Topical and trans-dermal delivery

Question 1

What are some of the functions of the skin?

Answer 1

To stabilize the body temperature (sweat secretions)
Acts as a sensory organ
Limits the entry of allergens into the body (acts as a physical barrier)
Protects internal body structures merging

Question 2

What are the two targets of topical application?

Answer 2

Skin softening (application of emoillents to treat dermatitis and ezcema)
Systemic treatment (HRT patches and contraceptives, steady release of hormones)

Question 3

What are the three core layers of the skin?

Answer 3

Epidermis
Dermis
Hypodermis

Question 4

What are the different layers within the epidermis?

Answer 4

Top to bottom of the epidermis:
Stratum corneum
Stratum lucidum
Stratum granulosum
Stratum spinosum
Stratum basale

Question 5

Where are keratinocytes made?

Answer 5

In the stratum basale

Question 6

What are the two possible outcomes of keratinocytes?

Answer 6

Remain in the stratum basale and continue to undergo mitosis to replenish keratinocyte store or begin to migrate and differentiate upwards.

Question 7

What is the function of keratinocytes?

Answer 7

To produce keratin, a filament for nail growth, strong hair, skin.

Question 8

How does the structure of keratin change through the layers of the epidermis?

Answer 8

As the migrate upwards the cells flattern and loose their nucelus. By the time the keratinocytes reach the stratum corneum layer they are dead flat cells. These cells are responsible for protecting from UV light, abrasions and heat.

Question 9

Where does metabolism of a pro-drug occur in the epidermis?

Answer 9

In the viable epidermis which is just below the stratum corneum and it contains squamos, stratified cells.

Question 10

What other cells are found in the epidermis?

Answer 10

Melanocytes responsible for producing melanin which provides pigment to the skin.

Question 11

Describe the structure of the dermis layer.

Answer 11

The dermis layer is composed of two layers of connective tissue that are connected by elastin and collagen fibres. The dermis layer also contains blood vessels, hair follicles and sweat glands.

Question 12

What are the two different layers within the dermis?

Answer 12

Papillary layer
Reticular layer

Question 13

What are the differences in the connective tissue structures between the two layers in the dermis?

Answer 13

Papillary layers consists of areolar connective tissue formed by elastin and collagen forming a ‘mesh’.
Reticular layer however consists of much denser irregular connective tissue.

Question 14

Explain the differences between the two types of sweat glands.

Answer 14

Eccrine sweat glands:
Occur all over the body and directly open to the skin.
Regulate temperature due to heat loss via evaporation
Watery sweat
Innervated by the sympathetic nervous system

Apocrine sweat glands:
Usually occur with areas of hair follicles and are released where there are hair follicles.
Respond to sex hormones
Protein rich sweat
Innervated by the adrenergic nervous system

Question 15

How is acne caused?

Answer 15

Due to overactivity of the holocrine glands that produce sebum that clogs up pores.

Question 16

What is the structure of the hypodermis?

Answer 16

Below the dermis is the hypodermis comprised of subcutaneous tissue. Specifically the tissue is well-vascularized, loose, areolar connective tissue and adipose tissue which provides thermal insulation and mechanical protection.

Question 17

What are some examples of drugs that target the stratum corneum?

Answer 17

Antibacterials: Benzoyl peroxide and Clindamycin used for the treatment of acne.
Anti-fungals: ketoconazole for fungal skin infections
Anti-perspirants

Question 18

Which types of drug target the viable epidermis?

Answer 18

Corticosteroids to reduce inflammation in conditions such as psoriasis.

Question 19

Which types of drugs target the dermal blood supply?

Answer 19

Transdermal medications such as contraceptoves, HRT and nicotine patches.

Question 20

Describe how the route across the stratum corneum differs for hydrophilic and hydrophobic drugs.

Answer 20

Hydrophilic drugs favour an aqueous environment whereas hydrophobic drugs favour a lipid environment. Therefore hydrophilic drugs travel intracellularly across the keratin filled coryneocytes partitioning in and out of the aqueous phase of the cell into the lipid phase of the inter-cellular space. Whereas hydrophobic/ lipophilic drugs travel through the continuous phase of the lipid environment around the keratin filled coryneocytes.

Question 21

How does increasing the concentration of drug applied to the skin increase the rate of absorption?

Answer 21

This is achieved by increasing the concentration of drug at the surface especially if saturated this pushes the drug into the skin due to greater/steeper concentration gradient.

Question 22

What other methods can be used to increase drug permeability across the skin?

Answer 22

Increasing the drug diffusion co-efficient which can be done by increasing the lipophilicity of the drug.
Alternatively absorption enhancers can be used to liquify repelling lipids in the stratum corneum layer.

Question 23

What method is used to determine the rate of skin absorption across a membrane?

Answer 23

Franz cell diffusion

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 24

What is kp and what is it dependent on?

Answer 24

Kp: permeability of the skin to the permeability of the drug.

Kp is dependent on the molecular size and logK.

Question 25

What is the ideal molecular weight and logK in order to maximise absorption across the stratum corneum?

Answer 25

A kp between 1 and 4, molecular weight less than 500 and an effective daily dose less than 10mg.

Question 26

What other factors are an issue with topical drug application?

Answer 26

The skin is metabolically active and therefore contains esterases, peptidases, proteases and hydrolyases which reduce the bioavailability.

Question 27

What is the equation for kp?

Answer 27

Hydrophobicity - Molecular Weight

Question 28

What are some of the key factors when designing a drug for transdermal drug delivery?

Answer 28

Physio-chemical properties- permeability increases as molecular weight increases however beyond a MW of 500- too large to pass through the epidermis, logP should be between 1 and 4.

Daily dose around 10mg due to a good permanent having a flux of 1mg per cm2 per day therefore given in a 10cm2 patch- would you want it to be any larger.

Release of the drug: the drug should be released at a constant partition rate.

Formulation factors: will the drug be given as a cream, ointment etc.

Question 29

What skin conditions considerations have to be made choosing a formulation?

Answer 29

Thickness and condition of the skin- the stratum corneum layer varies across the body, broken or inflamed skin are increasingly permeable.

Hydration the skin- if the skin is more hydrated (more water molecules present) the lipid layer is therefore more permeable due to the lipids being packed less tightly together.

Question 30

What can influence the ‘escape tendency’ or partitioning of a drug from the formulation into the stratum corneum?

Answer 30

If the drug applied is saturated, then it has a driving force to partition from the formulation into the stratum corneum.

Question 31

What are the differences between creams and ointments?

Answer 31

Creams are primarily water based (more water than oil) whereas ointments are oil based (more oil that water).

Question 32

How would the logP affect the partioning co-efficient from creams and ointments?

Answer 32

LogP is defined as partitioned conc. of drug in octanol/ partitioned conc. of drug in water.

The higher the logP the greater the lipophilicity (more of the drug is dissolved in oily ethanol). A low logP it suggests the drug is hydrophilic (more is dissolved in water).

Creams are water based and therefore can be said to have a hydrophilic base.
A drug with a high logK is as we said before more lipophilic based. A lipophilic drug will partition readily from the hydrophilic water based cream.
A drug with a low logK more hydrophilic based. A hydrophilic drug will not easily partition from a hydrophilic base such as a cream

Ointments are oil based and therefore can be said to have a lipophilic base.
A drug with a high logK is more lipophilic based. A lipophilic drug will not easily partition from the lipophilic base.
A drug with a low logK is more hydrophilic based. A hydrophilic drug will readily transition from a lipophilic base.

Question 33

Will drugs within gels partition the same as drugs within creams or ointments?

Answer 33

Creams as gels are also water based, they are free from oils

Question 34

What types of ointment bases are used?

Answer 34

Hydrophobic ointment bases such as white soft paraffin.
Fats and fixed oil bases such as arachis oil
Silicones
Absorption bases
Water soluble bases
Emulsifying bases

Question 35

What are creams defined as?

Answer 35

Semi solid emulsions of either w/o or o/w

Question 36

How are pastes defined?

Answer 36

They are semi-solid preparations for cutaneous/mucosal
application containing large proportions of solids finely
dispersed in the base

Question 37

What are some of the benefits of transdermal drug delivery?

Answer 37

Avoids first pass metabolism in the liver
Easy administration
Avoids possibility of overdosing
Increases patient adherence (only have to be applied once a every 3 days, 7 days etc).

Question 38

Describe the rate limiting trans-dermal patch design.

Answer 38

The outer layer is the impermeable backing layer which protects the outer layer of the drug. The drug is then dissolved in a layer which is adjacent to the controlling membrane which permits the the release of the drug from the matrix into the adhesive layer. The adhesive layer is protected by a strippable film.

Question 39

Which drugs can be used for micro-needle therapy?

Answer 39

Drugs that are long polypeptides/proteins. They can’t be taken orally as they are broken down by digestive juices and they are too large and hydrophilic to diffuse through the layers in the skin.

Question 40

How far do the micro-needles penetrate?

Answer 40

Into the epidermis but not as far as the nerve fibres.

Question 41

How does Iontophoresis work?

Answer 41

A medical device is used to pass an electric current through water which prompts the transfer of molecules across the stratum corneum.

Question 42

What is the condition hyperhidrosis?

Answer 42

Excess sweating from the palms of the hands or soles of the feet. An electrical current can be applied to water or glycopyrronium in severe cases.