transdermal drug delivery Flashcards
define transdermal drug delivery
Delivery of a drug across the stratum corneum
and into the systemic circulation
define topical delivery
Delivery of a drug across the stratum corneum and
into the deeper skin layers for local action
what are the advantages of transdermal delivery systems?
• Controlled release of drug into systemic circulation • Decrease in dosage frequency • Avoidance of liver metabolism • Increased bioavailability, administration of a lower dose • Safer –no G.I. side effects • Patient compliance
what are the limitations of transdermal drug delivery?
• Permeability barrier – Only small, lipophilic molecules can permeate through the skin • Low dose delivery – Potent molecule • Inter- and intra-patient variability in skin permeability – Wide therapeutic window • Skin irritation
what are the 3 tissue layers of the skin?
epidermis, dermis, subcutaneous fat tissue
what is the multicomponent organ the skin comprised of?
▪ Three tissue layers: epidermis, dermis, subcutaneous fat tissue
▪ Skin appendages: hair follicles, sweat glands
▪ Epidermal enzyme systems: e.g. esterases
what is the stratum corneum?
the main barrier to drug transport across the skin
how is drug removed in the skin?
• Drug removed from blood supply in dermis
▪ Concentration gradient between drug on skin surface and the dermal
vasculature –sink conditions
▪ Driving force for diffusion across the skin membrane
how does drug delivery occur in the skin?
Multi-step process of alternating partition and diffusion
▪ Dissolved drug molecules diffuse along the vehicle, towards the vehicle/skin interface
▪ Partitioning of drug from vehicle into the 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
what are the other potential dates of drug delivery in the 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
how does permeation occur through the stratum corneum?
“Brick and mortar” structure of stratum corneum
▪ “Bricks”: corneocytes (terminally differentiated keratinocytes)
▪ “Mortar”: intercellular lipid domain (ceramides, fatty acids, cholesterol)
what is the intrercellular pathway of the SC?
▪ Diffusion via the intercellular lipid domain
▪ Main pathway for small, uncharged, lipophilic molecules
▪ Pathlength of permeation (~ 500 μm)»_space; thickness of SC
what is the intracellular pathway of the SC?
▪ Sequential partition and diffusion across the corneocytes
▪ Pathlength of permeation ~ thickness of SC ~ 20 μm
what is appendageal transport?
▪ Significant in vivo contribution
▪ Important route for large, polar molecules and ions e.g. iontophoresis, and
vesicular structures
how do the pathways of the SC operate?
can operate concomitantly
what is the mathematical description of passive transdermal delivery?
▪ Significant in vivo contribution
▪ Important route for large, polar molecules and ions e.g. iontophoresis, and
vesicular structures
what does the diffusion coefficient D measure?
measures the diffusion speed of a molecule
what does the diffusion coefficient depend on?
▪ The viscosity of the diffusional pathlength (η)
▪ Size (radius) of diffusing molecule (r)
▪ Temperature of the skin (T)
what are the ideal therapeutic properties of a drug for passive transdermal delivery?
- Therapeutic properties
• Low daily dose (<10 mg/day)
• Short half-life (t1/2 ≤ 10 hours)
• Non-irritating or sensitizing to skin
what are the ideal physiochemical properties for transdermal drug delivery?
Low molecular weight (< 500 Daltons)
▪ D is inversely proportional to molecular size of drug
• Aqueous solubility
▪ > 1 mg/ml to be removed by blood supply
• Optimal partition coefficient K (log Ko/w = 1 to 3)
▪ Lipid solubility to diffuse across SC
• Low melting point (< 200 °C)
what are methods to increase drug diffusion via the skin?
• Alteration of K, D, Cv variables
– Increase Ksc/v of drug
– Increase D of drug across SC
– Increase Cs of drug in the vehicle
how do you make a hydrophilic drug into a lipophilic prodrug?
Attach a lipophilic functional group e.g. ester group
– Prodrug has optimal K
– Prodrug is converted to active drug by enzymes in viable
epidermis
what is cmax?
maximum solubility of drug in vehicle = saturation concentration of drug
in vehicle i.e. dissolved drug molecules are in equilibrium with solid drug
what is the purpose of chemical enhancers?
Diffuse into the skin and reversibly alter the properties of the
stratum corneum
what do chemical enhancers do?
• Increase D: disrupt the packing of the lipid bilayers
Accumulate within SC lipids
Aqueous channel formation
e.g. oleic acid, surfactants, sulphoxides (DMSO), azone, alcohols
• Increase D: disrupt protein structure
Alter keratin conformation
Proteins embedded in lipid bilayers
e.g. ionic surfactants, sulphoxides (DMSO, DMF, DMA)
• Alter K: change the solvent nature of stratum corneum
Pyrrolidones, propylene glycol, water, ethanol
what are the ideal properties with chemical enhancers?
– Pharmacologically inactive, non toxic/allergenic, compatible with drug
– Immediate & reversible effect
– Unidirectional action
what is the problem with chemical enhacners?
safety issues
what is an eutectic mixture?
Mixture of the drug with another component at a certain ratio where they
inhibit crystallisation of each other
what properties does an eutectic mixture have?
– Stable formulation
– Eutectic system has a lower melting point than either of the two components
what is the ideal solution therapy?
– “thelower the melting point of the drug the higher its solubility in the stratum corneum
lipids”
why us mp suppression, using eutectic mixture at or below 32 degrease desirable?
because it results in a liquid eutectic mixture
give examples of eutectic mixtures
Ibuprofen-thymol,
lidocaine-menthol, testosterone-menthol, lidocaine-prilocaine (EMLA cream)
what are liposomes?
Definition: Phospholipid vesicles
– Modify lipid component to imitate stratum corneum lipids (e.g.ceramides): “Cerasomes”
– Topical delivery- reservoir formation in stratum corneum
– Not effective for transdermal delivery
what are ethosomes?
– Liposomes with 30% ethanol
– Enhance transdermal delivery
what are transfersomes?
– Elastic liposomes: phospholipid + surfactant + ethanol
– Squeeze through pores in stratum corneum
– Hydration gradient –non-occlusive vehicle
define 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 substance(s) to the systemic
circulation after passing through the skin barrier”
how long should you apply transdermal patches for?
1-7 days, depending on the medication
what are the main patch components?
backing layer
liner
adhesive
what is the backing layer responsible for?
•Protects patch components from environment throughout application
–Occlusive (low water vapor transmission)
–Flexibility
what is the liner responsible for?
- Polymer material that covers the adhesive
- Removed to allow patch application on the skin
- Occlusive, to minimise loss of volatile patch components
what is the adhesive responsible for?
- Attaches patch to skin
- Polymer: acrylic, polyisobutylene (PIB), silicone
- Visco-elastic material
- May contain the drug and excipients
what are the two optional patch components?
membrane
matrix polymer
what is the purpose of the membrane?
Moderates the rate of drug release from drug reservoir into the adhesive
layer
• Steady-state drug release
what is the purpose of the matrix polymer?
Layer containing drug dispersed or dissolved in a polymer matrix
what does QC testing test for?
- Uniformity of dosage units BP
- Uniformity of content BP
- Dissolution BP
- Adhesive performance
what release patters does a resevoir( membrane controlled) system follow?
steady state release
what factors should be present in the BP dissolution for transdermal patches?
– Temperature of dissolution medium: 32 ±0.5C
– pH of dissolution medium ~ 5
how do you test adhesive performance?
- Peel test
- Tack test
- Rheological criteria for adhesive performance
how does active transdermal delivery work?
– Increasing the energy of drug molecules - Iontophoresis,
Electroporation, Sonophoresis
– Bypassing or removing skin barrier - Stratum corneum bypass or
removal
what is iontophoresis?
Movement of molecules across the skin under the influence
of an electric field
what would be the ideal properties dor iontophoresis?
broad range of drugs, ideally charged mol
what voltage is ued in iontophoresis?
use low voltage electric current <1V
how can drug transport rate be monitored in iontophoresis?
by adjusting the
electrical current
what are the properties of the drug resevoir in the iontophoretic patch?
– Aqueous, biocompatible gel
– pH to optimize iontophoretic delivery and skin tolerance
– +ve drug at anode, -ve drug at cathode
what is the purpose of the return resevoir in the iontophoretic patch?
Saline and charged molecules to complete circuit
what mechanisms does the ionotropic drug transport work by?
Electrophoretic mechanism
– Transport of molecules under direct interaction with electric field
– Charged molecules of low MW
• Electro-osmotic mechanism
– Transport of molecules under the influence of the electrically induced
solvent flow
– Solvent flow: Flux of skin cations from anode to cathode
– Uncharged, large molecules e.g. peptides, or +ve drug molecules
how does an E-trans fentanyl system work?
- 24-hour system, administration up to 6 times/hour
* Pain relief within a few minutes after pressing button
what is electroporation?
Formation of transient aqueous pores in the skin by short
electrical pulses of high voltage
what volts is used in electroporation?
100 -1000 Volts
what does electroporation disrupt?
Disruption of lipid structure of stratum corneum
how long does it take for electroporation effect to be reversed?
seconds to hours
what is sonophoresis?
Low frequency ultrasonic energy (~ 20 kHz)
• Thermal effect by absorption of ultrasound
how does microneedles work?
Array of m silicon needles or biodegradable needles
• Microneedles do not reach dermis: pain-free drug delivery
• Pre-treatment of skin or drug administration device
• Microneedles can be either drug-coated or drug-loaded
how does powderject system work?
Supersonic wave of helium gas
• Solid drug particles (20-100 μm) fired into lower skin layers
what does the laser alblation do?
Partial or complete removal of stratum corneum
• Has been used for cosmetic resurfacing of skin
• Requires specialised practitioner
• Reversible technique- skin regeneration
