Transdermal Drug Delivery Flashcards
Opportunities for skin delivery
Avoids issues with GI transit and first pass metabolism
Controlled/easily terminated
Companies can introduce transdermal products to extend the life cycle of products
Local delivery of dermatological and cosmeceutical products
New opportunities of passive and active technologies for local and systemic delivery
Why is skin an attractive route of delivery?
Skin protects us, warns us, maintains us and defines us
Skin is plentiful, readily accessible and can be monitored easily
Suitable portal for both local and systemic therapy (not first pass)
Drug delivery can be targeted, controlled and sustained
Effective and convenient for most
Potential benefits of transdermal delivery
Reduced dosage frequency
Improved patient acceptance (no needles), convenience (self-administration) and compliance
Sustained therapeutic action
Reduced first pass effect and GI incompatibility
Diminished side effects
More consistent delivery of drug
Retrievable dosage form that facilitates termination of dosing
Limitations of transdermal delivery
Only suitable for certain molecules (potent and permeable)
Skin irritation
Lag time
Cost
Direct trans-cellular path through stratum corneum
Solutes permeate directly across the stratum corneum, repeatedly partitioning between the lipophilic intercellular space and the hydrophilic corneocyte, passing across the cornified cell envelope
Biological factors affecting transdermal drug delivery
Age
Race
Cutaneous metabolism
Skin permeation
Most important determinants of rate and extent of permeation across skin are:
Skin/vehicle partitioning
Diffusivity through the stratum corneum
Most important attributes of a skin permeable molecule are:
Daily dose <10-20mg/day Half life 10 hours or less Molecular weight <500 daltons Melting point <200c Partition coefficient LogP 1-3 Non-irritating and non-sensitizing
Major limitations of models for predicting the permeability coefficient
The models are based on permeation from simple aqueous solutions
Physiological factors are not considered
Formulation effects are not considered
Competing processes
Competing processes can significantly modify the degree to which material within the SC is ultimately absorbed
Metabolism, exudation, abrasion, desorption, desquamation, washing
What molecules already work?
Scoploamine- motion sickness
Nitroglycerine- anti-angina
Clonidine- hypertension
Nicotine- smoking cessation
Estradiol +/- progestin, testosterone- HRT
Fentanyl, lidocaine, buprenorphine- pain management
How can we help molecules permeate?
Modify drug- improve properties Increase driving force- modify formulation Aid diffusion- loosen cells Alter partition- soften lipids Metabolise prodrug- change properties Increase clearance- induce vasodilation
Hair follicle permeation
Surface area of follicle wall much greater than area of follicle orifice, increasing area available for permeation into epidermis and dermis
Dense capillary networks around base of both hair follicles and sweat ducts provide good systemic access for most molecules that can permeate to those regions
Penetration enhancers
Work by:
Causing reversible damage to the SC (disrupt packing of the lipid bilayers)
Optimising thermodynamic activity of drug in the vehicle and/or skin
Increasing drug diffusivity in the SC
Establishing a drug reservoir in the SC
Increasing solubility of the active
Examples of chemical penetration enhancers
Dimethyl sulfoxide and related compounds
Azone and related compounds
Solvents and related compounds
Fatty alcohols, fatty acids and related structures
Fatty acid esters
Should be non-toxic, non-irritating and compatible
Components of transdermal system
Occlusive backing laminate
Reservoir
Rate controlling membrane
Adhesive protective liner
Iontophoresis
The migration of ionic drugs into skin using a physiologically acceptable DC electric current (direct or pulsed)
The drug is driven into the skin by electrostatic repulsion
Enhanced delivery through electrorepulsion, electro-osmosis or current induced skin permeability
Physiological counter-ions complete the circuit
Some success with lidocaine, dexamethasone, insulin, verapamil
Magnetophoresis
Application of a magnetic field enhances transdermal delivery of poorly permeable drugs through:
Altering the barrier properties of the SC
Magnetokinesis (where the octanol/water partition coefficient of drugs increases when exposed to the magnetic field)
Jet injection
MUNJIs (multi-use-nozzle jet injectors) for mass immunization programs, discontinued following reports of cross contamination
DCJIs (disposable cartridge jet injectors): sterile, single use delivery of proteins, e.g. insulin, growth hormone, erythropoietin, interferon, vaccines
Powder/particle injection
Devices include compressed gas, a compartment containing particulate drug formulation (and carrier) and a nozzle to direct flow
Propelled particles puncture micron-sized holes through SC by virtue of their momentum and density
Clinical trials have reported painless delivery at the time of injection with DNA vaccines being well tolerated
Radiofrequency/electroporation/ultrasound
Viaderm creates microchannels through radiofrequency ablation, demonstrates utility for pDNA delivery to skin, clinical data on granisetron, insulin, hPTH and hGH
Electroporation is the temporary disruption of lipid membranes with high voltage pulses, some success with tetracaine
Low frequency ultrasound creates cavitation, increasing permeability, may also act as physical adjuvant for transcutaneous immunization
Abrasive patch
Skin is pre-treated with an abrasive strip prior to patch application, antigen and/or adjuvants are delivered to the skin immune cells
Demonstrated efficiency and safety in more than 35 clinical trials (including seasonal and pandemic influenza)
Microdermabrasion (physical exfoliation) works in a similar way
Mouse studies of microneedle applications
Dose sparing: low dose influenza virus-like-particle vaccination via microneedles is more immunogenic and protective than low dose IM
Microneedle vaccination is also more effective in inducing recall antibody responses in lungs and bone marrow
Ex vivo human skin model
Excised human skin maintained at air-liquid interface of culture medium
Need to assure preserved histology and cellular functionality
Cellular response to vaccine
H1N1 swine flu vaccine:
Blank coat- skin treated with placebo microneedles
VLP MN- skin treated with microneedles coated with 2009 H1N1 swine flu VLP vaccine
Gene expression analysis- microarray
Skin from four different donors subjected to controlled MN insertion, ID injection of PBS, MN vaccination and ID vaccination
RNA recovered from skin samples 24 hours after injection, microarrays used to profile gene transcripts
Standardising microneedle application
Dummy microneedle patch applied to self and researcher
Microneedles applied with and without an applicator device
Force applied recorded using a digital force gauge
