drug transport through skin Flashcards
what is the definition of transdermal
local
topical
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)
what is the definition for penetration
Penetration; drug entering the skin (in particular the stratum corneum)
what is the definition of Permeation
Permeation; drug passing through the skin, to enter the systemic circulation / local sites
why is transdermal delivery good?
examples
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
what is the role of stratum corneum and
where is it found
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).
what are the possible ways of Drug permeation through skin
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
For drug delivery what are 3 main appendages to coinsider
hair follicles and associated sebaceous glands
eccrine (sweat) glands
apocrine (specialised, e.g. milk) glands
what does the appendageal route provides
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?
what are the structure and characteristics for stratum corneum
2 routes for permeation
“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.
what is stratum corenum lipid
main lipids
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)
how do these lipids pack together in the SC intercellular space to provide such an effective barrier?
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.
three potential routes through intact skin
how can they vary in time
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
what are the Numerous processes during permeation
Release from formulation (some chaotic), partitioning (multiple steps), diffusion in skin, metabolism etc etc
what does permeant mean?
Permeant: the molecule moving into or through skin
Usually the drug but may be an excipient as well
what does flux mean?
Flux (J): the rate of a permeant crossing the skin
E.g. g/cm2/h
what does Permeability coefficient (Kp) mean
Permeability coefficient (Kp): the speed of permeant transport
E.g. cm/h
what does Diffusion coefficient (D) mean
Diffusion coefficient (D): fundamental property of the permeant in a particular membrane (e.g. skin)
E.g. cm2/h
what equation is used with difussion
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
with a patch is it finite or infinite drug dosages
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)
with a topical (cream/gel) is it finite or infinite drug dosages
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)
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
