Transdermal and Dermal Drug Delivery Flashcards
Topical treatment
– treatment localised to skin as the organ being treated
• Not just for drug delivery, but also
• Excipients
• Cosmetics
• Typically 2% or less of a topically applied drug is bioavailable
Transdermal
– treatment through the skin
• HRT
• Pain relief
Topical Preparations
- Creams, Ointments, Gels
- Antibiotic creams – treating superficial skin infections e.g. impetigo
- Eczema – emollient creams and ointments, steroid creams
- Antisepsis – chlorhexidine skin cleanser
Transdermal Preparations
- Patches
- Nicotine replacement therapy (NRT)
- Glyceryl trinitrate (GTN)
- Fentanyl, Buprenorphine
- Hormone replacement therapy (HRT)
- There have been 17 approved transdermal drugs in the USA and Europe between 1979-2014
- The limited number of compounds reflects the difficulty of creating efficacious drugs in suitable formulations necessary for patient treatment
Skin structure
epidermis
dermis
Sc fat
Underlying tissue
Main features of skin
• Epidermis
- Made up of 5 distinct layers, the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, stratum basale
- Includes the major penetration barrier (stratum corneum)
- Up to 40% water (commonly 10- 25%), can be changed by disease, diet and environment
- Varies in thickness around the body
- Thickest – soles of feet (ca. 800µm)
- Thinnest – scrotum, behind the ear, eyelids (ca. 6µm)
- Melanocytes located in the basal layer, required for UV protection
Main features of skin
• Dermis
- Majority of skin thickness
- Connective Tissue
- Support structures
- Blood capillaries
- Lymphatic system
- Appendages
- Sweat glands
- Sebaceous glands
Appendages
- Hair follicles
* Effectively bypass the stratum corneum barrier
Why are appendage not always used to deliver drugs through the skin
- Only polar drugs can move through this route
- Competing outward flow of sebum
- Sebum is fatty and therefore may create an oil rich environment on the surface of the hair follicle, unsuitable for polar drugs to move across
- Different areas of skin have different numbers of hair follicles – cannot guarantee uniformity of concentration delivered
Sweat Gland
• Passive, diffusion-controlled absorption across the sweat gland is highly unlikely
The Stratum Corneum Barrier
• Outermost layer of skin and the epidermis
• The main (>95%) barrier to percutaneous absorption of
exogenous chemicals
• Very thin (ca. 15 microns on the forearm) but it is a very
lipophilic and very thin stratified epithelium
• Thickest – soles of feet
• Thinnest – eyelids, scrotum, behind the ears
Stratum Corneum
• Dead (no nucleus), flattened and compacted corneocyte
cells surrounded by extensive lipid bilayers
• The main barrier to letting things in and out of the skin
• Often considered the only barrier
• Mediates transepidermal water loss (TEWL)
• Very dense, highly lipid tissue
• Very thin
• Typically 15-30µm in thickness
• The lipid system between the corneocyte cells serves as
a cement and as a skin barrier.
• Together with water, its four main components — fatty
acids, triglycerides, ceramides and cholesterol — form the
lamellar liquid crystalline lipid system
• The stratum corneum is such a difficult barrier to
penetrate because of:
- Number and size of corneocytes
- Presence of lipid bilayers
- Presence of corneodesmosome “rivets”
- Number of skin layers
- Lipid cell envelope surrounding the corneocytes
Routes of drug permeation into and
across skin
Intracellular
Transcellular
Transappendageal
Factors affecting percutaneous absorption
• Physiological
- Skin condition
- Skin hydration
- Occlusion
- Skin stripping
- Skin age
- Regional variation
- Species variation
- Race
- Gender
- Cutaneous metabolism and blood flow
- Skin temperature
- Skin binding
Factors affecting percutaneous absorption
• Physicochemical
- Drug concentration
- Partition coefficient
- Degree of ionisation (Henderson equation)
- Solubility
- Chemical structure
- Molecular weight
- Particle Size
Factors affecting percutaneous absorption
• Drug/Vehicle
- Drug/vehicle interactions
* Solubility of drug in excipients
Formulations
Dusting powders
• Fine particle size with active ingredient
• Drying/lubricating
• For example antifungals such as miconazole
Liquids
• Soaks – active dissolved in an aqueous solvent
• Astringents
• Cooling
• Leaving a solid film (e.g. potassium permanganate; skin cleaners, antiseptics, and preparations for promotion of wound healing)
Applications
• Simple emulsions or solutions, usually containing a pesticide
• For example, benzoyl benzoate application
Lotions • Aqueous solutions, suspensions or emulsions • Cools inflamed skin • Deposits and film of solid material • For example, calamine lotion
Paints/Tinctures
• Ether concentration aqueous or alcoholic antimicrobial solutions
• For example trosyl nail solution (tioconazole 28% for fungal nail infections)
Collodions
• Usually organic solvents
• Mixtures of ether and alcohol
• Usually painted onto the skin and allowed to dry, leaving a flexible film
• Contains a polymer and an active
• For example, salicylic acid collodion for the treatment of warts and calluses
Ampiphilic drugs
exhibit both lipid and aqueous properties
Skin permeability
• “Like dissolves like”
• Drugs need to be lipophilic to penetrate into the stratum
corneum
• If they are too lipid they will stay there and not diffuse into the aqueous tissues (dermis)
• If they are too hydrophilic they will not get through the stratum corneum barrier
• A compromise is needed in physicochemical terms
Intracellular route is best for
hydrophobic drugs
transcellular route is best for
hydrophillic durgs
epidermis is..
lipophilic/hydrophobic
transappendageal route is best for
polar drugs
