Transdermal Drug Delivery: Concepts and Application

By Kevin Ita

Transdermal Drug Delivery: Concepts and Application provides comprehensive background knowledge and documents the most recent advances made in the field of transdermal drug delivery. It provides comprehensive and updated information regarding most technologies and formulation strategies used for transdermal drug delivery. There has been recent growth in the number of research articles, reviews, and other types of publications in the field of transdermal drug delivery. Research in this area is active both in the academic and industry settings. Ironically, only about 40 transdermal products with distinct active pharmaceutical ingredients are in the market indicating that more needs to be done to chronicle recent advances made in this area and to elucidate the mechanisms involved. This book will be helpful to researchers in the pharmaceutical and biotechnological industries as well as academics and graduate students working in the field of transdermal drug delivery and professionals working in the field of regulatory affairs focusing on topical and transdermal drug delivery systems. Researchers in the cosmetic and cosmeceutical industries, as well as those in chemical and biological engineering, will also find this book useful.

• Captures the most recent advancements and challenges in the field of transdermal drug delivery
• Covers both passive and active transdermal drug delivery strategies
• Explores a selection of state-of-the-art transdermal drug delivery systems

• Language: English
• Publisher: Academic Press
• Release date: Jun 12, 2020
• ISBN: 9780128225516

Kevin Ita

Dr. Ita holds a PhD in Pharmaceutics. His area of expertise is transdermal drug delivery. He has over 40 publications in this area and teaches Pharmaceutics to both first- and second year pharmacy students at the College of Pharmacy, Touro University, California. He joined the University in 2006 as an Assistant Professor and is now a Full Professor. He was awarded an ICRETT Fellowship by the International Union Against Cancer (IUCC).

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Ghimirey.

Chapter 1

Transcutaneous drug administration

Abstract

The first part of this chapter focuses on the benefits and limitations of transdermal drug delivery systems (TDDSs). Advantages include convenience, avoidance of presystemic metabolism (first-pass effect) and painlessness. Other benefits include noninvasiveness (or minimal invasiveness in the case of microneedles), the absence of gastric irritation, a more uniform absorption, as well as a faster onset of action. One of the limitations of the transdermal route is that externally introduced chemicals (including medications) have to overcome the stratum corneum before entering into systemic circulation. All drugs currently marketed in the form of TDDSs are very potent and typically, their molecular weights are lower than 500 Daltons. Proteins, peptides, and genes are hydrophilic, electrically charged macromolecules and therefore cannot cross the human skin in therapeutic quantities.

The second part of this chapter examines the classification of transdermal patches. Passive transdermal systems belong to three major categories: the reservoir (membrane-controlled), matrix without a rate-controlling membrane, and matrix systems with a rate-controlling membrane. In reservoir transdermal systems, drug flux depends on the diffusion rate across a polymer membrane. In a matrix transdermal system, the medication is incorporated into an adhesive polymer, from which the medication diffuses through the skin into the bloodstream.

Keywords

Transdermal; drug delivery; benefits of transdermal patches; passive transdermal systems; reservoir systems; matrix systems

Over the last few decades, it has been asserted that the transdermal route of drug administration represents an attractive approach in comparison to oral or parenteral drug delivery [1–3]. Delivering medications through the skin is important because it circumvents presystemic metabolism (first-pass effect), which is typically observed with the oral route. First-pass effect can lead to low bioavailability, adverse secondary effects, and uncomfortable drug dosing schedules [4]. Bacterial enzymes, gut wall enzymes, gastrointestinal lumen enzymes, and hepatic enzymes have all been implicated in the first-pass effect [5]. Recent experimental evidence has demonstrated the utility of transcutaneous drug transport in bypassing the first-pass effect, avoiding intestinal degradation, and providing transcutaneous permeation at controlled rates [6,7]. Percutaneous drug transport is also useful from a pharmacotherapeutic standpoint because there is no pain during drug administration, patients can self-administer, there is no chance of disease transmission by needle sharing, and a slow drug release can be achieved [8]. Transdermal drug delivery can provide effective blood levels for drugs [9]. A drug initially diffuses across the stratum corneum (SC), enters into the viable epidermis/dermis, and then becomes available for systemic absorption through dermal blood capillaries [10]. Transcutaneous drug administration is beneficial in comparison with the traditional administration routes such as oral or parenteral injections due to a number of factors: the oral route is characterized by partial drug absorption, gastrointestinal irritation, and slow onset of action, while hypodermic injections are invasive and painful, generates medical waste, pose risks of infection, and requires administration by medically trained professionals [11]. In contrast, transcutaneous drug administration is painless, noninvasive [12], or minimally invasive (in the case of transdermal microneedles). In addition, percutaneous drug administration usually requires a lower dosage of medications than oral administration due to a shorter diffusional length required to reach the vasculature [13]. Another advantage is the avoidance of side effects caused by erratic absorption and metabolism of the drug in the gastrointestinal tract [13]. Furthermore, transdermal therapeutic systems can be easily applied to the skin, are well accepted, and are relevant options when oral drug delivery is challenging (instances of coma or difficulty in swallowing) [9]. From an economic standpoint, it has been calculated that the global transdermal drug delivery market will grow to approximately $95.57 billion by the year 2025 [14]. The global transdermal drug delivery market is worth $32 billion [15].

The human skin, an organ that receives one-third of the total blood supplied throughout the body, was not used as a drug delivery route for systemic administration until the late 20th century [14]. Scopolamine-loaded transdermal patch was the first commercial patch, and it was approved for clinical use in 1979 [16]. After nearly 40 years of extensive transdermal drug delivery research, only 22 active pharmaceutical ingredients have been approved by regulatory authorities in the United States in the form of transdermal patches [12]. Only low molecular weight, low-dose, lipophilic medications can be developed into transdermal drug delivery systems (TDDSs) with a good chance of therapeutic efficacy and regulatory approval [4,17]. In addition, the daily dose of most approved transdermal medications is typically in the milligram range [4]. Another point worthy of emphasis is that skin sensitivity varies among patients and therefore it is difficult to predict the effect of a transdermal patch. Also, skin occlusion with a patch may induce erythema at the administration site [4]. Furthermore, some medications are intrinsically irritating and early investigation of such compounds should be undertaken early enough in the transdermal drug development [4].

The skin functions as an effective barrier that hinders the ingress of harmful substances from the environment and the efflux of body fluid [18]. This barrier function is ascribed to the intercellular lipids present in the outermost layer of the skin called the SC. One of the obvious limitations of the transdermal route is that externally introduced chemicals (including medications) have to overcome the SC before entering into the bloodstream [19]. The successful transcutaneous permeation of a drug is a function of the partition coefficient (1–3), molecular weight (<500 Da), and the potency of the drug [19]. Equally important is the water solubility of the drug which should preferably be more than 1 mg/mL with the dose being less than 1 mg per day [7]. It is not surprising that all drugs commercially available in the form of TDDSs are very potent and typically, their molecular weights are lower than 500 Da [9]. Even after the drug successfully crosses the SC, it may be degraded prematurely by epidermal enzymes, leading to a reduced bioavailability [13].

From the standpoint of pharmacotherapy, this is an obvious disadvantage as proteins, peptides, and genes are hydrophilic, electrically charged, or large molecules and therefore cannot cross the skin in therapeutic quantities [20]. Various techniques have been utilized over the years to surmount the barrier presented by the SC. Vesicles (elastic liposomes, ethosomes, etc.), chemical penetration enhancers, iontophoresis, sonophoresis, microneedles, electroporation, and other techniques have been used to overcome the SC barrier and increase transdermal drug delivery. The terms TDDSs, transdermal therapeutic systems, and transdermal patches can be used interchangeably. There are two major classes of TDDS: those that are based on passive delivery and those that are based on microneedles, electroporation, sonophoresis, or other physical methods.

Passive transdermal therapeutic systems

There has been a surge in the utilization of transdermal drug therapeutic systems over the past 40 years. The first generation of transdermal delivery systems focused on medications that traversed the skin through passive diffusion [16,21]. Scopolamine-loaded adhesive transdermal therapeutic system was given the FDA approval in 1979 for the management of kinetosis [22]. Subsequently, nitroglycerin patch was approved in 1981 and the nicotine TDDS in 1991 [22]. Developments in science and technology have enabled the utilization of mild electric current (iontophoresis), ultrasound (sonophoresis), and chemical penetration enhancers for enhanced transport of drug molecules that cannot be transported across the skin in therapeutic amounts via passive diffusion alone [16,21]. Third generation transdermal therapeutic systems utilize microscopic needles (microneedles) for transport of medications including high molecular weight agents [16,21]. These TDDSs breach the SC facilitating the transport of the drug molecules [16,21].

Passive transdermal systems belong to three major categories: the reservoir (membrane-controlled) [23], matrix without a rate-controlling membrane [22,24], and matrix systems with a rate-controlling membrane [7,24,25]. A schematic representation of a reservoir transdermal system is shown in Fig. 1.1.

Figure 1.1 A schematic representation of a transdermal patch. Reproduced with permission from D’Orazio JL, Fischel JA, Recurrent respiratory depression associated with fentanyl transdermal patch gel reservoir ingestion. J Emerg Med 2012;42(5):543–48 (Chapter 1).

Reservoir systems depend on the transport of the drug out of or through a nonporous or microporous polymer layer [26]. Diffusion through the membrane or the static aqueous diffusion layer may determine the rate of transport [26]. It is important to note that molecular mass and pore size also have significant effect on the diffusion coefficient [26]. In reservoir transdermal systems, the permeation rate is a function of the rate-determining polymer membrane [22]. An adhesive, a rate-controlling membrane, and a drug reservoir are normally used for the design and fabrication of reservoir systems [24]. The active pharmaceutical ingredient(s) as well as excipients are incorporated into the drug reservoir [24]. The adhesive component of the transdermal therapeutic system facilitates the adhesion of the patch to the skin [24]. There are two modes of adhesion: continuous and peripheral. If it is continuous, the adhesive completely covers the drug release area but in the case of a peripheral adhesive, a perimeter is created around a nonadhering drug release surface [24]. Examples of membrane-controlled transdermal therapeutic systems are Transderm Scop and Nicoderm CQ [27].

In a matrix transdermal system, the drug is introduced into an adhesive polymer, from which the medication diffuses transdermally into systemic circulation [22]. This transdermal delivery system is based on the following mechanisms: porosity (tortuous path) and polymer erosion [26]. Researchers typically fabricate matrix systems via drug dispersion in a lipophilic or hydrophilic polymer and subsequent molding of the drug-loaded polymer into a drug-loaded disk with a defined thickness and surface area [28]. The polymeric disk is then placed on a base plate with subsequent spread of an adhesive polymer to create a strip of rim along the drug-loaded disk [28]. The amount of transported medication is a function of the area of the TDDS administered to the skin and the quantity of the medication in the matrix [22].

Matrix systems are mostly thinner than reservoir systems and can provide greater comfort and cosmetic applicability [25]. One of the drawbacks of matrix transdermal systems is that the formulation of such devices is challenging, especially for medications in adhesive systems, since the adhesive incorporates the medication and regulates its delivery while being adhered to the skin [25]. Drug delivery rates are better controlled with reservoir TDDS but sometimes there may be an initial burst of drug release [22]. In addition, if the membrane is damaged, there is also a concomitant risk of overdose induced by the sudden release of the active pharmaceutical ingredient [22]. In matrix-based transdermal systems, an inactive polymer modulates drug delivery from the therapeutic system [27]. Commercially available transdermal matrix-based therapeutic systems include Nicotrol and Vivelle [27]. It is important to note that a drug is distributed evenly in a matrix patch [22]. A hybrid patch refers to a matrix patch with a silicon reservoir and a membrane [7,25]. Hair and coworkers published a paper describing a hybrid transdermal patch from which fentanyl was released over a 72-h delivery period [29]. The hybrid patch had a silicon matrix with a rate-modifying membrane [29]. Most TDDSs deliver medications into the skin at a constant rate over a specific time interval based on Fickian diffusion [27]. There is usually a zero-order drug release as long as the concentration gradient across the skin is constant [27]. As previously stated, the SC is the major impediment to percutaneous drug absorption.

Liu and coworkers formulated a transdermal patch loaded with benzoylaconitine [30]. The drug-in-adhesive patch was formulated using the solvent evaporation method [30]. The drug and skin sorption promoters were dissolved in ethyl acetate and then stirred thoroughly with pressure-sensitive adhesive (PSA) to obtain a homogeneous drug-PSA mixture [30]. The obtained mixture was coated onto the release liner using a laboratory coating unit. The fabric backing film was laminated onto the dry PSA layer with a rolling device to ensure the flatness of the backing film on the PSA layer [30]. Malaiya et al. loaded a transdermal delivery system with rivastigmine [31]. The backing membrane was prepared using an aqueous solution of a 6% w/v of polyvinyl alcohol. The solution was poured into a glass bangle placed on the surface of aluminum foil in a petri dish. Ethyl cellulose and polyvinylpyrrolidone were dissolved in chloroform and a homogeneous solution was prepared with the aid of a magnetic stirrer. The authors then added the drug and a plasticizer dibutyl phthalate to the mixture and stirred for 20 min until a homogeneous suspension was formed [31]. The authors next cast 5 mL of the homogeneous suspension on the backing membrane and dried the suspension at room temperature for 24 h, until a flat and uniform matrix patch was formed [31].

A matrix-type transdermal system loaded with lamivudine has also been formulated [32]. The authors prepared transdermal patches from Scotchpak 9733 (the backing membrane) and CoTran 9764 (polyethylene foam tape) and attached the system to each other using CoTran 9766 [32]. Then, the lamivudine-loaded polymeric monolithic films were attached to the hypoallergenic, pressure-sensitive acrylate adhesive coat of CoTran 9764 [32]. The drug layer was protected by Scotchpak 1022 (release liner).

References

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2. Abiandu I, Ita K. Transdermal delivery of potassium chloride with solid microneedles. J Drug Deliv Sci Technol. 2019;53:101216.

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20. Zorec B, et al. Combinations of nanovesicles and physical methods for enhanced transdermal delivery of a model hydrophilic drug. Eur J Pharm Biopharm. 2018;127:387–397.

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23. D’Orazio JL, Fischel JA. Recurrent respiratory depression associated with fentanyl transdermal patch gel reservoir ingestion. J Emerg Med. 2012;42(5):543–548.

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Chapter 2

Anatomy of the human skin

Abstract

The human skin constitutes a major obstacle to transdermal drug delivery. This chapter examines the anatomy of the skin. The human skin is divided into three layers: the epidermis, dermis, and the subcutaneous layer. The epidermis is a terminally differentiated and layered squamous epithelium, the main cell type of which is the keratinocyte. Keratinocytes from the stratum basale (SB) typically differentiate to form the stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC). The SC (the outermost layer of the skin) is the major barrier against drug transport into the body. The SC comprises fully keratinized corneocytes embedded in a lipid matrix. The viable epidermis is subdivided into SG, SS, SB, and stratum lucidum. The dermis is the load-handling portion of the human skin, and it is formed from collagen (about 70% of the dry weight of skin) and elastin (about 2%–4% of the dry weight of skin) fibers. Morphologically, the dermis is made up of two parts: (1) the upper or papillary dermis with a loose connective tissue and high cell density and (2) the reticular dermis in the deeper layers, which is densely packed with collagens and other connective tissue proteins but possesses a low cell density. The subcutis (subcutaneous layer) is the adipose-rich skin layer that provides insulation for the conservation of internal body heat. It is also an energy and fluid reserve that protects deeper tissues and organs and supports the dermis and epidermis. The human skin also possesses numerous appendages—sweat glands, sebaceous glands, and hair