Dermal Delivery

• Dermal Delivery

  Delivery of drugs into and through the skin

  
• Types of dermal delivery

  • Dermal
  • Transcutaneous
  • Transdermal
• Dermal


  Delivery where the aim is to get the drug in the skin, i.e. the skin is to be treated

  
• Transcutaneous


  Delivery where the drug is delivered to regions just beyond the skin, e.g. muscles, joints etc.

  
• Transdermal

  Delivery using the skin as means of direct entry to the systemic circulation

  
• Objectives of drug therapy into and through the skin

  • Delivery of the active drug to the site of action within the skin
  • Delivery of drugs to regions beyond the skin, for example, musculature and joints
  • Use of the skin as a portal entry to the system (rather than site of action) for appropriately formulated drug

  
• Advantages of using the skin as a systemic administration route


  • Avoidance of first-pass effect
  • Drug levels can be maintained in the systemic circulation within the therapeutic window
  • Frequency of dosing reduced
  • Improved patient compliance
  • Drug input can be terminated by removal of a patch

  
• Disadvantages of using the skin as a systemic administration route


  • Skin is a barrier (one of the most difficult)
  • Irritation and sensitization
  • Tolerance inducing drugs – washout period
• Skin is the largest organ in the body and covers an area of 1.65-1.85 m2
• Skin is a highly complex multi-layered organ designed to 'keep the outside out and the insides in', accounting for around 16% of total body mass

  
• Layers of the skin


  • Epidermis
  • Dermis
  • Hypodermis (aka subcutaneous layer)

  
• Areas of the skin where different products work

  • Surface: repellents, sun screens, antimicrobials, antiseptics
  • Local (active pharmaceutical ingredient works directly on skin): corticosteroids, cytotoxics, antiviral, antihistamines, anaesthetics
  • Appendages: antimicrobials, depilatories
  • Systemic: nicotine, hormones, scopolamine, fentanyl, nitroglycerin, clonidine

  
• For drug delivery and therapy, the intact skin presents a formidable barrier and a difficult challenge to formulation scientists

  
• The properties of the skin limit the range of active ingredients that can be delivered through the barrier to achieve therapeutic levels

  
• Epidermis


  The epidermis overlies the dermis and is itself multi-layered and contains various cell types, including keratinocytes, melanocytes and Langerhans cells
• Stratum corneum


  The epidermis of the skin is a closely meshed system of horny cells (corneocytes) and lipid layers

  
• Keratinocyte differentiation


  Keratinocytes in the basal layer (stratum basale) undergo division and then differentiate as they migrate outwards, forming the stratum spinous, then the stratum granulosum and finally the stratum corneum
• Keratinised squamous stratified epithelium


  A type of stratified epithelium that contains numerous layers of squamous cells, called keratinocytes, in which the superficial layer of cells is keratinized

  
• Keratinised squamous stratified epithelium


  • Stratified — many layers
  • Keratinised — the outermost cells have no nuclei and are effectively dead tissue
• As cells rise to the outer surface, they become more flattened, compacted and dead ("horny"), and increasingly hydrophobic
• In contrast to simple epithelia, the primary function of keratinised squamous stratified epithelium is protection (penetration barrier)
• Thickness of the epidermis varies: Scrotum, behind the ear (scopolamine, Trans-Derm Scop), eyelids (ca. 6 μm)
• The epidermis commonly has 10-25% water content, so is very hydrophobic
• Dermis


  The dermis overlies the fatty layer (hypodermis) and is typically 3 mm to 5 mm thick; it's the major component of the human skin
• Dermis


  • Composed of a network of mainly collagen and elastin in a mucopolysaccharide gel
  • Contains nerve endings, pilosebaceous units (hair follicles and sebaceous glands), and eccrine and apocrine sweat glands
  • Metabolically active and requires an extensive network of blood vessels

  
• The blood supply reaches to approximately 0.2 mm below the skin surface, near the dermis-epidermis boundary
• The rich blood flow keeps the dermal concentration of most transdermally delivered drugs low, which in turn provides a concentration gradient from the outside of the body into the skin
• The dermis has two layers: the papillary layer and reticular layer

  
• Hypodermis (aka the Subcutaneous Layer)


  The lowest layer in the skin, typically several millimetres thick, except for some areas such as the eyelids, where it is mostly absent
• Hypodermis


  • Provides mechanical protection against physical shock
  • Insulates the body
  • Provides a store of high-energy molecules
  • Carries the principal blood vessels and nerves to the skin

  
• The subcutaneous layer is seldom an important barrier to transdermal and topical drug delivery but may be a barrier to regionally targeted molecules such as ibuprofen for muscular pain relief

  
• Skin functions


  • Self-repairing barrier, allowing people to live by preventing the ingress of microorganisms and chemicals whilst regulating heat and water loss from the body
  • Protective organ, serving as a chemical barrier, blocking access of exogenous material, controlling loss of water, electrolytes and other endogenous materials, and resisting diffusion
• The main barrier is the stratum corneum (often considered the only one) as it stops most of exogenous material (95%)
• Although very thin (15 μm), the stratum corneum is very difficult to transverse: it is dense, lacks of water and it is lipophilic
• To understand percutaneous penetration of drugs (or chemicals in general), we need to focus on the stratum corneum
• Drug delivery through the skin

  1. Drug molecules must be presented to the skin surface

  2. If the formulation contains solid drug, then dissolution and diffusion through the formulation is the initial step

  3. If the formulation contains dissolved drug, then as the molecules nearest to the skin surface enter the tissue, these must be replaced by other molecules diffusing within the formulation towards the skin surface

  
• Pathways through the skin

  • Across the intact horny layer
  • Through the hair follicles with the associated sebaceaous glands
  • Via the sweat glands
• Transcellular (aka Intracellular) Route


  Drug molecule initially partitions into a keratin-filled corneocyte, which is essentially an aqueous environment, then diffuses through the corneocyte before partitioning into the intercellular lipid domains
• Transcellular transport is limited by solubility of penetrant in both phases and is a relatively minor pathway
• Topically applied drugs may form a depot or reservoir by binding within the stratum corneum, for example clotrimazole (antifungal) or sunscreens