Transdermal Flashcards
systemic drug admin/ anatomy of the skin
L.O:
* Explain the differences between dosage form design for local and systemic administration
* Describe the main barriers to transepidermal absorption
* Describe the profile of drug release from patches and other topical/transdermal formulations
* Discuss the different transdermal patches available
* Apply concepts to the selection and dispensing of transdermal drug administration systems
What does the skin do? 3
- vitamin D production
- protection against infection, hazards
- temperature regulation
3 layers of skin?
- epidermis
- dermis
- hypodermins
likely most important layer of skin in drug delivery and why?
epidermis as outer layer in contact with the world and drug must penetrate this physiological barrier
role of epidermis?
‘protective’ roles: provide strong physiological barriers to external hazards, including drugs.
what 4 layers is epidermis separated into?
Bottom/ base layer
prickle cell layer
granular layer
stratum corneum (outermost layer)
where do new cells form and then travel through?
base layer.
travel through prickle cell, granualr, and to SC layers.
undergo major changes
5 skin appendages?
- eccrine + apocrine sweat glands
- hair follicles
- sebaceous glands
- nerve endings
- nails
which two main skin appendages can provide an alternative route for drug delivery and is sometimes referred to as the ‘shunt’ route?
hair follicles and associated sebaceous glands
the shunt route avoids diffusion across the?
stratum corneum
give one limitation of the shunt route that limits its wide applicability?
only a small portion of skin surface may be available for drug absorption
name 3 cells found in layers of epidermis
Keratinocytes: main cells in (base layer) epidermis. Have normal cell structure including nucleus
Melanocytes: produce melanin- pigment of skin
Langerhans cells: part of immune defences, and role in T-cell responses
In prickle cell layer: still have nucleus but shape of cells has changed… keratinocytes and few Langerhans cells still there. Desmosome junction holds cells together
the SC (outermost layer) can be described as a what and why?
brick and mortar wall.
Bricks = protein based (keratin, hard even though more hydrophilic) found in the lipid based mortar. Holds structure together. (diagram)
what does the structure of the SC (outermost layer) dictate?
type of drug that can be administered through skin: need specific properties
As cells rise through layers in epidermis, what happens to them?
become thinner and flatter and are dying in process.
Skin cells shed are dead cells and regularly replaced by new cells produced in base layer.
how can process of regeneration of cells differ in skin of hands and soles of feet and why?
process of regeneration can take longer as lots of friction
how can process of regeneration of cells differ in diseases such as dandruff and psoriasis? + what does this ->
turnover increased a lot so new cells formed faster than skin can shed them. Instead of a month, process can happen in days = thickening of SC + epidermis.
Anything that can change integrity of skin alters what?
ability to protect us from outisde environment and role of skin
roles of epidermis?
Epidermis fills big role and protects from outside attacks, trauma, chemical exposure, losing too much water, heat, from sunrays etc.
blood supply in epidermis vs dermis?
No blood supply in epidermis: blood vessels in dermis.
(+no nerve supplt either)
Nutrients cells need (in base layer) come from what?
lymphatic vessels in dermis.= well developed lymphatic system: helps transport nutrients and take away any waste from the skin.
most important layer of skin with variable thicknesses? and is it a hydrophilic/phobic environment?
dermis
hydrophilic
dermis is hydrophilic with connective tissue mostly made with collagen and elastin. Would do they maintain and provide the skin with?
skin hydration and give strength, flexibility, elasticity
collagen is dispersed in dermis as a gel, what type?
semi solid hydrogel
hyaluronic acid (HLA) also found in dermis. role?
to maintain normal skin function and integrity
hair follicles in dermis have sebaceous glands which are responsible for formation of? what can this lead to
sebum
(oily substance)… if produce this, can -> seborrheic dermatitis and acne
muscle attached to hair follicle is responsible for creating what reflex that is part of fight or flight response?
goosebumps
vasodilation and increased blood flow is important to disspiate heat and return body to normal temperatures. What would happen if the body is cold?
vasoconstriction and stop heat escaping
meissner corpuscle important for sensing touch and many in which part of body?
hands and fingertips
Pacini corpuscle nerve endings sense what?
pressure and unmyelinated nerve fibres: sense pain, heat, cold temp changes, itch
2 types of sweat glands. dermis
eccrine
apocrine
eccrine sweat glands release sweat where? have lots of these where?
directly on surface of skin for temp reg
lots on soles of feet
where do appocrine sweat glands release sweat?
lots of these where?
into hair follicles and then onto surface of skin
scalp + armpits
which two types of immune cells can be found in the dermis?
mast cells and macrophages
Other immune cells may also accumulate in dermis in response to ? 2
stimuli or because of a disease
There is also some metabolic activity taking place in the dermis, this can have an impact for some drugs which may be susceptible to ?
first pass metabolism in the skin.
what is Hypodermis and why is it used in drug admin for?
SC layer of fat under dermis. For injections.
hypodermis = few mm thich layer and not present all over eg none in…
eyelids
main roles of hypodermis? and consequence if doesnt work?
insulation + protection against mechanical shunt… but doesn’t always work and shunt -> bursts capillaries = leakage and accumulation of blood :( = bruise
L: transdermal local admin
difference between local and sytemic topical drug admin?
local: drug only must go UP TO blood circ (to epidermis/dermis)
systemic: drug must go to blood circ
list some skin conditions treated by applying product to skin
eczema
acne
burns
itch
psoriasis
dandruff
hair loss
what to consider about solutions: liquid dosage forms to the skin? _ _ (for efficacy)
residence time and how long itll stay in contact w region
5 examples of medicated plasters?
Lidocaine
Capsaicin
5-aminolevulinic acid
Salicylic acid plasters
NSAIDs plasters
What is the structure of the horny layer and what is its role in drug delivery?
Brick like structure - keeratinised and hydrated
Where topical formulation is directly applied
What is the site of action for topically administered drugs?
(similar to transdermal patched but)
For local activity, it will be either the dermis or the epidermis
What are medicated plasters used for?
Applied to the skin for local effect like lidocaine, capsaicin, NSAID plasters
2 examples of NSAID drugs used in plasters for local pain relief?
ibuprofen
diclofenac
Essentially patches applied to skin for what effect? target what?
local -targeting nerve endings found in dermis, case for all 3 examples
Very similar to transdermal patches but….
..all of these drugs are destined for local activity
(Do need drug to cross epidermis and get to dermis where nerve endings are but no further)
Nails (appendages) are hard sites to deliver drugs to why?
made of keratinised tissue: 80% hard-keratin .
think of keratinised mouth areas SoM2
Topical treatment to nails for treatment of… (2)
Fungal infections (nail lacquer)- need some solveny/ excipient to increase epermeability of nail to drug= usually long treatment i.e. weeks before effect is seen as nails VERY impermeable to drug.
Nail Psoriasis
Transdermal: systemic drug administration is slow/ fast?
Systemic: drug travelling further in, to blood circulation eg capillaries in underlying tissue in skin
Takes time! So patches are not used for IR
nails are associated with a very low drug transport. What effect does this have on the duration of treatment?
long duration of treatment
List some of the advantages of transdermal drug administration?
avoids FPM,
non invasive,
ease of admin,
controlled release,
admin can be stopped quickly
easy to identify in case of emergency
list some of the disadvantages of transdermal drug delivery?
not suitable for bolus only potent drugs at low concs,
skin irritation,
skin FPM possible
what type/ sort of drugs is trandermal admin suited for?
potent drugs at low doses </= 10mg/day.. w right properties!
patches are not used for emergencies because?
takes time to reach high enough concentration in the blood to see effect
why might we still see some drug in the blood after removing a patch?
some of drug might form reservoir in the skin when a patch is removed
why is drug potency important?
if drug is not potent patch will need to be large and not appropriate for some patients
more drug= bigger patch needed
Physiological barriers: what helps form an effective protective barrier on skin?
HEALTHYepidermis
Mostly enacted by stratum corneum
Diseases affecting barrier function can affect ….
drug permeation + absorption
name one disease that affects the skins barrier function that can affect stratum corneum thus drug permeation?
Eczema
psoriasis causes the stratum corneum to be thicker, what effect does this have on drug absorption?
unclear, other factors at play so drug is absorption is not automatically reduced
type of corticosteroid used is dependent on site of use, true or false?
true
what anatomical site has highest permeability
epigenital region and eyelids
then scalp, head, neck, trunk…
what anatomical site has lowest permeability why?
Palms/soles
Thickest as gets a lot of pressure from walking etc.
with arms and legs what other factors should you consider in regards to patches?
friction and clothing
patches: what other factors to consider other than permeability of region?
- Blood supply, temperature, pH, etc.
- Age, metabolism: impact drug absorption but not always obvious, still consider
Physico-chemical barriers: criteria to fit to be suitable for transdermal administration
If doesn’t completely fit this, can still consider with some modifications, I.e.
- Add more drug into patch to drive diffusion and release
- Add excipients for right LogP, right solubility for absorption
for systemic abs anything that increases blood supply means more drug depleted from skin therefore there is a higher or lower conc in the blood?
higher
anything that increases blood supply to the skin increases blood absorption, true or false?
true
the MW of a drug for transdermal admin is ideally below 400-500 Da. What is the acceptable range that can actually be used?
100-800
why is the ideal MW for transdermal admin drugs between 400-500Da?
so it can diffuse easily through SC
the log P range for a drug being considered for transdermal delivery is between 1 and 4.5. What is the ideal range?
2-4
for transdermal drugs, the Octanol-Water Partition Coefficient/ log P what phase is preferred?
lipid phase (not aq)
Want lipophilic: solubility, due to nature of SC
logP must be right for absorption
the therapeutic dose should be approx 10mg/day (potency). what rate of permeation (mg/cm2/day ) would a good candidate have?
1mg/cm2/day
what does the potency of drug impact on?
size of patch needed…. thus acceptability for px
potent = smaller patch = more acceptable :)
what effect does high affinity for the vehicle have on release?
reduced
Matrix in patch, want it to have good affinity for vehicle but not too good, why?
else if has too much affinity for vehicle/ patch, wont be released from patch
Semi-solids for transdermal administration: 2 examples
hormonal replacement (HRT)
GTN
HRT such as oestrogens and testosterone are semisolids that can be used for transdermal admin. What is the benefit of formulations containing ethanol? 2
permeation enhancement (water soluble unlike the steroidal hormones)
and
evaporates to leave a film on the skin = mini reservoir where drug absorbed
GTN semi solid (ointment) used for treatment of?
angina
Give 3 ingredients in the formulations of GTN semi solid for the treatment of angina?
lanolin, white petroleum and water
why is there lots of patient variability between ointments? give one reason
patients apply diff amounts and spread differently
with ointments eg GTN, get some occlusion, which impacts on…
drug absorption
what are the 4 components of most transdermal patches?
protective film, backing layer, drug containing layer and protective liner
which type of patch involves the drug in a reservoir and has the prescence of a rate controlling polymer membrane in order to try and reduce interpatient variability?
reservoir
give 2 reasons why drug may be present in the adhesive layer of reservoir patches?
intentional or through diffusion/saturation in storage
problem with dryg in patch diffusing/ migrating to the adhesive layer?
Drug doesn’t start release once px opens package = some drug can migrate through rate controlling memb -> adhesive layer during storage.
Problem, adhesive layer thatll touch skin now really saturated with drug, drug has passed rate controlling memb and can be released right away… If have NTD (Fentanyl) could -> OD
the release rate of reservoir patches is controlled by changing the properties of the membrane. What order do these formulations typically follow?
0
stays constant over time independent of drug conc
are patients still okay to use patches with crystals or solid particles present on them due to saturation?
yes
what properties of a membrane can be changed to change the release rate of a reservoir patch?
porosity and thickness
steady state conc may require patch application 2 or 3 times in order to reach the therapeutic window, true or false?
true
patches arent used in emergencies explain why
Takes time to build up plasma conc high enough to be in therapeutic window and get effect
which type of patch has one or more layers with a drug dissolved or suspended in a polymer matrix?
matrix/ monolithic type layered patch
you can achieve close to 0 order for a matrix patch (usually variable kinetics) if suspended in a polymer matrix, true or false?
true
which rate is more likely for matrix patches where the drug is fully dissolved?
first
drug in adhesive layer patch: what is the matrix?
adhesive polymer
Matrix/ monolithic-type layered patch design?
- Always have a backing layer
- Can have matrix then have an adhesive
with the drug in adhesive layer patch, have some control over release rate by choosing composition of what?
adhesive layer thus affinity- hm does it have for polymeric adhesive compared to skin? Used to control release rate
what is the typical order release rate of drug in adhesive layer patches?
first
name the 3 types of transdermal patches
reservoir
matrix/ monolithic-type layered
drug in adhesive
what type of patch is:
backing layer,
drug in reservoir
adhesive layer
reservoir
what type of patch is:
backing liner
adhesive layer
matrix/monolithic type
what type of patch is:
backing liner
adhesive/drug layer
drug-in-adhesive layer
describe how the release rate of drug in adhesive layer changes over time
continually declines as surface layers are depletes
o So will decrease over time as mainly driven by conc gradient. Gets weaker as drug leaves patch= release rate slows down (graph)
how do the drug plasma conc vs time curves differ for oral vs transdermal route of admin?
- Oral : lot of up and downs- in+out of therapeutic window
- Patch: steady increase, constant conc at steady state, when patch removed, declines slowly depending on how good reservoir is formed in skin
- No rapid increase/ decrease with patch, slow both times
3 factors affecting drug transport?
application site
skin hydration and general condition
length of application
patients are recommended to change the sites where they apply patches. What is the main reason for this (not skin irritation and not sticking there as well a second time round)?
some occlusion when patch is removed,
already changes properties of skin making more hydrated and porous,
drugs from prev patchcan accumulate and form reservoir in SC so if saturated this changes the site of absorption so dont want to reapply
patches can be applied to broken skin, true or false?
false
skin not working as a barrier, so drug absorption will be higher (disease states).
why should use of scrubs be avoided where patches are?
they remove some of the stratum corneum making the skin thinner affecting absorption (inc)
what does occlusion affect regarding patch admin?
drug absorption and how well patch sticks to skin
list some advice that patients should be told about patch?
alternate sites of application, may need to cut hair, no wet shave or hair removal cream, skin should be clean, not oily, irritated, broken or callused
is it appropriate for patients to cut or modify patches?
no
why in theory is it better for a matrix patch to be cut? than reservoir?
uniformly spread therefore essentially reducing the dose in half if cut in half
is it ever appropriate for reservoir patches to be cut and what might happen if they are?
no and dose dumping -> OD and tox
3 problems/ things that may occur at site with patches that you should tell px?
Sensitivity/intolerance/irritation
what should px do with patch after removal?
fold in half so that the adhesive layers stick together. So drug in patch no longer accessible. As 80-90% dose may still be left in patch, problematic for some drugs e.g. fentanyl: problems with misuse and OD- toxic to children and pets.
ASSESSMENT OF TRANSDERMAL DOSAGE FORMS
Drug release 2 methods to see?
dissolution apparatus (similar to tabs, but w patch inserted in disc at bottom of vessel)
franz cell (to see how it permeates skin)
to assess bioequivalence of transdermal dosage forms, what must be the same?
generic and innovator
* API
* Dosage form
* Strength
* Route of administration
* Conditions of use
* Rate and extent of drug absorption
With patches: looking at plasma conc vs time curve to decide on bioequivalence for different product
For different types of patches, requirement in terms of bioeq to be used interchangeably?
- Reservoir patch must be bioequivalent to a matrix/drug-in-adhesive patch
- Depends on design, formulation, properties
- Must be confirmed before switching px between the two
one example of a physical permeation enhancement method where a small electric current is applied to support drug transport?
iontophoresis
how does iontophoresis work?
if drug is ionised it is put under an electrode with the SAME sign as drug so electrostatic repulsion drives diffusion of the skin
how can iontophoresis be used for neutral drugs?
supported by electro-osmosis
drug moved along with water and other neutral molecules + migrating ions
reverse iontophoresis can be used to measure + monitor the levels of X in diabetic patients?
glucose
sonophoresis uses ultrasound how does it work to aid permeation and drug transport?
ultrasound creates vibrations in skin and temporarily increase pore size between cells so more drug transported
2 drugs used for/in sonophoresis (physical permeation enhancement?) ?
lidocaine
salicylic acid: gels, creams, lotions
micro and nanoparticles can target delivery through hair follicles. in some cases, would a micro or nano particle be appropriate to create a reservoir for sustained drug release?
micro
microneedles can be used for small and large molecules and puncture which layer of the skin only, for drugs to be applied/ dleivered after through hollow needles
stratum corneum
how do microneedles help improve transdermal drug admin?
holes created in stratum corneum
for microneedling needles can be hollow so drug diffuses out of them into the skin. What is the other method?
apply microneedle to create holes and then apply formulation after
