Biopharmaceutics Transdermal Flashcards
(70 cards)
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)