PHARMAEUTICAL TECHNOLOGY II

TOPICAL AND TRANSDERMAL DRUG DELIVERY:

SKIN STRUCTURE AND FUNCTION.

Balqees Saeed
FACULTY OF PHARMACY, AL WADI INTERNATIONAL UNIVERSITY
(2019-2020)
 Topical and transdermal drug delivery: Skin structure and function

Table of Contents
Topical ........................................................................................................................................ 1
Transdermal ................................................................................................................................ 1
Regionally ................................................................................................................................... 1
1. Skin structure and function .................................................................................................. 2
1.1 The subcutaneous layer Fat layer ................................................................................. 2
1.2 The dermis ................................................................................................................... 2
1.2.1 The appendages ................................................................................................... 3
1.3 The epidermis .............................................................................................................. 3
1.3.1 The stratum corneum ........................................................................................... 3
1.3.2 The stratum lucidum ............................................................................................ 4
1.3.3 The stratum granulosum ...................................................................................... 4
1.3.4 The stratum spinosum .......................................................................................... 4
1.3.5 The stratum basale ............................................................................................... 4
1.3.6 Basement membrane ........................................................................................... 4
1.4 Skin microbiome .......................................................................................................... 5
2 Damaged skin ...................................................................................................................... 5
3 Transport through the skin .................................................................................................. 5
4 Factors affecting topical and transdermal drug delivery ....................................................... 6
4.1 Properties of permeant ................................................................................................ 6
4.2 Physiological factors .................................................................................................... 6

Topical drug delivery

The application of a formulation to the skin to treat a local disorder and aims to retain
the active pharmaceutical ingredient (API) within the skin (e.g. hydrocortisone
cream).
Transdermal drug delivery
The application of a formulation to the skin to deliver a drug to the systemic
circulation (e.g. estradiol patches).
Regionally acting
The API acts in the area close to where the formulation is applied (e.g. topically
applied ibuprofen gels to treat musculoskeletal conditions).
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 Topical and transdermal drug delivery: Skin structure and function

To understand the mechanism of drug penetration the anatomy of skin must be

recognized.

1. Skin structure and function

▪ The largest organ of the body (≈ 10%
of the body mass).
▪ Covers an area of ≈ 1.8 m2 (Figure 1).
▪ Acts as a barrier by
1. preventing the entrance of
microorganisms and chemicals.
2. regulating heat and water loss from
the body.
3. physical barrier to drug delivery.
▪ Skin consists of three layers: Figure 1 structure of the skin.

1.1 The subcutaneous layer (Fat layer)

1. Several mm thick (fatty layer), absent from some areas such as the eyelids.
2. Function
a. Provides mechanical protection against physical shock (insulates the body).
b. Provides a store of high-energy molecules.
c. Carries the blood vessels and nerves to the skin.
1.2 The dermis
▪ 3–5 mm thick and overlying the fatty layer.
▪ Consists of:
1. Collagen for mechanical strength and elastin for
flexibility in a gel-like matrix (water, glycoproteins, and
hyaluronan) (Figure 2).
2. Blood supply to
a. regulate body temperature
b. repair wound
c. deliver oxygen and nutrients to the tissue
d. remove waste
3. Lymphatic system to Figure 2 Composition of dermis
a. facilitate immunological responses to microbial attack
b. remove waste

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 Topical and transdermal drug delivery: Skin structure and function

▪ The blood supply and lymphatic system

reaches to the dermal–epidermal
boundary → so most molecules passing
through the outer layer of the skin are
rapidly diluted and are carried
systemically by the blood.
1.2.1 The appendages
▪ Nerve endings, hair follicles, sebaceous
glands and sweat glands (eccrine and
apocrine) (Figure 3).
▪ Stimulation of sweat glands by heat or
emotional stress→ secretion of sweat (a
dilute salt solution of ≈ pH 5) → to Figure 3 The dermis appendages.
produce cooling.
▪ The hair follicles and sebaceous glands secrete sebum (fatty acids, waxes and
triglycerides) to lubricate the skin and maintain the skin pH at ≈5.
▪ The hair follicles and sebaceous glands contain
drug-metabolising enzymes.
1.3 The epidermis
▪ Multiple layer, and overlies the dermis.
▪ Consists of five layers (the stratum corneum,
stratum lucidum, stratum granulosum, stratum
spinosum, and the stratum basale) (Figure 4).
1.3.1 The stratum corneum
▪ The outermost ≈10 µm thick when dry (swells to
several times when wet), consists of 10–15 layers
and its cells, keratinocytes (filled with keratin).
▪ Contains dead cells (the main barrier to
transdermal delivery of drugs), and the underlying
layers are called viable epidermis (four layer).
▪ Consists of keratinocytes, melanocytes and
Langerhans cells.
▪ Thinnest on the lips and eyelids and thickest on the
soles of the feet and palms of the hands. Figure 4 The epidermal layers.

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 Topical and transdermal drug delivery: Skin structure and function

▪ Keratin filled cells are contained largely of ceramides, fatty acids, triglycerides
cholesterol and water →acts as a plasticiser that prevents the stratum corneum from
cracking due to mechanical assault.
▪ Ceramides connecting bilayers together and keratinized cells cemented together by
desmosomes and dense lipid lamellae, the resulting structure can be likened “bricks
and mortar”.
▪ Contains little water (10–20%) for drug dissolution and the remainder lipid and
protein.
▪ The intercellular lipids lamellae that provide a pathway for lipophilic drug and a
pathway for hydrophilic drugs between the polar heads of two lipid arrays.
▪ The permeability differs from site to site (face more permeable than trunk or arms).
1.3.2 The stratum lucidum
▪ Thin and translucent layer, presents in thick skin (the soles of the feet and the palms).
1.3.3 The stratum granulosum
▪ Passes from the stratum spinosum to the stratum granulosum and contains granules
of keratin.
1.3.4 The stratum spinosum
▪ Found on top of the basal layer, consists of 2–6 rows of keratinocytes.
▪ Within this layer, the keratinocytes begin to differentiate and synthesise keratins.
▪ Desmosomes connecting the cell membranes of adjacent keratinocytes.
1.3.5 The stratum basale
▪ Single-cell layer that are attached to the basement membrane.
▪ Keratinocytes is the basal layer (stratum basale).
▪ They undergo division → differentiate → migrate outwards →forming the stratum
spinosum, the stratum granulosum, and the stratum corneum.
▪ The stratum basale contains:
1. Melanocytes → synthesis the pigment melanin (UV →↑melanin production).
2. Langerhans cells →participate in immune responses against microorganism.
3. Merkel cells →found on the dermal side of the basement membrane, associated with
nerve endings, and play a role in sensation.
1.3.6 Basement membrane
▪ Delineates the dermis from the epidermis.
▪ Acts as a barrier→ preventing large molecules from migrating to the dermis.
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 Topical and transdermal drug delivery: Skin structure and function

▪ It has a regulatory role in cell proliferation.

1.4 Skin microbiome
▪ Skin is populated with bacteria, yeasts, fungi, and viruses and varies from site to site.
▪ Microorganisms present on the skin surface, such as Staphylococcus epidermidis may
metabolise topically applied drugs.
▪ Keratinocytes sense microorganisms →immune responses →secretion of
antimicrobial agents → rapidly kill and inactivate microorganisms.

2 Damaged skin
▪ Radiation, irritant chemicals, allergens, trauma, and skin disorders (acne and
dermatitis) → damage the stratum corneum barrier → ↓ the stratum corneum
barrier→↑ topical and transdermal drug delivery.

3 Transport through the skin

▪ Drug molecule has three potential routes to cross the skin (intercellular, transcellular,
and shunt routes (appendages).
▪ Shunt routes→ partition into sweat or sebum of the intact skin (relatively small).
▪ Intracellular (transcellular) route → for an aqueous molecule→ partition and diffusion
through the corneocyte→ repeat partition and diffusion.
▪ Intercellular route → for lipid molecule → partition and diffusion through the lipid
bilayers between the corneocytes.

Figure 5 Transport through skin.

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 Topical and transdermal drug delivery: Skin structure and function

▪ The molecules have three potential ways after travelling through the stratum
corneum
1. The molecules diffuse through the epidermal layers → local effect.
2. The molecules may partition into the subcutaneous fatty layer may even reach
muscles →regional effect.
3. The molecule may also enter the systemic circulation → transdermal effect.
▪ Skin contains metabolic enzymes →↓the bioavailability of topically applied drugs.

4 Factors affecting topical and transdermal drug delivery

4.1 Properties of permeant
1. Drug must have some solubility in the formulation.
2. Lipophilic drug (intercellular route) are better than hydrophilic (intracellular route).
3. Un ionized drugs are better than Ionized.
4. Molecular weight (m.w) < 500 Da.
5. Low melting point (↓m.p).
6. ↑contact time → ↑drug absorption.
7. ↓Drug release →↓drug transport.
8. Should be effective at low doses (<10 mg/day).
9. ↓Particle size (PS)→↑dissolution rate→↑transdermal delivery.
10. Only molecules adjacent to the skin can partition from the vehicle into the tissue.
11. Saturated formulation → ↑tendency to escape from the formulation→ enter the skin.
12. Alcohols are good solvents →evaporate from the skin →↑drug delivery.
4.2 Physiological factors
1. Gender
2. Skin age
3. Body site and surface area
4. Race
5. Hydration of the stratum corneum
6. Temperature of the skin.