The Skin - Topical Drug Delivery W5

Question 1

What is the skin

Answer 1

• Largest organ in the body
• Weighs 2.5kg
• Complex, highly immune capable organ
• Protects us against contaminated atmosphere
• Performs protective, sensory and homeostatic functions

Question 2

The skin serves to ….

Answer 2

• 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)

Question 3

When skin comes in contact with noxious agent

Answer 3

◦ 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

Question 4

What are keratinocytes

Answer 4

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.

Question 5

What is keratinocyte differentiation

Answer 5

Differentiation of keratinocytes is critical for epidermal stratification and formation of a protective stratum corneum.

It involves a series of complex processes leading through gradual changes in characteristics and functions of keratinocytes 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.

Question 6

What is the epidermis

Answer 6

the top layer of skin in your body

Question 7

What is the stratum corneum

Answer 7

the outermost layer of the epidermis and marks the final stage of keratinocyte maturation and development.

• non viable epidermis
• 200-800 mions thick on palmar and plantar
• keratin rich dead cell layer and metabolically inactive

Question 8

What are Melanocytes

Answer 8

highly differentiated cells that produces a pigment melanin inside melanosomes which is taken up by keratinocytes

Question 9

What is the dermis

Answer 9

• 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

Question 10

What are skin appendages

Answer 10

Entry points

1. eccrine sweat glands
   - simple, coiled, tubular glands present throughout the body, most numerously on the soles of the feet
2. 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
3. hair follicles
4. nails

Question 11

Sebaceous glands

Answer 11

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)

Question 12

Subcutaneous tissue (hypodermis)

Answer 12

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

Question 13

Topical delvery

Answer 13

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)

Question 14

Targets for topical delivery

Answer 14

Skin surface treatment
◦ Sunscreens, surface antiseptics, deodorants,
protective films, drugs

Stratum corneum/appendage treatment
◦ Increase SC sloughing (e.g. in keratosis)
◦ Anti-perspirants
◦ Anti-bacterials: e.g. benzoyl peroxide, clindamycin, erythromycin for acne
◦ Anti-fungals: e.g. ketoconazole, terbinafine
applied to skin or nails

Viable epidermis:
◦ Steroids for psoriasis (inflammatory proliferation
of cells in epidermis)

Dermal blood supply
◦ i.e. transdermal drug delivery
◦ The epidermis, specifically the stratum corneum
is the barrier to drug absorption

Whether for local or systemic delivery the
drug must cross the stratum corneum

Question 15

Intercellular route vs trancellular route

Answer 15

transepidermal, when a drug permeates into the cells (intracellular) or through the cellular interspaces (transcellular)

Question 16

Stratum corneum lipids

Answer 16

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

Question 17

What determines the rate of drug
absorption across the skin?

Answer 17

Concentration of drug applied to the
skin
◦ This increases the concentration gradient
across the stratum corneum (Fick’s Law)
◦ triangleCsc is the concentration difference across
SC and & is the thickness of the SC

Diffusion coefficient of drug in stratum corneum
◦ Influenced by size, shape and charge of drug
(think about Stokes-Einstein equation)

Question 18

What determines the rate of drug
absorption across the skin?

Answer 18

Solute partition coefficient between formulation and skin
◦ Drug must partition into SC before diffusing across epidermal layers
◦ Formulation plays a huge role in topical therapy
◦ The SC is the absorption rate-limiting step,
except:
- When the SC is damaged (deliberately/accidentally)
- In these instances drug release from formulation
can be rate-limiting

Question 19

An equation to predict rate of drug
transport across the skin

Answer 19

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

Question 20

How to increase the rate (flux) of
drug across the skin

Answer 20

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

Question 21

How do we measure the rate of
drug transport across the skin?

Answer 21

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

Question 22

What does Potts & Guy tell us
about drug transport across skin?

Answer 22

Hydrophobicity
◦ Important for partitioning into SC lipids

Molecular size
◦ Affects the self-diffusion coefficient of drug in lipid

Question 23

Can all drugs be delivered across
the skin?

Answer 23

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

Question 24

Choice of drug candidates for transdermal delivery depends on:

Answer 24

◦ 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

Question 25

Potency of drug

Answer 25

Low amounts of drug crossing the skin means that
most drugs delivered transdermally are potent i.e.
have very low minimum effective concentration

Question 26

Factors that affect the rate of transdermal drug transport

Answer 26

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

Question 27

Factors that affect the rate of transdermal drug transport : formulation factors

Answer 27

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

Question 28

Ointments

Answer 28

Water-free semi-solids made from:

◦ Hydrophobic ointment bases
e.g. white soft paraffin used in calamine ointment,
difficult to wash off (no surfactants)

◦ Fats and fixed oil bases
E.g. arachis (peanut) oil, mono-, di-, tri-glycerides of
fatty acids, castor oil

◦ Silicones:
E.g. hydrophobic dimethicone acts like hydrocarbons
◦ Absorption bases:
soak up water to make o/w emulsions e.g hydrophilic petrolatum USP is a mixture of hydrocarbon bases with cholesterol and stearyl alcohol

Question 29

Ointments - Emulsifying bases

Answer 29

Anhydrous bases that contain emulsifying
agents that make them miscible with water

E.g. Anionic emulsifying ointment (used to make
aqueous cream), cationic cetrimide emulsifying
ointment and non-ionic cetomacrogol emulsifying
ointment

Can be used as soap substitutes in severe dry skin
conditions, eczema etc

Question 30

Ointments - Water-soluble bases

Answer 30

Prepared from low and high MW polyethylene glycols (e.g. macrogols)

Non-occlusive and washable

Question 31

Creams

Answer 31

Semi-solid emulsion of O/W or W/O
- Used as a base for topical drugs
- O/W creams vanish into skin and are non-occlusive
- W/O preferable to ointments

General method:
◦ Melt oil-soluble material
◦ Heat water-soluble materials to same temperature
◦ Add water to oil and stir continuously until room temp

Question 32

Other topical formulations

Answer 32

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