Non-invasive drug delivery technology: development and current status of transdermal drug delivery devices, techniques and biomedical applications

Developmental perspective: an introduction to TDDS

The transdermal drug delivery system (TDDS) is a painless, non-invasive method of drug delivery and takes precedence over other conventional delivery routes in this matter. Here, the drug is delivered in a discrete dosage form from a skin-sticker patch or other transdermal methods/device by crossing through the skin layers to the systemic circulation. The TDDS has made a significant influence on a number and variety of therapeutic agents’ delivery, especially in pain management, hormonal therapy, and cardiovascular and central nervous systems’ diseases. The technique has proven to be a successful substitute for various routes of administration, e.g. oral, parenteral, intravenous, intramuscular, hypodermal shots, and other invasive delivery modes. However, it is still far from utilizing its complete potential, and the basic TDDS/devices still deliver small doses of drugs which are preferably lipophilic in nature. However, more advances in the TDDS techniques and discovery of delivery devices over time have resulted in delivering both lipophilic and hydrophilic, as well as amphiphilic drugs, sometimes with the help of delivery/permeation enhancers as well as newer physical techniques of delivery with minimal damage to the soft tissues of the skin. Nonetheless, the dose levels are still not competitive in comparison to the traditional delivery options. In this connection, the ability to use voltage-gradient iontophoresis with proper and steady regulation of drug distribution has afforded better delivery choices and performance. Microneedles, thermal ablation, microdermabrasion, electroporation, radiofrequency usage, microporation, use of thermal techniques, micro and radio waves, electro-mechanical devices, nano deliveries and cavitational ultrasound techniques have immensely contributed toward making the initial TDDS techniques more user-friendly, competitive in dose delivery levels, cost-effective, viable to opt and feasible to use. The advent of innovative new approaches and continuous technology development has made the TDDS today a top contender for drug delivery modes preferences.

Historically, after the successful launch of scopolamine patch as the first TDDS to treat motion sickness and nausea, nicotine patches have turned out to be a mega medicine after a decade of launch, which has increased the acceptance and importance of transdermal delivery in therapy and prophylactics with greater interest for people in them. The transdermal route for administering a drug also has great potential in the medical device markets for both over-the-counter and prescription drug segments. The current (ca 2019) market of transdermal patches in the US and globally is estimated to be very high at between 1500 million and 4500 million USD (US Dollars), respectively, and is expected to rise at ~7% annually over the period until 2024 [1]. Patches for nicotine replacement therapy and female contraceptives are very popular, while patches made for insulin and other vaccinations are in early marketing and clinical trial levels, respectively, which may be commercialized soon (Table 1).

The TDDS technique helps to decrease the dose, enhance the therapeutic efficacy and therapeutic value, and circumvent the problem associated with a drug’s toxicity, drug formulation problems as well as related troublesome pharmacokinetics, if any. The technique also avoids therapeutic failures, losses of dose-frequency and chronological dosings for the patient. The technique works as a self-administered, non-invasive, painless tool and typically allows less frequent or one-time dosing application in comparison to oral and other routes of administration. It is also, by and large, inexpensive and convenient for patients who want to get rid of remembering to take tablets/pills, and is a relief for their caregivers [2], [3], [4], [5]. The delivery mode is helpful in maintaining the drug plasma levels due to consistent infusion and bioavailability of the drug. The drug spreads in the systemic flow by escaping the first-pass metabolism in the liver, and no obliteration of the drug takes place [4]. Moreover, the technique provides an extended period of bioaction, which also results in dropping of the dosing frequency, and as a result, the associated side effects, if any, are minimized. The estradiol patches, popular in millions of patients worldwide, avoid causing liver damage as compared to its oral formulations. The first transdermal patch, scopolamine for treating motion sickness and nausea, is more comfortable than medications such as Zofran (ondansetron) and Phenergan (promethazine). People suffering from angina wear the nitroglycerine patch for 12–14 h a day to relax blood vessels, which considerably lowers the frequency of angina and the consumption of sublingual nitroglycerin [5]. A comparative study among oral formulations (in tablet form of 50 mg, 3 times daily for 3 days) and a transdermal patch of diclofenac (applied once a day for 3 days) was carried out on 20 young pre-orthodontic patients, and statistical records of pain relief and pain intensity were recorded. Though both had nearly the same outcomes, the subjects were happier with using patches (as it was a one-time per day application) with comparatively less of systemic adverse effects [6]. However, skin reactions, skin decoloration, allergies, disruption of the skin-barrier layers and blood level alterations are the pitfalls of this technique. Skin reactions, although many, including contact dermatitis, with the most common and foremost being allergy and/or topical irritation, are wide-spread for certain patches but also depend upon the individual using them. Nonetheless, the majority of drugs’ adverse reactions (ADRs) are mild in nature and the cessation rate is low (1.7–6.8%) [7], [8], [9], [10]. The permeability levels and barrier functions of the skin keep on conditionally changing with the change of patch, sticking-site on the skin and the age of the person. However, some of the drugs necessitate high blood levels and hence cannot be administered topically. Another important disadvantage of the TDDS, especially for patches, includes an inherent adhesive system which may become the cause of the failure or the reason for problematic delivery. However, modified adhesives are continuously improving the situation but the same adhesive may or may not work for all skin types and its properties may get disrupted due to sweating, showering or swimming [2], [7], [11] and at certain times, the drug permeation may not be feasible due to compatibility reasons associated with the adhesive, and various problems may arise making the device uncomfortable to wear. Another major shortcoming of the TDDS patches is that they are late in performing the therapeutic action in comparison with other routes of administrations, especially intravenous delivery. Additionally, the drug infusion frequency may also fluctuate by the site of the TDDS application. Infusion rates are good at places like palms, face and genitalia, although some cases have been reported where an overdose of the drug was delivered by a broke-up, cut-open or chewed-upon TDDS patch/device, or too many non-compatible devices were worn, or multiple TDDS devices used by the patient. Over-dosing can also happen if a child wears the patch prescribed for an adult. At times, the TDDS can cause local edema, skin irritations and burns, which may be due to the drug’s nature, reactivity, nature of the formulation, the patch’s paste material, or other excipients, delivery enhancers and adhesives present or, used and retained in the TDDS preparations. Therefore, the transdermal patches have several limitations and they may act as hindrance to effective delivery of a variety of drugs.

Skin and drug permeation: routes and factors

For the TDDS to be effective, it is required that the drug loaded inside of the transdermal drug delivery device is absorbed into the systemic circulation after passing through skin layers at an effective level of consistent rate and continuous supply during the usage period. The percutaneous absorption facilitates the infusion of diverse but characteristically defined molecular entities across the skin barrier, and any further absorption of the substance gets it into the systemic circulation. The absorption ideally follows two ways, the trans-epidermal and the trans-follicular routes. The drug from the TDDS device comes to the blood tributary and enters the systematic circulation either from the stratum corneum (SC, a layer in skin), (trans-epidermal) or, from the appendage (trans-appendage) areas of the skin. In the case of the trans-epidermal route, the drug diffusion can further follow two likely paths: intracellular and intercellular. In the intracellular or transcellular route, the hydrophilic drug crosses through the cells with assistance from lipid lamellae, and the hydrophilic drugs cross the SC due to the hydrophilic nature of the keratinocytes, both ultimately reach to the systemic circulation. The intercellular route is considered the principal transdermal delivery route which lets molecules pass between the cells of the SC that facilitate the nonpolar, lipoid entities. Transfollicular penetration (shunt pathway) is also of great importance for delivering large polar products wherein the drug molecules sense their paths through hair cavities, the sebaceous gland of pilosebaceous units or the watery/fluid route. Although hair cavities and sweat glands merely encompass 0.1% of the entire skin layer zone, which comparatively is a very minor part, the shunt pathway entails minimum risk and is ranked the most feasible among all other skin routes [12], [13] (Figure 1).

Figure 1:

Drug absorption routing through the skin.

The physiochemical and physiological factors are vital in the drug infusion phenomenon through the skin. Moisture contents, anatomical location and age of the skin have important roles to play in controlling the absorption rate. Due to lack of moisture, aged skin does lesser and slower absorption than younger skin [14], [15]. The local metabolism and decreased blood flow results in a negative impact on drug influx through the skin [15], which is a passive process, and an increase in the temperature changes the dynamics of the absorption due to increase in drugs’ kinetic energy. As a consequence, some perturbations take place in SC and the tissues located below it which makes the drug material move faster [15], [16]. Nonetheless, there are issues affecting the drug absorption. For a molecule to get a clear path across the SC, it should have desirable physicochemical traits compatible with the skin barrier properties [17].

The SC, a selectively permeable and rate-determining layer, is a lipophilic coat [18]. The low levels of hydration in the living cells of the viable epidermis and other SC underneath layers of the skin together with the inherently present aqueous affinity therein allows the drugs having both hydrophilic and lipophilic properties to infuse through the skin layers [19], [20]. However, structural changes to adjust the required amphoteric solubility in a hydrophilic drug can be achieved by salt formation, esterification and methylation or capping of the hydrophilic moieties in the drug, as also approached for prodrug formation, and can help with the solubility issues and consequently enhances permeation. However, hydrogen bonding decreases drug permeation, and increased bonding tends to inhibit the drug permeation [15].

Diffusion through the skin needs drug partitioning in the skin layers [21], and based on this partitioning behavior, hydrophilic drugs pass easily via the intracellular paths while lipophilic drugs would normally use the intercellular pathway. Partitioning of the drug, represented by the partition coefficient, log P, is a crucial indicator of skin permeability of a drug [22], [23]. Again, the log D (distribution coefficient) value of a drug is also an important factor determining transdermal infusions. Under normal diffusion conditions, the skin easily allows drugs with an average molecular weight (MW) of <500 Da [15]. Molecular size and transdermal penetration follows an inverse relationship [24].

Among other physical factors influencing permeation are the drugs’ melting points, ionization capabilities and the crystallinity of the drug molecule. Drugs with higher melting points, generally above 150°C, show lower aqueous solubility [25], and therefore, drugs with a low melting point possessing increased solubility show enhanced permeation. A relationship between the melting point and solubility has been devised [26].

The partition coefficient of a drug is an other important factor determining the choice of the pathway of permeation. The log P values of drugs lower than −1 pose difficulty in permeation through SC, and molecules above log P − 1 are good enough for delivery. However, products with a log P value above 2 are stuck in the SC [22]. However, another report states that drugs with a log P value in the range of 1–3 have crossed the SC barrier and were delivered to the intended site [15]. A linear relationship between the partition coefficient and transdermal delivery has been noticed. Moreover, higher loading/higher concentrations of the drug are favored for elevated levels of the concentration gradient across the skin which facilitates the delivery. However, any injury to the skin affecting the SC disrupts the delivery [27], [28].

The degree of drug passage, in case of ionized drugs, is comparatively lesser than the unionized drug, and the shunt pathway is followed [15]. The pH value of the epidermis layer of the skin ranges from 7.3 to 7.4, while the pH in the SC layer is 4.2–5.6. The level of the uncharged drug passage at the site of absorption depends on its hydrogen ion concentration [H⁺] and the dissociation constant (D) [17], [29], [30], [31]. The SC favors hydrogen bonding, and the drug molecules’ H-bonding with various skin components have lengthy/paused duration of drug absorption and drugs infusion effectively stops through the skin albeit a little over time [15]. Melting point and drug solubility are inversely proportional [25], and an increase in drug solubility decreases the SC infusion and passage through the skin [32]. Moreover, saturated solutions have maximum thermodynamic activity [33] and are helpful in permeation.

Other physiological factors that influence drug absorption are temperature, blood flow to the skin and enzymatic activity of the skin. The anatomical location of the skin plays its part in the delivery. The genital areas have greater absorption capacity as compared to the head, neck, trunk, arms and legs [15]. Racial differences in relation to lipid contents in skin permeation have been researched and been found to vary according to the lipid component ratio in the skin layers [14], [15], [30], [31], [34], [35]. An increase in temperature increases the kinetic energy of the drug molecule and the molecule passes the skin-barrier easily and fast [15], [16].

The metabolic enzymes present in the skin cause biotransformation and may help the prodrug if it is designed to pass the skin barrier through structural changes sought by the metabolic bioconversions, making it one of the rate-determining steps, and the metabolic phenomenon is the highest in the epidermis section of the skin [36].

In this context of permeability, the obviousness lies in the size of the drug molecule. Low molecular weight (LMW) under 500 Da and smaller size and molecular volume of drugs have preferentially been found suitable for passive diffusion through the skin, although with some exceptions [37] suggesting that the upper limit of the MW range of a drug could indeed exceed 500 Da, but they still efficiently permeate the skin through passive diffusion. However, the drug cannot attain a very high level of concentration in the plasma, and periodic or pulsating drug delivery is not possible in the TDDS yet.

Product development approach: quality by design (QbD)

Several approaches have emerged over time to develop the desired TDDS products and devices. The development has centered on the physicochemical properties of the drug, formulating and device’s constitutional components, and their characteristics in considerations with the skin sites. Fundamentally, the initial development was focused on the indirect methods to cross the skin barrier and enhance the drug influx and permeability by design considerations. The membrane permeation, diffusivity, maintaining drug gradient in transport through the skin, adhesive properties and its role in drug release, the micro-reservoir of the drug for constant, uniform and sustained release kinetics are some of the factors. Membrane-moderated delivery systems were developed wherein the solid drug is dissolved in a solid polymer matrix or kept suspended in a viscous media inside a shallow compartment from where the drug was modulated through a drug-impermeable metallic plastic laminate and a rate-controlling polymer-based diffusible membrane. The drug molecules are allowed to be released only through the rate-controlling polymeric membrane, which needs to be a microporous or a non-porous entity with known drug permeability properties. To achieve an intimate contact of TDDS with the skin surface, a thin layer of the drug-compatible hypoallergenic adhesive is applied [28], [36], [38], [39], [40]. The intrinsic rate of the drug release from this type of drug delivery system has the delivery relationship expressed as follows:

dQ/dT=CR/(1/Pm+1/Pa)

where dQ/dT expresses release rate, and CR equals the drug concentration in the reservoir compartment, Pa denotes the permeability coefficient of the adhesive layer and Pm stands for the permeability coefficient of the rate-controlling membrane.

Thus, the TDDS drug release was maneuvered by polymer composition, the permeability coefficient, thickness of the rate-limiting membrane and the adhesive.

Another design approach, the adhesive diffusion control system, utilized a thin layer of the non-medicated, rate-controlled, adhesive polymer of constant thickness wherein the drug disperses into the adhesive polymer and then spreads across the medicated adhesive and onto the reservoir layer (Figure 2).

Figure 2:

Adhesive dispersion system.

The rate of drug release for the adhesive diffusion control system is denoted as follows:

dQ/dT=(Ka/r)×Da×(CR/δa)

where Ka/r equals the partition coefficient for interfacial partitioning of the drug from the reservoir layer to the adhesive layer, Da is equal to the diffusion coefficient in the adhesive layer, δa is equal to the thickness of the adhesive layer, and CR represents the drug concentration in the reservoir compartment.

The matrix dispersion type systems (Figure 3) were also developed where the reservoir was formed by homogeneously dispersing the drug in a hydrophilic or a lipophilic polymer matrix and then modulated into a medicated disc with a definite and predefined surface area and controlled thickness. For testing, this disc was then glued to an occlusive base-plate in a compartment fabricated from a drug-impermeable plastic backing. The adhesive polymer was spread in circumference to form an adhesive rim around the medicated disc.

Figure 3:

Matrix dispersion system.

The rate of drug release (dQ/dT) from this matrix dispersion system is defined as follows:

dQ/dT=√A×Cp×Dp/2T

where A is equal to the initial drug loading in the polymer matrix dispersal unit, and Cp and Dp are the solubility and diffusivity of the drug in the polymer, respectively, and T stands for the time.

The microreservoir system was formed by suspending the (solid form) drug in an aqueous solution of water-soluble polymer and homogeneously dispersing drug suspension in a lipophilic polymer through high shear mechanical force. The cross-linking of the polymer chain to the medicated polymer disc of constant surface area and defined thickness stabilized the transdermal drug delivery device/system [41], [42] (Figure 4).

Figure 4:

Micro-reservoir system.

Drug selection: physical, pharmacokinetic and biological parameters

Permeation across skin layers and reach out to the systemic circulation is a gradual process involving penetration, partition and passing through the SC to the epidermis, diffusion into the upper dermis, permeation through downward layers to final absorption into the systemic circulation. The drug in the TDDS is either stored as solid dosage form in a reservoir or is present as a liquid/gel-dissolved material. The flux across the skin is expressed as μg/cm²/h and the drug is released until the concentration gradient exists [43], [44]. An initial lag time, small or large, exists, and the drug typically follows steady-release kinetics.

The TDDS needs to provide the thermodynamic thrust toward passive diffusion across the skin. As the ability of drugs to penetrate the skin barrier varies, certain drugs have low fluxes and the delivery is constricted. Drug load in the TDDS first meets the challenge of being highly potent in pharmacological action, and secondly being compatible with the transdermal delivery by having a favorable set of physicochemical properties. Nonetheless, the low permeability of drugs owing to the skin barrier has been enhanced through a number of chemical-, physical-, physicomechanical-, radiative- and acoustics-based techniques to enhance the delivery output [44], [45].

Additionally, some of the pharmacokinetic parameters influencing the transdermal drug delivery include half-life of the drug, its volume of distribution, whole body clearance, therapeutic concentrations in plasma and its bioavailability. However, the physicochemical constraints to the TDDS applicability include favorable levels of the molecular properties, and available drug concentration including its solubility, crystallinity, molecular weight, polarity, melting point, partition coefficient (log P), dissociation constant, ionization capability, hydrogen bonding and distribution coefficient (log D) [46]. The biological factors restricting the transdermal drug delivery technique used in patients include skin irritation, site of application, skin toxicity, on-site metabolism, allergic reactions, permeability, and most importantly, the acceptability of the undesired effect(s) by the patient [17]. Nonetheless, an estimate of drug input from the TDDS is considered by accounting the volume of distribution (Vd), whole body clearance time (Cl_T) and the steady therapeutic concentration (CPss) of the drug in the plasma. The input rate is expressed as a function of dosing and the bioavailability factor, while the output rate of the drug is a function of whole body clearance time of the drug multiplied by steady-state plasma concentrations of the drug. The input and output rates are supposed to be equal and follow concentration gradient-based diffusion. For the majority of drugs, the whole body clearance equals to the volume of distribution and the drug’s elimination rate, and accordingly, the required flux of a drug is equal to a factor of whole body clearance and steady-state therapeutic concentration in the plasma divided by the surface area of the applied TDDS [47].

The influx of the drug, denoted as J, permeating the skin is considered as follows:

where D is the diffusivity, and dC/dT denotes the concentration gradient.

For a constant delivery situation, considering passing mass M of the drug in time T:

where M is the aggregate of the mass of drug per unit area per unit time passing through the skin layers, and Co is the concentration of the diffusing drug through the starting layer of skin, while h is equal to skin thickness.

Then:

where P is equal to the partition coefficient.

Now, from equations 2 and 3:

Therefore, the skin permeation is a function of diffusivity, skin thickness, partition coefficient of the drug and available effective concentration of the drug, C′o. Nonetheless, an ideal drug suitable to function as part of the TDDS/device needs to have a smaller dose, preferably below 20 mg/day, a half-life of 10 or lesser hours, molecular weight under 400 Da, partition coefficient between −1 and 3, permeability coefficient in excess of 0.5×10^–3 cm/h, and non-toxic, non-irritant, no adverse reaction, near zero or zero metabolism as well as low oral bioavailability and low therapeutic index to qualify as an ideal transdermal drug delivery candidate.

Drug delivery systems: transdermal patches and devices

Based on design considerations emanating from various formulation factors, inherent physicochemical and desired biological properties, including adhesives and excipient characteristics, several TDDS patches have been developed, which include single- and multiple-layered devices, vapor patches, drug and polymer matrix characteristic-based products, as well as reservoir-based delivery systems.

A transdermal patch consists of a liner which is in direct contact with the drug and inhibits losing the drug while under storage, and is required to be peeled off before use. The layer after peel-off of the liner consists of an adhesive which serves to adhere to the components of the patch along with working as the sticking platform of the patch to the skin. It provides the needed support to the patch and the loaded drug, while the membrane regulates the drug release from the reservoir and multi-layered patches to the skin and across the blood circulation over a fixed period of time. The backing membrane separates the TDDS from the outer environment [39], [54]. An adhesive serves two functions: it acts as the glue that keeps the patch adhered to the skin, and it also acts as the suspension that holds the drug. The major problem associated with this technique is the concentration of the drug within the adhesive, which directly affects the stickiness of the adhesive; so if large quantities of the drug are to be administered, either the size of the patch has to be increased or the patch needs to be reapplied again and again by the patient to supply enough, and continuously maintained doses of the drug. To overcome this problem, several biocompatible, biodegradable, pharmaceutical-grade chemicals, also termed as enhancers, have been combined with the formulation matrix to improve the existing drug’s penetration through the skin, from the TDDS device, in order to improve the drug absorption. A transdermal patch filled with the precise drug dose and stuck to the skin easily makes the drug enter into the blood circulation with help from enhancers [55], [56].

The sheathing system controlling diffusion-based transdermal drug delivery devices have a polymeric membrane to control the drug release rate, which depends on the polymer properties, permeability coefficient, membrane thickness and the adhesive. The drug compartment is completely embedded in the metallic plastic seal, with the polymeric membrane controlling the drug release according to the following expression:

The drug release rate dQdt equals CR1/Pm+1/Pa

where C_R represents the drug concentration, and Pm and Pa represent the permeability coefficients of the membrane and the adhesive, respectively. Thus, the membrane and adhesive permeability control the drug release, no matter how strong the drug concentration might be present in the reservoir.

Adhesive-dispersion type TTDS/devices use polymer, e.g. polyisobutylene or polyacrylate, as the adhesive which is applied on the upper side of the reservoir to a uniform piece of drug-resistant metallic support to make a thin drug reservoir layer beneath it. The polymer has specific permeability and controls the drug diffusion rate. In the micro-reservoir device, the drug material is uniformly suspended in the biocompatible polymer which regulates its release rate [38].

Single and multi-layered drug loads in adhesives are the fundamental concept. In the single-layered drug load, a drug is loaded onto the adhesive which is surrounded by the temporary liner and backing membrane. In the multiple-layered drug load, an instant drug release layer is available while the next layers are loaded onto the adhesives. This adhesive layer is responsible for the long-term release of the drug. The adhesive layer of the device is also surrounded by a temporary liner and a backing membrane.

The vapor patch releases the drug as a vapor, and the adhesive layer serves to contain all layers and constituents together. The device is used for releasing essential oils, usually for decongestion. Various other vapor patches are also available for improving the quality of sleep and to reduce the cigarette smoking status.

The reservoir system-based transdermal drug delivery device holds the drug reservoir embedded in between an impervious backing layer and a rate-controlling polymer-based permeable membrane. The drug releases are only through the rate-controlling membrane, which can also be microporous or nonporous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or be dispersed in a solid polymer matrix. The hypoallergenic adhesive polymer can be also be applied as an outer surface polymeric membrane, which needs to be compatible with the drug.

Matrix-based systems control drug diffusion more efficiently where the reservoir holds the dispersed drug in an adhesive polymer, and this medicated adhesive polymer is spread by solvent casting or melting (in the case of hot-melt adhesives) on an impervious backing layer. On top of the reservoir, unmediated adhesive polymer layers are applied for protection purpose. This system is classified as a drug-in-adhesive system [56]. In the other prototype, called matrix-dispersion system, the drug is dispersed homogeneously in a hydrophilic or lipophilic polymer matrix. The drug-containing polymer disk is fixed on to an occlusive base plate in a compartment fabricated from a drug-impermeable backing layer, and instead of applying the adhesive on the face of the drug reservoir, it is spread along the circumference to form a rim of adhesive. The drug storage compartment is supported by an impermeable membrane from one side and a drug release rate regulator from the other side.

The microreservoir system is a combination of the reservoir and matrix-dispersion systems. The drug reservoir is formed by suspending the drug in an aqueous solution of water-soluble polymer and then this solution is homogeneously dispersed in a lipophilic polymer to form microscopic spheres of the drug. The thermodynamically unstable dispersion is immediately stabilized by in situ cross-linking of the polymer by use of a cross-linking agent [57].

Micro-fabricated microneedle devices have the features of both the hypodermic needle and the transdermal patch. The device has very minute, needle-like outcrops. The device consists of a drug reservoir and projections (microneedles) extending from the reservoir to help in penetrating the SC and epidermis layers of the skin to deliver the drug [58]. The device pierces into the skin followed by the application of the drug patch at the site of treatment and is called as poke-with-patch. When the microneedles are loaded with the drug and inserted into the skin to release the drug, the approach is called a coat-and-poke approach. Other approaches utilize biodegradable polymeric microneedles for insertion into the skin, or hollow microneedles are used to inject the drug load [59]. The microneedle technique utilizes an array of several microscopic projections protruding from a support base or patch with 25–2000 μm height [60], [61], 50–250 μm of width on the support base and with 1–25 μm tip diameter [62], [63], [64], [65], [66]. The needle dimension avoids nerve contact upon insertion into the skin [63], [64], [67]. Several techniques are used to fabricate the microneedles, which include lithography, etching, injection molding, light amplification by stimulated emission of radiation (LASER) drilling, LASER cutting and electro-polishing [68].

Macro-flux devices or coated microneedle systems have an area of around 8 cm as well as 300 micro-projections per square centimeter with the length of individual micro-projections less than 200 μm. Three types of macro-flux devices have been made, and they include a dry-coated macro-flux system which is used for a short period of delivery and consists of micro-projection arrays coated with the drug that is adhered to the elastic polymer adhesive onto the backing strip. The other two types include D-Trans and E-Trans macro-flux systems, which are also used for administering the drugs through painless micro-projections and are used to deliver a variety of therapeutic agents including larger proteins, biodegradable macromolecular materials, insulin, hormones, vitamin B, calcein, bovine serum albumin (BSA), plasmid DNA, vaccine and other therapeutic agents [69]. These minimally invasive devices are microfabricated in mainly five types of configurations namely, solid, hollow, coated, dissolved and hydrogel-based [70]. Titanium-made micro-projections with a density about 300/cm² and less than 200 μm in length have been successfully used to deliver a variety of LMW and high-molecular-weight (HMW) larger drugs and biomacromolecules. These needles can be made of metal, carbohydrates and polymers [71]. The microneedles can also be made up of non-metals, such as silicon [72], mesoporous silicon [73], as well as metals such as stainless steel [74], titanium [75], and from synthetic and natural polymers. Among synthetic polymers, polylactic acid [76], polyglycolic acid, polylactide-co-glycolic acid [67], polycarbonate [77], polyvinylpyrrolidone (PVP) and polyvinyl acetate are used. Alginic acid, Gantrez AN-B9, carbopol 971 P-NF [78] and polyetherimide [79] are also employed. Starch [80], carboxymethylcellulose, amylopectins [81] and maltose [82] are other materials utilized for this purpose. The microneedles can also be made of natural and thermoplastic polymers. Polymer microneedles are considered better because of their controlled drug release property. Microneedles are feasible in fabrication, can be mass produced and are cost-effective [83]. Furthermore, microneedles in combination with techniques such as sonophoresis [84], electroporation [85], [86] and iontophoresis [74] are used to improve and further control the drug release rate to provide improved and exact delivery.

The metered-dose transdermal spray is a liquid preparation used topically and is made up of drug dissolved in a volatile liquid vehicle. The device achieves better permeation and desired dose levels of the drug are absorbed through the skin. The device improves delivery potential without skin irritation because of its non-occlusive nature. It also has dose flexibility, a simple manufacturing process and increased acceptability.

Evaluation of TDDS: system stability and parameters

Physicochemical, in vivo and in vitro evaluation tests are considered essential to establish the stability and viability of the TDDS/devices. Following evaluations are important in deciding the TDDS stability, especially of patches and other non-mechanical devices.

Skin permeability enhancers: increased drug absorption

Drug permeability enhancers lead to increased absorption by increasing the membrane permeation. An ideal permeation enhancer needs to be biocompatible with the applied biosystems, and preferably odorless, colorless and tasteless, with enough levels of chemical and physical stability. It also needs to be sterile, non-toxic and non-reactive to the drug without any adverse pharmacological activity including non-affecting the zero order skin permeation rate as well as rapid, sustainable and reproducible. The enhancers need to be tested in vitro before being applied in the TDDS. The enhancer is also required to not initiate body fluid leak. These permeation enhancer agents are functional excipients included in the TDDS formulation cocktail. The enhancement is achieved by SC hydration. The chemical enhancers act on lipid to alter the drug partition through changes in polarity of the environment and thereby changing the drug permeability, and the permeation in itself is the rate-limiting step for transdermal drug absorption. However, use of several enhancers at different concentrations at the same time is not recommended. Moreover, the same amount of single enhancer cannot be formulated with different drugs as part of a single TDDS [94].

Payload delivery enhancements

Various passive and active techniques have been developed to provide control over the drug release rate and transdermal permeation of drugs. The need for expedited delivery has led to various approaches in polymer-based drug delivery modulations constituting complete chemical/structural changes, chemical/structural modifications, as well as formulation modifications as an approach to increase the rate of drug release. These techniques constitute passive methods of enhancements and these enhancers work through an increase in the fluidity of the SC lipid bilayers and SC hydrations, interaction with skin proteins, disruptions of intercellular lipids, and an increase in the thermodynamic activity of the drug. Some of the important passive and active approaches for increased but under-control release of the drug include structure-based, electrical and velocity-based enhancements including some other methodologies to achieve targeted higher levels of drug delivery [125].

Payload delivery enhancement techniques

Payload delivery enhancement devices

Iontophoresis

A limited value, short-timed and localized milli-ampere (0.1–1.0 mA/cm²) current is applied to the skin through minor electrodes which remain in contact with the drug, and the drug can be delivered to both the entire and confined area beneath the skin layers (Figure 5). Pilocarpine delivery can be taken as an example to induce sweat in the diagnosis of cystic fibrosis. Iontophoretic delivery of lidocaine (LidoSite^®) is a good example of this type of delivery for rapid onset of anesthesia [129], [130], [131]. Acne, cystic fibrosis and inflammation are some of the conditions where iontophoretic delivery has been successfully applied. Lidocaine [132], retinoids and steroids [133], anticholinergics [134], pilocarpine [135], and ketoprofen [136] are some of the therapeutic agents which have been delivered through this approach to give enhanced and long-term dosage at increased levels of drug release. However, iontophoresis was not found to be transporting drug substances of HMW, over 7 kDa [137], but the use of chemical class of permeation enhancers and liposomal formulation of insulin and BSA through micro-needle delivery made it possible [138], [139]. The technique also delivered enhanced levels of the drug to hair follicles and nails [139]. A single-use transdermal patch approved by the Food and Drug Administration (FDA) utilized electrical current of 4 mA and released sumatriptan over the hour with a fast onset of therapeutic action in the treatment of migraine, where sustained delivery was achieved for 3 h using a 2-mA current [140], [141]. There is no mechanical penetration in iontophoresis, but very minor effects are on the skin structure for a short period of time [142], [143]. Multiple factors such as pH of the drug solution, molecular size of the drug, hydrophilicity of the drug, type of electrode (preferred Ag/AgCl), current strength (physiological threshold 0.5 mA/cm²), application time (maximum 3 min to avoid burns), pulsation of the current, intermittent application, type of current, etc. are responsible for controlling the delivery through this technique [65], [144], [145], [146]. Iontophoresis is also used in the diagnosis of cystic fibrosis [87], delivery of insulin and monitoring of blood glucose levels [147]. Recently, cytochrome c, ribonuclease A and human basic fibroblast growth factor (hbFGF), and a range of HMW biomacromolecular products over 12 kDa have been successfully delivered [148], [149], [150], [151], [152].

Figure 5:

Iontophoresis apparatus.

Sonophoresis

The desired range of ultrasonic frequencies are generated by an ultrasonic device for improved transdermal drug delivery (Figure 6). A low-frequency ultrasound is more effective and enhances transportation of drugs multifold which creates water paths in the perturbed bilayers through cavitation [205]. The drug substance is mixed with certain couplers as gel or cream which transfers the sonophoretic waves at the skin, which in turn perturb the skin layers to create water paths to infuse the drug [206]. The drug penetrates through the passage created by the ultra-sound energy perturbations, with the energy being usually between 20 KHz and 16 MHz [60]. The ultrasound also increases the temperature at the skin site, and thermal effects take place to facilitate the permeation [207], [208], [209]. The first US-FDA-approved device in 2004, SonoPrep^®, delivered local dermal anesthesia. A number of drugs belonging to various classes, irrespective of their solubility, dissociation and ionization constants, electrical properties including hydrophilic nature, such as mannitol, and HMW drugs such as insulin, have been delivered [210], [211]. However, the exact mechanism of drug penetration through this method is still not fully clear [212] and challenges include availability of the device, duration of exposure and treatment cycles for delivery, and undesirable side-effects including burns [213].

Figure 6:

Sonophoretic apparatus.

Velocity-based payload delivery devices

Delivery enhancements by micro-mechanical devices have entered the TDDS delivery enhancement scenario late. The need for mass delivery at a faster speed and in larger quantities seemed to be pertinent for the development of techniques. The fast-paced delivery, enough quantity, and need to cover a large population within a short period of time with a short span of therapeutic action and therapeutic control of the drug provided the impetus for velocity-based delivery devices.

Thermally assisted and controlled-heat-based devices

Miscellaneous approaches from magnetically driven devices, LASER and radiofrequency uses, and medicated tattoos including thermally-assisted devices have been reported for the purpose of delivery enhancement of several drugs.

Transdermal nanocarriers: a new approach

Nanoscale devices of solid, liquid and liquid crystalline phases have been used as a tool for transdermal delivery [241]. Solid polymeric lipid nanoparticles and colloidal nanogels, micelles, nanoemulsion and nanodispersions are some of the most used carriers for transdermal delivery purposes [242]. Tacrolimus, an immunosuppressive calcineurin inhibitor, was loaded into 10- to 50-nm-sized polymeric micelles to increase the penetration of the drug [243]. Lipid nanoparticles of tacrolimus measuring 20–100 nm showed increased skin targeting [244]. Fluticasone propionate was encapsulated into nano-lipid carriers [245], [246]. Positively charged polymeric chitosan nanoparticles of about 230 nm size were used to deliver hydrocortisone and hydroxyl-tyrosol through the skin, and an increased skin targeting and decreased systemic uptake were observed for the skin-specific delivery [247]. Nano-delivery illustrated lesser demand of the drug. Among other products reported utilizing the nanoscale device for transdermal drug delivery are retinoids, tazarotene and tretinoin encapsulated in polymeric nanocarriers [248], [249]. Methotrexate-coated 4-nm-sized nanoparticles have been used to enhance skin penetration and uptake of drug by keratinocytes [250]. Also, for lipid-based, drug-loaded nanocarriers, the in vitro penetration was greater [251], [252], [253], while sodium carbonate-mediated nanogels, 100 nm, also exhibited increased drug permeation than non-nano deliveries [254]. Cyclosporine-A polymeric nanoparticles [255] and 73-nm solid lipid nanocarriers [256] have also been utilized for dermatitis delivery. Antimicrobial loaded, 200-nm nano lipid-complexed and electrostatically bound silver ions have been delivered for atopic dermatitis [257]. Zinc oxide nanoparticles [258], nC60 fullerenes [259], 200-nm lipid-core capsules loaded with clobetasol propionate [260], 200-nm-sized ketoprofen-loaded chitosan nanoparticles [261] and interleukin (IL)-6 siRNA-loaded 200–270-nm liquid crystalline nanodispersions [262] are some of the examples of nano-based delivery to the skin. Transdermal vaccinations [263], antiparkinsonian and anti-hypertensive drugs [10], [264], several chemotherapeutic agents, and siRNA delivery to the skin for targeted gene knockout which has potential to be developed as personalized medicine, are among successful nano-delivery applications [265].

Tracking and sensing: diagnostic imaging for TDDS

Stimulated Raman scattering (SRS) microscopy is a label-free, nondestructive, chemical imaging tool which provides high-resolution three-dimensional (3D) images from the mammalian skin. Drug penetration through hair follicles and drug crystal precipitation on skin-surface are visualized along with kinetic information on the delivery [266]. This technique is very sensitive and shows highly resolved spatiotemporal images of chemical distribution in the skin without any fluorescent label employed as an imaging aid [267], [268], [269], [270], [271], while the older technique utilized adhesive tape-stripping wherein the SC was removed and analyzed to estimate drug concentrations across the skin [272].

Another technique called Terahertz (THz) imaging is also a nondestructive, label-free and rapid way to provide real-time tracking of the drug within the skin. Imaging results from the technique were compared with the standard in vitro skin absorption test, Franz cell diffusion test, and were found to be working better. The feasibility of the technique was studied to obtain dynamic images to visualize serial changes in penetration and distribution of the DMSO-ketoprofen formulation on excised mouse skins which reflected the component [273].

Safety concerns: sterility, burns and immunity issues

TDDS development and commercialization have been going on since its inception, and several safety issues have cropped up during the period. The issues in immunological safety of the devices, sterility of products, burns related to electromechanical devices, in-process preparation issues of TDDS, devices and products, Current Good Manufacturing Practice (cGMP) adherence, longer and continued use-related health-issues of patches and devices, as well as the use of patches during magnetic resonance imaging (MRI) procedure causing burns are prominent. Serious burns from metallic components of devices, and electrical burns are some of the concerns, although not all devices and patches contain metal components; nonetheless, the removal of the metallic component from MRI patches and finding replacements for devices causing troubles and burns are suggested [274]. Lately, the nanoparticle and other nanocarriers’ skin toxicity are recent concerns along with the safety of TDDS delivery [275].

Recent trends: concurrent developments in TDDS

The recent advances in TDDS span from the development of new techniques and improved procedures, up-gradation in/of devices, and TDDS, along with a foray into new fields of delivery for a new segment of diseases including stem cell therapy in conjunction with the TDDS techniques are still taking shape. The report informing the initiation of microneedle patch-mediated delivery of hair follicle stem cell (HFSC) activator systems toward hair regrowth, and pigmentation for the delivery of molecular drug (UK 5099), and mesenchymal stem cell (MSC)-derived exosomes in a reduced dose in a mouse model demonstrated the versatility of the TDDS by achieving the therapy in the shortest possible time of 6 days by two consecutive dosings [276]. The use of microneedles, Derma-Roller^®, with doxorubicin hydrochloride and celecoxib co-loaded liposomes provided a two-fold increased delivery which enhanced the antitumor effect and improved the tumor inhibition rate. The improved technique provided successful site targeting and increased inhibition efficiency with negligible side effects [277]. In another use of biocompatible, biodegradable and dissolvable quadrangular pyramid-shaped microneedles [278], the needles dissolved in 10 min with cumulative penetration at >95% and out-reach depth at 70 μm for the drug. There were no adverse effects as observed for 15 days. In another report, the microneedle array technology [279] was used for diagnostic and drug delivery purposes with continuous monitoring of the skin compartment through a closed-loop control method.

Among new vesicular drug delivery approaches through the transdermal route, transethosomes were employed for the delivery of low oral bioavailable, extensive first-pass metabolizing drug olmesartan medoxomil, which showed superiority in the dermatokinetic study as compared with the free drug suspension delivery [279]. Sadarani et al. [280] studied entrapped methotrexate in hydroxyethyl cellulose gel which showed high ex vivo transdermal flux (17.37±1.5 μg/cm²/h) without any irritation or toxicity and had sustained delivery for 48h with low accumulation in the liver, kidneys and gut. The formulation was biocompatible and safe with high therapeutic effects.

An alternative cavitation seed method for sonophoresis improved drug delivery through the sonication method [281]. The perfluorohexane core concentrated on the skin by gravity adaption and opened the channel for possible delivery of very HMW products. The incorporation of transdermal patches loaded with contraceptive hormone, levonorgestrel, into an earring, ring, necklace and wristwatch tested the viability of pharmaceutical jewelry as a novel method of drug delivery. The transdermal patch constituting nonwoven-electro-spun polycaprolactone microfibers for delivery of levonorgestrel as a long-acting contraceptive agent for in vitro steady delivery across the skin were developed [282]. Another procedure towards electromechanical advancements [283] demonstrated the sustained anesthetic effect of ropivacaine^® as part of reverse electrodialysis in combination with the transdermal patch, and showed high thermal threshold, lowered cool sensation and lesser depth of pain.

On penetration enhancers development front, terpene, d-limonene was discovered as a potential enhancer for TDDS components and was demonstrated to provide enhanced penetration with increased mechanical stability in various formulations for transdermal delivery at higher delivery rates [284]. In another development, Svenskaya et al., [285] reported the use of sub-micron-sized calcium carbonate-based microparticles as biodegradable carriers loaded with the drug. The topical application for transdermal delivery followed the therapeutic levels of ultrasound waves’ treatment resulting in deep penetration of the drug and filling of the hair follicles down to the bulb region, which may serve as an intrafollicular storage for in situ drug release also.

The non-woven, nanofibrous TDDS patch for treating local muscular pain was fabricated using the electrospinning technique. The diclofenac-loaded TDD patch was fabricated from cellulose acetate nanofibers that showed sustained release of the drug for a 12-h period with minimum direct skin-drug contact, no over-dosing, and without any burst release [286].

Curcumin-loaded, biodegradable, biocompatible and biocomposite films of carrageenan were prepared from locust-bean gum and montmorillonite by the solvent casting method upon addition of propylene glycol (2.5% v/v). The films were well characterized and evaluated for their physicochemical properties, moisture contents, drug-material uptake, film thickness and its folding capacity, as well as swelling and water vapor transmission rates. The in vitro drug release profiles showed that the compositional ratio of locust-bean gum and montmorillonite modulated the sustained release of the curcumin from the films [287].

In another development, piroxicam transdermal patch was developed to treat dysmenorrhea [287] with benefits to avoid oral/tablet delivery produced nausea, vomiting, gastric disturbances and ulcer. The patch was made using sustained-release polymers, hydroxypropyl methylcellulose E15, PVP K30, ethyl cellulose, PEG 400 and SLS as the permeation enhancer. The patch showed 12-h sustained release of the drug [288].

Transdermal delivery of the anti-Alzheimer’s drug, Donepezil^®, was achieved through the transdermal route as a nanogel formulation [289] to avoid many drawbacks in oral administration, and restrain highly prevalent non-adherence of regular dosing among patients. The nanostructured lipid carrier-based gels improved the skin delivery of the donepezil-free base, a hydrophilic entity in a lipid medium using stearic and oleic acids, surfactant lecithin, and a co-surfactant, sodium tauro-deoxy cholate in the formulation. In vitro testing showed increased drug penetration of the nanostructured material and also the lipoid gel being the penetration enhancer.

TDDS technology commercialization: marketed products

Major technologies and devices invented and developed for transdermal delivery of drug have been commercialized and are available in the market world-over. However, the North American and European markets take precedence in development, marketing and utilization of these products. The market size, latest trends, sales drivers, competition, threats and opportunities including the product segments of TTDS/devices have affected and are driving the technical advancements and commercialization of the products. Major players in the TDDS market include Novartis AG, Johnson & Johnson, GlaxoSmithKline, Boehringer Ingelheim GmbH, Biogel Technology Inc., Mylan Pharmaceuticals Inc., ProSolus Inc., Sanofi SA, Sandoz, The 3M Company, Watson Pharmaceuticals Inc. and Noven Pharmaceuticals Inc. contributing in the cardiovascular, central nervous system, pain management, hormone replacement therapy and smoking cessation segments. A representative list of products, brand-names, bio-applications and product progenitor pharmaceutical companies are listed (Table 2).

Conclusion: achievements and future prospects

Developments in TDDS technologies have made them widely accepted and more so with developments in bulk delivery methodologies which have made them the preferred medium of drug infusion across the skin for transdermal delivery to avoid first-pass metabolism and other sensitivities related to various routes of drug administrations. The transdermal infusion devices and transdermal drug delivery systems have inbuilt capabilities to deliver the drug and its pay-load through the skin layers to the systemic circulation. The drug is generally stable and safe from chemical reactivities in the transdermal drug delivery devices/systems, and normally safe and stable from biochemical transformations before reaching the intended site. Transdermal drug delivery devices/systems are non-invasive, non-allergenic, and have a fixed-time and dose delivery method with even distribution of drug at prescribed and controlled rates. Because of the easy administration route with feasibility for large doses over an extended period of time, formulation of many new and old drugs are in process to achieve improved bioavailability of poorly absorbed drugs. The TDDS technology is fast growing in the pharmaceutical sector and is successful in capturing major value in the market owing to their increasing biomedical applications as a topical formulation system and device which is capable of improving drug delivery through the topical route. A number of developments have been recorded in a plethora of information such as reviews, monographs, books and technical notes from academia and industry [290], [291], [292], [293], [294], [295], [296], [297], [298], [299], [300], [301].

A number of advanced transdermal drug delivery devices/systems and technologies have already been translated into marketed products which include improved-performance patches, fast and non-invasive infusion devices, and use of acoustics, LASER and thermal methods in drug delivery. The scenario is fast changing with a variety of new approaches in making and commercialization, advancements in delivery approach and drug formulation, and use of electro-mechanical, acoustics, LASER, sound, pressure and heating phenomenon in designing new devices and injectors including 3D printing of the transdermal drug delivery devices and other platforms including microneedle improvement which are being pursued. The advances in replacing the metallic components in transdermal drug delivery devices with biodegradable polymeric entities are under progress. The advancements in transdermal patches, skin-based immunomodulation, contact dermatitis allergy-control, and hydrogel fused TDDS patches as well as delivery-feasible conceptual devices, and transdermal drug delivery devices/systems are rapidly progressing toward commercialization [302], [303]. The prevalence of cardiovascular diseases, diabetes, central nervous system and neuromuscular disorders, genetic diseases including pandemics and localized epidemic control, vaccination advancements as well as preference for self-administration of drugs for long-term treatment are expected to be providing the necessary thrust for further development.