Skin drug formulation

Question 1

Advantages of transdermal drug delivery?

Answer 1

easy cessation of therapy
Large surface area so multiple sites for drug delivery
Good compliance 
Avoids first pass metabolism
Can get controlled systemic delivery

Question 2

What are the 2 main formulation rules applicable to drug delivery?

Answer 2

Lipophilic molecules are better delivered via skin

Lower melting point drugs usually better absorbed

Question 3

What is the main drug delivery barrier?

Answer 3

Stratum corneum.

Question 4

How do we measure diffusion of drugs across membranes?

Answer 4

We know that drug delivery is concentration gradient driven, we use. a franz cell to measure and use the flux equation
Flux = a D / y h
a =thermodynamic activity of permeant in the vehicle
D = diffusion coefficient
y = activity in the membrane
h = membrane (stratum corneum) thickness

Question 5

What are the ideal pharmacokinetic properties of a good candidate for transdermal delivery?

What does this not account for?

Answer 5

Molecular weight 300-500
LogP 1-3.5
Aqueous solubility >100mg/mL

This allows for ~delivery of 1mg/cm2/day

This does not account for potency e.g. there could be values that predict a drug not to go through e.g. if it has a differing logP/solubility etc but if the drug is very potent then it will go through (amount required to produce effect)

Question 6

How do we manage the formulation to deliver the drug appropriately?

Answer 6

We want the vehicle to be able to allow some solubility of the drug but NOT retain it by being a very good solvent - otherwise it would not release the drug. e.g. if you had a moderately lipophilic drug in a lipophilic oily base it would not release the drug out

Question 7

What type of solutions give maximum thermodynamic activity?

Answer 7

Saturated solutions (suspensions) give maximum thermodynamic activity and so we have maximum driving force for diffusion, maximum concentration gradient across the skin. 
There is no point going over the saturation

Question 8

What is occlusion? is it good?

Answer 8

Yes - occlusion stops water loss. It allows the stratum corneum to equilibrate with the underlying wet dermis to stop transepidermial water loss - this hydrates the tissue and helps drug delivery through the skin

But be aware that it can cause irritation

Question 9

Why are enhancers added to formulations?

Answer 9

Interact reversibly with skin to promote drug flux (they disrupt the SC intercellular lipid structure, intracellular keratin formation - all changes partitioning into tissue)

Question 10

Give examples of enhancers

Answer 10

solvents - EtOH, propylene glycol
Surfactants - SLS
Fatty acids - oleic acid
Hydrotropes - urea

Question 11

How can drug delivery be improved?

Answer 11

1. Liposomes

2. ionophoresis

Question 12

How do liposomes work ?

Answer 12

Lipid vesicles enclose the aqueous volume- they trap hydrophilic molecules in the core or lipid materials in the membrane to deliver the drug - they increase thermodynamic activity (driving force) of. the drug so enhanced permeation, (adsorb and fuse with the skin surface).

Question 13

Examples of liposomes used

Answer 13

Standard ones, niosomes, PEGosomes, Ethosomes
Standard. - phospholipid with or without cholesterol
Niosomes - non ionic surfactants
PEGosomes - increase circulation residence
Ethosomes - contain ethanol

Question 14

What is iontophoresis?

Answer 14

Electric charge to repel ionic molecules to drive molecule into the skin
e.g +ve cation repelled by +ve cathode

e.g. Vyteris - lidocaine phase III trials

Question 15

If you had - 
Oily 
normal/dry 
Dry
Skin, what formulation would you use?

Answer 15

Oily - gel formulation
Normal/dry - lotion
Dry - cream.

Question 16

What type of formulation. would. you use on these sites

• hairy
• interiginous areas (skin rub/touches)

Answer 16

Hairy - sprays, lotions, gels

interiginous - creams, lotions

Question 17

If you have a lesion that is wet, vesicular, weeping - what formulation?

Answer 17

Wet aqueous based e.g. cream, lotion, gel

NOT alcohol based if the SC is broken

Question 18

If you have a lesion that is dry, thickened, scaly - what formulation?

Answer 18

Ointment or paste as want. to keep the SC. hydration in and. reduce water loss

Question 19

what are formulation requirements?

Answer 19

• stable
• drug and excipients compatible
• must be released from dosage form after application
• cosmetically acceptable

Question 20

What is bioequivalence and what does it mean for transdermal delivery?

Answer 20

No difference in the rate and extent of absorption i.e the rate at which drug leaves the formulation, and rate at which the drug crosses the stratum corneum

Question 21

Why can some patients be non-adherent to skin formulations?

Answer 21

Lack of efficacy or patient dissatisfaction with efficacy
Side effects or fear e.g. CCS
Complex / inconvenient e.g. BD creams etc
Cosmetic properties, smell of drugs

Question 22

What are conclusions on the use of natural products for skin?

Answer 22

difficult to determine thrapeutic value. Some safety of. cutaneous use is well documented e.g. arnica cream (bruising).
But pharmacological data weakly support traditional use through. the knowledge on bioavailability of constituents is limited.

Question 23

What would make you consider topical drug. delivery?

Answer 23

If a drug has low oral bioavailability
short half life
long term. treatment

Question 24

General lessons for natural products for topical use

Answer 24

many natural products are available for natural. use e.g. arnica, glucosamine, turmeric (curcumin), aloe vera, capsaicin.
Many have some proven pharmacological activity bu often tested in vivo and in isolation

They are v complex mixtures with many phytochemicals and we do not know if these chemicals work synergistically

Quality control of natural products is patchy

Need to consider the patient and their safety - will it do them harm, systemic or local e.g. irritation?
Will it interact with other medicines?
Does it mean that they may not use evidence based therapies anymore e.g. hydrocortisone?
– professional judgement