drug transport through skin

Question 1

what is the definition of transdermal
local
topical

Answer 1

Transdermal; delivery across the skin for systemic action (e.g. estradiol patch)

Local; to act at a site close to where formulation applied (e.g. ibuprofen gel for muscular relief)

Topical; to act at a site in the skin, usually epidermis / dermis (e.g. hydrocortisone cream)

Question 2

what is the definition for penetration

Answer 2

Penetration; drug entering the skin (in particular the stratum corneum)

Question 3

what is the definition of Permeation

Answer 3

Permeation; drug passing through the skin, to enter the systemic circulation / local sites

Question 4

why is transdermal delivery good?
examples

Answer 4

Transdermal delivery is controlled systemic delivery.

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

Dosage forms as patches, films or suspensions
scopolamine, nitroglycerin, clonidine, nicotine, estradiol, testosterone, fentanyl
but skin is metabolically active - glyceryl trinitrate ~ 56% bioavailable

Topical drug delivery is intended for local / regional action
E.g. ibuprofen gel

Question 5

what is the role of stratum corneum and
where is it found

Answer 5

Multi-layered tissue.
Outer stratum corneum main barrier to delivery
Permeation possible through follicles/sweat ducts (shunt route).
Most drugs permeate through the bulk stratum corneum (~20 cell layers).

Question 6

what are the possible ways of Drug permeation through skin

Answer 6

Permeation possible through follicles/sweat ducts (shunt route).

At steady state (e.g. a patch), permeation is predominantly through the bulk stratum corneum (~20 cell layers).

BUT, some via appendages
And maybe more important for finite dosages e.g. application of a cream

Question 7

For drug delivery what are 3 main appendages to coinsider

Answer 7

hair follicles and associated sebaceous glands
eccrine (sweat) glands
apocrine (specialised, e.g. milk) glands

Question 8

what does the appendageal route provides

Answer 8

The appendageal route provides a pathway for drugs to traverse intact stratum corneum
but, only around 0.1% of the skin area
important for early time point diffusion
important for large polar molecules, ions, macromolecules?

Question 9

what are the structure and characteristics for stratum corneum
2 routes for permeation

Answer 9

“Brick and mortar” model:
Keratin filled cells as bricks in multiply bilayered lipid mortar

2 micro routes for permeation:
transcellular.
intercellular.

For both routes, multiple lipid bilayers are the rate limiting structure for most drugs.

Question 10

what is stratum corenum lipid
main lipids

Answer 10

Stratum corneum lipids are unique and they are quite different to the lipids in other membranes in the body.

The main lipids in human abdominal stratum corneum are:

Ceramides: 41%
Fatty acids: 9.1%
Cholesterol: 27%
Cholesteryl sulphate: 1.9%
Sterol/wax esters: 10%

These are approximate compositions and do vary a bit between different body sites.
NOTE: phospholipids are largely absent
the bilayer structure is maintained by the cholesteryl sulphate and amphiphilic lipids (ceramides)

Question 11

how do these lipids pack together in the SC intercellular space to provide such an effective barrier?

Answer 11

They do not pack homogeneously and the lipid domains have a variety of phases within them:
Some lipids are packed closely together providing crystalline areas.
Others are more loosely associated to give liquid crystalline areas.

Can increase transdermal drug delivery, or expand the range of drugs that can be given transdermally, by disrupting (or make more fluid) these highly ordered lipid domains. This can be done with penetration enhancers.

Question 12

three potential routes through intact skin
how can they vary in time

Answer 12

Shunts, intercellular, transcellular

Intercellular is usually the major route

But molecules are not intelligent and can’t choose how they permeate

ALL three routes operate, balance may vary with molecule and time
- Early time course maybe shunt routes predominate, and for charged molecules that cant cross lipids
- At steady state, intercellular may predominate

Question 13

what are the Numerous processes during permeation

Answer 13

Release from formulation (some chaotic), partitioning (multiple steps), diffusion in skin, metabolism etc etc

Question 14

what does permeant mean?

Answer 14

Permeant: the molecule moving into or through skin
Usually the drug but may be an excipient as well

Question 15

what does flux mean?

Answer 15

Flux (J): the rate of a permeant crossing the skin
E.g. g/cm2/h

Question 16

what does Permeability coefficient (Kp) mean

Answer 16

Permeability coefficient (Kp): the speed of permeant transport
E.g. cm/h

Question 17

what does Diffusion coefficient (D) mean

Answer 17

Diffusion coefficient (D): fundamental property of the permeant in a particular membrane (e.g. skin)
E.g. cm2/h

Question 18

what equation is used with difussion

Answer 18

We often use Fickian diffusion equations.
But actually they only apply to isotropic media
Skin is clearly not and is heterogeneous

And assume stratum corneum not affected by excipients
It often is!

But Ficks laws tend to describe the data ok

Driving force for diffusion across the membrane is the “concentration gradient”. Assume concentration in skin is zero (drug cleared to circulation)

We often use concentration in our calculations.
flux = Kp x concentration

MORE ACCURATE
Flux = aD/γh

a = thermodynamic activity of the permeant in its vehicle
D = diffusion coefficient
γ = activity in the membrane
h = membrane (stratum corneum) thickness

Think of thermodynamic activity as “escape tendency”
Why would the molecule want to leave the formulation?

If in different vehicles but both saturated though at different concentrations, escape tendency is the same so delivery is the same

Question 19

with a patch is it finite or infinite drug dosages

Answer 19

Essentially an “infinite dose”
Drug leaving the patch surface continually replaced by that in rest of patch
Sustained controlled delivery for up to 7 days

Initial lag phase whilst equilibrium set up across membrane
Continues to deliver by zero order until ~10% of drug activity lost
Or until >10% present in receiver solution
Driving force for delivery is concentration gradient (really activity
(steady going up)

Question 20

with a topical (cream/gel) is it finite or infinite drug dosages

Answer 20

Finite dose applied - e.g. one fingertip unit….
So drug applied will enter and pass thorough skin, then deplete
Can measure AUC for dose delivered / bioavailability

Some drugs well know to sit in stratum corneum as a reservoir
Lipophilic so stay in lipids
e.g. corticosteroids. If cover again a few days later get a second pulse of delivery
(Up and down like action potentiol)

Question 21

SUMMARY
Stratum corneum main barrier to drug delivery
In particular the unique lipid composition and organisation

Three routes that a drug can use
All operate but usually intercellular dominates at steady state

Thermodynamic activity is the driver for drug delivery

Finite and infinite dosing for different indications

Basis for next lecture on how we design and test formulations (links to workshop)

Often measure using a Franz cell
Skin between donor and receptor chamber
Receptor must dissolve the drug
Stir, keep at 32 degrees
Take samples and assay with time

Can also use to assess drug release from a product
Use an inert / permeable membrane

Apply formulation as clinical use

Clearly different for a patch or a cream/gel