The Skin - Topical Drug Delivery W5 Flashcards
What is the skin
- Largest organ in the body
- Weighs 2.5kg
- Performs protective, sensory and homeostatic functions
The skin serves to ….
- Protect the internal body structures by merging with respiratory, genitourinary and digestive tracts
- Limit entry into the body of noxious chemicals, allergens etc
- Stabilise body temperature, BP
- Act as sensory organ (heat, cold, touch, pain)
When skin comes in contact with noxious agent
◦ Some may pass across the top layer (stratum corneum)
◦ Some may be metabolised in the lower layers (viable epidermis)
◦ Sensing of and reaction to chemical damage in epidermis and dermis
◦ Removal of chemical by bloodflow through vessels in the dermis
What are keratinocytes
Keratinocytes represent the major cell type of the epidermis, the outermost of the layers of the skin, making up about 90 percent of the cells there.
They originate in the deepest layer of the epidermis, the stratum basale and move up to the final barrier layer of the skin, the stratum corneum.
What is keratinocyte differentiation
critical for epidermal stratification and formation of a protective stratum corneum.
involves a series of complex processes leading through gradual changes in characteristics and functions of up to their programmed cell death via cornification.
Keratinocytes at the basal layer of the epidermis are proliferative, and as the cells mature up the epidermis, they slowly lose proliferative potential and undergo programmed destruction.
What is the epidermis
the top layer of skin in your body
What is the stratum corneum
the outermost layer of the epidermis and marks the final stage of keratinocyte maturation and development.
- keratin rich dead cell layer and metabolically inactive
What are Melanocytes
highly differentiated cells that produces a pigment melanin inside melanosomes which is taken up by keratinocytes
What is the dermis
- Middle skin layer, 1-5mm fibrous and elastictissue
- Supportive and cushioning tissue composed mainly of collagen (70%), elastin and fibrillin
- Sparse cellular population
◦ Nerve endings
◦ Blood vessels
◦ Lymph vessels
◦ Hair follicles
◦ Sweat glands
◦ Sebaceous glands
What are skin appendages
Entry points
- eccrine sweat glands
- simple, coiled, tubular glands present throughout the body, most numerously on the soles of the feet - apocrine sweat glands
- Most apocrine glands in the skin are in the armpits, the groin, and the area around the nipples of the breast and have odour - hair follicles
- nails
Sebaceous glands
Together with the hair follicle forms the pilosebaceous unit
Holocrine glands that produce a lipid-rich secretion called sebum
Overactivity, especially during puberty, causes common acne (acne vulgaris)
Subcutaneous tissue (hypodermis)
Subcutaneous fat layer acts as a:
◦ Mechanical protector
◦ Thermal insulator
◦ Energy store
Heat regulation uses subcutaneous fat pad (hypodermis) and skin blood supply
Thickness depends on whole body adiposity but need a minimal amount for skeletal and organ protection
Topical delvery
Delivery of a medicament to the skin or mucous
membrane
1. Local treatment:
◦ Skin softening (emollient)
◦ Delivery of active agent to skin tissue
2. Systemic treatment (transdermal):
◦ Delivery of drug across skin into dermal blood
vessels → systemic circulation
◦ Potent drugs including nicotine, hormones
(contraceptive and menopausal hormone
replacement)
Targets for topical delivery
Skin surface treatment
◦ Sunscreens, surface antiseptics, deodorants, protective films, drugs
Stratum corneum/appendage treatment
◦ Anti-perspirants
◦ Anti-bacterials: e.g. benzoyl peroxide, clindamycin, erythromycin for acne
◦ Anti-fungals: e.g. ketoconazole, terbinafine
applied to skin or nails
Whether for local or systemic delivery the
drug must cross the stratum corneum
Intercellular route vs intracellar
Intercellular means between cells.
Intracellular, which means within the cell
Stratum corneum lipids
20% total volume of stratum corneum
Form lamellar sheets in intercellular
(between cellular) spaces
Composition:
◦ Ceramides
◦ Cholesterol
◦ Fatty acids
100-150mg produced per day to replace lipids lost in desquamation
What determines the rate of drug absorption across the skin?
Concentration of drug applied to the skin
◦ This increases the concentration gradient across the stratum corneum (Fick’s Law)
Diffusion coefficient of drug in stratum corneum
◦ Influenced by size, shape and charge of drug
An equation to predict rate of drug
transport across the skin
J = (DP / S) triangle Cv
J = flux (units: cm/s)
D = diffusion coefficient in SC (see Stokes-Einstein)
P = partition coefficient between formulationand skin
S = thickness of the stratum corneum
TriangleCv = conc. difference between formulation
and skin
How to increase the rate (flux) of
drug across the skin
Increase TriangleCv
◦ Achieve this by maintaining high conc of drug at skin surface
◦ Use supersaturated drug formulations
Increase the drug diffusion coefficient, D
◦ Make drug more lipophilic by masking polar groups
◦ Use absorption enhancers to liquify the SC lipids
How do we measure the rate of
drug transport across the skin?
Franz diffusion cell
Place skin tissue between two glass pieces
Apply drug solution or formulation
Take sample through side arm
Measure drug levels with sensitive analytical
technique
What does Potts & Guy tell us
about drug transport across skin?
Hydrophobicity
◦ Important for partitioning into SC lipids
Molecular size
◦ Affects the self-diffusion coefficient of drug in lipid
Can all drugs be delivered across
the skin?
Transdermal drug delivery market is worth $2 billion
per year (year 2000)
In 2000 only eight drugs were in the market:
- Scopolamine, nitroglycerin, clonidine, estradiol, nicotine testosterone, fentanyl and norethisterone
Why?
- Maximal steady state flux in the order of micrograms per hour
Choice of drug candidates for transdermal delivery depends on:
◦ Physicochemical nature of the drug (above)
◦ Potency of the drug
◦ Timescale of drug exposure
◦ Site and condition of skin
◦ Formulation
◦ Alteration of skin barrier by formulation
◦ Skin hydration
Potency of drug
Low amounts of drug crossing the skin means that most drugs delivered transdermally are potent
Factors that affect the rate of transdermal drug transport
Timescale of drug exposure:
◦ Creams, lotions, ointments applied OD, BD/TDS
◦ Patches applied OD or every 72 hours
Site and condition of skin
- SC thickness varies across body
- Broken or inflamed skin more permeable
- Hirsute skin may be more permeable (especially to hydrophilic drugs that diffuse slowly through SC but faster through hair follicles)
Skin hydration state
◦ Hydrated skin is generally more permeable to
drug
◦ Thought to be due to looser packing of SC
lipids → less restrictive path to drug diffusion
◦ Opens up the SC and can increase SC
penetration 10-fold
Factors that affect the rate of transdermal drug transport : formulation factors
Ointment, cream, lotion, gel
◦ Aim is to maximise drug concentration
gradient across SC
◦ Use formulation techniques to achieve
supersaturated concentrations
Alteration of skin barrier by formulation
- Can include penetration enhancers
- Ointments are greasy and restrict water loss from
skin → stratum corneum become more permeable
Ointments
Contain 80% oil (O/W)
Stay on top of skin rather than being absorbed straight away
This offers more protection against moisture loss
Thicker than creams and can spread further
Greasy feel
Lotion
More water than oil (W/O)
Thinner than creams
Absorb quickly and leave little residue
Creams
Equal parts oil and water
Easily absorbed and oil means it can stay on the skin surface
Non-greasy
Other topical formulations
Pastes:
◦ semi-solid preparations for cutaneous/mucosal
application containing large proportions of solids
finely dispersed in the basis.
Gels:
◦ consist of liquids gelled by means of suitable
gelling agents e.g Ibugel
Others:
◦ Poultices, medicated plasters, powders, aerosols
