Oral Gels in Drug Delivery: A Patient-Friendly Approach to Enhancing Therapeutic Efficacy

Oral gels are semi-solid dosage forms specifically designed to improve drug delivery within the oral cavity and gastrointestinal tract. They are characterized as semi-rigid systems in which the mobility of a liquid medium is restricted by a three-dimensional network of polymers or colloidal particles, resulting in desirable properties such as muco-adhesion, spread-ability, and localized or systemic drug delivery potential. The term gel, derived from “gelatin” and rooted in the Latin gelu (frost) and gelare (to freeze), reflects their transformation from a liquid to an elastic, solid-like matrix capable of entrapping fluids. Historically, gels were recognized as a distinct pharmaceutical system in the late 19th century, when formulations were classified based on their physical and phenomenological characteristics.[1]

According to the United States Pharmacopeia (USP), gels are defined as semisolid systems containing either suspensions of small inorganic particles or dispersions of large organic macromolecules in a liquid medium. They may exist as two-phase systems, where discrete particles form a colloidal network or as single-phase systems, in which polymers are uniformly distributed without visible boundaries. For oral gels, water and hydroalcoholic solutions are the most widely used dispersion media.[2]

From a pharmaceutical standpoint, oral gels offer distinct advantages over conventional dosage forms. Their viscosity and mucoadhesive properties prolong residence time in the oral cavity, improve drug absorption, sustain therapeutic action, and enhance patient compliance. Many formulations exhibit reversible sol–gel transitions, allowing a switch between liquid and semisolid states under specific physiological conditions, while others form irreversible networks that improve stability. The physical appearance of oral gels may vary from transparent to turbid depending on the drug and excipients, with gelling agents typically employed in concentrations of 0.5–2.0%. Despite such small quantities, these agents impart a broad range of rheological and mechanical properties, making gels highly versatile carriers for drugs including antifungal, antimicrobial, analgesic, anti-inflammatory, and more recently, antidiabetic agents.[3]

Evolution of Oral Gels in Drug Delivery

The development of oral gels as pharmaceutical systems has undergone significant transformation over the last century. Originally, gels were limited to topical, dental, and cosmetic applications, where their semi-solid consistency, spreadability, and ease of local application were valued. With advances in polymer science and colloidal chemistry, their potential as carriers for oral and systemic drug delivery gradually emerged. [4,5]

1. Early Stage (Topical & Dental Applications): Oral gels were initially used for local treatment of infections, inflammation, and pain within the oral cavity, such as antifungal (clotrimazole gels) or analgesic gels. [6,7]
2. Expansion to Systemic Delivery: The introduction of biocompatible polymers (e.g., carbopol, hydroxypropyl methylcellulose) allowed gels to be adapted for oral administration of drugs intended for systemic absorption. [8,9]
3. Mucoadhesive Gels: By the late 20th century, research shifted toward mucoadhesive formulations that adhered to oral or gastrointestinal mucosa, improving residence time and bioavailability. This was especially valuable for drugs with poor solubility or rapid degradation.[10]
4. In-situ Gelling Systems: The next step was in-situ gels, which are administered as liquids but transform into gels under physiological triggers such as pH, ionic strength, or temperature. These systems offered better patient compliance and controlled release.[11]
5. Smart/Stimuli-Responsive Gels: Recent innovations focus on responsive gels that can react to external or internal stimuli (e.g., pH-sensitive, temperature-sensitive, enzyme-sensitive, or glucose-sensitive). These systems have opened opportunities for precision medicine, particularly in chronic conditions such as diabetes. [12,13]

Table 1 : Routes of Administration and Delivery Pathways for Oral Gels [14,15,16]

The rigidity and stability of oral gels are primarily derived from the three-dimensional network formed by gelling agents. This network results from the interconnection of particles, and its structural characteristics depend on both the nature of the gelling agent and the type of intermolecular forces involved.[17]

In oral gels, hydrophilic colloids can exist either as spherical units, aggregates of smaller molecules, or as long polymeric chains. These components interconnect to create a gel matrix through different arrangements, such as entangled polymer chains or ordered crystalline alignments. The degree of cross-linking and organization directly influences the viscosity, spreadability, and drug release properties of the formulation.[18]

The interactions that stabilize the gel framework vary in strength, ranging from strong covalent linkages (as in certain inorganic gels like silica-based systems) to weaker forces such as hydrogen bonding, ionic interactions, or van der Waals attractions. In gels dominated by weaker interactions, a minor increase in temperature can disrupt the structure and lead to liquefaction. This property is particularly important in designing oral gels, as it determines their thermal stability, shelf-life, and patient acceptability.[19]

Figure 1: shows different types of gel network structures, including spherical particle aggregates, rod-like frameworks, crystalline junctions, and covalent junctions.

Advantages of Gels: [20,21,22]

1. Improved Patient Compliance easy to administer, especially for pediatric, geriatric, and dysphagic patients.
2. Controlled Drug Release can sustain or localize drug release depending on the gel matrix (physical or chemical network).
3. High Stability of API protects sensitive drugs (e.g., peptides, proteins) from degradation in liquid solutions.
4. Better Bioavailability enhances solubility and absorption of poorly water-soluble drugs.
5. Ease of Formulation simple preparation with biopolymers (e.g., polysaccharides, cellulose derivatives).
6. Non-greasy & Pleasant Texture preferred over ointments and creams in topical use.
7. Targeted Delivery can adhere to mucosal surfaces (buccal, oral, vaginal) and provide site-specific action.
8. Reduced Side Effects lower systemic absorption in topical/oral gels compared to oral solid dosage forms.

Disadvantages of Gels: [23,24,25]

1. Limited drug loading not suitable for drugs requiring high doses due to solubility and viscosity constraints.
2. Physical instability prone to dehydration, shrinkage (syneresis), or microbial contamination during storage.
3. Chemical instability some gels are sensitive to pH, temperature, or ionic strength, altering drug release.
4. Short residence time in oral gels, rapid dilution or swallowing may reduce contact time with mucosa.
5. Irritation potential certain gelling agents or preservatives may cause irritation/allergic reactions.
6. Sterility issues aqueous gels can support microbial growth, requiring preservatives or sterile handling.
7. Viscosity variation environmental conditions (temperature, ionic content) can alter gel consistency.
8. Not suitable for all drugs poor choice for lipophilic drugs unless modified with surfactants or cosolvents.

Key Properties of Gels: [26,27,28]

1. Network Structure

The firmness and rigidity of gels arise from the three-dimensional network formed by interconnected particles of the gelling agent. The type of particles and the forces linking them whether physical (hydrogen bonding, van der Waals) or chemical (covalent cross-links) determine the mechanical strength, elasticity, and overall properties of the gel.

2. Swelling Behavior

Gels can absorb liquids and expand in volume, which represents the initial stage of gel-solvent interaction. When a solvent penetrates the gel matrix, the original gel-gel interactions are replaced by gel-solvent interactions. The extent of swelling is often restricted by cross-linking within the gel network, which prevents complete dissolution. Swelling is maximized when the solvent's properties closely match the gelling agent’s solubility characteristics.

3. Syneresis (Contraction of Gel)

Over time, gels may undergo shrinkage, releasing interstitial fluid to the surface a phenomenon known as syneresis. This occurs in hydrogels, organogels, and inorganic gels. The process is influenced by polymer concentration, pH, electrolyte levels, and relaxation of elastic stresses formed during gel setting, which reduces the available space for solvent, forcing its expulsion.

4. Ageing

Gels are dynamic systems and may continue to change after initial formation. Ageing refers to slow, spontaneous structural rearrangements in the gel, resulting in a denser network of gelling agent over time. This process resembles the initial gelation and can lead to gradual loss of free fluid from the gel matrix.

5. Rheological Properties

Gels typically show non-Newtonian, pseudoplastic flow behavior, where viscosity decreases under increasing shear stress. In particulate gels, applied stress disrupts interparticle associations, while in polymer-based gels, macromolecules align along the direction of flow, reducing internal resistance. This property is crucial for processing, application, and ease of administration.

6. Transparency

Many gels exhibit optical clarity due to uniform dispersion of gelling agents and solvents, which can enhance patient acceptability and allow visual assessment of homogeneity or phase separation.

7. Adhesiveness

Gels often possess mucoadhesive or surface-adhesive properties, allowing them to adhere to mucosal membranes (oral, buccal, vaginal) or skin, which facilitates localized drug delivery and prolongs residence time.

Classification of Gel:[29,30]

Table 2: Classification of Gels Based on Composition, Cross-linking, and Application.

In oral gel formulations, gel-forming agents play a crucial role in establishing a stable semisolid structure when dispersed in a liquid medium. These agents can be hydrophilic natural hydrocolloids or synthetic polymers, which form a three-dimensional network that provides viscosity and consistency without making the gel overly stiff. Natural polymers like fenugreek gum, xanthan gum, and tragacanth are widely used for their biocompatibility, mucoadhesive properties, and ability to control drug release in the oral cavity.

Synthetic polymers such as carbomers (cross-linked acrylic acid derivatives) and hydroxypropyl methylcellulose (HPMC) are frequently employed due to their excellent thickening efficiency across a broad pH range, ease of formulation, and reproducible gel properties. Even at low concentrations, these polymers impart a smooth semisolid texture, improving the gel’s residence time on oral mucosa and enhancing patient compliance. Additionally, gelling agents help maintain uniform dispersion of the active pharmaceutical ingredient, prevent sedimentation, and contribute to controlled or sustained release of the drug at the site of action.

Table 3: Natural gelling agents used in pharmaceutical formulations.

Semi-synthetic polymers, particularly cellulose derivatives, are extensively utilized in pharmaceutical and cosmetic formulations due to their versatile physicochemical and mechanical properties. These derivatives are primarily classified into cellulose ethers and cellulose esters, each exhibiting distinct solubility and functional characteristics. Cellulose derivatives are valued for their uniform molecular arrangement, surface activity, film-forming ability, and resistance to oxidation, biodegradation, and hydrolysis. Cellulose ethers, such as methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, and sodium carboxymethyl cellulose, are water-soluble and widely applied as gelling agents, bioadhesives, stabilizers, and thickeners. In contrast, cellulose esters, including cellulose acetate, cellulose acetate phthalate, and cellulose acetate butyrate, have limited water solubility and are mainly used for controlled-release coatings and protective films. Compared to natural gelling agents like starch, acacia, sodium alginate, agar, and gelatin, cellulose derivatives are less susceptible to microbial contamination, making them ideal for semisolid preparations such as gels, creams, ointments, and shampoos. Their stability, adaptability, and broad applicability have established them as essential excipients in both pharmaceutical and cosmetic industries.[39]

Table 4: Semi-synthetic polymer used in pharmaceutical formulation

Carbomer, a member of the Carbopol family, is one of the most widely used synthetic polymers in gel formulations. Introduced in the 1950s, carbomers are available as powdered substances with high bulk density and are typically used to prepare aqueous gels with an acidic pH of around 3. When the pH is increased to 5–6, carbomer dispersions swell significantly and achieve high viscosity, ranging from 0 to 80,000 centipoise, depending on concentration and polymer grade. These polymers can expand several times their original volume upon hydration, providing efficient gel formation and stability. Other commonly used synthetic gelling agents include poloxamers, polyacrylamides, and surfactant-based polymers, which contribute to the rheological control, spreadability, and structural integrity of gel products.[50]

Table 5: Synthetic polymer used in pharmaceutical formulation.

Hydrogels:

Hydrogels are three-dimensional polymeric networks capable of absorbing and retaining large amounts of water while remaining insoluble in aqueous solutions due to physical or chemical cross-linking between polymer chains. Hydrophilic hydrogels possess unique physicochemical properties that make them highly suitable for biomedical applications and drug delivery systems, unlike hydrophobic polymers such as poly(lactic acid) (PLA) or poly(lactide-co-glycolide) (PLGA), which exhibit limited water absorption. Hydrogel formation usually occurs at room temperature without the need for organic solvents. They are further distinguished by their ability to undergo in situ gelation and encapsulate cells or therapeutic agents. Depending on the source of the polymer, hydrogels can be derived from either natural or synthetic materials.[58]

Organo gels

Organo-gels are semisolid systems in which the continuous phase is a non-aqueous solvent. Examples include Plastibase (a formulation of low molecular weight polyethylene dissolved in mineral oil and cooled) and dispersions of metallic stearates in oils. Structurally, organo-gels are thermo-reversible, non-crystalline materials composed of an interconnected organic liquid phase, which may include mineral oil, vegetable oil, or other organic solvents. Their rheological and stability properties largely depend on the solubility and molecular interactions of the gelators. Organo-gels are widely explored for applications in pharmaceuticals, cosmetics, food, and industrial products. In some cases, undesirable thermo-reversible gels may form, such as wax crystallization in crude petroleum.[59]

Xerogels:

Xerogels are solid forms of gels obtained after the removal of solvent from the gel matrix, usually through evaporation or heating. They possess small pore sizes (1–10 nm), high surface areas (150–900 m²/g), and moderate porosity (~25%). Common examples include dried gelatin, acacia, tragacanth, cellulose derivatives, and polystyrene. Although xerogels generally retain their overall structure, they often undergo significant shrinkage during drying, which can lead to cracking and brittleness. When exposed to higher drying temperatures, the porous network collapses further, converting the gel structure into a dense, glass-like material.[60]

Aerogels:

Aerogels are lightweight, highly porous materials formed when the liquid component of a gel is replaced with gas under supercritical drying, preventing network shrinkage. They exhibit high porosity, large surface area, and excellent thermal insulation properties, making them useful in pharmaceuticals, catalysis, and biomedical applications.[61]

Methods of Gel Preparation:

Gels can be produced by a variety of techniques, depending on the type of polymer, solvent system, and desired final properties. While many gels are prepared at room temperature, some polymers require specific conditions such as thermal treatment, cross-linking, or solvent exchange. The major methods include thermal variation, flocculation, chemical reaction, solvent exchange, diffusion, irradiation, and enzymatic cross-linking.

1. Thermal-Induced Gelation

Temperature plays a critical role in the solubility and hydration of certain polymers. Many hydrogen-bond–forming colloids are more soluble in hot water than in cold. On cooling, hydration decreases, causing the polymer chains to associate and form a three-dimensional gel matrix. Examples include gelatin, agar, sodium oleate, guar gum, and cellulose derivatives. Conversely, some polymers like cellulose ethers undergo gelation upon heating due to the disruption of hydrogen bonds with water, which reduces solubility and promotes network formation.[62]

2. Flocculation-Induced Gelation

This method relies on partial precipitation by adding controlled amounts of salts or non-solvents. The precipitant concentration is carefully maintained to avoid complete precipitation, allowing only a loose network structure to form. Quick and uniform mixing is essential. For instance, ethyl cellulose or polystyrene dissolved in benzene can be gelled using petroleum ether as a non-solvent. Such gels often display thixotropy, meaning they liquefy upon agitation and regain their gel structure when allowed to rest.[63]

3. Chemically-Induced Gelation

Here, gelation is achieved through chemical reactions that cross-link the polymer chains, producing stable three-dimensional structures. A common example is aluminum hydroxide gel, formed by the reaction of aluminum salts with sodium carbonate in aqueous solution. Additionally, polymers such as polyvinyl alcohol (PVA) and cyanoacrylates can be cross-linked with agents like glycidyl ethers, toluene diisocyanate (TDI), or methylene diphenyl diisocyanate (MDI) to generate durable gels with enhanced mechanical strength.[64]

4. Solvent Exchange Method

In this process, the solvent in a polymer solution is gradually replaced with a non-solvent, leading to phase separation and gel formation. This technique is particularly useful in preparing hydrogels and organo-gels, where the solvent exchange drives the polymer chains to aggregate into a network structure.[65]

5. Diffusion Method

Gelation can also occur by controlled diffusion of a gelling agent into a polymer solution. The slow penetration of ions, solvents, or reactants promotes a gradual network formation. This approach is commonly used in the preparation of ionotropic gels such as calcium alginate beads, where calcium ions diffuse into a sodium alginate solution and induce cross-linking.[66]

6. Irradiation-Induced Gelation

High-energy radiation such as gamma rays, electron beams, or UV light can induce cross-linking in polymeric materials, leading to gel formation without requiring additional chemical cross-linkers. This method is especially valuable for producing sterile biomedical hydrogels and drug delivery matrices.[67]

7. Enzymatic Cross-Linking

Enzymes such as transglutaminase, peroxidases, or laccases can be used to catalyze the cross-linking of natural polymers like proteins and polysaccharides, resulting in biocompatible gels. This method is particularly attractive in pharmaceutical and food applications because it avoids toxic reagents and allows mild processing conditions.[68]

Formulation Considerations for Oral and Topical Gels:

The successful development of pharmaceutical gels relies on the careful selection of excipients to ensure stability, safety, and therapeutic effectiveness. A critical factor in gel formulation is the choice of vehicle or solvent, with purified water being the most commonly used base. Co-solvents such as glycerol, propylene glycol, polyethylene glycol (PEG 400), or alcohol are often included to enhance drug solubility and facilitate permeation across biological membranes. Buffers, including phosphate and citrate, help maintain the pH within an optimal range for both drug stability and patient comfort, though their solubility may be reduced in hydroalcoholic gels. Preservatives are incorporated to prevent microbial growth; since they can interact with hydrophilic polymers and reduce their active concentration, slightly higher amounts of parabens or phenolic compounds are often necessary. Antioxidants, such as sodium metabisulfite or sodium formaldehyde sulfoxylate, are added when the active ingredient is prone to oxidation, with the choice depending on the nature of the gel vehicle. For oral formulations, flavoring and sweetening agents are included to improve palatability and patient compliance, particularly in gels intended for conditions like infections, inflammation, or ulcers. Sweeteners such as sucrose, sorbitol, glycerol, saccharin sodium, and aspartame, and flavors like mint, cherry, citrus, butterscotch, or vanilla, enhance taste and mouthfeel, directly influencing patient acceptability and adherence to therapy. [69,70]

Table 6: Formulation consideration for oral and topical gel.

The effectiveness of drug delivery via topical or mucosal gels depends on multiple interrelated factors:

1. Physiological Factors

• Skin or mucosal properties such as thickness, hydration level, and hair follicle density.
• Variability due to age, gender, race, anatomical site, general health, and environmental conditions (temperature, humidity).
• To minimize variability, the rate-limiting step should be within the formulation rather than the biological barrier.[78]

2. Drug Physicochemical Properties

• Molecular weight and size, which affect diffusion.
• Partition coefficient between vehicle and application site.
• Melting point, stability, and chemical functionality (influences ionization potential, binding affinity, solubility).
• These properties determine the drug’s ability to diffuse through the vehicle and permeate the skin or mucosa.[79]

3. Formulation Components and Vehicle Factors

• Effect on drug: Influences drug diffusion, thermodynamic activity, stability, and ionization.
• Effect on site of application: Alters barrier properties via chemical or physical changes, promoting hydration or increased penetration.
• Vehicle consistency and viscosity: Determines adhesion, retention, and duration of contact at the application site.[80]

4. Topical Vehicle Classification

• Vehicles can be liquid, semisolid, or solid.
• Semisolid forms (gels, creams, ointments) are the most widely used due to their ease of application, retention, and controlled drug release.[81]

Evaluation of Formulated Gel:

The evaluation of gels involves key parameters to ensure stability, effectiveness, and suitability for their intended use. pH is measured using a digital pH meter after dispersing the gel in distilled water. Drug content is assessed by dissolving the gel in a suitable solvent, filtering, and quantifying via spectrophotometry using calibration curves. Viscosity and rheology are evaluated with rotational viscometers, influencing spreadability, retention, and patient acceptability. Spreadability is determined by measuring the ease with which a gel moves between slides, while extrudability assesses the force required to dispense the gel from containers. For topical or mucosal gels, irritation studies are conducted to ensure safety. Collectively, these evaluations provide a comprehensive understanding of the gel’s physicochemical properties and therapeutic potential across oral, topical, and specialized applications.[82]

Table 6: Evaluation parameter of gel

Table 7: Examples of commercial gel formulations with their active ingredients, gelling agents, and routes of administration.