In-Situ Gel: A Smart Drug Delivery System for Mouth Ulcer Pain Relief

An ulcer that develops on the oral cavity's mucous membrane is known as a mouth ulcer, oral ulcer, or mucosal ulcer. These are uncomfortable round or oval mouth sores that mainly develop on the inside of the lips or cheeks. Although Mouth ulcers are a common condition and can arise from a variety of causes and in conjunction with numerous illnesses, there is typically no significant underlying cause. Nutritional deficiencies, particularly in iron and vitamins B12 and C, poor dental hygiene, infections, stress, indigestion, mechanical injury, food allergies, hormonal imbalances, skin conditions, etc., are common causes of mouth ulcers. Aphthous ulcers, another name for mouth ulcers, can hurt when you eat, drink, or wash your teeth.⁽¹⁾ The most common oral mucosal illness in humans, recurrent aphthous stomatitis, usually first manifests in childhood or adolescence and is also known as aphthous ulcers or canker sores. Aphthous ulcers are round or oval in shape, with a grayish yellow color that resembles a bowl encircled by mucosal inflammation. The non-keratinized oral mucosa, which includes the lips, buccal mucosa, bottom of the mouth, and therefore the ventral surface of the tongue, is where the ulcer typically develops inside the mouth.⁽²⁾ One of the most prevalent conditions in the population is oral illness. They have an impact on people's quality of life and pose a significant financial and health burden. Dental cavities, tooth loss, lip and oral cancer, and periodontal illnesses including gingivitis are the most common. The efficacy of pharmacotherapy is negatively impacted by the administered dosage type and the administration method.⁽²⁾

Figure No.1: Mouth ulcer

TYPES OF MOUTH ULCER:

Herpetiform ulcers: This kind of ulcer is made up of several dozen tiny, pinhead-sized lesions.⁽³⁾

Figure No.2: Herpetiform ulcer

Traumatic Ulcers: A traumatic ulcer is the most prevalent kind of ulcer and is acute in nature. Causes of traumatic ulcers are physical, thermal, or chemical trauma to the oral mucosa, which can be brought on by routine activities like brushing or flossing, sharp edges of teeth or dentures, or self-harm by the patient while under local anesthesia during a dental procedure. Most common causes of thermal burns are hot food or beverages like pizza, coffee, or tea, or by a heated dental instrument during a dental procedure.⁽³⁾

Figure No.3: Traumatic ulcer

Primary Herpetic Gingivostomatitis: Primary herpetic gingivostomatitis is the most typical oral sign of a herpes simplex virus (HSV) infection. Over 90% of cases that happen above the waist are caused by HSV-1. Infection with HSV-2 happens below the waist. HSV-2 is frequently cultured from oral sores as a result of varying sexual practices. With a high incidence between two and three years, Usually, the age of occurrence falls between six months and five years. Prodromal symptoms include irritability, anorexia, fever, and nausea.⁽³⁾              

Figure No. 4: Primary Herpetic Gingivostomatitis ulcer

Recurrent Aphthous Stomatitis (Canker sore): Hippocrates is credited with coining the term "aphthae," which comes from the Greek word "aphthi," which means "to set on fire" or "to inflame," to describe the agony associated with a common oral ailment at the time (possibly aphthous stomatitis). Common mouth ulcers have been linked to a number of etiological reasons, including immunological or endocrine disorders, bacterial and viral infections, dietary inadequacies, local damage, and hereditary factors. Some patients get recurrent aphthous stomatitis (RAS) when the cause is unclear. RAS is divided into three categories: herpetiform (10%), major (10%), and minor (> 70% of cases).These subcategories vary in their appearance, distribution, severity, and prognosis.⁽³⁾

Figure No.5: Recurrent Aphthous Stomatitis (Canker sore)

Traumatic Ulcerative Granuloma (Eosinophilic Ulcer of the Tongue) : Hippocrates is credited with coining the term "aphthae," which comes from the Greek word "aphthi," which means "to set on fire" or "to inflame," to describe the agony associated with a common oral ailment at the time (possibly aphthous stomatitis). Common mouth ulcers have been linked to a number of etiological reasons, including immunological or endocrine disorders, bacterial and viral infections, dietary inadequacies, local damage, and hereditary factors. Some patients get recurrent aphthous stomatitis (RAS) when the cause is unclear. RAS is divided into three categories: herpetiform (10%), major (10%), and minor (> 70% of cases). These subcategories vary in their appearance, distribution, severity, and prognosis.⁽³⁾

Figure No.6: Traumatic Ulcerative Granuloma

IN-SITU GEL:

The term "gel" comes from Gelu, which illustrates how liquid settles to create a semi-solid mixture. Gels consist of dispersions of tiny or large molecules in an aqueous liquid medium thickened with a gelling agent. They are transparent or translucent, non-greasy, semisolid systems. Gels may be a biphasic system or a single phase.⁽⁴⁾A growing number of in-situ forming systems for a range of biomedical uses, such as drug administration, cell encapsulation, and tissue repair, have been documented in the literature in recent years. These systems include of injectable fluids that can be minimally invasively injected into the body before they gel or solidify in the targeted tissue, organ, or bodily cavity.⁽⁵⁾ The insitu gel phenomenon is based on a medication formulation in a liquid solution that is transformed into a semi-solid mucoadhesive key depot. It enables the medication to be administered as a liquid or solution.⁽⁶⁾

IMPORTANCE OF IN-SITU GEL:

• Its special "Sol Gel transition" facilitates the controlled and extended release of the medication.
• It aids in lowering the frequency of drug administration to the body.
• A low dosage of the medication is necessary, and there won't be any adverse effects or drug accumulation.
• The drug's bioavailability will be higher.
• The in situ gel method reduces medication waste.
• Some unwanted side effects could arise from decreased systemic absorption of the medication discharged through the nasolacrimal duct.⁽⁷⁾

ADVANTAGES OF IN-SITU GEL:

• Sustained and regulated medication release.
• Easy administration of drugs.
• Increased comfort and compliance from patients.
• Reducing the frequency of doses and the toxicity of the medicine.
• Enhanced bioavailability.
• Utilizing natural polymers promotes biodegradation and biocompatibility.
• The structures of synthetic polymers are often well-defined and can be altered to produce acceptable functionality and degradation.
• In order to enable drug targeting, particularly across mucous membranes, for non-invasive drug administration, in situ gels can also be designed to be bio adhesive.⁽⁷⁾

DISADVANTAGES OF IN-SITU GEL:

• High fluid levels are necessary.
• When the medicine is in its sol form, it is more likely to degrade.
• Chances of stability issues brought on by deterioration of chemicals.
• Eating and drinking may be restricted for a few hours after taking the medication.
• There can be limitations on how much and how consistently drugs can be loaded into hydrogels, particularly for hydrophobic drugs.
• Reduced mechanical strength could cause the hydrogel to dissolve too quickly or to flow away from a specific local location.⁽⁷⁾

MECHANISM OF IN-SITU GEL:

Diffusion: The physical method known as Diffusion is employed in the formation of in-situ gels. This process involves the solvent from the polymer solution diffusing into the surrounding tissue, causing the polymer matrix to precipitate or solidify. N-methyl pyrrolidone (NMP) is a polymer that is frequently used to create in-situ gelling systems.⁽⁷⁾

Swelling: When substance absorbs water from their surroundings and expands to take up the desired space, in situ creation can also happen.⁽⁸⁾

Chemical reaction: Chemical reactions that can result in in situ gelation include enzymatic, photo-initiated, and precipitation of inorganic particles from supersaturated ionic liquids.

Ionic crosslinking: Phase transitions in polymers can occur when different ions are present. A subset of poly saccharides are classified as ion-sensitive. I-carrageenan primarily produces elastic gels in the presence of Ca2+, whereas k-carrageenan creates stiff, brittle gels in response to tiny amounts of K+. Commercially marketed as Gelrite, An anionic polysaccharide is gellan gum. that gels in situ when mono- and divalent cations such as Ca2+, Mg2+, K+, and Na+ are present. Divalent cations, particularly Ca2+, can induce the low-methoxy pectins to gel. Similarly, when divalent or polyvalent cations, such as Ca2+, are present, alginic acid gels because of its interaction with the guluronic acid block in alginate chains.⁽⁸⁾

Enzymatic cross-linking: The use of natural enzymes to catalyze in situ formation has not been thoroughly examined, but appears to have some benefits over chemical and photochemical approaches. For instance, an enzymatic process can function effectively in physiological settings without the use of potentially hazardous substances like initiators and monomers. Hydrogels with insulin-releasing capabilities have been used in intelligent stimuli-responsive administration devices. When blood glucose levels rise, cationic pH-sensitive polymers that contain immobilized insulin and glucose oxidase can swell, pulsatilely releasing the trapped insulin. The mixes can be administered prior to gel formation because varying the enzyme concentration also offers a practical way to regulate the rate of gel formation.⁽⁸⁾

Photo-polymerization: The in-situ gelling system is formed using electromagnetic radiation in the photo-polymerization process. Electromagnetic radiation can be utilized to create gel after injecting either a reactive macromere or monomer solution and intruder into a tissue location. The best polymers for photo polymerization are those that, when exposed to a photo initiator such as acrylate or a comparable monomer or macromer with a long wavelength (usually ultraviolet and visible), undergo dissociation by a polymerisable functional group. Due to their limited tissue penetration and potential biological injury, short wavelength ultraviolet light is not frequently used. This technique uses a ketone as the initiator for ultraviolet photo-polymerization, such as 2,2dimethoxy-2-phenyl acetophenone. In visible light systems, initiators such as camphor Quinone and ethyl eosin are employed.⁽⁸⁾

APPROACHES OF IN-SITU GEL:

There are some several Approaches used to obtain an in-situ gelation system.⁽⁹⁾

Temperature triggered in-situ gel: Temperature is the most widely used stimulus in in-situ gelling formulation for environmentally responsive polymer systems. Both in vitro and in vivo, the temperature change that is employed is simple to regulate and apply. Body warmth causes gelation in this system; external heat is not necessary. These hydrogels are liquid at normal temperature (20–25°C), but when they come into contact with bodily fluids (35–37°C), the temperature rises and causes them to gel. Three different kinds of temperature-induced systems exist. They are both positively and negatively thermosensitive, such as poly (nisopropylacrylamide) and thermally reversible polyacrylic acid. For instance, Tetronics, Plurionics, and Poloxamer. In this system, temperature-responsive or thermoresponsive polymers—which exhibit a sharp and abrupt change in their physical characteristics with temperature—are employed. There is a miscibility gap between these polymers at high and low temperatures, as well as an upper and lower critical solution temperature.⁽⁹⁾

Figure No.7: Temperature Triggered in-situ gel (Adapted and modified from reference no-7

pH-Triggered in-situ gel: In this system, pH variations cause gel formation. This technique uses pH-responsive or pH-sensitive polymers. These polymers have basic or acidic groups that react to variations in the natural pH by releasing or receiving proteins, which subsequently break down and release the medication. Although polyacrylic acid (PAA)-based polymers are also useful, many pH-sensitive polymers are based on carbopol, carbomer, or variants. Polyelectrolytes are the many polymers of ionizable groups. The presence of poly electrolytes in the formulation raises the pH outside, which causes the hydrogel to enlarge and create in situ gel.⁽¹⁰⁾

Figure No.8: pH-Triggered in-situ gel (Adapted and modified from reference no-7

Ion activated in-situ gelation: With this approach, a shift in the ionic strength causes the injected solution to gel.⁽¹¹⁾ The osmotic gradient across the gel's surface is thought to be the determining factor in the gelation rate. Gelrite or gellan gum, hyaluronic acid, alginates, and other polymers exhibit osmotically driven gelation.^(12),(13) Monovalent or divalent ions like Na + and Ca+ cause the sol-gel transition process. A few other elements have an impact on the phase transition are the polysaccharide concentration, the preparation temperature, and the type and concentration of cations. Gelrite was chosen to create the in-situ gel.⁽¹⁴⁾

Figure No.9: Ion activated in-situ gel (Adapted and modified from reference no-7)

IDEAL CHARACTERISTICS OF POLYMERS FOR PREPARATION OF IN SITU GEL:

• The polymer has to be able to stick to the mucosal membrane.⁽¹⁵⁾
• It must not be harmful and should exhibit high compatibility.⁽¹⁵⁾
• When applied to the ulcer, the polymer should change from a liquid (sol) to a gel state at body temperature, which is approximately 37°C, to provide a protective barrier.⁽¹⁶⁾
• To preserve its integrity and functioning, the polymer must remain stable within the oral cavity's physiological pH range.⁽¹⁶⁾
• When the polymer comes to contact with the oral mucosa, it should swiftly change from a sol to a gel, relieving discomfort and irritation.⁽¹⁶⁾

POLYMERS USE FOR PREPARATION OF IN SITU GEL:

Pectin, xyloglucan, and gellan gum are natural polymers utilized in in situ forming oral drug delivery systems. Pectins represent a class of polysaccharides characterized by a polymer backbone predominantly consisting of α-(1-4)-D-galacturonic acid residues. Tamarind seeds contain xyloglucan; a polysaccharide made up of a (1-4)-β-Dglucan backbone chain with (1-6) (1-2)-β-Dgalactoxylose partially substitutes the -α-D xylose branches. Pseudomonas elodea secretes gellan gum, an anionic deacetylated exocellular polysaccharide containing a tetrasaccharide repeating unit consisting of one α-L-rhamnose, one β-D-glucuronic acid, and two β-D-glucuronic acid residues. Gellan gum is commercially marketed as Gelrite TM or Kelcogel TM. It has a propensity to gel, which can be caused by cations or temperature.⁽¹⁷⁾

• Pectin: The cell walls of terrestrial plants include pectin, an anionic polysaccharide hydrogel, also called as poly (1,4-galacturonic acid). In recent years, it has gained attention from the biomedical community despite its historical use as a gelling agent in the food business. When it comes to biodegradation, pectin aerogels outperform wheat starch, which is the industry standard.⁽¹⁸⁾
• Xyloglucan:      Xyloglucan (XG), a neutral polysaccharide, has been the focus of numerous investigations due to its mucoadhesivity, and other novel XG-based formulations have made it to the clinical trial stage, proving its advantageous effects as a mucosal protector. By adhering to mucosal membranes, XG forms physical barriers that prevent the spread of bacteria, allergies, and undesirable species. The FDA has approved XG, a nonionic polysaccharide that is thought to be fully biocompatible and biodegradable, as a food additive and as a medicine delivery excipient. Afzelia africana, Tanacetum ptarmiciflorum, Detarium senegalense, Detarium microcarpum, and Hymenaea courbaril (jatoba) are only a few of the several edible plants that contain XG. Commonly grown species like Lactuca sativa (lettuce) and Daucus carota (carrots) are also included.⁽¹⁹⁾
• Poloxamer 188: A hydrophobic chain of polypropylene oxide (PPO) in the middle and two hydrophilic chains of polyethylene oxide (PEO) on either side make up Poloxamer 188 (P188), a nonionic triblock copolymer.⁽²⁰⁾
• Poloxamer 407: Poloxamers are composed of two hydrophilic blocks of polyethylene oxide (PEO) along with tri block co polymerson either side of a hydrophobic polypropylene oxide (PPO) center block. Among these copolymers, poloxamer 407 is a non-ionic surfactant that exhibits reversible gelation characteristics above a specific temperature and polymer concentration.⁽²¹⁾
• Carbopol 934P: Carbopol 934P is a cross-linked polyacrylic acid polymer with a high molecular weight. In pharmaceutical formulations, it is a frequently utilized excipient, especially for topical and oral applications. Because of its high viscosity, carbopol 934P can be used as a thickening agent. Carbopol 934P dissolves in alkaline medium but is insoluble in acidic ones. Because of its mucoadhesive qualities, carbopol 934P can be used in formulations meant for mucosal application.⁽²²⁾

POLYMER USE FOR ORAL IN-STU GEL PREPARATION: ⁽²³⁾ 

Table: 1 Various natural and synthetic Polymers and their use

Table: 2 Polymer-Drug Combinations and Their Route of Administration

Cold Method:

Curcumin's carbopol–poloxamer gel was made using the cold technique. Here Curcumin is active pharmaceutical ingredients. Using a magnetic stirrer, carbopol P934 (1% w/v) was first dissolved in deionized water. After the solution had completely dissolved, it was chilled in an ice bath before gradually adding 30% w/v pluronic F127 while stirring constantly. The liquid was refrigerated at 4 °C for 24 hours in order to guarantee full soaking and eliminate any trapped air bubbles. Curcumin powder, either 1% or 2% w/w, or curcumin that had been dissolved in a suitable amount of PEG400 (140 mg/ml) or ethanol (100 mg/ml) was gradually added to the prepared polymer solution while being stirred in an ice bath. After Each sample was then put into an amber bottle and kept in a refrigerator. The formulation for the in-situ gel that contained Curcumin dissolved in ethanol was placed on stirrer overnight to allow the ethanol to evaporate before being stored in a refrigerator.⁽³¹⁾

General Method of In-situ gel Preparation: ⁽³²⁾

Figure 10: General Method of In-situ gel Preparation Adapted and modified from (Musmade N., et.al 2019)