Skin deep : overcoming barriers for effective transdermal drug delivery

Ancient art, modern science   One shared medicinal practice among disparate ancient societies was the application of primitive ointments to the skin to treat almost all and any ailments. A vast plethora of poultices and plasters have been described, including in Babylonian and Greek medicine texts1 among others, suggesting that the magical health-restoring powers of ointments were well-recognized to traverse the skin. Thus, it was no coincidence that the skin was the preferred therapeutic route over surgical (and oral) intervention since the former method was likely to result in reduced mortality rates compared to the latter; undoubtedly an important consideration, given that the top ancient physicians were likely charged with the health of the royal courts.     Although the art of transdermal delivery of medicines dates back millennia, it is only in more recent times that the science of transdermal drug delivery in man has advanced significantly2. The choice of modern drugs for topical applications is, however, relatively limited compared to the seemingly infinite choice available for oral delivery. This is perhaps not surprising since the gut is an organ that has evolved with the main purpose of absorbing food (chemicals when it comes to it) whereas the skin, despite being the largest organ, has evolved primarily as a protective layer to prevent desiccation of underlying tissues and to keep out harmful environmental chemicals. As this includes medicinal drugs, the pursuit of transdermal administration would appear, at first sight, to be an illogical choice. However, there are several compelling reasons why transdermal delivery routes are an important alternative to pills, injections or inhalation routes:  It avoids poor absorption after oral ingestion—especially in animals, the absorption of a drug can vary between the omnivore (e.g., human) and herbivore (e.g., horse) stomach.  It avoids first-pass effect where the blood circulation from the gut passes through the liver to remove absorbed drugs.  It can reduce systemic drug levels to minimize adverse effects.  The design of sustained release formulations overcomes the frequent dosing necessitated by oral and injectables to achieve constant drug levels.  It enables ease and efficacy of drug withdrawal.  Transdermal drug delivery is painless and non-invasive, thereby potentially allowing longer treatment when daily injection is unacceptable or impractical.  It has the potential to target local administration such as for the treatment of flexor tendon disease because the tendons are subcutaneous.      Challenges for transdermal drug applications   The skin is made up of three key layers: the epidermis, dermis and hypodermis (figure 1) and the water-attracting (hydrophilic) or water-repelling (hydrophobic) properties within each raise unique challenges for topical or transdermal drug applications.        Figure 1 – Anatomy of the skin with expanded illustration showing the cells of the stratum corneum (“bricks”) embedded in lipid matrix (“mortar”).      Topical applications, such as insect repellents and sunscreen creams, target the surface of the skin or deliver a drug locally such as for the control of inflammation (insect bite or reaction to an allergen). In contrast the aim of transdermal, or subcutaneous, applications are to deliver the drug deeper to either an adjacent organ, or, more commonly, to the blood circulation as an alternative to oral or needle routes to reach distant organs. The main barrier to local or transdermal delivery is the outermost layer of the skin, called the  stratum corneum  in the epidermis (figure 1). This consists of dead skin cells, the corneocytes, that combine with lipid bilayers into a tightly packed “bricks-and-mortar” layer that form alternating hydrophilic (the water rich corneocytes) and hydrophobic (lipid bilayer) regions (figure 1). The  stratum corneum  therefore not only forms a mechanically robust layer but also presents a challenge in designing drugs with chemical properties that can negotiate their way into and through these contrasting hydrophobic and hydrophilic environments to reach the lower region of the epidermis. The epidermis consists of living skin cells but has no blood vessels for the drug to diffuse into, so instead the drug must penetrate further to the dermis where it can finally enter the bloodstream or the subcutaneous layers.      Routes for drugs through the skin   Most transdermal drugs are designed so that they diffuse through the skin in a passive fashion. The routes for drug can be through the skin cells (transcellular), around them (intercellular) or using the skin components—hair follicles, sweat glands and sebaceous glands (produce lipids)—to bypass the  stratum corneum  (so-called “appendageal” routes).      Transcellular  route: Drugs pass through the corneocytes of the  stratum corneum  rather than the lipid ‘mortar’ that surrounds them (figure 2). However, the drug has to exit the cell to enter the next corneocyte and therefore through the skin. It means that it has to encounter the external hydrophobic environment between the cells multiple times as it moves through the alternating cell and lipid layers of the epidermis. Drugs therefore have to have balanced hydrophilic and hydrophobic properties to enable this to happen.       Figure 2 – Path of molecules through (A) the stratum corneum for the transcellular route (Note the drug has to enter and exit the aqueous environment of the cells into the surrounding lipid matrix requiring an ability to be soluble in both); (B) Intercellular route (Note the tortuous path for molecules passing through the stratum corneum via this route which delays diffusion.)       Intercellular  route: The drug predominantly diffuses through the lipid rich “mortar” around the corneocytes of the epidermis. This lipid matrix can form a continuous route through the epidermis (avoiding entering the cells), but this route has been suggested to be less efficient because it increases the distance 50-fold3 compared to the direct route through the  stratum corneum  due to the interdigitating brick and mortar arrangement (figure 2). Again, the chemical formulation used to carry the drug is important and drugs that more readily dissolve in lipids benefit from this route.      Appendageal  route: The hair, sweat glands and sebaceous glands provide a direct channel to the deep layers of the skin circumventing the hazardous barriers of the epidermis and dermis. The main challenge for this relatively easy route is that the amount of drug that can be taken up is limited by the density of hair follicles and sweat glands, although in haired animals, such as the horse, the density can be as high as 1-5% of the skin surface area. Furthermore, sweat from an active sweat gland would be travelling against the direction of drug flow, washing out the drug and its carrier and severely limit drug uptake. It is likely that all skin applications use this appendageal route as it’s unavoidable but probably more efficient for drugs that are large molecules.      Optimising skin penetration   Newer approaches can incorporate physical and active methods to improve drug movement, such as:   Chemical formulations : This is the most common approach for preparing a drug for skin applications. The basic principle is to prepare a supersaturated solution or suspension of the drug. However, the uptake of the drug depends on the nature of the solvents used to resuspend the drug, which can include among other things water, various alcohols and esters, which provide different amounts of positive and negative charges that can interact with the drug and the components of the skin such as water, lipids and proteins. The exact combination that most efficiently drives the movement of the drug through the skin has to be empirically tested in the laboratory. A database of critical parameters can be derived from which to determine the ideal combination to achieve optimum drug levels for topical or systemic administration.      Liposome formulations : Chemical formulations have been modified to include lipids that mimic the outer bilipid layer of the cells. These bilipids can spontaneously form into small spheres (liposomes) within which drug molecules can be enclosed acting as a protective transport vehicle to carry the drug through the skin (figure 3).           Figure 3 – Liposome structure used to carry drugs through the skin. The drug of interest is shown as the large red or blue dots.      This arrangement can help avoid difficulties such as poor drug solubility. The current view is that the liposomes absorb into and fuse with the skin, and the broken lipid components boost the penetration of the drug. The efficiency can vary depending on conditions such as the size of the liposome and other chemical characteristics that can be introduced into the liposome structure. Introducing a mild detergent leads to a highly elastic liposome, which has been proposed to enable the structure to squeeze into narrow spaces in the bricks and mortar of the  stratum corneum .      Microneedles : This approach uses minute needles arranged on a surface which when applied to the skin can penetrate the  stratum corneum  (figure 4). As they do not penetrate the dermis where the nerves are located, this is painless. Solid microneedles form very tiny channels in the  stratum corneum  so that the drug can travel into the dermis bypassing the  stratum corneum  barrier. In some cases the drug is coated onto the surface of the microneedle tips to deposit a drug below the  stratum corneum . Microneedles are made from silicon or various metals and can have a hollow centre to act like a hypodermic needle through which a drug can be transferred deep into the skin. Other variations include those made from materials that are soluble such as sugars. These biodegradable types can be packed with the drug, and the whole microneedle deposited into the skin to release the drug as the soluble scaffold dissolves with time. The packing density of the microneedles can determine the drug dose to be delivered and is pain-free. The key challenges with using microneedles is the volume of drug that can be loaded and delivered and the skin surface area they can currently cover. This can be an issue for drugs that are not highly potent in their action (as more drug is required).           Figure 4 – Microneedles. Left panel is a typical template with microneedles on the end of a fingertip to show its relative size; the middle panel shows a magnified view of the microneedles; and the right panel is a roller-type applicator with the microneedles on the roller surface.    (Credit: UNC Chapel Hill)4       Horse skin properties and the potential for transdermal applications   Our work, has exploited emerging state-of-the-art strategies from human medicine to develop scientifically-based transdermal drug delivery systems. However, horse skin is structurally different from human, and there has been only limited characterization of the barrier properties of horse skin based on the diffusion of a few specific drugs in vitro. Consequently, this route of administration is poorly developed for horse and the fundamental properties of skin from different anatomical locations has not been systematically investigated.  We have found that while horse and human skin have remarkably similar overall thickness, the horse skin has a range of thicknesses dependent on its anatomical location with the metacarpal and croup skin being the thickest and the inner thigh the thinnest. The skin thickness does not appear to be related to the epidermis since this is thickest in the metacarpal and inner thigh skin and thinnest in the neck skin. However, the ratio of the dermis to epidermis is greatest for the croup skin (40-fold) compared to the inner thigh (15-fold). In addition, the density of hair follicles also varies with the neck and metatarsal skin having the greatest density and the croup and inner thigh the lowest, which suggests that appendageal routes could be more efficiently exploited in the neck or metatarsal skin.     To complicate things further, two other parameters influence the delivery of drugs to the body—the lag time and rate of “flow” of the drug through the skin. To maximize the delivery of a drug through the skin, we need one that has a high flux and low lag time. Consequently, we have devised an “FLT ratio” to provide an objective measure of this—the higher the value the better the drug can be delivered. The flank and croup had the highest values for hydrophilic drugs (e.g., caffeine), while the inner thigh was highest for the hydrophobic drugs (e.g., ibuprofen).     Our work highlights the site-to-site variations in drug delivery through equine skin when designing transdermal formulations for clinical applications to optimize treatment. To maximize delivery to the systemic blood, drugs that are hydrophilic in nature could be targeted via the flank or croup, whereas hydrophobic molecules could be targeted via the inner thigh skin.      Exciting new applications for the technology   In addition to the obvious usefulness in delivering established drugs for therapy, transdermal drug delivery could potentially be used to deliver new small therapeutic molecules locally. We are particularly interested is harnessing this technology as a preventative strategy for injuries to the superficial digital flexor tendon (SDFT). The SDFT of the forelimb is frequently injured in athletic and sports horses and can be career ending. It is also a major cause of wastage in the industry. Our previous work shows that the damage to the tissue starts before there are obvious clinical signs and that specific classes of enzymes are actively involved in this pre-clinical phase. Since the SDFT lies just under the skin, we propose that a transdermal approach to deliver inhibitory drugs to the metacarpal region skin could deliver the drug directly to the SDFT. This would overcome the side effects reported when such drugs are delivered to the whole body. In addition, application during or soon after exercise, when the degradative processes are most active, could be a more effective preventative approach and our current work, also supported by the Horserace Betting Levy Board, is evaluating such small molecule inhibitors with this in mind. Challenges still remain but our systematic analysis of the horse skin properties is a step in the right direction for this and other disorders.      References   J Dudhia1, S Bizley1,2, A Williams2, RK Smith1  2Department of Clinical Sciences and Services, Royal Veterinary College, University of London North Mymms AL9 7TA UK; 2School of Pharmacy, Whiteknights Campus, University of Reading, RG6 6AF UK     [1] Geller MJ (2010). Ancient Babylonian Medicine, 1st edn. Wiley-Blackwell: Malden, MA.  [2] Williams, AC (2003) Transdermal and Topical Drug Delivery from Theory to Clinical Practice Pharmaceutical Press.  [3] Potts RO, Francoeur ML. Lipid biophysics of water loss through the skin. Proc Natl Acad Sci USA 1990; 87: 3871-3.  [4] Zhang Y, Liu Q, Yu J, Yu S, Wang J, Qiang L, Gu Z. Locally induced adipose tissue browning by microneedle patch for obesity treatment. ACS Nano 2017; 11: 9223-30.      Acknowledgement   We are grateful to the British Horserace Betting Levy Board for funding this research.

By Professor Roger Smith

Ancient art, modern science

One shared medicinal practice among disparate ancient societies was the application of primitive ointments to the skin to treat almost all and any ailments. A vast plethora of poultices and plasters have been described, including in Babylonian and Greek medicine texts1 among others, suggesting that the magical health-restoring powers of ointments were well-recognized to traverse the skin. Thus, it was no coincidence that the skin was the preferred therapeutic route over surgical (and oral) intervention since the former method was likely to result in reduced mortality rates compared to the latter; undoubtedly an important consideration, given that the top ancient physicians were likely charged with the health of the royal courts.

Although the art of transdermal delivery of medicines dates back millennia, it is only in more recent times that the science of transdermal drug delivery in man has advanced significantly.  The choice of modern drugs for topical applications is, however, relatively limited compared to the seemingly infinite choice available for oral delivery. This is perhaps not surprising since the gut is an organ that has evolved with the main purpose of absorbing food (chemicals when it comes to it) whereas the skin, despite being the largest organ, has evolved primarily as a protective layer to prevent desiccation of underlying tissues and to keep out harmful environmental chemicals. As this includes medicinal drugs, the pursuit of transdermal administration would appear, at first sight, to be an illogical choice. However, there are several compelling reasons why transdermal delivery routes are an important alternative to pills, injections or inhalation routes:

  • It avoids poor absorption after oral ingestion—especially in animals, the absorption of a drug can vary between the omnivore (e.g., human) and herbivore (e.g., horse) stomach.  

  • It avoids first-pass effect where the blood circulation from the gut passes through the liver to remove absorbed drugs.

  • It can reduce systemic drug levels to minimize adverse effects.

  • The design of sustained release formulations overcomes the frequent dosing necessitated by oral and injectables to achieve constant drug levels.

  • It enables ease and efficacy of drug withdrawal.

  • Transdermal drug delivery is painless and non-invasive, thereby potentially allowing longer treatment when daily injection is unacceptable or impractical.

  • It has the potential to target local administration such as for the treatment of flexor tendon disease because the tendons are subcutaneous.

Challenges for transdermal drug applications

The skin is made up of three key layers: the epidermis, dermis and hypodermis and the water-attracting (hydrophilic) or water-repelling (hydrophobic) properties within each raise unique challenges for topical or transdermal drug applications.  

Topical applications, such as insect repellents and sunscreen creams, target the surface of the skin or deliver a drug locally such as for the control of inflammation (insect bite or reaction to an allergen). In contrast the aim of transdermal, or subcutaneous, applications are to deliver the drug deeper to either an adjacent organ, or, more commonly, to the blood circulation as an alternative to oral or needle routes to reach distant organs. The main barrier to local or transdermal delivery is the outermost layer of the skin, called the stratum corneum in the epidermis. This consists of dead skin cells, the corneocytes, that combine with lipid bilayers into a tightly packed “bricks-and-mortar” layer that form alternating hydrophilic (the water rich corneocytes) and hydrophobic (lipid bilayer) regions (figure 1). The stratum corneum therefore not only forms a mechanically robust layer but also presents a challenge in designing drugs with chemical properties that can negotiate their way into and through these contrasting hydrophobic and hydrophilic environments to reach the lower region of the epidermis. The epidermis consists of living skin cells but has no blood vessels for the drug to diffuse into, so instead the drug must penetrate further to the dermis where it can finally enter the bloodstream or the subcutaneous layers.

Routes for drugs through the skin

Copy of shutterstock_625969397.jpg

Most transdermal drugs are designed so that they diffuse through the skin in a passive fashion. The routes for drug can be through the skin cells (transcellular), around them (intercellular) or using the skin components—hair follicles, sweat glands and sebaceous glands (produce lipids)—to bypass the stratum corneum (so-called “appendageal” routes).

Transcellular route: Drugs pass through the corneocytes of the stratum corneum rather than the lipid ‘mortar’ that surrounds them. However, the drug has to exit the cell to enter the next corneocyte and therefore through the skin. It means that it has to encounter the external hydrophobic environment between the cells multiple times as it moves through the alternating cell and lipid layers of the epidermis. Drugs therefore have to have balanced hydrophilic and hydrophobic properties to enable this to happen. 

Intercellular route: The drug predominantly diffuses through the lipid rich “mortar” around the corneocytes of the epidermis. This lipid matrix can form a continuous route through the epidermis (avoiding entering the cells), but this route has been suggested to be less efficient because it increases the distance 50-fold3 compared to the direct route through the stratum corneum due to the interdigitating brick and mortar arrangement. Again, the chemical formulation used to carry the drug is important and drugs that more readily dissolve in lipids benefit from this route.

Appendageal route: The hair, sweat glands and sebaceous glands provide a direct channel to the deep layers of the skin circumventing the hazardous barriers of the epidermis and dermis. The main challenge for this relatively easy route is that the amount of drug that can be taken up is limited by the density of hair follicles and sweat glands, although in haired animals, such as the horse, the density can be as high as 1-5% of the skin surface area. Furthermore, sweat from an active sweat gland would be travelling against the direction of drug flow, washing out the drug and its carrier and severely limit drug uptake. It is likely that all skin applications use this appendageal route as it’s unavoidable but probably more efficient for drugs that are large molecules.

Optimising skin penetration…

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