Transdermal drug delivery system Pradip Sontakke

Transdermal drug delivery system

1. TRANSDERMAL DRUG DELIVERY SYSTEM Presented By: Mr. Pradip F. Sontakke Assistant Professor Dept. of Pharmaceutics SHREE SAMBHAJI COLLEGE OF PHARMACY KHADKUT , NANDED .

2. Transdermal drug delivery (TDD) is a method of administering medications through the skin for systemic effects. It involves the application of a drug-containing patch or other formulation on the skin, allowing the active ingredients to be absorbed into the bloodstream over time. This method offers an alternative to oral, injectable, or intravenous drug delivery, providing benefits like sustained drug release, improved patient compliance, and avoidance of first-pass metabolism in the liver. Key Features of Transdermal Drug Delivery: Non-invasive : It avoids the discomfort and potential complications of needles and injections. Controlled release : Drugs can be delivered at a steady rate over a period of hours or days. INTRODUCTION OF TRANSDERMAL DRUG DELIVERY SYSTEM

3. Bypasses gastrointestinal system : It avoids drug degradation by stomach acids and enzymes and circumvents first-pass metabolism by the liver, which can reduce drug efficacy in oral forms. Enhanced patient compliance : TDD is user-friendly, as patients often prefer a patch or gel to repeated injections or pills. Reduction of side effects : Since the drug is slowly absorbed, it can minimize peak blood concentrations and the associated side effects. Types of Transdermal Delivery Systems: Patches : The most common form, consisting of an adhesive backing and a reservoir or matrix containing the drug. Gels and creams : Drug formulations that are absorbed through the skin once applied. Iontophoresis and Sonophoresis : Techniques that use electrical currents or ultrasound to enhance drug penetration.

4. Challenges: Skin barrier : The outermost layer of the skin (stratum corneum) acts as a strong barrier, limiting the types and sizes of molecules that can be delivered transdermally. Drug limitations : Only drugs that are lipophilic (fat-loving) and have low molecular weight are suitable for this method. Potential skin irritation : Prolonged use of patches or exposure to certain chemicals can cause irritation or allergic reactions.

5. ADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEM 1. Non-invasive and Painless: Unlike injections or intravenous administration, transdermal delivery is non-invasive, avoiding the pain and discomfort associated with needles. It reduces the risk of infections that can occur with invasive procedures like injections. 2. Avoidance of First-pass Metabolism: Transdermal drugs bypass the first-pass metabolism in the liver, which can degrade or metabolize a drug before it reaches systemic circulation when taken orally. This allows for better bioavailability and can reduce the required dosage. 3. Controlled and Sustained Release: Transdermal patches and systems can provide a steady, controlled release of the drug over time, often lasting hours to days. This reduces fluctuations in drug levels in the bloodstream, avoiding peaks and troughs that can lead to side effects or decreased efficacy. 4. Improved Patient Compliance: TDDS is convenient, as patients can simply apply a patch and receive medication over an extended period without having to remember to take multiple doses (e.g., daily pills). The ease of use enhances adherence, especially in chronic conditions where long-term therapy is needed.

6. 5. Reduction of Gastrointestinal Issues: Since the drug is not ingested orally, it avoids the gastrointestinal (GI) tract, preventing irritation or damage to the stomach and intestines. This is particularly beneficial for drugs that can cause nausea, vomiting, or GI bleeding when taken orally. 6. Minimal Involvement of Healthcare Professionals: Unlike injectable forms, which often require healthcare professionals for administration, transdermal systems can be applied by the patients themselves at home. This reduces the need for frequent medical visits and allows for better self-management. 7. Improved Drug Efficacy: Because transdermal systems bypass the harsh conditions of the GI tract (e.g., acidic pH, digestive enzymes), the drug can remain more stable and effective by the time it reaches systemic circulation. 8. Less Frequent Dosing: Transdermal patches can provide medication over extended periods (24 hours or more), reducing the need for multiple daily doses. This is particularly advantageous for medications requiring precise, continuous dosing, such as hormone therapies or pain management drugs.

7. DISADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEM 1. Limited to Small, Lipophilic Drugs Molecular size and lipophilicity are significant factors in determining whether a drug can effectively penetrate the skin. Only drugs with relatively low molecular weight (generally less than 500 Daltons) and sufficient lipophilicity can pass through the stratum corneum. Hydrophilic drugs (water-soluble) are poorly absorbed through the skin, limiting the types of drugs that can be delivered transdermally. 2. Skin Barrier Limits Permeation The stratum corneum , the outermost layer of the skin, acts as a strong barrier to most substances. It prevents many drugs from permeating in sufficient quantities to achieve therapeutic levels in the bloodstream. Enhancing drug permeation often requires chemical or physical enhancers, which may cause skin irritation or damage. 3. Skin Irritation and Sensitization Continuous or prolonged use of transdermal patches can lead to skin irritation, redness, itching, or allergic reactions at the application site. Some patients may be sensitive to the adhesives, excipients, or permeation enhancers used in the patch. This can lead to discomfort and compliance issues, especially for patients who need long-term transdermal therapy.

8. 4. Variable Drug Absorption Individual variations in skin permeability (due to factors like age, skin thickness, hydration levels, and skin conditions) can lead to inconsistent drug absorption. Environmental factors like temperature and humidity can also affect how well the drug is absorbed through the skin. Body location for patch application (e.g., arms, chest, or back) can influence drug absorption rates, making consistent dosing difficult to maintain in some cases. 5. Potential for Low Drug Delivery Efficiency TDDS typically delivers lower doses of medication compared to oral or injectable routes. For drugs requiring high doses to be effective, transdermal systems may not provide sufficient drug levels, making them unsuitable for certain conditions. The skin’s low permeability limits the amount of drug that can pass through, which can be a drawback for medications that need rapid onset or higher concentrations. 6. Slow Onset of Action For most drugs delivered via TDDS, the onset of action can be slower compared to oral or injectable forms. This is because the drug must first penetrate the skin layers before entering systemic circulation. While this controlled release is advantageous in some cases (e.g., chronic conditions), it may not be ideal for acute conditions where a rapid therapeutic effect is required.

9. PERMEATION THROUGH SKIN Anatomy of skin To enhance the existing potential of TDDS, it is essential to understand the fundamental aspects of skin anatomy. Skin is multi-layered organ composed of many histological layers. The major divisions of the skin, from top to bottom, are the, epidermis, the dermis and the hypodermis.

10. The epidermis is the outermost layer of the skin and plays a critical role in transdermal drug delivery systems (TDDS). It acts as a primary barrier to the penetration of drugs. Understanding the structure and function of the epidermis is essential for optimizing drug delivery through the skin. 1. Stratum Corneum (SC) Structure : The outermost layer of the epidermis, consisting of dead, flattened keratinocytes embedded in a lipid matrix. It is often described as a "brick-and-mortar" structure where keratinocytes are the bricks and lipids are the mortar. Function in TDDS : The stratum corneum is the major barrier to drug penetration. Its low permeability means only small, lipophilic molecules can easily pass through. Strategies to enhance drug delivery often focus on disrupting this layer (e.g., through chemical enhancers, microneedles , or iontophoresis ). Epidermis

11. 2. Stratum Lucidum Structure : A thin, transparent layer found only in thick skin areas like the palms and soles. Function in TDDS : Although it is not always present, it contributes minimally to the barrier function compared to the stratum corneum. 3. Stratum Granulosum Structure : This layer contains keratinocytes that are undergoing a process of keratinization, where they produce keratin and lipids before eventually moving upwards to become part of the stratum corneum. Function in TDDS : While it offers more structural stability than the SC, the granulosum is not as strong of a barrier .

12. 4. Stratum Spinosum Structure : Composed of keratinocytes connected by desmosomes, this layer provides strength and flexibility to the skin. Function in TDDS : Like the granulosum, it is deeper and provides less resistance to drug molecules than the SC but still plays a role in structural cohesion.

13. 5. Stratum Basale Structure : The deepest layer of the epidermis, consisting of basal cells that continuously divide to produce new keratinocytes. Melanocytes and other cells are also found here. Function in TDDS : Drugs typically do not need to reach the stratum basale for transdermal delivery, as their therapeutic action is usually systemic or confined to the layers above. However, drug penetration to this level can be significant for treating deeper skin conditions.

14. Dermis The dermis is the layer of skin located below the epidermis and plays a supportive but significant role in TDDS. While the primary barrier for drug penetration is the epidermis , particularly the stratum corneum , the dermis serves as a duct for drug diffusion once the barrier is bypassed. Structure of the Dermis: The dermis is composed of two main layers: Papillary Dermis (upper, thin layer) Reticular Dermis (deeper, thicker layer) Both layers contain a dense network of collagen and elastin fibers, blood vessels, nerve endings, and other skin appendages.

15. 1. Papillary Dermis Structure : This is the thin, upper layer of the dermis located just below the epidermis. It contains loose connective tissue with small blood vessels and capillaries, which provide nutrients to the epidermis. Function in TDDS : The papillary dermis is the first layer of the dermis that drugs encounter after crossing the epidermis. The rich capillary network here allows for rapid absorption of drugs into systemic circulation. Drugs that penetrate this layer can be quickly absorbed into the bloodstream for systemic distribution. 2. Reticular Dermis Structure : This is the deeper and thicker layer of the dermis. It contains dense, irregular connective tissue, larger blood vessels, lymphatic vessels, nerve fibers, and skin appendages like hair follicles and sweat glands. Function in TDDS : Once drugs reach the reticular dermis, they can diffuse further into the body. The extensive vascularization helps in the efficient absorption of drugs into systemic circulation. However, this layer does not act as a significant barrier for drug penetration compared to the epidermis.

16. The hypodermis , also known as the subcutaneous layer or subcutis , is the innermost layer of the skin located below the dermis. While the primary barriers to transdermal drug delivery are the epidermis and dermis , the hypodermis plays an important role in the absorption, storage, and systemic distribution of drugs delivered through the skin. Hypodermis

17. Structure of the Hypodermis: The hypodermis is primarily composed of: Adipose (Fat) Tissue : The bulk of the hypodermis consists of fat cells (adipocytes) that store energy and provide insulation. Connective Tissue : Fibrous connective tissue that binds the skin to the underlying muscles and bones. Blood Vessels : Larger blood vessels than those found in the dermis, including arteries and veins. Lymphatic Vessels : Vessels that drain excess interstitial fluid and aid in immune responses. Nerve Fibers : Sensory and autonomic nerves extend into this layer.

18. Routes of skin penetration 1. Transcellular Route (Across Cells) Pathway : Drugs pass directly through the cells (keratinocytes) of the stratum corneum. This means they must cross both the cell membranes and the intracellular spaces multiple times. Mechanism : The drug penetrates the lipid membranes of keratinocytes and moves into the intracellular matrix. After crossing each cell, it re-enters the lipid matrix before crossing the next cell. Drugs using this route face the hydrophilic and lipophilic barriers of the cell membranes, so they need to be both lipophilic (fat-soluble) to pass through the lipid-rich regions of the cell membrane and hydrophilic (water-soluble) to pass through the aqueous cytoplasm.

19. 2. Intercellular Route (Between Cells) Pathway : In this route, drugs move between the corneocytes (the cells of the stratum corneum) through the lipid matrix rather than passing through the cells. Mechanism : The drug diffuses through the lipid layers (mainly ceramides , cholesterol, and free fatty acids) that surround the corneocytes . These lipids are organized into layers, creating a tortuous pathway. The stratum corneum is about 15–20 layers thick, so drugs must navigate this long, winding lipid-rich pathway to penetrate the skin.

20. 3. Appendageal Route (Shunt Route) Pathway : Drugs penetrate through skin appendages, such as hair follicles , sebaceous glands , and sweat glands . These appendages provide alternative pathways for drug penetration, bypassing the stratum corneum’s barrier. Mechanism : Drugs diffuse into the skin via the sweat ducts or hair follicles and reach the deeper layers (dermis) more easily than through the transcellular or intercellular routes. This route is referred to as a "shunt pathway" because it represents a way to bypass the stratum corneum’s tough barrier to drug penetration.

21. FACTORS AFFECTING PERMEATION 1. Physicochemical Properties of the Drug MolecularSize /Weight : Smaller molecules tend to permeate membranes more easily than larger ones. For example, molecules with a molecular weight under 500 Daltons show better permeation through biological barriers such as the skin or intestinal lining. Lipophilicity : Lipid-soluble (lipophilic) drugs cross biological membranes (composed of lipid bilayers) more effectively than hydrophilic (water-soluble) drugs. Lipophilicity is measured using the partition coefficient (log P), where drugs with higher log P values (more lipophilic) tend to permeate membranes better.

22. IonizationState ( pKa ) : Drugs can exist in ionized or unionized forms depending on the pH of their environment and their pKa (acid dissociation constant). Only the unionized form of a drug can easily cross lipid membranes. Weak acids are more permeable in acidic environments (where they remain unionized), while weak bases are more permeable in basic environments. Solubility : A drug must be soluble in water to be dissolved and then in lipids to cross the membrane. Poor water solubility can limit a drug’s dissolution in biological fluids, while poor lipid solubility can hinder its passage through lipid membranes. Polarity : Nonpolar (hydrophobic) drugs permeate membranes more readily compared to polar drugs because the cell membrane’s hydrophobic core favors the diffusion of nonpolar substances.

23. 2. Membrane Properties Thickness : Thicker membranes present a larger barrier to diffusion. For instance, skin (stratum corneum) is much thicker than the membranes of the intestine, meaning it is generally harder for drugs to permeate through skin than through the intestinal lining. Composition : Biological membranes are made of lipids, proteins, and carbohydrates. The lipid composition determines the ease of lipophilic drug permeation, while hydrophilic drugs may depend on membrane proteins (such as pores or channels) for transport. Surface Area : Larger surface areas facilitate faster drug permeation. The intestines, for example, have a large surface area due to villi and microvilli, which enhances the absorption of drugs.

24. Tight Junctions : Some tissues, like the blood-brain barrier, contain tight junctions that restrict paracellular transport (the movement of substances between cells). This limits the permeation of drugs unless they can actively cross the membrane through other mechanisms. 3. Concentration Gradient Permeation through membranes often occurs via passive diffusion, which follows Fick's law. Drugs move from an area of high concentration to an area of low concentration. A higher concentration gradient across the membrane results in faster drug permeation. 4. Temperature Higher temperatures increase the fluidity of biological membranes, allowing molecules to diffuse more easily. Moreover, temperature increases the kinetic energy of drug molecules, enhancing their movement and diffusion across the membrane.

25. 2. Membrane Properties Thickness : Thicker membranes slow down drug permeation. Composition : Membranes rich in lipids favor the permeation of lipophilic drugs, while those with high protein content may provide channels for hydrophilic drugs. Surface Area : Larger surface areas facilitate faster drug permeation, as seen in structures like the small intestine with its villi and microvilli. Tight Junctions : The presence of tight junctions (e.g., in the blood-brain barrier) restricts paracellular transport, limiting permeation. 3. Concentration Gradient Drugs move from areas of higher concentration to areas of lower concentration via passive diffusion. A greater concentration gradient accelerates the permeation process. 4. Temperature Increased temperature generally increases membrane fluidity and enhances permeation. Higher temperatures also increase the kinetic energy of drug molecules, promoting faster diffusion.

26. 5. pH of the Environment The pH of the surrounding environment can influence a drug’s ionization, which in turn affects its permeation. For example: Weak acids are more unionized in acidic environments (like the stomach) and can permeate more easily. Weak bases are more unionized in basic environments (like the intestines) and show better permeation there. 6. Formulation Factors Vehicle/Excipient : The formulation in which a drug is delivered can significantly impact its permeation. Certain excipients or carriers in the formulation can enhance drug solubility or disrupt the structure of the membrane to improve permeation. For example, surfactants can increase membrane permeability by interacting with the lipid bilayer

27. Particle Size : Smaller particle sizes (such as in nanoparticle formulations) increase the surface area available for dissolution and permeation. Nanoparticles and micelles can enhance permeation by bypassing biological barriers more effectively than larger particles . Drug Delivery System : Specialized delivery systems like liposomes, micelles, and solid lipid nanoparticles can encapsulate drugs and enhance their permeation by improving drug solubility, stability, and targeting specific tissues. 7. Permeability Modifiers Certain compounds can be used to increase the permeability of biological membranes. These compounds, often referred to as permeation enhancers , include: DMSO (Dimethyl sulfoxide) : A solvent that can increase membrane permeability by altering the structure of the lipid bilayer. Bile Salts : These can disrupt the integrity of the cell membrane and enhance drug absorption. Surfactants : Surface-active agents that reduce surface tension and disrupt membrane integrity, promoting drug permeation.

28. BASIC COMPONENTS OF TDDS The basic components of Transdermal Drug Delivery Systems (TDDS) are designed to control the release of drugs and help their passage through the skin. These systems consist of several layers, each helping a specific purpose to ensure effective drug delivery. 1. Drug The active pharmaceutical ingredient (API) intended for therapeutic action. The drug should ideally have properties that allow it to be absorbed through the skin, such as appropriate molecular weight (usually under 500 Da), lipophilicity, and adequate potency to require only small doses. 2. Polymer Matrix/Reservoir The polymer helps as a carrier for the drug, controlling its release rate. It can either directly hold the drug or regulate the diffusion of the drug to the skin.

29. Types : Matrix systems : The drug is dispersed in a polymer matrix, and drug release occurs via diffusion from the matrix to the skin. Reservoir systems : The drug is enclosed in a reservoir, which is separated from the skin by a rate-controlling membrane. Materials : Silicone, polyisobutylene, ethylene-vinyl acetate (EVA), and other biocompatible polymers. 3. Permeation Enhancers These substances enhance the permeation of the drug through the stratum corneum, the outermost barrier of the skin. Examples : Alcohols (ethanol), fatty acids (oleic acid), surfactants (sodium lauryl sulfate), and DMSO (dimethyl sulfoxide). Mechanism : They work by disturbing the lipid bilayer of the skin, increasing its permeability, or by altering protein structures within the skin.

30. 4. Adhesive The adhesive layer keeps the patch attached to the skin for the desired duration. It should be non-irritating, non-allergenic, and compatible with the drug and other components. Types : Pressure-sensitive adhesives such as silicone, polyacrylate, or polyisobutylene. 5. Backing Layer This layer provides structural support and protects the drug and other components from the external environment (e.g., moisture, light). It also ensures that the drug does not escape from the back of the system. Materials : Polyester, polyethylene, or aluminum foil. 6. Rate-Controlling Membrane (in reservoir systems) : In reservoir-type systems, this membrane controls the rate at which the drug is released from the reservoir to the skin. Materials : Polyethylene, ethylene-vinyl acetate, or silicone.

31. 7. Release Liner The release liner is a protective layer that covers the adhesive and drug-containing layers before application. It is removed before the patch is applied to the skin. Materials : Silicone-coated paper or plastic film. 8. Additional Components Plasticizers : Enhance the flexibility of the polymer matrix and improve the skin's compatibility with the system (e.g., glycerol, PEG). Stabilizers and Preservatives : Ensure the stability of the drug and other components throughout the product’s shelf life. Moisturizers : Sometimes included to hydrate the skin and improve drug permeation (e.g., glycerin).