Biopharmaceutics Transdermal 1 Flashcards
Parenteral drug delivery is any route other than…
GIT
This includes pulmonary, nasal, injection and transdermal
Parenteral drug delivery systems represent what fraction of all formulations on the market?
2/3
What is percutaneous drug delivery?
Through the skin i.e. injections
What is transdermal drug delivery?
Through unbroken skin, does not include injections
What are some of the advantages of parenteral drug delivery? (7)
Improved control of onset of action, serum levels, tissue concentration and elimination
Rapid action
Enhanced efficacy via local delivery or for drugs that cannot be formulated for oral admin
Ease of use
Increased compliance
Local/targeted delivery
Fall back route
What is one disadvantage of parenteral drug delivery?
Absorbance is still hampered by poor and/or variable blood flow
Why is transdermal delivery limited?
Due to the significant barrier to penetration across the skin, primarily associated with the stratum corneum (SC)
What is a typical daily dose that can be administered from a transdermal patch?
5-25mg
What does the typical daily dose indicate?
This route is only appropriate for potent drugs
How is maximal penetration of the SC achieved?
Choice of drug and formulation of delivery vehicle
Modification of the SC
Powered penetration enhancement devices
How can choice of drug and formulation of delivery vehicle be manipulated to achieve maximal SC penetration?
By choosing a very permeable drug or formulating that drug with excipients which make it more permeable
How can the SC be modified to achieve maximal penetration?
Include excipients that disrupt or damage the SC
What are powered penetration enhancement devices?
Use an electric current or sound wave to enhance penetration of drug through the outer skin barrier
How do powered penetration enhancement devices work? (3)
Iontophoresis
Phonophoresis
Electroporation
What are the 3 transdermal penetration routes?
Directly across the SC
Through the sweat ducts
Via hair follicles and sebaceous glands
Which of these 3 penetration routes is the most important?
The majority of skin penetration enhancement is focused on increasing transport across SC
The other routes comprise a very small s.a. (~0.1%) for penetration so do not contribute to the steady state flux of most drugs
Which penetration route is associated with iontophoretic drug delivery?
Uses an electric current
Primarily via sweat ducts, hair follicles and sebaceous glands as these offer the least electrical resistance
How can the structure of the SC be described?
Brick and mortar-like
Explain this description (B+M).
The bricks are 10-15 layers of keratin-rich corneocyte cells which are 0.2-1.5μm thick and 34-36μm in diameter (these cells are dead and in the process of being removed)
The mortar is an intercellular lipid matrix, extruded by keratinocytes and including long chain ceramides, free FA’s, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters
How thick is the SC?
10-15μm (dry) to 40μm (hydrated)
What is the function of keratin?
Gives the skin strength
Does the extruded lipid behaviour of the SC differ to that of a biomembrane?
Yes, biomembrane is primarily made up of phospholipids
How is the intercellular lipid matrix arranged?
Hydrocarbon chains are arranged into crystalline, lamellar gel and lamellar liquid crystal phase domains within the lipid bilayer
First few layers rearrange into broad intercellular lipid lamellae
What is the role of water in transdermal delivery?
Water is essential as a plasticiser in promoting transdermal drug delivery to prevent cracking of the SC and to maintain suppleness
What can happen to both drugs and excipients in the skin?
Hydrolysed by enzymes e.g. esterases, which can affect absorption
Hydrolysis of drugs and excipients may…
Inactivate drugs (decrease absorption) or activate a prodrug (increase absorption)
What are the 2 routes of skin penetration?
Intercellular
Transcellular
Intercellular penetration…
Is a major pathway for most drugs, drug is either soluble in lipid region or in a formulation disrupting lipid region
Transcellular penetration…
Is a route for more hydrophilic drugs penetrating aqueous regions of keratin filaments, must also transverse intercellular lipid region
How are the lipid lamellae structured?
Lipid lamellae are the ‘mortar’ between the corneocyte-rich ‘bricks’
The lipid lamellae have alternating layers of both aqueous and lipid-rich regions
How does the alternating structure of the lipid lamellae impact drug delivery?
Means that even if drugs move by the intercellular route through the lipid-rich layer, within that layer itself it must pass through alternating aqueous and lipid-rich regions
What causes this alternating structure?
The lipids forming the structure of the lipid lamellae have both hydrophobic domains, which comprise the lipid rich regions, and hydrophilic domains, where they have their charged functional groups forming the aqueous regions
For effective penetration, a drug must be…
Lipid soluble enough to move through the lipid-rich regions and water soluble enough to move through the aqueous regions
What are the physiochemical factors involved in transdermal delivery?
Diffusion coefficient (D) Diffusional path length or membrane thickness (h) Partition coefficient (P) of the drug between the skin and the vehicle Drug concentration (C) (assumed to be constant)
What equation/law relates these physiochemical factors together?
Fick’s Law of Diffusion
States that steady state flux (J) is related to D, h, P and C
How does partition coefficient affect drug diffusion?
An ‘intermediate’ logP in octanol/water of 1-3 is ideal
Need adequate drug solubility within the lipid domains but also must be sufficiently hydrophilic to allow partitioning into tissues of the epidermis and the aqueous regions of the lipid lamellae
What are the ideal drug properties for a transdermal patch?
MW <1000 Da and preferably <500 Da MP <200ᵒC Log P 1-3 No or few polar centres, like carboxylate or zwitterionic structures Kinetic half-life of 6-8 hours 50cm² max. size 5-25mg/day maximum feasible dosage
Why do you want a drug to have no or few polar centres when formulating as a transdermal patch?
If you have charges associated with the molecule, the drug will be too hydrophilic which will significantly affect diffusion through the lipophilic areas of the skin
Why do we want a drug to have a kinetic half-life of 6-8 hours when formulating as a transdermal patch?
When you put the patch on you want rapid uptake and establishment of plasma conc. but similarly, when you take the patch off you want concentrations to drop, good ‘on-off’ dosing
Why do we want a 50cm² max. size for a transdermal patch?
Not feasible to ask patients to wear huge patches
How do reusable and needle-free injectors work?
Some are spring powered and can be used 1000’s of times
Others use high pressure gas to force drug through the skin
When can reusable and needle-free injectors be used?
For SC, IM or intradermal admin (need to be more powerful for IM or intradermal admin)
Are reusable and needle-free injectors bioequivalent to regular needle-based injections?
Yes
What is an example of a reusable and needle-free injector? How does it work?
Powderject (Novartis injector)
Powered by helium gas, burst of gas that is so powerful that it actually forms a physical channel in the skin
There is cell damage immediately around the site but this is not extensive
Allows penetration deep into the skin (through SC to epidermis and dendritic cells)
No inflammation, pain or swelling
Used for highly potent drugs and vaccines e.g. HepB, influenza
What is a microneedle patch?
Structure is similar to a standard transdermal patch but you have microneedles on the adhesive part
How do microneedles work?
SC is pierced with short needles to deliver drugs into the skin in a minimally invasive manner
Actively drive drugs into the skin during microneedle insertion (for drug-coated needles)
What formulations are microneedles used in?
Used for small molecule drugs, proteins and nanoparticles to form extended release patches e.g. naltrexone, PTH, vaccines
How do microneedles increase permeability?
Create micron-scale pathways in the skin
Which layer of the skin do microneedles target?
SC, as this causes minimal damage and disruption, but they typically pierce across the epidermis and into the superficial dermis too
What are some different types of microneedle? (5)
Solid Hollow Rapidly separating Drug coated Drug containing dissolving
Are microneedle patches painful?
No, nerve endings are much lower down, you don’t feel pain as they are not stimulated
How do drug containing dissolving needles work?
When needles contact fluid within the skin, they dissolve and the drug is carried into the skin
How does a patch powered by iontophoresis work?
The patch has electrodes on it so you can apply an electrical current through it
Uses low-voltage current to increase the permeability of highly charged and weakly charged/uncharged drugs
How does iontophoresis increase the permeability of highly charged drugs?
The charge of the electrical current moving across the skin will promote and encourage highly charged drugs to enter the skin as they follow the electric current
How does iontophoresis increase the permeability of weakly charged/uncharged drugs?
By increasing the electroosmotic flow of water because of mobile cations, e.g. Na⁺, and fixed anions, e.g. keratin
The rate of delivery by an iontophoresis powered patch…
Increases with electrical current
How is the electrical current of an iontophoresis powered patch controlled?
Either by a microprocessor or the patient to allow for personalised delivery
The maximum current…
And therefore delivery rate, is limited by skin irritation and pain
How does iontophoresis provide control over dosing?
Because delivery is proportional to amount of charge i.e. it is the product of current and flow
How does electroporation work?
Short, high-voltage electrical pulses reversibly disrupt the cell membrane and skin lipid lamellae in SC to create pores in the skin
The electro-pores created persist for hours and increase diffusion by orders of magnitude for drugs, peptides, proteins and DNA
SC has a higher resistance than deeper tissues, resistance drops dramatically upon application of the electrical field
In which products is electroporation utilised?
Microneedle patches
What happens over time after use of an electroporation patch?
The lipids spontaneously rearrange to recover their original confirmation
Are electroporation patches painful?
The electrical field distributes into deeper tissues which contain sensory and motor neurons, which can cause pain and muscle stimulation
How can the pain be avoided?
By using closely spaced microelectrodes that constrain the electrical field to the SC
What is ultrasound?
An oscillating pressure wave at a frequency too high for humans to hear
How do phonophoresis powered patches work?
Ultrasound is used to chance the skin permeability of small, lipophilic drugs by disrupting the lipid lamellae of the SC
Low frequency ultrasound causes formation, oscillation and collapse of bubbles
Cavitation energy at the site of the bubbles causes small holes to form in the skin, enhancing delivery
What drugs are phonophoresis powered patches used for?
Lidocaine, insulin, heparin and tetanus toxoid vaccine
What other mechanism can skin permeability be increased by that works by a related mechanism?
Pulsed lasers
Use a related/similar shockwave mechanism
