topical formulation design

Question 1

what is transdermal delivery?

Answer 1

Transdermal delivery is controlled systemic delivery.

Question 2

how does transdermal delivery work?

Answer 2

Large surface area so potentially numerous sites.
Good patient compliance
Easy cessation of therapy in problematic cases
Avoidance of first pass hepatic metabolism

Question 3

would higher or lower melting point be absorbed faster?

Answer 3

lower

Question 4

is lipophilic molecules or hydrophilic molecules better delivered

Answer 4

lipophilic

Question 5

how can you find a good candidate for topical formulation?

Answer 5

1. From experience (and literature), want a drug with:
   MW 300-500
   Log P(octanol/water) 1- ~ 3.5
   Aqueous solubility >100 mg/mL
2. estimate drug fux
3. After estimating flux from equations, looking at physico-chemical properties (MW, solubility, log P, melting point), calculating dose and comparing molecule with similar ones in literature, take a reality check!

If within an order of magnitude of dose required, may have a chance of delivering to therapeutic levels in vivo (possibly using formulation strategies)

If 2 orders of magnitude, unlikely!
(unless delivery to broken skin barrier, e.g. psoriasis)

4. The formulation should be designed to ensure appropriate release of the drug
   Rapid release for a locally acting drug
   Sustained and slow release for a 7-day patch

If the formulation contains a moderately lipophilic drug in a lipophilic oily base, the drug is less likely to partition out of the formulation and enter the lipophilic skin barrier than if it is applied from a more aqueous base.

Essentially, the vehicle should allow some solubility of the drug but should not retain the drug by being a very good solvent

5. flux = conc. x permeability coefficient (Kp)
   So, saturated solutions deliver most (Kp fixed for a given molecule from a given solvent).
   Saturated solutions (suspensions) give maximum thermodynamic activity
   So, can use a low conc. of a saturated drug to deliver drug

rule 6: occlusion helps covering the skin
Allows the SC to equilibrate with underlying (wet) epidermis
Stops Transepidermal Water Loss (TEWL)
Hydrates tissue – up to 400% water content
Promotes delivery of hydrophilic and hydrophobic compounds
Can cause irritation of underlying skin
Patches typically occlude, thus promoting drug delivery
Some preparations require occlusion to deliver the required dose to therapeutic levels, such as EMLA cream, applied as a thick layer under an occlusive dressing
Or, occlusion can also be inadvertent such as when applying hydrocortisone ointments or creams to treat nappy rash when tightly-fitting waterproof pants can occlude the area.

Question 6

when is semisolid formulation used?

Answer 6

Semisolid formulations selected for increased residence on the skin

Question 7

when is transdermal patches used?

Answer 7

Transdermal patches for extended drug delivery through the skin

Question 8

when is liquid formulation used?

Answer 8

Liquid formulations for a rapid short-term drug input into the skin.

Question 9

for normal to oily skin type what is preffered?

Answer 9

For normal to oily skin types, gels are often preferred.

Question 10

for normal to dry skin types what is preffered?

Answer 10

For normal to dry skin types, lotions are often preferred.

Question 11

for dry skin what is preferred?

Answer 11

cream

Question 12

what vehicle should be chosen for hairy areas?

Answer 12

lotions, gels or sprays

Question 13

what vehicle is used for intertriginous areas (sites where skin may touch or rub)

Answer 13

creams or lotions

Question 14

what type of formulation should be used for skin lesions - wet or weeping?

Answer 14

aqueous based - cream, lotion or gel

Question 15

what type of formulation should be used for thickened scaly lesion - dry

Answer 15

fatty formulation - ointments, paste

Question 16

what are the rules for a topical formulation?

Answer 16

Normal rules apply! Must be:

Stable
Drug and excipients must be compatible
Drug must be released from the dosage form following application.
Should be cosmetically acceptable with a good skin feel, texture and fragrance
- But depends on indication!
- Alcoholic gel formulation to broken skin is unlikely to enhance patient compliance

Question 17

in topical formulation how much percentage is bioavailable?

Answer 17

For topical products (e.g. creams and gels), typically only between 1 and 3% of the applied dose is bioavailable

Question 18

what is the bioavailability of patches?

Answer 18

Bioavailability from patches is typically 30-70% for drugs such as buprenorphine and fentanyl.

Question 19

what are enhancers?

Answer 19

Chemicals that interact reversibly with skin to promote drug flux

Typically disrupt stratum corneum inter-cellular lipid structure
Described in lecture 2 that lipids have to be crossed by a molecule either intercellular or transcellular pathways

May also alter intra-cellular keratin conformation

Can also change partitioning into the tissue (reservoir effect)

Question 20

what is the Hawthorne effect?

Answer 20

We know what we should be doing… but don’t… and then “remember” just before we go to visit the doctor / dentist/ pharmacist!

Question 21

what are the reasons for non-adherance?

Answer 21

Lack of efficacy or patient dissatisfaction with the efficacy

Side effects or fear of side effects.
The fear of side effects of topical corticosteroids may have a larger impact on adherence than actual side effects

The complexity or inconvenience of the treatment regimen
Even twice a day can be challenging!
Patches adherence better than creams / ointments

The cosmetic properties of topical agents or even the smell of the drugs may be very important factors contributing to adherence.

Question 22

Permeation through human skin well know to be variable to what?

Answer 22

Little / no difference male:female or with age (mature skin)
Neonatal skin more permeable

Variable with skin site
Also different follicular densities (shunt routes) with skin site

Little racial variability to most drugs

Possible variations with skin treatments
Moisturisers, soaps?

Significant variations with diseased states
Psoriasis etc
Also less obvious conditions, dry skin