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The book includes both science and technological aspects of new drug delivery systems. Its unique focus is that it is on new drug delivery systems that are considered to be "non-invasive". Other unique features include a chapter on Regulatory Aspects of non-invasive systems and one on FDA guidance for topical nano-drug delivery. Two chapters covering market trends and perspectives, as well as providing guidance to those marketing such systems are also included.
Topical and Transdermal Drug Delivery
S. Narasimha Murthy and H. N. Shivakumar
Department of Pharmaceutics, the University of Mississippi, MS 38677, USA
1.1 Structure of the Skin 1
1.1.1 Dermis and hypodermis 3
1.2 Topical vs. transdermal drug delivery 3
1.2.1 Topical drug delivery 3
1.2.2 Transdermal patch systems 4
1.3 Percutaneous absorption pathways 5
1.4 Approaches to enhance passive cutaneous drug absorption 6
1.4.1 Supersaturation of drug 6
1.4.2 Eutectic systems 7
1.4.3 Prodrug approach 7
1.4.4 Ion pair formation 8
1.4.5 Complexation 8
1.4.6 Liposomes 9
1.4.7 Microemulsions 13
1.4.8 Organogels 14
1.4.9 Solid lipid nanoparticles 15
1.4.10 Liquid crystalline systems 16
1.4.11 Chemical permeation enhancers 16
1.5 Conclusions 26
1.1 STRUCTURE OF THE SKIN
Skin is the largest organ of our body, which acts as a protective barrier against the entry of foreign material and possible invasion of pathogens. The skin also prevents the loss of excessive endogenous material such as water (Brown et al., 2006). In addition, the skin serves to reduce the damaging impact of solar UV radiation (Hadgraft, 2004).
The structure of human skin is portrayed in Figure 1.1. The skin is about 0.5 mm thick and is made up of two distinct layers, the inner dermis and the overlaying epidermis. The dermis that forms the bulk of the skin (1–2 mm thick) is made up of connective tissue elements. Dermis is highly vascular and filled with pilosebaceous units, sweat glands, adipose cells, mast cells, and infiltrating leukocytes (Menon, 2002). The epidermis is avascular in nature, consisting of several types of cell (corneocytes, melanocytes, Langerhans cells, and Merkel cells) and a variety of catabolic enzymes (esterases, phosphatases, proteases, nucleotidases, and lipases) (Jansen and Hopsu-Havu, 1969; Mier and van den Hurk, 1975). The stratified epidermis is about 100–150 mm thick and comprises four distinct layers, namely the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum.
The stratum corneum is the outermost layer of skin that forms the main barrier for diffusion of the permeants through the skin (Wertz and Downing, 1989). Stratum corneum consists of 18–21 layers of flat, roughly hexagonal cells called corneocytes that are constantly shed and renewed (Menon, 2002). These keratin-rich dead cells, measuring 20–40 mm in diameter, are interspersed within crystalline lamellar lipid matrix to assume a "bricks and mortar" arrangement (Elias, 1983). The extracellular lipid contributes 10% of the dry weight of this layer, while 90% is the intracellular keratin. The barrier function of the skin can be attributed to the lamellar lipids that are synthesized in the granular layer and subsequently organized into the extracelluar lipid bilayer domains of the stratum corneum (Landmann, 1986). The barrier function of the skin depends on specific ratios of various lipids present and studies reveal that relatively polar lipids play a critical role in maintaining the barrier integrity of the stratum corneum (Elias et al., 1984; Menon et al., 1986; Elias and Feingold, 1988).
The viable epidermis is made up of keratinocytes at various stages of differentiation. Lipid catabolic enzymes, namely acid lipase, phospholipase, sphingomyelinase, and steroid sulfatase, are distributed throughout the epidermis, though mainly found in the stratum granulosum and stratum corneum (Menon et al., 1986). The phospholipid content decreases while the sphingolipid and cholesterol content gradually increases as the cells differentiate during their migration to the surface.
1.1.1 Dermis and hypodermis
The dermis is rich in blood vessels, lymphatic vessels, and nerve endings. An extensive capillary network connects to the systemic circulation with substantial horizontal branching from the arterioles and venules in the papillary dermis. These in turn form plexus and supply capillaries to the hair follicles and the glands. The lymphatic vessels serve to drain the excess extracellular fluid and clear the antigenic materials. The dermis is filled with scattered fibroblasts, macrophages, leukocytes, and mast cells, in addition to the hair follicles, sebaceous glands, and sweat glands. On average, about 10 hair follicles, 15 sebaceous glands, 12 nerves, 100 sweat glands, 360 cm of nerves, and three blood vessels are present in one square centimeter of skin (Barry, 1983). The hypodermis constitutes the deepest layer of the skin, and consists of the subcutaneous tissue filled with fat cells, fibroblasts, and macrophages.
1.2 TOPICAL vs. TRANSDERMAL DRUG DELIVERY
1.2.1 Topical drug delivery
Topical drug delivery is the term used for localized treatment of dermatological condition where the medication is not targeted for systemic delivery (Osborne, 2008); examples include treatment of dermatological conditions like eczema or psoriasis by topical application. Examples of drugs delivered topically include corticosteroids, antifungals, antivirals, antibiotics, antiseptics, local anesthetics, and antineoplastics. Topical agents that act by physical action would include protectives, adsorbents, emollients, and cleansing agents, whereas the astringents, irritants, rubefacients, and keratolytic agents are the ones which act by chemical means.
Conventional topical drug delivery systems include semisolid dosage forms and liquid dosage forms. The semisolid dosage forms include ointments, creams, gels, or pastes, while the liquid dosage forms include lotions that may be an emulsion, suspension, or a solution (Buhse et al., 2005). Ointments usually contain <20% of water and >50% hydrocarbons, waxes, or polyols as vehicles. Ointments are used as vehicles for topical application of the actives and basically function as skin protective and emollient.
Creams are emulsion semisolid dosage forms usually containing more than 20% water or volatile components and typically less than 50% hydrocarbons, waxes, or polyols as vehicles (Osborne, 2008). A gel is a semisolid dosage form that contains a gelling agent to provide stiffness to the dispersion. Gels can be water based (hydrogels) or organic solvent based (organogels) (Gupta and Garg, 2002). A paste can be defined as a semisolid dosage form, containing a large proportion of solids (20–50%) finely dispersed into a suitable vehicle. A lotion may be in the form of a solution or a suspension or an emulsion. Typically these formulations are intended to be applied to the intact skin, generally without any friction.
1.2.2 Transdermal patch systems
Transdermal delivery is the term that is confined to a situation in which the drug diffuses through different layers of the skin into systemic circulation to elicit the therapeutic response (Brown et al., 2006). An example would be management of hypertension using a transdermal clonidine patch. In a broader sense transdermal delivery also includes local anesthetic patches in which the drug is intended to diffuse regionally in the skin to elicit the pharmacological action only in the treated area of the skin. Often, delivery of local anesthesia has been classified under topical drug delivery. An overview of cutaneous drug delivery system is shown in Figure 1.2.
Transdermal drug delivery systems also termed as "patches" are self-contained discrete dosage forms designed to deliver a therapeutically effective amount of drug through intact skin (Wokovich et al., 2006). Most commercially available transdermal drug delivery systems are of three different types, namely reservoir systems, matrix systems with rate-controlling membrane, and matrix systems without rate-controlling membrane. The reservoir system is made up of three major components, namely the drug reservoir, the rate-controlling membrane, and the adhesive. The drug present in the reservoir, along with the other excipients, has to permeate through the rate-controlling membrane before reaching the skin. The adhesive that holds the system in place on the skin can completely cover the drug release area or only the perimeter around the non-adhering drug release surface. In the matrix type, the drug may be embedded in the adhesive matrix. A rate-controlling membrane may be present between the drug-loaded matrix and the adhesive or sometimes the matrix itself can control the rate of release of the actives from the system.
The drugs that have made it into the transdermal market include scopolamine, nitroglycerine, nicotine, clonidine, fantanyl, estradiol, testosterone, lidocaine, and oxybutinin (Langer, 2004). Recent additions to this list include lidocaine-tetracaine, selegiline, methyl phenidate, and rotigotine. However, the future focus is production of transdermal systems capable of delivering peptides and proteins including insulin, growth hormone, and vaccine across the skin.
1.3 PERCUTANEOUS ABSORPTION PATHWAYS
The lipid-rich and structurally complex intercellular region of stratum corneum is said to play an important role in percutaneous absorption (Elias and Friend, 1975). The stratum corneum is known to be selectively permeable and allows relatively lipophilic molecules to diffuse to the lower skin layers (Brown et al., 2006). The transport of such molecules across the stratum corneum barrier is mainly by passive diffusion (Scheuplein and Blank, 1971). The permeation rate through the stratum corneum has been represented by a simple equation (equation (1.1)) (Barry, 1983):
dm/dt = DC0K/h (1.1)
where dm is the amount of the diffusant passed through the membrane in time dt, C0 is the drug concentration in the donor solution, K is the partition coefficient of the diffusant between the membrane and the solution, D is the diffusion coefficient of the diffusant in the membrane, and h is the membrane thickness. Considering the tortuous intercellular pathway between the corneocytes, the diffusional path length for the permeants is much longer than the thickness of the stratum corneum and is estimated to be ~500 µm (Hadgraft, 2004).
The other potential routes of entry for the permeants from the skin surface to the subepidermal tissues are through the hair follicles with their associated sebaceous glands and via the sweat ducts or through the stratum corneum between these appendages (Barry, 2001). These follicles passing from the skin surface through the epidermis and reaching the dermis or even the underlying subcutaneous region are the most important appendages of human skin.
1.4 APPROACHES TO ENHANCE PASSIVE CUTANEOUS DRUG ABSORPTION
For a substance to be well absorbed from the skin it should have a molecular weight of less than 0.6 kDa (Schafer-Korting et al., 2007), and a balanced solubility in both oil and water with a log partition coefficient value between 1 and 3 (Hadgraft, 2004). Drug absorption across the skin could be enhanced by adapting one or more of the several strategies discussed subsequently in this chapter.
Excerpted from Handbook of NON-INVASIVE DRUG DELIVERY SYSTEMS by VITTHAL S. KULKARNI. Copyright © 2010 Vitthal S. Kulkarni. Excerpted by permission of Elsevier.
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1. Topical and Transdermal Drug Delivery
2. Micellar Nanoparticles: Applications for Topical and Passive Transdermal Drug Delivery
3. Emulsions and Microemulsions for Topical and Transdermal Drug Delivery
4.Iontophoretic Transdermal Drug Delivery
5. Ultrasound-based Technology for Skin Barrier Permeabilization
6. Microneedles - Minimally Invasive Transdermal Delivery Technology
7.Recent Advances in Ophthalmic Drug Delivery
8. Nasal Delivery of Micro- and Nano-encapsulated Drugs
9. Pulmonary Drug Delivery
10. Regulatory Aspects of Nasal and Pulmonary Spray Drug Products