Chapter 6

Transdermal Drug Delivery Systems: Basic Concepts

One of the faster developing and patient-focused methods of drug delivery is transdermal drug delivery, which is an alternative means of drug delivery in place of conventional oral and injectable methods. Transdermal systems are able to circumvent first-pass hepatic metabolism and gastrointestinal tract whilst allowing the delivery of controlled, sustained and specific therapy because they deliver drugs directly to the systemic circulation or the local tissues through the skin. This route of delivery is most beneficial with drugs that have limited oral bioavailability, require a consistent plasma concentration, or drugs that need a lengthy time to administer. The new developments in formulation science, material engineering and improvement methods, including patches, gels, and creams, iontophoresis, microneedles, and sonophoresis have increased the list of drugs that can be used transdermally. Transdermal drug delivery has become a perennial pillar in current therapeutic practices and has set the stage between efficacy, safety, and patient compliance to set the pace in date of new therapeutic strategy development because it has increased efficacy and reduced side effects and patient convenience.

6.1.  Structure and Function of Human Skin

Human skin is a very specific, multi-functional organ that forms the key part of the overall homeostasis and becomes the main source of the contact of the body with the external environment. As the greatest tissue of the body, the skin serves as a dynamic barrier, which prevents a broad variety of environmental hazards, such as mechanical trauma, ultraviolet (UV) radiation, pathogenic microorganisms, and chemical toxins. This is added to its protective role by its active role in thermoregulation, immune defense, and sensory perception, which underlines its complex structural and functional complexity. The skin keeps the body temperature at a healthy level through the combined efforts of the sweat glands, sebaceous glands, and cutaneous blood vessels cooling the body or warming it up, respectively, to keep the interior environment in balance. Its complex web of sensory receptors, such as mechanoreceptors, nociceptors, and thermoreceptors, allows the fine tactile, pressure, pain, and temperatureTasks, perhaps essential feedback to safeguard responses as well as environmental communication.

Figure 6: Transdermal drug delivery

At immunological level, the skin is the primary barrier to attack with different specialized immune cells including Langerhans cells, dendritic cells, mast cells as well as T lymphocytes which identify and react to the invading pathogens or foreign materials. The immunosurveillance provides the skin with a passive defensive mechanism that the skin also helps in identifying and eliminating potential threats to the system, providing immunity to the rest of the body. The combination of the structural elements and immune processes produces a selectively permeable barrier that limits the flow of destructive factors and allows the regulated intake of nutrients, gases, and other factors of importance.

The skin is structurally identified as being made of three major layers namely epidermis, dermis and hypodermis with all of them possessing distinct characteristics which can be used in drug delivery. The most superficial layer (epidermis) especially the stratum corneum is composed of strongly packed cells which are keratinized and embedded within a lipid-laden matrix which forms the main barrier to foreign substances. Below it is the dermis, a layer, a connective tissue highly endowed with collagen, elastin, blood vessels, lymphatics as well as sensory nerve endings of the dermis that are involved in systemic absorption of drugs that have been diffused through the skin as well as structural support. The hypodermis is the deepest layer; it mainly contains adipose tissue and connective tissue as its components; it helps in storing energy, thermal resistance, and other vascular network which determines the distribution of the drugs especially when using lipophilic agents.

The transdermal drug delivery is quite challenging and has opportunities that are presented by the multilayered nature of the skin. Although most molecules are restricted by the stratum corneum, the dermis and hypodermis provide entry to an absorbance into systemic circulation or localized action. Dependent on that, skin anatomy, physiology, barrier properties and regional variation of skin demand an in depth knowledge of skin structure in the rational design of transdermal systems. The knowledge is useful in critical decision making in terms of drug choice, formulation plans and permeation improvement methods, which eventually allow to control and maintain delivery, enhance bioavailability and therapeutic activity with minimal systemic toxicity and limiting patient discomposure.

6.1.1. Epidermis and Stratum Corneum

Epidermis is the most surface of the skin and it provides the first line of defense against the threats of the environment including physical trauma, microbial infiltration, additional ultraviolet radiation, and chemical irritants present. Organizational, the epidermis belongs to stratified squamous epithelium mostly made up of keratinocytes and goes through a highly controlled differentiation, proliferation, and maturation process. The deepest (stratum basale) layer consists of keratinocytes, melanocytes and Merkel cells committed to undergoing mitosis to help assure electrolyte and pigmentation levels, and mechanosensory processes linked to continuous epidermal renewal. Keratinocytes migrate to the surface moving through the stratum spinosum and stratum granulosum where they go through gradual keratinization and developing intracellular keratohyalin granules. This differentiation process leads to the differentiation of stratum corneum that is the final layer of the epidermis which is essential in barrier.

The stratum corneum is composed of 15-20 layers of the enucleated keratinocytes, also referred to as corneocytes, embedded in an elaborate, highly organized extracellular lipid matrix which is composed of ceramides, cholesterol and free fatty acids. The resulting special state-of-the-art brick-and-mortar architecture offers outstanding structural integrity, mechanical strength as well as withstands of chemical, biological and physical abuse. The stratum corneum reduces the transepidermal water loss, excludes the penetration of pathogens and toxins and preserves the deep-lying tissues against environmental destruction. Its high lipophilic properties though render it the major obstacle to transdermal delivery of drugs, and therefore present a major adversarial to the systemic or local administration of therapeutic agents.

The drugs permeate through the stratum corneum through three major routes namely; the intercellular pathway where the drug diffuse through the lipid-rich space between cells; the intracellular or transcellular pathway in which the drug moves through hair follicles, sebaceous glands, and sweat ducts that offer localized entry points to the drug. The pathways also have different permeability properties based on physicochemical properties of the drug such as molecular size, lipophilicity, ionization and hydrogen bonding capacity. Smaller, moderately lipophilic molecules are more likely to penetrate through the intercellular pathway, whereas hydrophilic or larger macromolecules might either depend on the pathway of the appendageal route or demand permeation enhancement methods.

Stratum corneum is quite different in structural and in biochemical characteristics among different anatomical sites, which affects the kinetics of drug absorption. The palms, soles and back have a more dense stratum corneum, and are less permeable as compared to areas like the inner forearm, stomach and behind the ear, which are thinner and will allow the drug to penetrate more quickly. Barrier functionality is also determined by hydration, lipid content and turnover with increased hydration promoting permeability. Such site-specific variations are a crucial point of knowledge to design the transdermal system rationally, choosing appropriate drugs, formulations, and localization. Also, it guides the selection of chemical or physical permeation enhancers, microneedle shape, and dosage form formats to maximize therapeutic effect, reduce systemic side effects and enhance compliance.

In short, the epidermis and the stratum corneum in particular is a powerful hindrance as well as one of the vital determinant conditions in transdermal drug delivery. One can put into practice the innovative delivery systems with successful use of the structural and functional properties of this layer which can enable the controlled, sustained and site-specific administration of the drugs and delineate the barrier protection versus therapeutic efficacy gap.

6.2.  Mechanisms of Transdermal Permeation

Transdermal drug delivery is based on the fact that therapeutic agents can be capable of passing through multilayered structure of skin and accessing systemic circulation of the body or the local target tissues. The stratum corneum is the top-most layer of the epidermis; it is the main barrier to the penetration of the drugs throughout the skin. The stratum corneum is made of very tight, keratinized corneocytes deep rooted in a very structured lipid structure which prevents excessive water loss, acts as a barrier against microbial invasion, and inhibits most exogenous penetration. This makes it particularly inaccessible to hydrophilic molecules or high-molecular-weight molecules and poses a major challenge to the delivery of most therapeutic agents by the transdermal route due to its tightly packed lipophilic nature. Therefore, the physicochemical and biological determinants of the skin permeation need to be understood to create a good transdermal system of drug delivery.

Passive diffusion is the major and simplest method of drug absorption through the skin. Drug molecules in this direction travel in a concentration gradient; that is, they travel away in a region of high concentration in the applied formulation through an area of lesser concentration in the deeper layers of the skin or the systemic circulation. Passive diffusion may take place by three major routes:

·       Intercellular (lipid) pathway: The initiatives of drugs between the lipid space between the corneocytes. Preferential following the path is lipophilic drugs that dissolve through the lipid matrix and diffuse through the lipid matrix.

·       Intracellular (transcellular) pathway: The hydrophilic molecules can be directly penetrating through the keratin-filled corneocytes. Although this route is directly able to traverse cells, it proves to be more limiting through tight cell gratifications and that of water content in the cells.

·       Appendageal pathway: Drugs may penetrate the stratum corneum through hair follicles, sebaceous glands and sweat ducts as microchannels. This pathway is specifically significant in the case of macromolecules and nanoparticles which lack the ability to diffuse through intact lipid layers very efficiently.

Passive diffusion is predictable and effective with small, moderately lipophilic molecules, but tends to be ineffective with larger, hydrophilic, or charged molecules and hence does not always allow extension of the range of the range of drugs that can be delivered transdermally. In order to address these drawbacks, different improvement plans have been drawn up:

·       Chemical enhancers: alcohols, surfactants, fatty acids and urea will temporarily disorganize the ordered lipid matrix of the stratum corneum to enhance its diffusion permeability and allow drugs to infiltrate. These enhancers may change the lipid fluidity, lipid extraction or modify protein structures to enhance absorption.

·       Physical and mechanical techniques: Ultrasound-mediated Strategy (sonophoresis): larger and charged molecules can easily penetrate impossible barriers by temporarily disarranging their properties through physical and mechanical means, which includes sonophoresis (ultrasound induced enhancement), iontilogenic methods (delivery of drugs using low electric currents), creation of transient microchannels (microneedles), and thermal ablation. The processes of mechanical exfoliation through tape stripping or microabrasion may be used to eliminate part of the stratum corneum to decrease drug diffusion resistance.

·       Combination methods: Most of the transdermal systems in the present-day are comprised of synergist methods, involving the use of optimizable formulations in combination with chemical or physical delivery enhancers that will increase the amount of drug delivered whilst still keeping the system safe and minimal irritation.

These mechanisms and improvement methods allow the use of transdermal drug delivery in the delivery of a great variety of therapeutic agents, including small molecules and other small molecules up to proteins, peptides, and even vaccines. These modalities provide a means of delivering drugs in a controlled, sustained and targeted fashion, to provide a non-invasive method of drug delivery to patients, representing an alternative to oral or injected therapy, and increasing clinical utility of this versatile method of delivery.

6.2.1. Passive Diffusion

The simplest and the most commonly occurring process through which drugs delivered through transdermal systems are carried into the body is the Passive Diffusion. This is done by diffusion of the drug molecules along a concentration gradient where it passes through a region of higher concentration within the applied formulation to a region of lower concentration within the underlying skin layers, and eventually into the systemic circulation. The movement does not need any external force and depends only on the physicochemical nature of the drug and on the structure features of the skin.

Passive diffusion is performed in three major ways:

•       Intercellular Lipid Pathway: The most common pathway of lipophilic drugs is this one. Drug molecules are diffused across the lipid bi-layers which enclose the corneocytes of the stratum corneum. There is the lipid matrix, which is a semi-permeable medium and most preferable to drugs which are highly lipid soluble. The painful circuitry of the intercellular diffusion retards the movement in drugs but provides the possibility to maintain and regulated absorption overtime.

•       Intracellular Route: Hydrophilic drugs can permeabilize using the corneocytes per se which are packed with keratin and encircled by lipids. This route is constrained as compared to the intercellular one because of the tight junctions and high protein contents of the cells, which limits the rate and extent of permeation. Polar or charged drugs are the ones that usually have low levels of transport via this route.

•       Appendageal Pathways: Hair follicles, sweat glands and sebaceous ducts are sources of microchannels bypassing the stratum corneum barrier. Such structures act as shortcuts to drug delivery, especially to macromolecules or formulations that are meant to take advantage of these routes, e.g. nanoparticle-based systems. Despite the fact that the overall surface area of the appendages is rather small, they might play a major role in preliminary drug absorption and local targeting.

There are many factors which affect the efficiency of passive diffusion. The characteristics of drugs including molecular weight, lipophilicity, ionization degree and solubility dictate the ease with which a molecule is able to penetrate the skin. The rate of diffusion is also modulated by formulation characteristics such as drug concentration, excipients and type of vehicle. Further, skin physiology, which comprises stratum corneum thickness, level of hydration, differences between sites of the body and the existence of disease or damage, can significantly influence absorption. These parameters can be learned and guided to optimize transdermal systems with controlled and predictable drug delivery, which is therapeutically effective, through passive diffusion.

6.3.  Advantages over Oral and Injectable Routes

Transdermal delivery of drugs has many benefits compared to traditional oral and injected intake, and it is a very appealing and patient-friendly option in a large variety of treatments. The first category of benefits is the elimination of the first-pass metabolism. Oral drugs are first gained access to the liver to go through the systemic circulation where a large percentage may be metabolized and inactivated, lowering bioavailability. Transdermal delivery avoids the gastrointestinal tract and first-pass into hepatic phase to a larger extent, owing to which a higher percentage of the dose applied goes unmodified and reaches systemic circulation, enhancing the therapeutic capacity. This is more so in case of drugs which are highly broken down in the liver i.e. some hormones, cardiovascular drugs and peptides.

Improved patient compliance and safety is another value. Transdermal systems are also non-invasive and painless unlike injections, which contain a source of both discomfort and anxiety, and have the potential to lead to complications (e.g. infections or tissue damage). Patches, gels, and creams offer eating-take-as-you-go value; this is particularly true to elderly patients, children, or that one has a needle phobia. The continuous delivery of the drugs during a long duration lessens the number of doses taken hence minimizing missed doses, minimizes chronic therapy regimens and enhances adherence.

Controlled and sustained drug delivery is also possible in transdermal delivery and extends plasma concentration in a therapeutic window. This avoids peaks and troughs that could be characteristic of oral dosing which minimize side effects and improves the safety of drugs with narrow therapeutic indices. Moreover, those that can be designed in this way are transdermal systems, which are able to deliver drugs to a site or area locally, enhances therapeutic specificity and minimizes systemic exposure where desired.

Moreover, the delivery via transdermal is flexible and versatile. It has a broad ability to cover a variety of class of drugs, such as small molecule, hormones, analgesics and even a few biologics with enhancement methods such as microneedles, iontophoresis, or chemical permeation enhancers. The possibility of taking off the patch or gel in case of undesirable reactions provides an added safeguard and versatility provided by the limitation of the patient being able to withdraw the drug in case of adverse reactions in oral or injectable formulations, which is not always possible in that case.

All of these characteristics, including increased bioavailability, patient compliance, minimized systemic side effects, plasma prescription persistence and nonexistent intrusion, make transdermal drug delivery a useful and frequently superior substitute to conventional oral and injectable pathways. It is especially useful in the context of long-term treatment, long-term diseases, and medications that need a specific pharmacokinetic management and, as such, position transdermal systems as the pillars of contemporary, patient-centered treatment plans.

6.3.1. Avoidance of First-Pass Metabolism

The possibility to avoid hepatic first-pass metabolism is one of the greatest benefits of the transdermal drug delivery method, which can usually diminish the efficacy of orally delivered drugs. Under the condition of oral administration, drugs are absorbed in the gastrointestinal tract and can be transferred to the liver by the portal vein. In this initial liver circulation, much of the drug could be enzymatically metabolized, decreasing the quantity which will eventually get to the systemic distribution. This decreased bioavailability can result in the need to increase or appear more often in dosing and this may affect more negative side effects or non-compliance among the patients.

Transdermal delivery bypasses this metabolic route, as drugs are taken directly into the dermal capillaries and enter systemic circulation and are available in a higher percentage concentration of an active drug. There a few advantages associated with this:

•       The increased Bioavailability: A larger proportion of the administered dose reaches the systemic system intact making lower dosages to be effective as a therapeutic agent. This is especially beneficial to drugs of large first-pass metabolism, e.g., some hormones, cardiovascular drugs and painkillers.

•       Increased Therapeutic Effect: Transdermal systems exhibit longer and predictable absorption profiles and as such, will maintain steady plasma concentrations of drug and therefore maintenance of the plasma levels without peaks and valleys that oral dosing entails. Not only does this form of controlled exposure maximize efficacy but it also minimizes the risk of developing efficacy dependent side effects that affects the safety profile of the therapy.

•       Applicability in Labile Drugs: There are a large number of drugs i.e. peptides, proteins and some cases of small molecules that may be susceptible to the enzyme destruction or hydrolysis in the stomach or intestines. These labile molecules are safe under transdermal delivery and their activity is preserved, rendering them therapeutically effective in a form that is reached into systemic circulation.

•       Dose Flexibility and Safety: The ability to effortlessly adapt or remove the delivery device with transdermal systems in the case of adverse reactions provides a safety benefit over oral or injectable route where the delivered drug cannot be removed.

Transdermal delivery does not only improve the pharmacokinetic properties of a vast majority of drugs but also increases the number of drugs that can be safely delivered, leading not only to better therapeutic outcomes, patient convenience and compliance.

6.4.  Types of Transdermal Systems

The passive topical systems and the active delivery methods can be largely classified under transdermal drug delivery systems (TDDS), all of which are specifically designed to overcome the barrier properties of the skin which would otherwise hinder the delivery of drugs and the therapeutic administration of said drug. The outermost epidermis cell layer, the stratum corneum, is an extremely difficult barrier to the process of drug penetration because of its dense keratinized cells that are wrapped in a lipid matrix. Passive systems: Passive systems take into account the diffusion of drugs across this barrier, which is mainly based on the technical characteristics of the natural processes of diffusion; active systems: In active systems, the use of the external energy or mechanical intervention is aimed at increasing permeability.

Passive topical preparations such as patches, gels, creams and ointments use the physicochemical characteristics of the drug and the formulation vehicle to ensure gradual penetration of the drug into the deeper layers of the skin and into deep systemic circulation. These systems are specifically best suited to small, lipophilic molecules and offer sustained/controlled release of drugs, which enhances therapeutic regularity and reduces unpredictability in plasma concentrations of drugs. They are non-invasive, easy to use, and patient-friendly, which makes them suitable in the case of long-term therapy, chronic disease management as well as a localized treatment procedure.

Active transdermal delivery techniques, conversely, include physiological or physical enhancement techniques to transcend the shortcomings of passive diffusion to enable the transfer of larger, hydrophilic or otherwise poorly permeable molecules. To create transitory spaces in the stratum corneum or increase the mobility of molecules, iontophoresis (permeation using electric current), sonophoresis (permeation using ultrasound), microneedle arrays, and electroporation have been used in order to deliver drugs directly into the dermis or systemic circulation in a precise, rapid and targeted way.

Thus, through a combination of passive and active techniques, transdermal systems will be flexible and versatile and effective enough to provide therapeutics that could otherwise be applied in a non-invasive manner. Through not just the optimization of absorption and constant therapeutic level maintenance, but also increased patient adherence, less frequent dosing, and less of side effects being emitted systemically, transdermal drug delivery has become a fundamental principle of the contemporary approach to pharmacotherapy, where patients are at its heart.

The conventional types of dosage preparations comprising of a passive topical preparation are transdermal patches, gels, creams, and ointments. The basis of these formulations is mainly based on the physicochemical characteristics of the drug, which include the molecular size, the lipophilicity and solubility of the drug to penetrate the skin. Drugs move slowly slowly through the stratum corneum by establishing a concentration gradient between the formulation and the underlying tissues into either the systemic or localized tissue. It is the case of many passive formulations, which are constructed with special functions in order to regulate drug release, such as polymer matrices, rate-limiting membranes, or multi-layered patch designs that can enable a delivery that lasts several hours or days. Such systems have found application especially in chronic therapies where the plasma concentrations need to be steady in order to sustain therapeutic effects.

Active delivery methods on the other hand utilize external energy or mechanical aid in order to increase drug permeation across the skin. The commitment uses stronger electrical currents to push charged molecules of drugs to the epidermis using techniques like iontophoresis and ultrasound waves to temporarily loosen lipid packing and raising skin permeability using sonophoresis. Microneedle-based systems form microscopic tracks that avoid the stratum corneum, thereby facilitating the administration of macromolecules, vaccines, and biologic substances, which otherwise cannot penetrate to the skin barrier. Such dynamic approaches permit to strictly regulate the rate of the drug delivery and its depth, provide the possibility of targeted therapy and possibly lead to a decrease in the necessary dose.

Passive and active transdermal systems will enable versatile platform that can accommodate a broad localisation of drugs, such as small molecules, peptides, proteins, and hormones. With the distinct benefits of either method, the therapeutic effect on the transdermal delivery can be controlled and sustained in one location and minimized systemic toxicity, and can also be reduced in dose, and increased compliance and ease of use in the patient. These features render transdermal systems an effective and heavily favored option to traditional oral or injectable treatments, specifically to chronic ones, and long-term treatments, as well as therapies that would need consistent plasma levels.

REFERENCES

1.     Alkilani, A. Z., Nasereddin, J., Hamed, R., Nimrawi, S., Hussein, G., Abo-Zour, H., & Donnelly, R. F. (2022). Beneath the skin: a review of current trends and future prospects of transdermal drug delivery systems. Pharmaceutics, 14(6), 1152.

2.     Ashtikar, M., Nagarsekar, K., & Fahr, A. (2016). Transdermal delivery from liposomal formulations–Evolution of the technology over the last three decades. Journal of Controlled Release, 242, 126-140.

3.     Chauhan, I., Yasir, M., Verma, M., & Singh, A. P. (2020). Nanostructured lipid carriers: A groundbreaking approach for transdermal drug delivery. Advanced pharmaceutical bulletin, 10(2), 150.

4.     Devarajan, P. V., & Jain, S. (Eds.). (2015). Targeted drug delivery: concepts and design.

5.     Economidou, S. N., Lamprou, D. A., & Douroumis, D. (2018). 3D printing applications for transdermal drug delivery. International journal of pharmaceutics, 544(2), 415-424.

6.     Jain, K. K. (2019). An overview of drug delivery systems. Drug delivery systems, 1-54.

7.     Jeong, W. Y., Kwon, M., Choi, H. E., & Kim, K. S. (2021). Recent advances in transdermal drug delivery systems: A review. Biomaterials research, 25(1), 24.

8.     Kumar, V., Praveen, N., Kewlani, P., Arvind, Singh, A., Gautam, A. K., & Mahalingam Rajamanickam, V. (2023). Transdermal drug delivery systems. In Advanced Drug Delivery: Methods and Applications (pp. 333-362). Singapore: Springer Nature Singapore.

9.     Maiti, S., & Sen, K. K. (2017). Introductory chapter: Drug delivery concepts. In Advanced technology for delivering therapeutics. IntechOpen.

10.  Matharoo, N., Mohd, H., & Michniak‐Kohn, B. (2024). Transferosomes as a transdermal drug delivery system: Dermal kinetics and recent developments. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 16(1), e1918.

11.  Mishra, B., & Bonde, G. V. (2020). Transdermal drug delivery. In Controlled drug delivery systems (pp. 239-275). CRC Press.

12.  Ng, L. C., & Gupta, M. (2020). Transdermal drug delivery systems in diabetes management: A review. Asian journal of pharmaceutical sciences, 15(1), 13-25.

13.  Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9), 855.

14.  Phatale, V., Vaiphei, K. K., Jha, S., Patil, D., Agrawal, M., & Alexander, A. (2022). Overcoming skin barriers through advanced transdermal drug delivery approaches. Journal of controlled release, 351, 361-380.

15.  Rabiei, M., Kashanian, S., Samavati, S. S., Jamasb, S., & McInnes, S. J. (2020). Nanomaterial and advanced technologies in transdermal drug delivery. Journal of drug targeting, 28(4), 356-367.