Biopharmaceutics Transdermal Flashcards
What is parenteral?
- any other route of administration other than oral
- 2/3rds of the pharmaceutical market
What are the advantages of parenteral drug administration?
- improved control
- rapidity of action
- enhanced efficacy (local effects)
- ease of use (unconscious/uncooperative)
- increased compliance (don’t need to remember to take tablets multiple times a day)
- local/targeted drug delivery
- fall back route (unconscious)
What is the main disadvantage of parenteral drug administration?
absorbance is hampered by poor and/or variable blood flow
What is the main limitation for transdermal drug delivery?
- the stratum corneum skin barrier (the outermost layer)
- prevents drug penetration into the vasculature that sits below the skin
How is maximal penetration of the stratum corneum achieved?
- choice of drug (with appropriate properties)
- formulation/delivery vehicle
- powered penetration enhancement devices
What are the three main transdermal penetration routes?
- directly across the stratum corneum (major route)
- through sweat ducts
- through hair follicles and sebaceous glands
2 & 3 make up a very small surface area (0.1%) and don’t contribute to the steady state flux of most drugs
- but this is where powered delivery devices work as there is less electrical resistance here than in the stratum corneum
What is the general structure of the stratum corneum?
bricks & mortar (cells & lipid matrix)
How thick is the stratum corneum?
10 - 15 um when dry
40 um when hydrated from swelling
What is the structure and characteristics of the cells of the stratum corneum?
- cells that make up the SC are the corneocytes
- corneocytes are largely made up of keratin
- 10 - 15 layers of these cells in the SC
- 0.2 - 1.5 um thick, 34 - 46um diameter
- these cells are the dead cells that are ‘sloughing off’
What is the structure and characteristics of the lipid matrix of the stratum corneum?
- lipid matrix is expelled by keratinocytes as they move up the dermis layer
- composition of the lipids is different to normal cells (which usually contain a lot of phospholipids)
- this expelled lipid phase behaves very different to that of normal biomembranes
- made up of: ceramides, fatty acids and cholesterol
- the hydrocarbon chains arrange into: crystalline, lammellar gel and lamellar liquid crystal within the bilayers
- first few layers are broad intercellular lipid lamellae
- lipid lamellae: alternate regions of aqueous and lipid regions
Why is water essential to the skin?
- acts as a plasticiser to prevent the SC from cracking
- maintains suppleness
What are the enzymes found in the skin?
- esterases
- drugs and excipients may be hydrolysed by these
What are the two major routes for penetrating the stratum corneum?
- intercellular route - pass between the cells, through the lipid matrix (this is the MAJOR route for most drugs)
- transcellular route - pass through the corneocytes
What type of drugs typically penetrate via the intercellular route?
- lipid soluble drugs
- formulations that can disrupt the lipid regions
What type of drugs typically penetrate via the transcellular route?
- more hydrophilic drug (penetrating the keratin filaments within the corneyocytes)
- but still has to move across the intercellular lipid region
What are the physiochemical factors that govern drug permeation?
steady state flux (permeation/uptake of drugs) based on:
- diffusion coefficient of the drug (D)
- diffusional path length or membrane thickness (h)
- partition coefficient (P) of the drug
- drug concentration (C)
What is the ideal Log P of a drug for transdermal drug diffusion?
1 - 3
- want it to be lipid soluble enough to pass through the lipid domains of the SC
- want it hydrophilic enough so that it partitions into the tissues of the epidermis
a higher log P may result in a depot effect as there is high lipid association
What are the ideal drug characteristics for transdermal delivery?
- MW < 1000 Da, and preferable less than 500Da
- Melting point < 200 degrees (influences solubility and therefore skin penetration)
- Log P 1 - 3
- No/few polar centres (no charge or will impair lipid solubility)
- Half Life < 6 - 8 hours, rapidly absorbed and rapidly metabolised (transdermal delivery has continuous delivery of a drug)
What are the ideal characteristics of a patch for transdermal delivery?
- 50cm2 maximum patch size
- 5 - 20mg max daily dose (potent drug)
What are the main structures of a transdermal patch?
- outer plastic covering
- drug reservoir
- membrane (controls the drug release)
- adhesive contact
How is skin permeation enhanced by the drug/vehicle?
- drug selection
- pro-drug (reduce the number of charged centres)
- ion pairs/complexes (reduce the number of charges)
- chemical potential
- eutectic systems
- liposome/vehicle based formulations
- optimal permeability
How is skin permeation enhanced by manipulating the SC?
- hydration (layers will separate to form a channel)
- lipid fluidisation
- powered electrical devices
What are the different types of powered electrical devices?
- iontophoresis
- phonophoresis
- electroporation
How do saturated/supersaturated drug solutions maximise skin penetration?
- maximum rate of skin penetration
- changes the chemical potential of the system
- drug then has its highest thermodynamic activity
(produces a high drug concentration reservoir, forming a concentration gradient for rapid uptake)
How are supersaturated/saturated drug solutions formed?
- evaporation of the solvent
- mixing co-solvents
so that the same concentration of drug is in less and less of the solvent, so that it is more concentrated
What common mechanism of supersaturation drug solutions is seen for topically applied formulations?
evaporation of the solvent occurs by the warm surface of the skin so that the drug then becomes super saturated
What happens when water is absorbed into the supersaturated vehicle of the drug?
- water from the skin absorbed into the vehicle
- acts as an anti solvent
- increases the thermodynamic activity of the drug 5-10 x
- increases the flow of the drug
Supersaturated systems are stable, true or false?
FALSE
- they are unstable
- require the incorporation of anti-nucleating agents to stabilise
- ceramides, cholesterol and fatty acids do provide and contribute to this effect
What is a eutectic systems/mixture?
- made up of two components
- inhibit the crystallisation of each other
- this decreases the melting point
- many have a penetration enhancer as the second component (fluidises the lipid lamellae)
crystals - highly organised structures that require more energy to break, and therefore have higher melting points
inhibit crystallisation = decrease energy
How does melting points of drugs affect skin permeation?
- lower melting points = better solubility
- solubility then enhances the skin permeation
- MPs below or around skin temperature can enhance drug solubility
Examples of permeation enhancers
- ibuprofen & terpenes
- methyl nicotinate & menthol
- propranolol & fatty acids
- lignocaine & menthol
How is the effectiveness of a permeation enhancer measured?
- the enhancement ratio (ER)
ER = drug permeability coefficient after enhancer treatment/drug permeability coefficient before enhancer
How is the stratum corneum modified?
- disruption of the lipid lamellae (fluidising)
- interactions with intracellular proteins of the SC
- improvement of partitioning of drug (with co-solvent/co-enhancer)
What are the different formulations available to modify the stratum corneum?
- needles/skin roller (puncture holes in the skin)
- micro needle based patches
- molecules (chemically alter skin)
What is the most widely used and safest method for increasing skin penetration of both lipophilic and hydrophilic drugs?
water
How does water increase skin penetration?
- alters drug solubility and partitioning
- increases hydration and therefore swelling, opening of the SC
- provides more channels and routes for the diffusion of drugs
Alcohol diffusion coefficients are higher in dry skin, true or false?
FALSE
- formulations with high levels of alcohols will improve with HYDRATED skin
- diffusion coefficient is 10x higher
What is the water content of the stratum corneum?
15-20% of the dry weight
- varies with the external environment
How do you improve the hydration of the SC with formulations?
OCCLUSION - prevent water evaporation/loss
- transdermal pathces
- plastic films
- paraffins/oils/waxes for ointments
- water in oil emulsions
- oil in water emulsions that can donate water to the skin
How do liposomes/other lipid nanoparticles aid penetration through the SC?
small size aids their penetration
What are the different types of lipid nanoparticles?
- liposomes
- deformable liposomes (transfersomes)
- ethosomes
- niosomes
- solid lipid nanoparticles
How do LIPOSOMES aid penetration through the SC?
- hydrate and/or alter lipid layers
- if the lipids used are similar to the lipids of the SC, can readily enter/fuse with lipids of the SC
- exchange of lipids = fluidisation and fusion
What are deformable liposomes made up of?
- 10 - 25% surfactant
- 3 - 10% ethanol
- lipids
they become flexible and fluid, easily deformable so that they can squeeze through channels in the SC (that are less than 1/10 of the diameter of the transferosome itself)
What are ethosomes?
- high alcohol content liposomes
- fluidises lipids & makes them more flexible
What are niosomes?
- vesicles composed of non-ionic surfactants
What are solid lipid nanoparticles (SLN)?
carriers for enhanced delivery of
- suncscreens
- vitamins A & E
- triptolide
- glucocorticoids
What is an SLN and an NLC?
- solid lipid nanoparticle
- nanostructure lipid carrier
What is the structure of an SLN?
perfect solid matrix
this forces the encapsulated drug molecules to the surface of the particle
= rapid release of the drug from the surface of the particle
What is the structure of an NLC?
- solid lipid matrix immersed in oil droplets
= imperfect liquid crystal lattice
solid lipid matrix - immobilises the drug and stops nanoparticles from coalescing
liquid lipid - increases the drug loading capacity
= no rapid release of drugs from the surface of the particle
What excipients can cause keratin fibres to be disrupted?
- decylmethylsulphoxide
- urea
- surfactants
What excipients can cause the lipids in the lamellae to be fluidised?
- DMSO
- alcohols
- fatty acids
- terpenes
What are the different mechanisms of the excipients to cause keratin and lipid disruption?
- excipients MIX homogeneously with skin lipid
= fluidises the lipids and changes drug solubility - excipients EXTRACT skin lipids
= disrupts the structure, leaving aqueous channels/microcavities - excipients POOL with lipid domains (only at high conc)
= creates permeable pores that provide less resistance to polar molecules
What factors of the permeating agents affect the permeation of the skin?
- chain length
- polarity
- unsaturation
- functional groups
What is the optimal factors for a permeating agent to increase their effect?
SATURATED
- chain length C10 - 12
- attached to a polar head group
UNSATURATED
- chain length C18
What is the main disadvantage of penetration enhancers?
skin irritation
significant disruption to keratin/lipids may cause an immune response and cause damage
What is the meaning of recovery in relation to permeation of the skin?
- how much of the drug has passed THROUGH the skin barrier to reach systemic circulation
What is the meaning of absorption in relation to permeation of the skin?
- how much of the drug has been STUCK in the lamellae and hasn’t partitioned into the blood
Painless and Needle Free Injectors
- spring powered/high pressure gas
- reusable
- subcutaneous, IM or intradermal
- bioequivalent to normal needle injections
What are painless and needle free injectors used for?
- vaccines
e. g. powderject
- uses helium gas to create holes in the tissue to form a channel
- forces drug through at supersonic speeds
- causes cell death on entry BUT
- has limited damage and pain
Microneedle Patches
- stratum corner pierced with needles (minimally invasive)
- delivery of small molecues/proteins/nanoparticles
- create micron scale pathways in the skin (channels)
- actively drive drugs through the skin, insertion
- targets the stratum corneum, but can target further down with longer needles
What are the different types of microneedle?
- solid microneedles
- hollow microneedles
- rapidly separating microneedles
- drug coated microneedles (metal)
- dissolving microneedles (biodegradeable polymer, limited disruption to the skin)
Powered Patches: Ionophoresis
uses low-voltage current to increase the permeability of charged and uncharged drugs
How does ionophoresis enhance permeation of CHARGED drugs?
- 2 electrodes on the patch will encourage the movement of charged drugs from the patch to the skin
How does ionophoresis enhance permeation of UNCHARGED/WEAKLY CHARGED drugs?
by changing the electroosmotic flow of water:
- electrical current moves cations (Na+) into the skin
- keratin is negatively charged and is fixed
- flow of the cations creates an osmotic imbalance
- water from the patch then flow into the skin
- the drug then moves with the water
Rate of delivery of drugs is proportional to the electrical current in ionophoresis, true or false?
TRUE - proportional to the charge
- so you can personalise dosing according to a patient by increasing/decreasing the electrical current
What is the maximum delivery rate in ionophoresis?
- maximum delivery rate is the maximum current the patient can tolerate
- this is the rate limiting step
- electrical current will reach underlying nerve tissue which can cause skin damage
Powered Patches: Electroporation
electric current & microneedles
- short, high voltage pulses disrupts the cell membranes and lipid lamellae
- creates electropores that can last hours (reversible disruption)
- stratum corneum has higher resistance than the deeper tissues - this decreases on application of the electrical filed
What is the rate limiting step of electroporation?
electrical field distributes to deeper tissues which contain sensory and motor neurons:
- muscle twitching and pain
avoid/minimise this using closely spaced micro electrodes that constrain the strength of the electrical field just to the stratum corneum
Power Patches: Phonophoresis
ultrasound - an oscillating pressure wave at a frequency too high for humans to hear
- for small lipophilic compounds
- disrupts the lipid structure of the stratum corneum
- low-freuqency ultrasound causes formation, oscillation and collapse of bubbles
- bubbles collapse, release energy and disrupts the lipids around the bubbles
= causes small holes in the skin
What are the advantages of phonophoresis?
- no electric current so no pain issues
- enhances delivery of lidocaine, insulin, heparin, tetanus vaccine
