INTRODUCTION:

It is a medication delivery method that is initially in solution form before being administered to the body, but transforms into a gel form once it has been¹. There are numerous methods, including oral, ophthalmic, vaginal, rectal, I/V, intraperitoneal, etc.

One of the greatest innovative drug delivery systems is the "in situ gel" technology, which helps with regulated and sustained medication release, increased patient comfort, and patient compliance².

System's unique attribute of 'Sol to Gel' transition aids in the continuous and controlled release of the medicines, better patient compliance, and comfort³.

An in-situ gelling system is a formulation that, before entering the body, is in solution form but transforms into a gel under certain physiological conditions. Temperature, pH change, solvent exchange, UV light, and the presence of certain molecules or ions are only a few of the variables that influence the sol to gel transition⁴.

The production of sustained delivery vehicles for bioactive compounds can be done using drug delivery systems with the mentioned "sol to gel transition" features⁵. It is possible to administer medications by oral, ophthalmic, transdermal, buccal, intraperitonial, parenteral, injectable, rectal, or vaginal routes using a variety of natural and synthetic polymers that go through in situ gel formation. Recent developments in in situ gels have made it possible to take advantage of the physiological variations in various GI tract regions for better drug absorption as well as patient convenience and compliance⁶.

IMPORTANCE OF IN-SITU GELLING SYSTEM:

1) In-situ gel helps for the controlled and sustained release of the drugs by its Sol-Gel transition⁷.

2) It helps in reducing frequency of drug administration in the body.

3) Low doses of the drugs are required and there will be no drug accumulation and side effects.

4) It increases bioavailability of drugs.

5) Residence time of drug will be increased due to gel formation⁸.

6) The in-situ gel drug delivery system decreases wastage of the drug.

7) Liquid dosage form that can sustain drug release & remain in contact with targeted area for extended period of time is ideal.

ADVANTAGES:

1) Provide controlled and sustained release of the drug.

2) Ease of the drug administration.

3) Can be administered to unconscious patients.

4) Increased patient compliance and comfort.

5) Decrease the dose frequency and drug toxicity.

6) Increased bioavailability.

7) Provide biocompatibility and biodegradation due to use of natural polymers.

8) Natural polymers have characteristic properties of biocompatibility, biodegradability, and biologically recognizable moieties that support cellular activities⁹.

9) Synthetic polymers usually have well-defined structures that can be modified to yield tolerable degradability and functionality.

10) In situ gels can also be engineered to exhibit bio-adhesiveness to facilitate drug targeting, especially through mucus membranes, for non-invasive drug administration¹⁰.

11) In situ gels offer an important “stealth” characteristic in vivo, owing to their hydrophilicity which increases the in vivo circulation time of the delivery device by evading the host immune response and decreasing phagocytic activities.

DISADVANTAGES:

1) It requires high level of fluids.

2) The sol form of the drug is more susceptible for degradation.

3) Chances of stability problems due to chemical degradation.

4) After placing the drug eating and drinking may become restricted up to the few hours.

5) The quantity and homogeneity of drug loading into hydrogels may be limited, particularly for hydrophobic drugs¹¹.

6) Only drugs with small dose requirement can be given.

7) Lower mechanical strength, may result into premature dissolution or flow away of the hydrogel from a targeted local site.

IDEAL CHARACTERSTICS OF POLYMERS FOR PREPARATION OF IN-SITU GEL:

1) The polymer should be capable of adhering to the mucous membrane¹².

2) It should be well compatible and should not provide any toxic effects.

3) It should have pseudo plastic behaviour.

4) The polymer should be capable of decreasing the viscosity with increase in shear rate.

5) Preferred pseudo plastic behaviour of polymer¹³.

6) Good tolerance and optical clarity are more preferred.

APPROACHES:

There are 4 mechanisms for triggering the in-situ gelling formation of biomaterials. These include:

1. IN -SITU GEL FORMATION DUE TO PHYSIOLOGICAL STIMULI:

A) Temperature triggered in-situ gelling systems

B) pH triggered in-situ gelling systems

2. In-situ gel due to ion activation system:

3. In-situ gel due to physical mechanism:

A) Swelling

B) Diffusion

4. In-situ gel due to chemal reactions:

A) Ion cross linking

B) Enzymatically cross linking

C) Photo polmerization

1. In -situ gel formation due to physiological stimuli:

There are a few polymers which go through enormous and sudden physical and chemical changes because of little outer changes in their environmental conditions¹⁴. Such polymers are called Stimuli-responsive polymers. They are likewise called as smart, intelligent, stimuli responsive polymers. These polymers perceive an upgrade as a sign, judge the level of the signal and afterward change their chain confirmation accordingly.

A) Temperature Triggered In-situ gelling systems:

Thermosensitive polymers are most widely considered class of naturally responsive polymer frameworks in medication conveyance¹⁵. This is on the grounds that temperature is moderately simple to control and furthermore effectively pertinent to both in vitro and in vivo. In this system, gelling of solution is set off by modification in temperature, consequently sustaining medication discharge. These hydrogels exist in fluid structure at room temperature (20-25°C) and converts in gel when interacts with body fluids (35-37°C)¹⁶. An intriguing way to approach in situ formulations is to use biomaterials that change from sol-gel when the temperature rises. The optimal fundamental temperature range for such a system is ambient and physiological temperature, with the purpose of promoting clinical management and eliminating the requirement for external heating sources other than the body's own heat to cause gelatin to form. The thermosensitive sol-gel polymeric framework is designed using three main methods¹⁷. Consequently, they are ordered into:

a. Negatively thermo sensitive, which contract upon heating

b. Positively thermo sensitive, which contract upon cooling

c. Thermo-reversible gel

Polymers which show temperature incited gelation are poloxamers/Pluronic, cellulose subsidiaries [HPMC, ethyl (hydroxy ethyl) cellulose (EHEC), methyl cellulose], xyloglucan, tectonics, and so forth.

B) pH Triggered in-situ gelling systems:

pH is another physiological enhancement that encourages the placement of in situ gel¹⁸. Remembered polymers have an acidic or an alkaline group that, depending on the pH of the environment, either accepts or donates protons. These are now referred to as pH responsive polymers. It is common practice to use this type of mechanism for ocular medication delivery systems. Utilizing in situ gel systems will increase the medication's precorneal time of residence, improving its bioavailability.

The formulation exists as a normal solution at pH 4.4, but gelation takes place at pH 7.4, which is, for instance, the pH of tear liquid. Polyelectrolytes are polymers with a significant number of ionisable clusters. While polymers having necessary (cationic) groups show reduced swelling, hydrogel swelling increases with an increase in the external pH if pitifully acidic groups (anionic) should appear¹⁹. The majority of anionic-containing polymers with sensitive pH levels rely on PAA (Carbopol®, Carbomer) and its derivatives. While at neutral pH conditions, polyvinyl acetal diethylamino acetate (AEA) arrangements which have a less viscosity at pH 4, forms hydrogel. Different polymers which show pH incited gelation are cellulose acetic acid derivation phthalate (CAP) latex, polymethacrylic corrosive (PMMA), polyethylene glycol (PEG), pseudo latexes, and so forth.

2. In-situ gel due to ion activation system:

Here, gelling of the imparted solution is prompted by the adjustment in ionic strength. It is accepted that the osmotic gradient across the surface of the gel decides the pace of gelation²⁰. In presence of mono and divalent cations commonly present in the tear liquids, the watery polymer solutions shape a reasonable gel. The electrolyte presents in the tear liquid, particularly Na+, Ca2+ and Mg2+ cations assume a significant job in inception of gelling when the arrangement is ingrained in the conjunctival cul-de-sac. Polymers that display osmotically initiated gelation incorporate gel rite or gellan gum, hyaluronic acid, alginates, and so on²¹.

3. In-situ gel due to physical mechanism:

A) Swelling:

In this strategy gelling happens as the material absorbs water present in the external environment and afterward grows to consume wanted space. Illustration of such a substance is mineral 18-99 (glycerol mono-oleate).

B) Diffusion:

This technique includes dispersion of solvent from polymer arrangement into side by tissue and results in precipitation of polymer grid. N-methyl pyrrolidone (NMP) is one of the helpful solvents for such system.

4. In-situ gel due to chemal reactions:

A) Enzymatically cross linking:

In situ development catalysed by common catalysts has not been concentrated generally however it has a few favourable circumstances over chemical and photochemical approaches. For instance, under physiologic conditions, an enzymatic cycle works productively without need for possibly unsafe chemicals like monomers and initiators. Changing the number of enzymes gives an advantageous system to controlling the rate of gelling, which permits the combination to be infused before gel formation²².

B) Photo polymerization:

Photo-polymerization is typically used to convert biomaterials in situ. When electromagnetic radiation is used to create gel, a monomer or reactive macromer and initiator mixture is injected into a tissue location²³. Since acrylates and related polymerizable groups photo-polymerize quickly in the presence of the right photo initiator, they are frequently used as the polymerizable groups on individual monomers and macromers. Particularly visible and UV wavelengths are used. Short-wavelength UV isn't usually used because it can only penetrate a little amount of tissue and is hazardous.

When photo-polymerizable structures are introduced to the ideal location through infusion, they are photocured in place with the aid of fiber optic linkages and then release the medication over a delayed period of time. The photo-responses provide rapid polymerization rates at physiological temperatures. According to Sawhney et al., a tissue-reaching substance and regulated delivery transporter is a photo-polymerizable, biodegradable hydrogel²⁴.

C). Ion cross linking:

There are some ion sensitive polysaccharides, for example, gellan gum, gelatine, sodium alginate which go through phase change in presence of different ions. An anionic polysaccharide, Gellan gum, goes through in situ gelling in event of mono-and divalent cations, for example Ca2+, Mg2+, K+ and Na+.

Drug release from hydrogels:

Diffusion conyrolled mechanism:

A) Matrix system:

The powerful expert spreads the same as the power of an idle hydrogel grid that is as easily damaged. The release of drug depends on:

· The separation of water in the matrix is followed by the dissolution of the tree and finally the dispersal of the dissolved tree from the matrix.

· Polymers interact with drugs that lead to moderate drug release.

· The size of a hydrated matrix is considered the length of the tree path. If we consider the polymer matrix as inert and drug release is controlled by distribution, then the drug release rate can be defined by the Higuchi equation.

B) Reservior system:

The drug is contained in a substance (often referred to as a reservoir) surrounded by a hydrogel regulating membrane that allows the spread of drugs. As the system interacts with water, water evaporates from the system and dissolves the drug, and drug transport (from the cavity through the outer polymer membrane) occurs with the removal of another membrane interface and gradient-driven distribution in thermodynamic activity²⁵. Drug trafficking can be defined by Fick's first law, if the activity of the drug in the pool remains constant and unlimited immersion conditions are maintained, then the rate of drug release may continue unchanged because it depends on fluid availability and will be independent of time, so zero-order kinetics can be achieved. When the drug is finished, the discharge gradually increases with concentration following the first order of kinetics. These types of drug delivery systems are used to deliver an active agent through oral channels.

Swelling controlled mechanism:

C) Solvent activated system:

Occurs when drug distribution is faster than hydrogel inflammation²⁶. When a hydrogel is placed in an aqueous solution, water molecules will enter the polymer network taking up some space, and as a result other network metals will begin to multiply, allowing other water molecules to enter the network. However, inflammation is not an ongoing process; the strength of the connected network or physically connected will balance the network's constant advice to prevent its destruction. For example, extracting drugs from (HPMC) hydrogel is usually done using this method.

D) Osmatic swelling:

In hydro gels, the total inflammatory pressure of the gel may be related to volume fraction, free network volume, and cross-link density while independent of gel pH and inflammatory time.

Chemically controlled mechanism:

It can be categorized by type of chemical reaction that occurs during drug release within the delivery matrix in:

a) Pendant chain system is the most common response when the drug is firmly attached to the polymer core. The bond between the drug and the polymer has a lab and can be broken by hydrolysis or enzymatic degradation and the drug is released.

b) Erodible drug delivery system in which the release of a drug is controlled by melting during erosion or severe damage to the polymer spine where the drug is distributed to the moving systems. Depending on whether the dispersion or degradation of the polymer controls the rate of extraction²⁷, the drug is dispensed according to various methods; if polymer erosion is much slower than drug dispersion through polymer, drug extraction can be treated as a controlled control process. While the dispersion of wood from the polymer matrix is slow, but degradation of polymer or erosion is a prominent method, for example erodible hydrophobic polymers.

Polymers Used in in-situ Gel:

SODIUM ALGINATE:

Sodium alginate is a polymer of natural origin. Chemically, sodium alginate is an alginic acid salt, which contains β-D mannuronic acid and α-L-glucuronic acid residues linked to 1, 4-glycosidic links. A solution of alginates in water forms solid files in the presence of di- or trivalent ions (e.g., magnesium and calcium ions). Sodium alginate is widely used to prepare a gel-based solution, delivery of drugs, peptides and proteins. Alginate salt is considered to be highly desirable due to its decaying and non-toxic nature, with additional adhesive properties²⁸. This has shown that alginates form cohesive structures where the ionic radical beneath is low. Sodium alginate used in pharmacies as a water-soluble polymer is very useful in the continuous preparation of oral administration fluids, acting as a stabilizing agent; viscosity-increasing agent.

PECTIN:

These plant origins anionic properties can be divided into two polysaccharides separated by a cell wall of many plants and contain - (1-4) -D-galacturonic acid residues. Pectin counteracts gel formation in the presence of moderate; strong gel is produced. Pectin is a complex polysaccharide that binds to D- galacturonic acid residues mainly in the series (1-4). On the basis of methyl esterification of galacturonic acid, there are two different types of pectin-high methoxy and low methoxy gelation. Maturity of high methoxy pectin is usually possible at pH <3.5. Low-methoxy pectin is loaded with calcium ions and does not depend on the presence of acid or solid content.

GELLAN GUM:

Gellan gum is a water-soluble anionic polysaccharide, commercially known as Phytagel or Gel rite. Gellan gum (FDA approved) prescribed by Sphingomonas elodea (Pseudomonas elodea) and chemically anionic deacetylated polysaccharide duplicating tetra saccharide units composed of β-D-glucuronic acid (1 unit), α-L-rhamn (1 unit) and β- D-glucose residues (2 units). Gellan gum undergoes gel formation due to temperature changes or due to the presence of cations (e.g., Na + K +, Ca2 + and Mg2 +). Gellan gum can be used in pharmacies as a water-soluble polymer that serves as a potential carrier for a wide variety of solid oral float types.

XYLOGLUCAN:

Plant-based polysaccharide found in tamarind seeds. Chemically, this polysaccharide is composed of a series of (1-4) -Dglucan with units (1-6) -D of xylose as particles with partial selections (1-2) - D- galactoxylose. Xyloglucan composed of heptasaccharide, octasaccharide, and nonasaccharide oligamers, differing in the number of galactose side chains. Although xyloglucan itself does not use gel, xyloglucan solutions that have been slightly degraded by galactosidase show a sol to gel in the hot spot²⁹. It is used for rectal, oral and ocular delivery of pilocarpine and timolol.

XANTHAN GUM:

Xanthan gum is a high molecular weight extracellular polysaccharide produced by Xanthomonas campestris. Long chain polysaccharide with a number of chains on the side of trisaccharide. The main chain contains two units of glucose. The side chains are made up of two units of mannose and one unit of glucuronic acid. Xanthan gum can form a strong gel when mixed with well-charged polymers. This gum creates a weak structure in water, which creates high viscosity solutions at low concentrations.

PlURONICF-127:

Poloxamers or Pluronic (marketed by BASF Corporation) is a series of difunctional copolymers available for sale in non-ionic organisms. They consist of a central block of hydrophobic polypropylene oxide surrounded on both sides by blocks of hydrophilic polyethylene oxide. Due to the PEO / PPO ratio of 2: 1, when these molecules are concentrated in aqueous solvents, they form micellar structures beyond the critical micellar concentration. They are considered to be PEO-PPOPEO copolymers. Pluronic triblock copolymers are available in various stages of body composition and molecular weight. Depending on the body position of the assigned marks, such as F of flakes, P paste, L liquid. Pluronic‟s or Poloxamers are also prone to temperature changes with temperature changes.

CHITOSAN:

Chitosan is a natural and flexible polymeric polymer derived from the alkaline deacetylation of chitin. It is rotten, hot and non-toxic. Chitosan is a biocompatible-based cationic polymer, which is constantly dispersed in strong solutions up to a pH of 6.2³⁰. Neutrality of an aqueous solution of chitosan to a pH above 6.2 leads to the formation of a hydrated gel-like precipitate. The solution of pH gelling cationic polysaccharides is converted into powerful gel-based pH solutions forming a gel by adding polyol salt, without chemical modification or bonding.

CARBAPOL:

Carbopol is a pH-based polymer, which forms a small gel of viscosity in alkaline pH but remains in solution form at acidic pH. HPMC is used in combination with Carbopol to transfer viscosity to the Carbopol solution while reducing the acidity of the solution. Various water copolymers change in melting and changes in ambient temperature.

GENERAL METHOD OF IN-SITU GEL PREPARATION:

The following Fig illustrates the general method of preparing the in-situ gelling solution.

Applications of In-situ gelling system in drug delivery systems:

Oral drug delivery system:

pH-sensitive hydro gels have a greater use in local drug delivery in specific areas of the GI tract. Hydro gels are made up of a variety of cross-linked elements in PEG and PAA that are approved for the preparation of silicone microspheres, producing prednisolone in the centre of the abdomen or showing the protective properties of the abdomen³¹. Cross-linked hydro gels have rapid inflammation under high pH conditions, while other polysaccharides such as amidated pectin's, inulin and guar gum are investigated with the aim of improving the potential drug delivery system. The formation of gellan and sodium alginate both contain a complex calcium ion that undergoes a gelation process by releasing these ions into the acidic environment of the stomach.

Ocular drug delivery system:

In the ocular delivery system natural polymers such as alginic acid, inulin, and xyloglucan, inulin is widely used³². In the local system the delivery of various ophthalmic compounds such as independent drugs, anti- inflammatory agent & antimicrobial agent, are used to relieve intra ocular intolerance in glaucoma. The standard delivery system is often found to be unavailable and therapeutic response due to excessive fluid retention and energy leading to the rapid elimination of the drug in the eye and therefore, overcoming the problem of ophthalmic bioavailability in-situ gel was performed. Improving bioavailability viscosity enhancers such as Carboxy Methyl Cellulose, Hydroxy Propyl Methyl Cellulose, Carbomers, Poly Vinyl Alcohol is used to improve the viscosity of the composition to extend the earlier stay and increase availability, which is easier to do. Entry enhancement as a protective, deceptive agent, surfactants used to improve corneal drug penetration.

Nasasl drug delivery system:

In the nasal in-situ gel system xanthan gum and gallan gum are used as in-situ gel polymers Momethasone furoate used to test its effectiveness in the treatment of allergen rhinitis. Animal studies are used to model allergen rhinitis and the effect of in-situ gel on nasal antigen signals in rat awareness. In-situ gel has been found to prevent an increase in nasal symptoms compared to nosonex marketing adjustments (Momethasone furoate suspension 0.05%).

Rectal and vaginal drug delivery system:

Rectangular line can be used to deliver a wide range of synthetic drugs such as liquids, semisolids (oils, creams and bubbles) and solid dosage forms (suppositories). Acetaminophen is an anti-inflammatory drug made as rectal in situ gel using polycarbophil and poloxamer F188 and poloxamer 407 as a synthetic polymer that forms situ gelling liquid suppository which is considered to be polymers made to form situ gelling liquid suppository which is considered a method. active increases the availability of natural resources³³.

Injectable drug delivery system:

In this drug delivery system, it has also been developed as an gel available over the past decade due to its use as no surgical procedure is required and patient compliance. Many synthetic polymers and block copolymers are used in the construction of injectable in situ gel injection. One example of an anti- inflammatory drug is Bupivacaine which is formulated as an injection in situ gel using poly (D, L-lactide), poly (D, L-lactide coglycolide) and PLGA as the polymer shows to extend the drug action in gel conditions.

Dermal and transdermal drug delivery system:

Pluronic F127 in heat-releasing gel has been tested as an Indomethacin administration vehicle. In-vivo research suggests that a 20% w/w aqueous gel may be used as an effective base for drug topical administration. The combination of iontophoresis and chemical enhancements has led to the development of insulin permeation interactions.

Evaluation and characterization of in Situ gel:

Following parameters are used for evaluation and characterization of in situ gel:

CLARITY:

The clarity of the solution made is determined by visual inspection under a black and white background.

TEXTURE ANALYSIS:

The durability and consistency of the hydrogel were tested using a texture analyzer that showed syringe ability of sol so that the structure could not be easily controlled in vivo. High values of adhesion of gels are required to maintain close contact with the surface.

PH OF GEL:

The composition is taken with a beaker and 1ml NaOH added by subtraction by continuous stirring, the pH is measured using a pH meter.

SOL-GEL TRANSITION TEMPERATURE AND GELLING TIME:

In in-situ systems with thermosensitive polymers, sol-gel transition temperature can be defined as the temperature at which the sol meniscus phase transformation is first observed when stored in a sample tube at a certain temperature and then heated to a certain degree³⁴. The formation of the gel is indicated by the absence of meniscus movement in the tilt of the tube.

GEL STRENGTH:

This parameter was tested using a Rheometer. Depending on the gelling agent injection machine used, the specified amount of gel is prepared in the beaker which forms sol form. This beaker-containing gel is elevated to some degree, so it presses a little investigation into the gel. Changes in the load on the probe are measured as a function of the depth of the immersion of the probe under the surface of the gel.

RHEOLOGICAL STUDIES:

This is one of the most important parameters to test for gel gels. The viscosity and rheological properties of in gel delivery systems are tested using a Brookfield rheometer, or other viscometer such as Ostwald's viscometer. The viscosity of in situ gelling systems should be such that there are no difficulties encountered during their patient management, especially in parental and eye care. The construction should have a viscosity of 5-1000 mPas.

High Performance liquid Chromatography:

The HPLC system when used in the reversed phase mode. Analysis is performed in the full Nova pack C18 column (150 mm long X 3.9 mm i.d)

DRUG POLYMER INTERACTION STUDY AND THERMAL ANALYSIS:

Collaborative studies were performed with Fourier Transform Infra-Red (FTIR) spectroscopy. During the gelation process, the nature of the interaction energy can be determined using this method using the KBr pellet method. Thermo gravimetric analysis (TGA) can be used in an in-situ gelling system to determine the percentage of water in a hydrogel. Different scanning calorimetry (DSC) were used to determine whether there was a change in thermograms compared to the pure active ingredients used for gelation.

IN VITRO DRUG RELEASE STUDIES:

In-situ gel formulations administered by oral, ocular or rectal doses, drug extraction studies were performed using a plastic dialysis cell. The cell is made up of 2 and a half cells, a donor room and a reception room and both rooms are separated with the help of cellulose membranes. The sol form of the composition is arranged in the donor room. The assembled cell is then moved horizontally to the incubator. The total amount of receptor solution is analyzed in drug release using analytical methods. In situ gel injections, the formulation is arranged in containers containing the receiving media and placed in a water- free shaker bath at the required temperature and temperature measurement, the samples are periodically withdrawn and analyzed.

ANTIMICROBIAL ACTIVITY:

Antimicrobial research was performed to determine the biological activity of sol-gel-system antibodies. This is done using the agar diffusion medium using the 'Cup Techniques'. The microbial growth rate is measured by a combination of antibiotics and compared with those produced with a known concentration of standard antimicrobial formulations and a microbial assay serial dilution method is used³⁵.

STERLITY TESTING:

Sterility tests were performed for each 1996 IP. The formulation is applied for a period of not less than 14 days at 30-35 ° C in this liquid thioglycolate medium to detect bacterial growth and at 20-25 ° C in Soya casein digest to detect fungal growth in formulation.

ACCELERATED STABILITY STUDIES:

The formulation is replaced by amber-coloured containers and is sealed with aluminium foil in a fast-paced course at 40 ± 2°C and 75 ± 5% RH according to the International Conference of Harmonization (ICH) guidelines. The sample is analyzed monthly for clarity, pH, gelling strength, drug dosage, drug content, rheological testing and in vitro elimination.

CONCLUSION:

In conclusion, the primary requirement of a successful controlled release product focuses on increasing patient compliance which the in-situ gels for controlled release of various drugs provides a number of advantages over conventional dosage forms. Sustained and prolonged release of drug, good stability and biocompatibility characteristics make the in-situ gel dosage forms very reliable. Use of biodegradable and water-soluble polymers for the in-situ gel formulations can make them more acceptable and excellent drug delivery system

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Received on 06.11.2023 Modified on 01.12.2023

Asian J. Pharm. Tech. 2024; 14(1):79-86.

DOI: 10.52711/2231-5713.2024.00015