A Review on Mucoadhesive Drug Delivery System and Transdermal Drug Delivery System

1. MUCOADHESIVE DRUG DELIVERY SYSTEM:

Since the early 1980s, mucoadhesion has attracted significant attention in the field of pharmaceutical technology. Adhesion refers to the bond that forms when a pressure- sensitive adhesive comes into contact with a surface. According to the American Society for Testing and Materials, it is the condition in which two surfaces are held together by interfacial forces, which may involve chemical bonds, physical interlocking, or both (1,2,3).

Mucoadhesive drug delivery systems are designed to extend the retention time of a dosage form at its site of application or absorption. By ensuring close contact between the dosage form and the absorption surface, these systems can enhance the drug’s therapeutic effectiveness. (4,5). In recent years, various mucoadhesive delivery systems have been developed for different routes—oral, buccal, nasal, rectal and vaginal—to achieve either local or systemic effects (6).

These systems are often used to anchor a drug delivery device at a specific site within the body. Certain water-soluble polymers become adhesive upon hydration, and mucoadhesive systems take advantage of this characteristic to deliver drugs to targeted areas for extended durations. When a drug is administered through the mucosal membranes to exert either local or systemic effects, the system is referred to as a mucosal drug delivery system (7).

1. Mucoadhesive Drug Delivery System

A delivery system that takes advantage of the bioadhesive properties of certain water- soluble polymers, which become adhesive upon hydration, allowing for prolonged drug delivery (7).

2. Use of Mucoadhesive Preparation

The concept of mucoadhesion emerged from the need to localize drugs at specific sites within the body. Often, drug absorption is limited by how long the drug remains at the site of absorption. For instance, in ocular drug delivery, drug solutions typically have less than two minutes for absorption after being administered to the eye, as they are quickly washed away due to tear drainage. Therefore, enhancing the contact time of an ocular drug delivery system on the eye’s surface could significantly improve the drug’s bioavailability.

Since many drug administration routes—such as ocular, nasal, buccal, respiratory, gastrointestinal, rectal, and vaginal—are lined with a mucus layer, using mucoadhesive agents can help increase the residence time of the drug at these sites (8).

3. Advantages of Mucoadhesion

1. The dosage form can be directed and retained at a specific site for targeted drug delivery.
2. Mucoadhesive systems ensure close contact between the formulation and the mucosal surface, leading to increased drug absorption at the site of uptake (9).
3. For drugs with poor bioavailability, localizing them to a specific area can significantly enhance their absorption and effectiveness.
4. This route avoids the harsh acidic conditions of the stomach, making it suitable for drugs that are unstable or irregularly absorbed in gastric environments.
5. The mucosal membrane has rich blood supply and higher permeability compared to the skin, facilitating better drug absorption.

4. Disadvantage of Mucoadhesion

1. Characteristics such as an unpleasant taste, odor, mucosal irritation, and instability at the site of administration limit the effectiveness of this route.
2. Ensuring patient compliance with this method is often challenging.
3. Limited permeability, a relatively small surface area, and the metabolic breakdown of certain drugs present significant obstacles for drug delivery via this route.

5. Mucous Layer

The tissue layer which responsible for creating the adhesive interface is mucus. Mucus is a clear, sticky secretion that forms a thin, continuous gel layer adhering to the surface of the mucosal epithelium.

6. The general composition of mucus is as follows:

• Water: 95%
• Glycoproteins and Lipids: 0.5–5%
• Mineral Salts: 1%
• Free Proteins: 0.5–1% (10).

7. Mechanism of Mucoadhesion

Mechanism of mucoadhesion typically involves two main stages: the contact stage and the consolidation stage.

In the contact stage, the mucoadhesive material comes into initial contact with the mucosal surface. During this phase, the formulation begins to spread and swell, enabling a more intimate interaction with the mucus layer (11).

The consolidation stage follows, during which the mucoadhesive material becomes activated in the presence of moisture. This moisture acts as a plasticizer, softening the material and allowing the adhesive molecules to move more freely. As a result, weak interactions such as van der Waals forces and hydrogen bonds can form between the mucoadhesive and the mucus.

8. Two main theories describe the consolidation stage:

1. Diffusion theory suggests that mucoadhesive molecules and mucus glycoproteins interpenetrate and form secondary bonds. For this to happen effectively, the mucoadhesive should possess certain characteristics—such as functional groups capable of hydrogen bonding (e.g., –OH and –COOH), a negative surface charge, high molecular weight, chain flexibility, and surface activity to help distribute the material across the mucus layer.
2. Dehydration theory typically refers to adhesion caused by water removal, which increases physical entanglement and bonding (11).

THEORIES OF MUCOADHESION

1. Wetting Theory

Wetting theory is relevant to liquid systems that exhibit an attraction to surfaces, enabling them to spread effectively. This surface affinity can be assessed using methods like contact angle measurements. A key principle is that a smaller contact angle indicates a higher affinity for the surface. Ideally, the contact angle should be close to zero to ensure effective spreading. The spreadability of a substance can be determined using the spreading coefficient (SAB), which is calculated from the difference in surface energies (γA and γB) and the interfacial energy (γAB). This theory highlights how essential it is to reduce surface and interfacial tension to achieve strong mucoadhesion (1).

2. Diffusion Theory

Diffusion theory explains mucoadhesion through the intermingling of polymer and mucin chains, forming a semi-permanent bond. The strength of adhesion is directly linked to how deeply these chains can penetrate one another. Factors like the polymer’s flexibility, the diffusion coefficient, and the contact duration influence this penetration. Research suggests that effective bioadhesion occurs at an interpenetration depth of 0.2–0.5 μm. This depth can be calculated using the formula:

L = (tDb)½,

Where t is the time in contact, and Db is the diffusion coefficient of the polymer in mucus. For successful diffusion, the polymer and mucus must be chemically similar, enhancing their compatibility and resulting in stronger adhesion (1).

3. Fracture Theory

Fracture theory is one of the most widely used methods for evaluating the mechanical strength of mucoadhesion. It focuses on the force needed to separate two surfaces after adhesion has occurred. The separation force, denoted as σm, is often calculated by dividing the maximum detachment force (Fm) by the total contact area (A?).

4. Electronic Theory

According to the electronic theory, adhesion results from the transfer of electrons between the mucus and the mucoadhesive material due to differences in their electronic configurations. This transfer leads to the formation of an electrical double layer at the interface, creating attractive electrostatic forces that hold the two surfaces together (12).

5. Adsorption Theory

This theory attributes adhesion to various surface-level interactions between the mucus and the adhesive polymer. These interactions can be divided into primary and secondary bonds. Primary interactions, or chemisorption, involve strong bonds like covalent, ionic, or metallic bonds, which are usually avoided due to their permanent nature(12). In contrast, secondary interactions—such as hydrogen bonding, van der Waals forces, and hydrophobic interactions—are weaker and reversible, making them more favorable for mucoadhesion since they offered a stable yet non-permanent attachment(13).

1. POLYMER IN MUCOADHESIVE DRUG DELIVERY SYSTEM

Polymers can be either natural or synthetic and are produced through a process known as polymerization, during which many small molecules, or monomers, chemically combine to form large macromolecular structures. (14,15)

2. IDEAL PROPERTIES OF MUCOADHESIVE POLYMER

1. The material should be non-toxic and not absorbed through the digestive tract.
2. To confirm that a product is non-irritating to mucous membranes, it should contain mild, gentle ingredients that do not cause irritation upon contact.
3. To achieve strong non-covalent interactions with mucin and epithelial surfaces, materials with high mucin affinity—such as specific polysaccharides or glycoproteins can be used.
4. These characteristics describe desirable traits for a medical adhesive, where strong tissue adherence and site-specific action are essential for effective performance.
5. The polymer must remain stable throughout storage and its shelf life to preserve its structure and functionality

3. FACTOR AFFECTING ON MUCOADHESION

1. Molecular Weight

Mucoadhesive strength tends to increase for polymers with molecular weights exceeding 100,000. A direct relationship has been observed between the mucoadhesive properties of polyoxyethylene polymers and their molecular weights, particularly within the range of 200,000 to 7,000,000. (16)

Flexibility

The initial stage of mucoadhesion involves the diffusion of polymer chains into the contact interface. Therefore, a high degree of polymer chain flexibility is essential for effective entanglement with the mucus layer.(17) Greater flexibility, often enhanced by adding polyethylene glycol, allows deeper chain penetration. Generally, a polymer’s viscosity and diffusion coefficient are indicative of its flexibility, more flexible polymers diffuse more efficiently into the mucus network.

2. Cross-Linking Density

Key structural features such as pore size, number and molecular weight of polymer chains, and cross-link density significantly influence mucoadhesion. As cross-linking density increases, water penetration into the polymer matrix slows down, resulting in limited polymer swelling and reduced interpenetration with mucin. This negatively affects mucoadhesive strength.(18)

3. Polymer Concentration

According to Bremecker, there exists an optimal polymer concentration that maximizes bioadhesion. When polymer concentrations are too high, adhesive strength tends to decrease.

Environmental Factors Affecting Mucoadhesion

1. Applied Pressure

Applying a specific amount of pressure is essential when positioning a solid mucoadhesive system. Whether using polyacrylic acid or Carbopol 934, increased pressure or longer application time generally improves adhesion, up to an optimal point. (19)

2. Choice of Medical Substrate

How the biological substrate is handled during mucoadhesive testing is crucial, as changes in mucus or tissue can occur under experimental conditions. It is important to assess the substrate’s viability by examining characteristics like tissue permeability and histology.

4. APPLICATION OF MUCOADHESIVE DRUG DELIVERY SYSTEM

1. Buccal Mucoadhesive Drug Delivery – For systemic delivery of drugs that undergo first- pass metabolism (e.g., propranolol, nitroglycerin). (20)
2. Nasal Mucoadhesive Drug Delivery – Used for peptide and protein delivery (e.g., insulin, vaccines) to enhance absorption and bypass hepatic metabolism. (21)
3. Ocular Mucoadhesive Drug Delivery – To increase precorneal residence time and improve ocular bioavailability of drugs (e.g., pilocarpine, timolol). (22)
4. Vaginal Mucoadhesive Drug Delivery – For local treatment of infections or contraception (e.g., clotrimazole, metronidazole). (23)
5. Gastrointestinal Mucoadhesive Systems – For controlled and prolonged drug release in the GI tract (e.g., amoxicillin, metformin). (24)
6. Rectal Mucoadhesive Delivery – For systemic and local drug delivery when oral administration is not feasible (e.g., antipyretics, anti-inflammatory agents). (25)

7. CHALLENGES OF MUCOADHESIVE DRUG DELIVERY SYSTEM

1. Mucus Turnover and Clearance – Continuous secretion and shedding of mucus reduce the residence time of the formulation at the mucosal site.
2. Limited Drug Permeability – The epithelial barrier and mucus layer restrict the absorption of large molecules such as peptides and proteins.
3. Enzymatic Degradation – Enzymes present in mucosal tissues may degrade certain drugs, particularly proteins and peptides, reducing bioavailability.
4. Irritation and Toxicity – Some mucoadhesive polymers can cause local irritation or damage to mucosal tissues upon prolonged contact.
5. Variation in Mucus Properties – pH, viscosity, and thickness of mucus vary between individuals and sites, affecting adhesion and drug release. (26)

2. TRANSDERMAL DRUG DELIVERY SYSTEM:

Transdermal drug delivery systems (TDDS) provide a non-invasive route for the systemic administration of drugs through the skin. This mode of delivery offers numerous benefits over conventional oral and parenteral routes, including the avoidance of hepatic first-pass metabolism, sustained plasma drug levels, improved patient adherence and reduced gastrointestinal side effects (27, 28)

The primary challenge in transdermal delivery is the skin’s natural barrier function, particularly the stratum corneum, which restricts the penetration of most therapeutic molecules. Advancements in formulation science, permeation enhancers and innovative technologies such as microneedles and nanocarriers have enabled the delivery of both small and large molecular weight drugs (29,30)

8. SKIN STRUCTURE AND DRUG PERMEATION

The skin is the largest organ of the human body and serves as the primary barrier to transdermal drug delivery. It consists of three major layers: the epidermis, dermis, and subcutaneous tissue (31). The epidermis includes the stratum corneum, the outermost layer, which is primarily responsible for the skin’s barrier function. The dermis contains blood vessels, lymphatics, and nerves, while the subcutaneous tissue provides cushioning and energy storage.

• Stratum Corneum: The Barrier Layer: -

The stratum corneum is composed of dead keratinized cells embedded in a lipid matrix. Its “brick-and-mortar” structure makes it highly impermeable to most substances. Only small, lipophilic molecules with a molecular weight below 500 Da can efficiently penetrate this barrier (32).

• Routes of Drug Permeation:-

Drugs can cross the skin via three primary pathways:

1. Transcellular Route: Directly through the corneocytes. This route involves repeated partitioning into the lipid and aqueous phases of the cell, which can slow down permeation.
2. Intercellular Route: Drugs diffuse between the cells via the lipid domains. This is the dominant pathway for most lipophilic drugs.
3. Appendageal Route: Drugs penetrate through hair follicles, sebaceous glands, and sweat ducts. Though the surface area is small (~0.1% of total skin), this pathway can facilitate the delivery of hydrophilic and macromolecular drugs (33).

9. FACTORS AFFECTING PERMEATION

Several factors influence the transdermal permeation of drugs:-

• Physicochemical Properties of Drugs:- Molecular Weight, Lipophilicity, and Solubility.
• Skin Condition: - Thickness, Hydration, Temperature, and Integrity.
• Formulation Factors: - Use of penetration enhancers, vehicle type, and pH (34).
• External Factors: - Application area, Duration and Occlusion.

10. IMPLICATIONS FOR TDDS:-

Understanding the structure of skin and permeation routes is critical for designing effective TDDS. Strategies such as chemical penetration enhancers, microneedles, iontophoresis, and nanocarriers are designed to temporarily overcome the stratum corneum barrier without causing permanent damage (35,36).

11. TYPES 0F TRANSDERMAL DRUG DELIVERY SYSTEMS (TDDS):-

Transdermal drug delivery systems are designed to provide controlled and sustained drug release through the skin into systemic circulation. Over the years, several types of TDDS have been developed, each with unique mechanisms, advantages and applications.

1. Matrix-Type System:-

In the matrix system, the drug is uniformly dispersed within a polymeric matrix. The drug diffuses gradually from the polymer to the skin surface. These systems are simple to manufacture, provide controlled drug release, and are widely used in commercial patches (37).

Advantages: -

• Simple design and low cost
• Steady drug release
• Easy to scale up

Limitations:-

• Limited drug loading capacity
• Potential for burst release if matrix is not uniform

 2. Reservoir-Type System

The reservoir system consists of a drug-containing compartment separated from the skin by a rate-controlling membrane. The drug diffuses across the membrane at a predetermined rate, providing zero-order kinetics. These systems are often preferred for potent drugs requiring precise dosing (38).

Advantages:-

• Precise control over drug release rate
• Can deliver potent drugs effectively

Limitations:-

• Complex manufacturing process
• Risk of dose dumping if the membrane is damaged

2. Micro-Reservoir System: -

The micro-reservoir system combines the features of matrix and reservoir systems. The drug is present in microscopic reservoirs embedded in a polymer matrix, allowing controlled diffusion (39).

Advantages:-

• Improved control over release
• Minimizes burst effect

Limitations:-

• More complicated design than matrix systems
• Moderate manufacturing complexity

3. Drug-in-Adhesive System :-

In this system, the drug is incorporated directly into the adhesive layer, which sticks to the skin. This design is simple, reduces the number of components and improves patient comfort.

Advantages:-

• Minimal thickness and comfortable for the patient
• Direct contact with skin improves absorption
• Simple to manufacture

Limitations:-

• Limited drug loading
• Adhesive properties may change over time.

12. MECHANISMS OF DRUG RELEASE FROM TDDS:-

The effectiveness of a transdermal drug delivery system depends on the controlled release of the drug from the patch and its subsequent permeation through the skin into systemic circulation. Drug release mechanisms are influenced by the system type, formulation, and physicochemical properties of the drug.

1. Partitioning into the Stratum Corneum:-

Before diffusion occurs, the drug must partition from the formulation into the stratum corneum. This depends on the lipophilicity of the drug and the composition of the vehicle. Drugs with an optimal log P (partition coefficient) between 1 and 3 typically exhibit maximum transdermal permeation.

2. Rate-Controlling Membranes

In reservoir-type and micro-reservoir systems, a rate-controlling membrane regulates the drug flux. This membrane acts as a barrier to prevent burst release and maintain a constant rate of delivery over time. The thickness, porosity and material composition of the membrane directly influence drug release kinetics.

3. Drug Release from Matrix Systems :-

In matrix-type patches, the drug is dispersed within the polymer matrix. Release occurs via:

1. Diffusion through the polymer network
2. Partitioning into the adhesive layer
3. Penetration into the skin

Matrix patches often show first-order release kinetics, meaning the rate of drug release decreases over time as the concentration in the matrix diminishes (40).

4. Enhanced Drug Release Techniques

Several advanced techniques can enhance drug release from TDDS:

Chemical Enhancers: Substances like alcohols, fatty acids or surfactants increase skin permeability.

Physical Methods: Microneedles, iontophoresis and sonophoresis temporarily disrupt the stratum corneum to facilitate faster and controlled drug delivery.

Figure Schematic illustration of drug release from a TDDS patch:

1. Drug in reservoir/matrix
2. Diffusion through polymer
3. Partitioning into stratum corneum
4. Passive diffusion through epidermis and dermis
5. Entry into systemic circulation (41)