INTRODUCTION:

In situ gels are solutions or suspensions that go through the gelation process after arriving at a specific location. This can be caused by contact with body fluids or physicochemical changes (such as changes in pH, temperature, ionic concentration, UV radiation, the presence of specific molecules or ions, external triggers, etc.). In situ gels can be classified as either solids or liquids. Gels have the potential to be utilised for a variety of in-situ administration routes, including buccal, intraperitoneal, nasal, ophthalmic, oral, parenteral, rectal, subcutaneous, transdermal, and vaginal.

During the discovery phase, the gel formulations improve both the local and systemic exposure of potential lead compounds. This makes them ideal for establishing animal models for a variety of conditions in a quick and cost-effective manner^1-5.

In spite of the enormous variety of gels, one category in particular, known as smart polymer gels, has emerged as a central topic of investigation in the field of pharmaceutical research over the past few decades. These intelligent polymers can adapt their physicochemical characteristics in response to changes in their surrounding environment. In recent developments, in situ gels have made it conceivable to utilize physiological individuality^6-9.

In situ gels, which have emerged as one of the best innovative drug delivery systems (NDDS), have been the subject of much research in the process of creating them. In this article, we will attempt to explain the following topics: introduction, advantages, and disadvantages, different types of polymers, and features that are ideal for the manufacture of in situ gels. In addition to this, it concentrated on commercially available preparations as well as new developments and progress made in the formulation of in-situ gels¹⁰.

Figure 1: Phase Transition by the influence of pH

Figure 2: Phase Transition by the influence of Temperature

Features of polymers those are desirable^11-12:

Polymers are required in the production of any kind of gel. They are a vital element.

The following is a list of some of the important polymer properties for in situ gels:

· It ought to be suitable for use.

· It should have an effect on the behavior of the tears, and it should not have any poisonous effects.

· It should exhibit characteristics of pseudo-plasticity.

· It should have a high tolerance as well as clear optical qualities.

· It should have the ability to adhere to the mucous membrane.

· When the shear rate is increased, it should be able to reduce the viscosity of the substance.

Organizing the several types of in-situ gel polymers:

Polymers can be categorized either by the process by which they gelate or by their place of origin. According to a source located on location, there are two distinct categories of gelling systems^13-16:

i. Natural polymers, such as (but not limited to) alginic acid, carrageenan, chitosan, guar gum, gellan gum, pectin, sodium hyaluronate, xanthan gum, xyloglucan, and others.

ii. Man-made or partially-man-made polymers (such as cellulose acetate phthalate, hydroxypropyl methylcellulose, methylcellulose, polyacrylic acid, polyethylene glycol, and polyvinyl alcohol, for example) (lactic-co-glycolic acid, poloxamers).

i. Polymers that occur naturally¹³

Alginic acid or sodium alginate: Residues of b-D-mannuronic acid and -L-glucuronic acid are linked together via 1, 4-glycosidic connections to form a biodegradable, hydrophilic, non-toxic linear block copolymer polysaccharide. It is a carrier that is utilised in the formulation of ophthalmic products. When exposed to divalent cations (Ca+2, Mg+2), alginate undergoes a transformation that causes it to become a stable gel. This occurs as a result of the cross-linking of the carboxylate groups, and this gel is not easily dissolved by tear fluid.

Carrageenan:

Based on the sulphate group number and location, these compounds can be divided into the following three types:

a. Iota carrageenan: This type of carrageenan is totally soluble in hot water and, in the presence of calcium or potassium ions, it transforms into an elastic gel.

b. Kappa carrageenan: In the presence of potassium ions, it transforms into a "gel" and demonstrates features comparable to those of locust bean gum, such as being soluble in hot water.

c. Lambda carrageenan: This type of carrageenan does not result in the production of gels, but it does produce highly viscous solutions that are entirely soluble in cold water.

Chitosan:

Chitin is alkaline deacetylated to produce this biodegradable, biocompatible, thermosensitive, pH-dependent, cationic, amino polysaccharide. It possesses the following characteristics: Alterations in pH and temperature both contribute to the gelling of chitosan. Because of the electrostatic interaction that takes place between positively charged chitosan and negatively charged mucosal surfaces, it possesses exceptional mucoadhesive characteristics. Gels were generated by electrostatic forces at temperatures below the critical point of the solution as a result of extremely hydrophobic contacts. During the gelation process of chitosan, displaying polymers are utilised at temperatures over the upper critical solution temperature.

After cellulose, this is the polysaccharide that is used the second most frequently since it is readily available, non-toxic, and economical, among other reasons.

Guar gum or guar gum:

It is soluble in water but insoluble in hydrocarbons, lipids, ester, alcohols, and ketones. However, water is the only solvent that it is compatible with. It has better dispersibility and can generate highly viscous colloidal solutions with tiny volumes of hot and cold water. Alterations in temperature bring about a change that can be reversed in the process of gel formation.

Gellan gum:

It is a linear, water-soluble, temperature-dependent, extracellular, hetero, anionic polysaccharide that is known commercially as Gelrite or Kelcogel; similar to alginate, this gellan gum forms gel in the presence of metal cations (mono or divalent). Gelation can be triggered by monovalent cations like Na+ or K+, as well as divalent cations like Ca+2 or Mg+2, which are both divalent cations. The development of double-helical junction zones is an important step in the gelation process. This step is followed by the aggregation of double-helical segments into three-dimensional networks through complexation with cations and hydrogen bonding with water. It is one of the polymers that is utilised the most frequently when it comes to the production of in situ gels.

Pectin:

A group of cationic linear polysaccharides that include -(1, 4)-d galacturonic acid residues is referred to as the galacturonic acid family. Pectin, which is a source of monovalent, divalent, and trivalent ions, will gel when hydrogen ions are present and cause the process of gelatinization. It is not suitable to formulations using organic solvents and can only be used with water-soluble substances. Pectin and pectic acid salts that include monovalent cations, often known as alkali metals, are soluble in water. Divalent and trivalent cationic salts, on the other hand, dissolve very poorly or not at all in water. Clumps, also known as semi-dry packets, formed as a result of the addition of water to dry powdered pectin because of the pectin's natural propensity to hydrate. The clumps could only be dissolved in water by combining them with a water-soluble carrier. The degree of methylation, often known as DM, can be thought of as the proportion of carbonyl groups that have been esterified with methanol. Pectins were divided into two categories according to the degree of esterification they possessed:

a. Low methoxy pectins, in which less than fifty percent of the pectin's carboxyl groups are methylated.

b. High methoxy pectins, in which more than fifty percent of the carboxyl groups in the pectins have been methylated.

Sodium hyaluronate:

It is a type of hyaluronic acid that is soluble in water and is composed of sodium salt. It is an endogenous polysaccharide that occurs naturally and helps the body produce collagen, which is important for keeping the skin supple. In addition to this, it boosts the stability of the formulation and decreases the likelihood of oxidation.

Xyloglucan, also known as tamarind gum:

Because of its non-toxic, biocompatible, and biodegradable nature, xyloglucan is a plentiful hemicellulosic polysaccharide that has the potential to be utilised in numerous different delivery strategies. It passes through the process of gelation via the thermoresponsive process while also being partially destroyed by the b-galactosidase enzyme. When employed in oral delivery, the gelation duration can be as little as minutes, and it can even take place in the stomach even when it is chilly. Similar to poloxamer, it will gel when subjected to heating/refrigerator temperature or cooling after being subjected to higher heat. In a wide pH range, xyloglucan is able to gel when sugars (40-65%) or alcohols are present. This capacity is independent of the sugar concentration. However, in the combination (20% alcohols), a significant reduction in the sugars is necessary for the formation of a gel.

Chitosan that has been thiolated or thiomers:

In modern times, thiol groups display significantly greater adhesive qualities (mucoadhesive characteristics) than other types of polymers. Thiomers have the ability to engage with cysteine-rich subdomains or mucus glycoproteins by crosslinking intra- and inter-disulfide linkages through a straightforward oxidation process. This ultimately results in gel formation in the physiological environment. They are the most promising multi-functional, cationic, hydrophilic macromolecules, and in addition to that, they operate as permeability enhancers more so than chitosans do. It possesses positive charges that cause it to interact with the cell membranes, which in turn causes a structural remodelling of the proteins that are involved with the tight junctions. In addition to this, it possesses a solid and cohesive nature.

Xanthan gum:

Xanthan gum is soluble in both cold and hot water, and it maintains a high degree of stability in acidic as well as alkaline environments. Because it also contains pyruvic acid groups in addition to glucuronic acid groups, it possesses an anionic character.

ii. Polymers made from synthetic or semi-synthetic substances^14-18:

Cellulose acetate phthalate (CAP): Cellulose acetate phthalate, or CAP for short, is a material that's sometimes referred to as "faux latex." It is a synthetic form of latex that is produced in an aqueous media through the dispersion of a latex-like polymer that already exists. It is pH sensitive, cross-linked polyacrylic polymers with potentially useful properties for sustained drug delivery to the eye because latex is a free-running solution at a pH of 4.4, which undergoes coagulation tear fluid, which raises the pH to pH 7.4. This is due to the fact that latex is made from rubber, which has a pH of 4.4. In -scintigraphy, CAP is utilised to monitor the ocular residence duration of an ophthalmic treatment, and its manufacturing does not call for the utilisation of organic solvents.

HPMC:

Hydroxypropyl methylcellulose, often known as HPMC, is a polymer that is mucoadhesive, biocompatible, and thermoreversible. Because of its great swellability, thermal gelation capabilities, and usage as a hydrophilic matrix and in oral drug delivery systems, it is a form of cellulose ether. When used in conjunction with carbopol, HPMC increases the solution's viscosity while simultaneously neutralising the acidity of the solution. Because of the interaction between the hydrophobic components that make up the polymer, HPMC gels at higher temperatures. It was actively contributing to the creation of an aqueous solution that was used for the topical treatment of the eye. It was discovered that formulating a vaginal mucoadhesive film with a CR of S-nitroso glutathione and impacts on the gelling behaviour was absolutely necessary^19-24.

Methylcellulose (MC) is another type of cellulose derivative that can be utilised as a polymer for in-situ gelling:

Several cellulose derivatives behave like liquids at room temperature but transform into gels when the temperature is raised. For instance, the aqueous solution of MC and HPMC passes through a phase transition into gels between the temperature ranges of 40-50 °C and 75-90 °C, respectively. However, the temperature at which the phase transition occurs in MC and HPMC is higher than the temperature at which physiological processes occur. This temperature can be decreased, however, by introducing chemical and physical modifications into the polymers. The formation of gels in HPMC and MC solutions is due to hydrophobic interactions between molecules that contain methoxy groups. As a result of hydration taking place at a lower temperature, polymer-polymer interaction can take place between macromolecules. As the temperature rises, there is a slow but steady loss of hydration, which results in a decrease in viscosity. At the transition point where sufficient dehydration of the polymers takes place, the polymers begin to associate with one another, and the thickness begins to rise, indicating the formation of a network structure.

When the temperature was raised from 40 to 50 degrees Celsius, gelation took place. The solution is in liquid form at a low temperature of 30 degrees Celsius²⁵.

Polyacrylic acid (PAA):

PAA is most commonly referred to by its commercial name, carbopol. Enhancing pre-corneal retention is a common purpose for its application in ophthalmology. In comparison to other derivatives of cellulose, it has the potential to demonstrate superior mucoadhesive qualities. After examining a number of grades, including carbopol 910, 934, 940, and 941, among others, researchers came to the conclusion that 940 displayed excellent characteristics.

PLGA, also known as poly (lactic-co-glycolic acid):

It is a polymer that is both biocompatible and biodegradable. It is a synthetic copolymer made of polyglycolic acid and polylactic acid (PLA) (PGA). These systems are utilised for the purpose of regulated drug delivery and can be purchased on the market in the form of implants, microparticles, or in situ implants. Because of its extensive history of usage in clinical settings, PLGA is widely considered to be among the most capable polymers now in use for the fabrication of drug delivery and tissue engineering applications^26-27.

Poloxamers:

In the business world, poloxamers are referred to as pluronic, and they are utilised in thermosensitive in situ gels. It has great thermal setting properties and lengthens the amount of time that the medicine is in residence. It is a tri-block copolymer that is soluble in water and is made up of two different types of polyethylene oxide (PEO) and polypropylene oxide (PPO). As a result of its ability to make colourless and translucent gels, pluronic F127 is the poloxamer polymer that is utilised in the pharmaceutical industry the most frequently. It is made up of PEO (70%) and PPO (30%) respectively. It was found that using a copolymer pluronic F127-g-poly (acrylic acid) as in situ gelling vehicles resulted in a longer residence time for the ocular medicines as well as improved bioavailability.

Poloxamines:

Poloxamines are also referred to as tetronics in popular parlance. These block copolymers are made of ethylene and propylene oxide, and they have tetra functionalities. They are also biocompatible. It would appear that the formation of X-shaped poloxamines by four arms of PEO-PPO that are connected by an ethylenediamine group is essential for the osteoinductive capacity of tetronics. It has been utilised up until this point for the twin purpose of rendering temperature and pH-responsive micelles and gels. There hasn't been a report of any other polymer being osteoinductive on its own. One that is hydrophilic is more cytocompatible than one that is hydrophobic, and both types exhibit higher compatibility as their molecular weight increases²⁸.

Poly (N-isopropyl acrylamide) or PNIPAAm:

The acronym PNIPAAm stands for poly (N-isopropyl acrylamide). It is a thermosensitive polymer that undergoes a reversible phase transition between 32 and 35 degrees Celsius; it is closer to the temperature of the human body, which makes it more effective in achieving therapeutic aims^29-30.

CONCLUSION:

For the formation of in-situ gels, the utilization of polymers that are biocompatible, biodegradable, and water-soluble can result in the production of outstanding and exceptional drug delivery systems. In recent years, there has been an uptick in interest in research, which has opened up a number of doors for innovative medication delivery strategies. These delivery mechanisms can be included into a unique carrier, which would allow for significantly enhanced and prolonged sustained drug administration. Last but not least, in situ gels are simple to apply, and they provide patients with both comfort and compliance.

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Received on 25.08.2022 Modified on 09.12.2022

Res. J. Pharma. Dosage Forms and Tech.2023; 15(2):138-142.

DOI: 10.52711/0975-4377.2023.00023