Flashcards in Biopharmaceutics Transdermal Deck (70)
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?
- 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?
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?
- 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