In which method of parenteral drug administration is the drug injected within the upper layer of the skin?

4.4.3 Transdermal Drug Delivery (TDD)

Transdermal drug delivery (TDD) has been focused on a medicating advantage as the promising topical method for medical treatment without patient intention. The transdermal drug passes through the surface layers of the skin and reaches blood capillaries, which distribute the bottom layer of the skin. The permeated drug is transported by blood streaming to the whole body without the first-pass effect, which is a metabolism on the digestive system that reduces the effect of drug (Prausnitz and Langer, 2008). The skin has mainly three layers, which consist of the epidermis, the dermis, and the hypodermis as shown in Fig. 4.4.3. Once the transdermal patch is put nearby target-affected tissues, the continuous dosing would be efficiently available a couple of hours or days later, and it is easily removable by soap washing (Franz and Lehman, 1988). Moreover, the drug absorption increases gradually and keeps stably the drug efficacy without obvious dose changing over time. It would reduce the side effects on the body by an extra dosing of drug. The essential problems of TDD that the differences of drug dosing amount by human, parts of the skin, and gender, however, have not been solved. In case of the inflamed skin, it is a serious problem that TDD does not control precisely dose absorption through injured and irritated skins, which are not predictable drug permeability.

The permeability of drug at the skin layers depends on person’s gender or healthiness. The barrier function of stratum corneum, which is hardened-flatted-stacked dead cells with 10–20 μm in thickness, provides a waterproof protection (Fig. 4.4.3) and is the most serious problem of inhibition of permeating hydrophilic drug through the stratum corneum by its barrier effect, because the stratum corneum is composed of proteins (79%–90%) and lipids (5%–15%) (Patel and Baria, 2011). The stratum corneum inhibits also to permeate the relatively larger drug molecules into the epidermis for more than 500 Da in molecule size (Bos and Meinardi, 2000). The stratum corneum does have not only a barrier function but also roles of regulating for natural water loss by water evaporation from our skin, pH, and temperature as being 5–30 g/m2 h, pH 5.0–5.4, and 31–33°C, respectively (Yosipovith et al. 1998).

Recently, the TDD has been utilized for several disease treatments by transdermal drugs on the US market as shown in Table 4.4.1. Since the relatively large molecular weight of transdermal drugs is restricted by the barrier function of the epidermis that disables to pass through the drug, the commercial transdermal drug distributed typically the smaller molecular weights than 500 Da. Since a transdermal drug flux has an inverse proportion with its molecular size of the drug, an ideal molecular size of drug would be less than 400 for TDD (Marwah et al., 2016). In general, most of the transdermal drugs are not absorbed well by the oral medication, which is indeed indicated as a quite small bioavailability; then, the topical method has been applied for high drug efficacy. Even a large bioavailability of drug has been employed due to other benefits of TDD, cf. long-term healing and self-medication management.

Table 4.4.1. Current Transdermal Drug for Medical Uses on US Market Listed From Paudel et al. (2010)

Properties referred by www.drugbank.ca.

Not only the transdermal drug has been considered in terms of the molecular weight of drug, but also the partition coefficient Pow plays an important role, which indicates a solubility of lipophilicity (hydrophobicity) and defined as follows:

(4.4.4)logPow=logCoCw

Here, Co and Cw are concentrations in oil and water solutions, respectively. The Pow of chemicals is measured experimentally by using chromatographic instrumentation, for example, a funnel extraction and high-pressure liquid chromatography. The log Pow = 1.0 means that the solubility of drug behaves 10 times in lipophilic solution (octanol) than in water. The reason why the transdermal drugs are usually applied for lipophilic one is related to the oil/water compatibility of cell membrane, which consists of phospholipid double layers (lipid bilayer). The cell membrane passes the lipophilic rather than the hydrophilic drug because of the lipophilicity of cells.

5.48.1 Introduction

Transdermal drug delivery has been used for decades to deliver drugs. The process is, however, limited by the outer layer of the skin, the stratum corneum, which protects the body by preventing the entry of foreign substances [1]. Over the past few years, different methods have been proposed to increase the permeability of this barrier. Such methods include the use of chemical penetration enhancers [2], iontophoresis [3], sonophoresis [4], and others. However, the high cost, the complexity, and the difficulty to deal with these methods at home pose problems for the users [2–4]. Microneedles have been developed as a minimally invasive means to deliver drugs in a painless manner while overcoming the barrier of the stratum corneum. The micron-sized needles penetrate the upper layer of the skin without reaching the nerves, thereby delivering drugs transdermally in a painless manner [5].

Wise et al. [6] first proposed the idea for fabricating ‘microprobes’ using an integrated circuit method to achieve more precision and reproducibility in the resulting structures. The microprobes designed were used in the recording of biopotentials generated by individual nerve cells. However, it was not until the mid-1990s when the technique was more readily available that microneedles were applied to improve cell uptake of genes and molecules [7]. Microneedles were later proposed for application in transdermal drug delivery by Henry et al. [5]. The group performed experiments which proved that inserting microneedles into the skin enhanced the permeation of substances through the skin. These pioneering works have since been followed by a wide range of studies on microneedles to explore the possibilities of their applications in drug delivery. Today, the possible benefits of their applications range from providing a more controllable insulin delivery system that better mimics the body’s natural hemostatics to delivering vaccines to people faster than the disease can spread.

The aim of this article is to review the area of drug delivery using microneedles. This section gives an introduction to the concept of microneedles while the following section describes the skin structure and the variation in the skin structure due to factors such as age and anatomical region and the effect of this variation on the effectiveness of microneedles. The third section then looks at different techniques of microneedle applications and discusses the ‘hollow’ and ‘solid’ types of microneedles giving examples of studies where such microneedles have been applied. In the fourth section, the fabrication of microneedles is discussed with a general description of a silicon-based process, a hollow glass microneedle fabrication process, and a metal microneedle fabrication process. This is then followed by a section describing the different materials that have been used in various experiments. The method for coating solid microneedles is then described in the sixth section with a diagram illustrating the process while the applications of microneedles in drug delivery are discussed in the seventh section with subsections discussing transdermal drug delivery, drug delivery to neurons, intravascular drug delivery, and ocular drug delivery. Advantages and limitations of using microneedles for transdermal drug delivery are then discussed in the eighth section and the final section discusses the mathematical models that have been developed for analyses of drug delivery using microneedles. In order to explain the technique of microneedle insertion into the skin, it is essential to first give an outline of the skin structure. This is discussed in the following section.

1 Introduction

Transdermal drug delivery has witnessed great advances over the last 4 decades.1,2 This drug delivery route has been and continues to be an attractive as well as a challenging area for research. The attractiveness comes from the transdermal delivery that offers several advantages in comparison with other delivery routes, which is well-documented in literature including improved patient compliance, sustained and controlled release, avoidance of gastric irritation, as well as elimination of presystemic first-pass effect.3 In fact, the transdermal dosage forms are the most successful nonoral systemic drug delivery systems accounting for over 12% of the global drug delivery market. In 2010, the transdermal delivery market was valued at $21.5 billion, yet it is based on only 20 drugs.4

The greatest challenge with transdermal drug delivery is the barrier nature of skin, which is provided by its outer layer, that is, the stratum corneum (SC).3 This barrier limits the number of drugs, which are capable of being administered via this route.3,5 The suitable drug candidate has moderately low-molecular weight, its octanol-water partition coefficients should be moderately favor lipids, unionized, and also exhibit reasonable potency (low dose).3,6–8 Due to the selective nature of the skin barrier, the whole segment of the transdermal drug market is limited to a small pool of drugs.2 Until recently, the transdermal administration of macromolecules, peptides, or hydrophilic drugs has, to date, remained relatively unexploited.

To enhance drug transdermal absorption, number of different approaches have been investigated, developed, and patented including nanomedicines (NMs) and microneedles (MNs).1,9–13

MNs is a novel technology, which has shown the potential to revolutionize the transdermal drug delivery. The concept of MNs was first proposed in the 1970s, it combines the benefits of hypodermic needle injections and transdermal patches.1 The MNs are long enough to penetrate the SC, but too short to stimulate pain receptors that are in the dermis.13

This technology has been the subject for extensive research over the last 2 decades which led to great advances in the field. The number of published articles, over the last 15 years, broke the record of 2450 articles with 339 articles in 2016 itself (data obtained from ISI Web of Knowledge). The MNs have shown to be a promising minimally invasive devices which could enable transdermal delivery not only potent lipophilic drugs with appropriate physicochemical properties but also other transdermally difficult-to-deliver molecules, such as hydrophilic drugs, vaccines, and macromolecules.1,2,14,15

NM is a new discipline which has emerged recently. It is simply defined as the application of nanotechnology or nanoparticles (NPs) to medicine or more precisely the utilization of nanosized structures for the diagnosis, prevention, and treatment of diseases.16,17 The application of nanotechnology to the field of drug delivery and therapy is termed as nanotherapeutics.17 The term NPs is used to describe structures with size ranges from 1 to 100 nm. However, in the field of nanotherapeutics the prefix “nano” is often used to refer to particles much larger than 100 nm.17 In this subchapter, the term “nanoparticle” will be used for particles with sizes smaller than 1000 nm.

In the forthcoming sections, NPs and NMs terms will be used interchangeably.

Nanotechnology or NPs is an innovative approach which has been widely investigated to enhance drug delivery through various routes including parenteral, nasal, pulmonary, oral, and transdermal route.9,16,18 This technology has exhibited several advantages over traditional drug delivery systems allowing for sustained drug release and provide protection of encapsulated materials against chemical or proteolytic degradation.10,17 In addition, effective cell-specific targeting can be achieved by attaching drugs to individually designed NP carriers.17

Using nanotechnology to enhance the transdermal drug and vaccine delivery has received a substantial interest in the scientific community over the last 2 decades.10,17–20 Over the last 15 years, more than 1800 articles concerning NPs application in transdermal drug and vaccine delivery have been published (data obtained from ISI Web of Knowledge).

In comparison with the conventional dosage forms, NMs have several advantages. These include (1) enhancing the chemical stability of the drugs, (2) extending or enhancing their penetration into skin, (3) protecting drug from enzymatic degradation, and (4) moderately enhancing percutaneous penetration of both hydrophilic and lipophilic molecules.9,10,17 Nevertheless, there has been strong evidence that these systems only achieve minimal enhancement for drug permeation through the intact skin, but they may deposit drug into the SC and/or hair follicles.9,20 Subsequently, NM-mediated drug delivery into deeper layers of the skin (epidermis and dermis) without breaching the SC has met with limited success.9,17,20

This limitation has prompted investigators to explore the use of NMs in combination with other novel drug delivery systems including MNs to enhance the transdermal drug and vaccine delivery.

Combining both technologies, that is, NMs and MNs has emerged as novel outstanding approach to capitalize on the advantages of both systems to enhance the transdermal drug and vaccine delivery. This approach has received a substantial interest over the last 15 years. Number of excellent reviews that have been published contain detailed discussions concerning many aspects of using both technologies and their combinations in transdermal drug delivery.13,16–18

The present subchapter shows an updated overview on the development of using both technologies in transdermal drug and vaccine delivery, namely MNs and NMs. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and it will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for NMs and MNs.

Firstly, the fundamental aspects of skin structure and its barrier properties were outlined. Following on from this, MNs types and their application in transdermal drug delivery were described. NMs types and the advances in their exploitation in transdermal drug and vaccine delivery were also reviewed. This subchapter concluded by highlighting some of the novel delivery systems which have been described in literature exploiting the combination of these two technologies.

Introduction

Transdermal drug delivery has been used for decades to deliver drugs. The process is, however, limited by the outer layer of the skin, the stratum corneum, which protects the body by preventing the entry of foreign substances (Teo et al., 2006). Over the past few years, different methods have been proposed to increase the permeability of this barrier. Such methods include the use of chemical penetration enhancers (Pathan & Setty, 2009), iontophoresis (Panchagnula et al., 2000), sonophoresis (Maruani et al., 2009) and others. However, the high cost, the complexity, and the difficulty to deal with these methods at home pose problems for the users (Pathan & Setty, 2009, Panchagnula et al., 2000; Maruani et al., 2009). Microneedles have been developed as a minimally invasive means to deliver drugs in a painless manner while overcoming the barrier of the stratum corneum. The micron-sized needles penetrate the upper layer of the skin without reaching the nerves, thereby delivering drugs transdermally in a painless manner (Henry et al., 1998).

Wise et al., 1970 first proposed the idea for fabricating ‘microprobes’ using an integrated circuit method to achieve more precision and reproducibility in the resulting structures. The microprobes designed were used in the recording of biopotentials generated by individual nerve cells. However, it was not until the mid-1990s when the technique was more readily available that microneedles were applied to improve cell uptake of genes and molecules (Hashmi et al., 1995). Microneedles were later proposed for application in transdermal drug delivery by (Henry et al., 1998). The group performed experiments which proved that inserting microneedles into the skin enhanced the permeation of substances through the skin. These pioneering works have since been followed by a wide range of studies on microneedles to explore the possibilities of their applications in drug delivery. Today, the possible benefits of their applications range from providing a more controllable insulin delivery system that better mimics the body's natural hemostatics (Zhang et al., 2013) to delivering vaccines to people faster than the disease can spread (Donnelly et al., 2014).

The aim of this article is to review the area of drug delivery using microneedles. This section gives an introduction to the concept of microneedles while the following section describes the skin structure and the variation in the skin structure due to factors such as age and anatomical region and the effect of this variation on the effectiveness of microneedles. The third section then looks at different techniques of microneedle applications and discusses the ‘hollow’ and ‘solid’ types of microneedles giving examples of studies where such microneedles have been applied. In the fourth section, the fabrication of microneedles is discussed with a general description of a silicon-based process, a hollow glass microneedle fabrication process, and a metal microneedle fabrication process. This is then followed by a section describing the different materials that have been used in various experiments. The method for coating solid microneedles is then described in the sixth section with a diagram illustrating the process while the applications of microneedles in drug delivery are discussed in the seventh section with subsections discussing transdermal drug delivery, drug delivery to neurons, intravascular drug delivery, and ocular drug delivery. Advantages and limitations of using microneedles for transdermal drug delivery are then discussed in the eighth section and the final section discusses the mathematical models that have been developed for analyses of drug delivery using microneedles. In order to explain the technique of microneedle insertion into the skin, it is essential to first give an outline of the skin structure. This is discussed in the following section.

Abstract

Transdermal drug delivery offers a number of advantages for the patient, due to not only its noninvasive and convenient nature, but also factors such as avoidance of first-pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedles can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum, creating a pathway for drug permeation to the dermal tissue below. Microneedles have been extensively investigated for drug and vaccine delivery. The different types of microneedle arrays and their delivery capabilities are discussed in terms of drugs, including biopharmaceutics and vaccines. Patient usage and effects on the skin are also considered. Microneedle research and development are now at the stage where commercialization is a viable possibility. A number of long-term safety questions relating to patient usage will need to be addressed moving forward. Regulatory guidance is awaited to direct the scale-up of the manufacturing process alongside provision of clearer patient instruction for safe and effective use of microneedle devices.

4.2.2.8 Applications

Transdermal drug delivery: Dendrimers have been found to improve solubility and plasma circulation time via transdermal formulations and to transport drugs competently. PAMAM dendrimer complexes and NSAIDs (e.g., ketoprofen, diflunisal) have been reported to improve drug access through the skin as penetration enhancers.

Oral drug delivery: Studies for oral drug delivery, using the human colon adenocarcinoma cell line, Caco2, have specified that low generation dendrimers cross cell membranes, through a combination of two processes: paracellular transport and adsorptive endocytosis.

Ocular drug delivery: Dendrimers can be employed for ocular drug delivery by synthesizing hydrogels, cross-linked networks that increase in volume in aqueous solution and are more like living tissue than any other synthetic compound. Furthermore, by adding polyethylene glycol groups to the dendrimers, these hydrogels have applications including production of cartilage tissue and for sealing ophthalmic injuries (Spataro et al., 2010).

As nanodrugs: Dendrimers possess some antiviral properties due to their functional groups. Some studies indicated that poly(lysine) dendrimers reformed with sulfonated naphthyl groups have antiviral potential

4 Advantages of Transdermal Drug Delivery Compared to Other Routes of Administration

Transdermal drug delivery is an attractive alternative to conventional drug delivery systems such as oral and parenteral routes. It provides many advantages over other routes of administration for five reasons:

It is a noninvasive drug delivery system that maintains the steady plasma level of drug and increased drug efficacy (Thomas and Finnin, 2004).

It maintains the drug level in the systemic circulation within the therapeutic window (i.e., above the minimum effective concentration but below the level at which side effects become apparent) for prolonged periods of time, so the drug remains within its therapeutic level.

The transdermal drug delivery system, compared to an oral and intravenous route of administration, avoids peaks and valleys in plasma level by providing steady blood concentration (Thomas and Finnin, 2004).

It also avoids degradation of the drug in the gastrointestinal tract, eliminates the first-pass effect, and improves patient compliance and acceptability of drug therapy.

The patch can be removed easily by the patient on an appearance of side effects.

Transdermal Drug Delivery

Transdermal drug delivery is the transport of drug molecules across the skin, and it has several advantages over the traditional methods [9]. It eliminates gastric irritation, prevents hepatic first-pass metabolism, prevents gastric degradation of drug, provides sustained release of drug, is noninvasive, and improves patient compliance.

The skin of an average adult body covers a surface of approximately 2 m2 and receives about one-third of the blood circulating through the body. The skin surface contains an average of 200–250 sweat ducts and 10–70 hair follicles in each square centimeter. Therefore, it provides a large surface area for drug absorption and is one of the most readily accessible organs of the human body. Transdermal drug delivery systems (TDDS) make use of the opportunity of this easy accessibility of the skin.

Compared to oral drug delivery, transdermal drug delivery has several advantages:

First-pass effect, which is an added limitation of oral drug delivery, can be evaded through the transdermal route.

Drugs that cause gastrointestinal (GI) irritation can be administered through the transdermal route as this route circumvents direct irritant effects on the GI tract. Drugs that undergo enzymatic degradation or acid degradation in the GI tract can be administered through the transdermal route.

Transdermal delivery also provides steady and consistent permeation of drug through the skin. This leads to more constant drug levels in plasma, which is usually the goal of therapy. Lack of peaks and troughs in plasma concentration can reduce the risk of side effects. Drugs that require relatively consistent plasma levels are generally good candidates for transdermal drug delivery.

An added advantage of TDDS is that, if toxicity develops from a transdermal system, this effect could be limited by removing the patch. TDDS can also provide sustained release of the drug for up to 7 days; therefore, TDDS require once-weekly application. Such a dosage regimen is simple and greatly improves patient compliance.

TDDS may be utilized as an alternative route of drug administration in patients who cannot tolerate oral dosage forms, are nauseated, or are unconscious.

Compared to intravenous, hypodermic, and other parenteral routes, TDDS has major advantages like elimination of pain, possibility of infection, and risk of disease transmission by needle reuse. Hence, with all these qualities, TDDS generally offer better patient compliance.

5.4.3 Skin Patch

Transdermal administration of l-dopa may yield more continuous drug delivery (CDD). ND0611, a continuously delivered carbidopa solution administered subcutaneously by a patch, was developed. An adjunctive use of ND0611 to carbidopa/l-dopa IR was found to increase l-dopa half-life, area under the curve, and trough concentrations of l-dopa in preclinical studies and in a phase I study in healthy volunteers (Hauser, 2011).

ND0612 is a soluble carbidopa/l-dopa formulation for continuous subcutaneous delivery through a custom patch pump. The results of a phase I trial in healthy volunteers showed stable carbidopa/l-dopa plasma levels over 24-h infusion cycles, with peak concentrations of around 500 ng/mL at the highest infusion rate (Caraco, Oren, & LeWitt, 2013). In an early phase II study with fluctuating PD, patients on ND0612 showed reductions in “off” time and plasma l-dopa concentration fluctuations with complete abolition of the low trough levels compared with placebo (Giladi et al., 2015).

Abstract

Transdermal drug delivery offers a number of advantages due to its minimally invasive and painless approach as well as the avoidance of first-pass drug metabolism and gastrointestinal degradation. However, most of the transdermal drug delivery systems face the challenges of low drug permeability across the skin. The outermost layer stratum corneum and the entire epidermis pose a significant barrier. To overcome this problem researchers have developed microneedles as therapeutic vehicles to transport drugs across the different layers of skin. After many decades of research, scientists have developed microfabrication technologies to fabricate microneedles of different size and types depending on the type of drug to be administered, injection site, and depth of skin where drug needs to be injected. The early development of microneedle produced solid microneedle for skin pretreatment to enhance drug permeation. Drug-coated microneedles dissolve in the skin upon application, dissolving microneedles encapsulating drug fully dissolve in the skin producing no sharp waste, and hollow microneedles can help drug infusion into the skin. Finally, advancement led to the development of hydrogel-forming microneedles with reservoir, it allows drug diffusion through swollen microneedles. This type of microneedle has been developed with an idea to overcome the disadvantages of previously developed devices. Microneedles have been successfully introduced in preclinical and clinical studies to deliver a wide range of drug molecules, including vaccines, small and large molecules, and biotherapeutics such as proteins, peptides, and hormones. In this chapter we have discussed the current microneedle devices and drug delivery systems.