage form to float on the surface of the gastric fluid, prolonging its contact time with the gastric mucosa.

One of the key advantages of floating in-situ gels is that they provide site-specific release for an extended period of time. By floating in the stomach, the drug delivery system remains localized in the desired region, increasing drug absorption and bioavailability. This extended contact time also allows for less frequent dosing, which can greatly improve patient compliance, especially in elderly and pediatric populations.

There are several biodegradable polymers available in the market that exhibit in situ gelling activity. These polymers have the ability to undergo a sol to gel transition in response to specific physiological conditions, such as changes in pH or temperature. By understanding the behavior of these biodegradable polymers, researchers can optimize the floating behavior of the dosage form, leading to improved gastric retention and enhanced drug delivery.

In situ gels offer several advantages over traditional dosage forms. They provide improved drug release profiles, ensuring a controlled and sustained release of the drug. They also exhibit superior stability, reducing the risk of premature drug degradation. Additionally, these gels are biocompatible, meaning they are well-tolerated by the body and do not cause significant adverse effects.

Overall, in situ gels represent a reliable and effective dosage form for drug delivery. Their ability to float in the stomach, provide sustained release, and improve patient compliance makes them a promising option for long-term drug delivery, particularly in cases where prolonged gastric retention is desired.

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Received on 12.06.2023 Modified on 08.01.2024

Research J. Pharm. and Tech 2024; 17(6):2990-2996.

DOI: 10.52711/0974-360X.2024.00467

Polymers	Basic Chain	Solubility Behaviour	References
Alginates	1-4'-B-D-mannuronic acid and α -L-glucuronic acid	Insoluble in ethanol, ether, chloroform and slowly soluble in water	21
Pectin	d-galacturonic acid units joined in chains by α-(1–4) glycosidic linkages	Soluble in water, insoluble in ethanol and organic solvents	22
Gellan Gum	D-glucose, D-glucuronic acid and rhamnose in B-1, 4 linkage	Soluble in hot water	22
Carbopol	a block copolymer of polyethylene glycol and a long chain alkyl acid ester.	Water soluble	23
HPMC	partly O-methylated and O-2-hydroxypropylated cellulose ether	Soluble in water and soluble in both organic and inorganic solvents	23
Poloxamer	central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene.	Soluble in water	24
Chitosan	Deacetylated P-1, 4-Nacetyl-1-D glucosamine	Insoluble in neutral and alkaline pH	25
Guar Gum	linear chain of (1 → 4)-linked β-D-mannopyranosyl units with (1 → 6)-linked α-D-galactopyranosyl residues as side chains	Swells in water, insoluble in organic solvents	26
Xanthum Gum	α-(1,4)-linked D-glucose	Soluble in water and any pH conditions	27