Topical drug delivery

Question 1

What is Topical drug delivery?

Answer 1

Delivery of drugs at the surface or to the skin

This is to treat skin conditions

Question 2

What is Transdermal drug delivery?

Answer 2

Delivery of drugs to the bloodstream through the skin

Question 3

Types of drugs administered to the skin for topical delivery

Answer 3

CLAAAAP

Anti-inflammatory drugs (corticosteroids) - Eczema, skin allergy, insect bites…

Local anaesthetics (lidocaine, benzocaine)

Antiseptics – wounds, leg ulcers

Anti-infectious agents (antibacterial, antifungal, antiviral, parasiticidal)

Anti-acne (benzoyl peroxide)

Psoriasis drugs (dithranol, vitamin D analogues, retinoids)

Cytostatics – skin cancer

Question 4

What are the advantages of topical drug delivery?

Answer 4

Easy + Painless delivery

High patient compliance

Avoid FPM in the liver

Increased efficacy

Decreased side effects

Question 5

Wha are the disadvantages of topical drug delivery?

Answer 5

FLOPS

Frequent allergies

Only a few drugs have suitable properties for drug delivery

Prescence of enzymes in the skin

Low drug penetration in skin

Skin is a very efficient barrier

Question 6

Describe the structure of the skin

Answer 6

Question 7

What is the function of the skin?

Answer 7

Effective barrier against penetration of chemicals/microorganisms - That includes drugs!

Control of body hydration and temperature

Protection against UV radiation

Mechanical barrier

Question 8

What is the main barrier for drug permeation?

Answer 8

Stratum Corneum

Question 9

Describe the Stratum Corneum

Answer 9

10-15 layers of corneocytes - (dead cells derived from keratinocytes)

Tightly compacted cell layers

Polygonal, elongated, flat cells

Cells mostly contain keratin

Embedded in lipid bilayers (ceramides, fatty acids, cholesterol but no phospholipids)

« brick and mortar » model

Question 10

Name the penetration pathways through the Stratum Corneum

Answer 10

Transappendageal

Transcellular

Intercellular

Question 11

What is the Transappendageal pathway?

Answer 11

Transports substances via sweat glands and the hair follicles with their associated sebaceous glands

This route is considered negligible because of its relatively small surface area (0.1%).

Question 12

What is the Transcellular pathway?

Answer 12

Polar route for hydrophilic molecules

Unfavourable (drugs need to partition into lipid bilayers between the cells)

Question 13

What is the Intercellular pathway?

Answer 13

Less polar route for hydrophobic molecules

Favourable (continuous pathway)

Question 14

What are the main factors that affect drug permeation?

Answer 14

Biological factors

Drug properties

Vehicle properties

Question 15

What are the Biological factors?

Answer 15

Skin hydration - Increases drug penetration (both for hydrophilic and lipophilic molecules)

Age - Decreased skin moisture content with age

Body site - Thickest SC on the palms of the hands and sole of the feet, thinnest on the lips and eyelids

• Order of permeability: Genitals > head and neck > trunk > arm > leg

Pathological disorders - Damaged stratum corneum if infection, eruptions, tumours

Question 16

What are the drug properties?

Answer 16

Molecular weight - Poor penetration if >500 Da

Partition coefficient between vehicle and skin - Log P (octanol/water) between 1 and 3 - Drug with Log P > 3 might accumulate in the stratum corneum

pKa - Drug must be neutral at the pH of the skin (-5)

Concentration in vehicle - Diffusion into the skin depends on the concentration gradient

Question 17

How can we modify drug physicochemistry for increase drug permeation into the skin?

Answer 17

Prodrugs

Attach lipophilic moieties to increase partitioning into stratum corneum

Esters cleaved by esterases to release parent molecule

Dramatic increase in skin permeation

Question 18

What are the drawbacks of using prodrugs?

Answer 18

They are new chemical entities - toxicity tests + clinical trials must be performed before approval

Question 19

What should be the Vehicle properties?

Answer 19

Occlusion - ointment + w/o cream prevents evaporation from the skin

• increases hydration + drug permeation

Permeation enhancers used in many components

• chemical agents which decrease the barrier properties of the stratum corneum w/out damaging underlying cells

Question 20

Examples of prodrugs for topical delivery

Answer 20

Betamethasone-17-valerate

Hydrocortisone Butyrate (Potent)

Question 21

Types of formulations for topical drug delivery

Answer 21

Liquid formulations - lotions

Semi-solid formulations

Question 22

Examples of Liquid formulations

Answer 22

Solutions (cetrimide, scalp lotions)

Emulsions (hydrocortisone)

Question 23

Examples of Semi-solid solutions

Answer 23

Ointments

Creams

Gels

Question 24

What are Ointments?

Answer 24

Greasy preparations

Mixture of waxes, fats + oils

One single hydrophobic phase

Question 25

What are Creams?

Answer 25

Semi-solid emulsions - w/o or o/w

2 liquid phases - internal phase dispersed as globules in external phase

Question 26

What are Gels?

Answer 26

Continuous liquid phase thickened by polymers

Question 27

Mechanism of action of permeation enhancers

Answer 27

Modification of keratin conformation - swelling - increased hydration

Disruption of the lipid bilayers = increased permeability

Alteration of solvent properties of stratum corneum = increased partitioning

Question 28

What helps topical drug delivery?

Answer 28

Vehicle - increase water content - decrease barrier properties of stratum corneum

Question 29

Examples of permeation enhancers

Answer 29

Solvents (dimethylsulfoxide, ethanol, propylene glycol)

Fatty acids, surfactants

Urea

Terpenes (essential oils)