transdermal drug delivery Flashcards
What is transdermal delivery?
delivery of drug across the stratum corneum and into the systemic circulation
What is topical drug delivery?
delivery of a drug across the stratum corneum and into the deeper skin skin layers for local action
advantages of transdermal route vs oral/IV route
- controlled release of drug into systemic circulation (dec dose frequency)
- avoidance of liver metabolism (inc bioavailability, admin of a lower dose)
- safer (no GI s/e)
- patient compliane
limitations of transdermal route vs oral/IV route
- permeability barrier (only small, lipophilic molecules can permeate through skin)
- low dose delivery (potent molecules)
- inter and intra patient variability (wide therapeutic window)
- skin irritation
3 layers of skin
epidermis
dermis
subcutaneous fat tissue
main barrier to drug transport across the skin
stratum corneum (SC)
How are drugs removed from the skin?
blood supply in dermis
- conc gradient between drug on skin surface and the dermal vasculature
- driving force for diffusion across the skin membrane
steps for drug delivery via the skin
- dissolved drug molecules diffuse along the vehicle towards the vehicle/skin interface
- partitioning of drug from vehicle into SC, diffusion through SC
- partitioning from SC into viable epidermis, diffusion through viable epidermis (aqueous)
- partition from epidermis into dermis, diffusion through dermal tissue
- partition into capillaries and removal by systemic circulation
other fates of drug delivery via skin
- '’reservoir effect’’ - drug binds to keratins in SC
- enzymatic metabolism - drug degradation or activation (pro-drug) by skin enzymes in viable epidermis
- partitioning into subcutaneous fatty layers
structure of stratum corneum
- corneocytes - differentiated keratinocytes
- intercellular lipid domain - ceramides, FAs, cholesterol
- > no phospholipids, ceramides insetad
- > ceramined only in lipids in skin, no where else in body
- > '’brick and mortar’’ structure
intercellular pathway through stratum corneum
- diffusion via the intercellular lipid domain
- main pathway for small, uncharged, lipophilic molecules
- pathlength of permentation 500 microm > thickness of SC
intracellular/transcellular pathway through stratum corneum
- sequential partition and diffusion across the corneocytes
- pathlength of permeation = thickness of SC (20 microm)
appendageal transport in stratum corneum (hair follicles, sweat/oil glands)
- significant in vivo contribution
- important for large, polar molecules and ions
What is diffusion of a drug in transdermal delivery?
spontaneous flow of molecules across an area
from a region of high concentration to a region of lower concentration, driven by a concentration gradient
slow, random movement - Brownian motion
Mr of a drug and its diffusion through SC
larger = slower diffusion through SC
smaller = higher diffusion coefficient, faster
-> low Mr drugs best for transdermal dosage forms
temperature and diffusion coefficient of drug transdermally
higher/inc T of skin = higher/inc diffusion coefficient, quicker drug release
- > can casue s/e if it exceeds MSC
eg. fentanyl patches, inc skin temp will inc diffusion of drug and can cause side effects
ideal properties of a drug for passive transdermal delivery
- therapeutic properties
2. physiochemical properties
therapeutic properties of drug for passive transdermal delivery
low daily dose (<10mg/day)
short half life (<10hrs)
non-irritating/sensitising to skin
physiochemical properties of drug for passive transdermal delivery
low Mr (<500 Da) - D (diff coeff) inversely proportional to molecular size of drug
aqueous solubility
- needs >1mg/ml to be removed by blood supply
optimal partition coefficient K
- lipid solubility to diffuse across SC
- logK o/w = 1-3
low melting point (<200 degC)
methods to increase drug diffusion via skin
- prodrug
- super-saturation
- chemical enhancers
- eutectic mixtures
- colloidal drug cerrier systems
prodrug approach
hydrophilic drugs to lipophilic prodrug
- attach lipophilic fxn group (ester group)
- prodrug has optimal K
- prodrug converted to active drug by enzymes in viable epidermis
examples of prodrug approach
topical anti-inflammatory steroids
- betamethasone 17 valerate
problem with using prodrug approach
needs extra toxicological studies - new chemical entity being made
super-saturation approach
max flux (Jmax) when Cv = Cmax
Cmax = max sol of drug vehicle = saturation conc of a drug in vehicle (dissolved drug molecules are in equilibrium with solid drug
but will create an unasable formulation, high tendency to crystlalise
-> add anti-nucleating excipients to prevent drug crystallisation
use of chemical enhancers
diffuse into the skin and reversibly alter the properties of the stratum corneum
inc D
- disrupt packing of the lipid bilayers
- disrupt protein structure
alter K
- change the solvent nature of stratum corneum
ideal properties of chemical enhancers
- pharmacologically inactive, non-toxic/allergenic, compatible with drug
- immediate and reversible effect
- unidirectional action
problems with chemical enhancers
safety issues
can be toxic, need to use in low concs for formulation
What is a eutectic mixture?
mixture of drug with another component at a certain ratio where they inhibit crystallisation of each other
- stable formulation
- eutectic system has a lower MP than either of the 2 components
'’ideal solution theory’’
the lower the MP of the drug the higher its solubility in the stratum corneum lipids
MP for drugs for eutectic mixtures
< 200 degC
using eutectis mixture at or below 32 degC (skin temp) is desirable because it results in a liquid eutectis mixture
examples of eutectic mixtures
ibuprofen-thymol
lidocaine-menthol
testosterone-menthol
lidocaine-prilocaine (EMLA cream)
3 types of colloidal drug carrier systems
- liposomes
- ethosomes
- transfersomes
liposomes for colloidal drug carrier systems
modify lipid component to imitate stratum corneum lipids - ceramides (‘cerasomes’)
topical delivery - reservoir formation in stratum corneum
not effective for transdermal delivery
ethosomes in colloidal drug carrier systems
liposomes with 30% ethanol
enhance transdermal delivery
transdersomes for colloidal drug carrier systems
elastic liposomes - phospholioid + surfactant + ethanol
squeeze through pores in stratum corneum
move across hydration gradient - non occlusive vehicle
(move from dry to moist surface)
What are transdermal drug delivery patches?
flexible pharmaceutical preparations containing one or more active substances, intended to be applied on unbroken skin in order to deliver the active substances to the systemic circulation after passing through the skin barrier
forumlated med deviced that allow controlled release of drug from intact skin surface into systemic circulation
applied for 1-7 days
patch components
backing layer
liner
adhesive (pressure sensitive adhesive)
optional:
membrane
matrix polymer
backing layer of a patch
protects patch components from environment throughout application
- occlusive (low water vapour transmission)
- flexibility
liner of a patch
- polymer material, covers adhesive
- removed to allow patch application onto skin
- occlusive, min loss of volatile patch components
adhesive of a patch
- attaches patch to skin
- common polyers - acrylic, polyisobutylene, silicone
- visco-elastic material
- may contain the drug and excipients
membrane of patch (optional)
- reservoir patch design
- moderates the rate of drug release from drug reservoir into the adhesive layer
- steady state drug release
matrix polymer of a patch (optional)
layer containing drug dispersed or dissolved in a polymer matrix
QC tests
- uniformity of dosage units
- uniformity of content
- dissolution
- adhesive performance
drug release patterns of transdermal delivery
- reservoir (membrane controlled system)
- steady state release - drug in adhesive and matrix systems
- Higuchi sq root of time fxn, assuming drug in suspension
When to use diffusion cells (Franz cells)?
for in vitro drug release studies
How do diffusion/Franz cells work?
- dosage form applied on donor compartment
- membrane can be artificial or human/animal skin
- samples are collected for analysis at regular intervals
tests for adhesive performance
peel test
tack test
rheological criteria for adhesive performance
Why to use active transdermal drug delivery?
- drugs that can’t be delivered by passive diffusion
- increase the drug transoport rate
How to create active transport drug delivery?
- increasing the energy of drug molecules -> iontophoresis, electroporation, sonophoresis
- bypassing or removing skin barrier -> stratum corneum bypass or removal
iontophoresis
- movement of molecules across the skin under the influence of an electrical field
- broad range of drugs, ideally charged molecules
- use of low voltage electrical current <1V
- ionophoretic drug transport rate > passive transport rate
- drug transport rate can be monitored by adjusting the electrical current
3 parts to iontophoretic patch
- drug reservoir
- aqueous, biocompatible gel
- pH to optimise iontophoretic delivery and skin tolerance
- +ve drug at anode, -ve drug at cathode - return reservoir
- saline and charged molecules to complete circuit - electronic controller
- battery and monitor
2 methods of iontophoretic drug transport
- electrophoretic mechanism
2. electro-osmotic mechanism
electrophoretic mechanism of iontophoretic drug transport
transport of molecules under direct interaction with electric firle
charged molecules of low MW
electro-osmotic mechanism of iontophoretic drug transport
transport of molecules under the influence of the electrically induced solvent flow
solvent flow - flux of skin caitons from anode to cathode
uncharged, large molecules
eg. peptides, +ve charged drug molecules
E-TRANS Fentanyl system
24hr administration up to 6 times/hr
pain relief within a few mins after pressing button
electroporation
formation of transient aqueous pores in the skin by short electrical pulses of high voltage
electrical currents 100-1000 volts
electric field within the stratum corneun - pain free
disrutpion of lipid structure of stratum corneum
reversibility of effect from seconds to hrs
possible skin damage
sonophoresis
low frequency ultrasonic energy (20 kHz)
thermal effect by absorption of ultrasound
‘fluid velocity’ - acoustic streaming
disruption of lipid packing by cavitation
deactivation of skin enzymes
safety and effectiveness issues
microneedles
micrometer silicon needles or biodegradable needles
don’t reach dermis - pain free
pre-treatment of skin/drug admin device
needles can be drug coated OR drug loaded
Macroflux microneedle system
needles drug coated
can use any type of drug
PowderJect system
supersonic wave of helium gas
solid drug particles (20-100um, micronised) fired into lower skin layers
into systemic circulation
laser ablation
partial/complete removal of stratum corneum
used for cosmetic resurfacing of skin
specialist practitioner
reversile technique - skin regeneration
combination strategies
active with passive transport enhancement
synergistic effect
