formulation TD Flashcards
skin anatomy
- Stratum corneum
- Top 10um layer of skin
- epidermis
- Cells flatter, more keratinised moving up through layers
- Dermis
- Blood vessels, macrophages, mast cells
- Sebaceous glands, hair glands
stratum corneum (main barrier)
- Top 10um layer of skin
- 10-20 layers of flattened, stratified, fully keratinised dead cells
- Primary barrier to drug crossing the skin
- Brick and mortar structure
○ Ordered, rigid bilayer structure
○ Access primarily via: intracellular lipidic domains - Lipids, cholesterol, fatty acids, ceramides
- Brick and mortar structure
skin delivery 2 ways
topical
transdermal
topical
- Shallow skin penetration
- Local delivery
- Cosmetics, antiseptics (local wound that affects only surface layer), anti-inflammatories
transdermal
- Deep skin penetration (across stratum –> epidermis –> adipose tissue –> dermis –> blood vessels)
- Systemic delivery
- Nicotine, pain relief, hormonal regulation
- Protects pdt + retain on surface of skin
adv of TD
- Controlled release
○ Reservoir: (amt of drug + conc loaded into reservoir)
○ Duration of conTDtact: (size of patch, duration)
○ Decr dosing freq - No GI degradation/ irritation
○ More local skin irritation - Bypass hepatic 1st pass effect
- Easy termination of input
○ Peel off and admin of drug stops, not high plasma conc left - Non-invasive
○ Painless, no skin breeched
disadv of TD
- Variability b. people and location of admin on body
○ Thickness of skin differs - SC
○ Slows absorption, barrier
○ Rate limiting step - Skin irritation
○ Adhesive layer – removal
○ Drug int on skin surface - Easily removed by pt
- Metabolic enzymes (specific chemical functional grps?)
- BBB (via systemic delivery)
- Systemic SE
8 factors that affect delivery
- Skin condition: age, disease, injury, site
- Skin thickness (diffusion layer)
- Hydration of skin (stratum corneum)
- Stimulation of skin
- Phonophoresis/ ultrasound – vibration
- Iontophoresis – heat
- Physicochemical properties of drug
- Lipophilicity, diffusion coefficient – LogP, size
- Permeation enhancers (eg ethanol)
- Reversible reduction in barrier resistance of SC w/o damaging viable cells
- Conc gradient
- Patch reservoir –> skin
- 50% of Drug left in patch as there must be FLUX
- Area of contact b. formulation & skin (SIZE)
hydration by
- Natural: hydration, humidity
- Manufactured:
○ Chemically (moisturise)
○ Physically (occlusive layer to trap water at site)
hydration affects
Water absorbed by lipid channels in between
Lipid channel widens, facilitate flow/ permeation of drug
- Size of corneocytes remain the same
- The gaps between WIDENS, better permeation
brain access via TD
Skin (barrier) –> blood –> (barrier) brain
* Drug sol flows through circ system ○ Reticuloendothelial system (RES) ○ Unless active targeting, drug is distributed everywhere =unwanted SE * Drug bypass BBB to access the brain ○ Blocks ~98% of small mole drug candidates ○ Paracellular (tight junctions) << transcellular transport
transcellular transport via
1) Active efflux transporters (REMOVE from organs into lumen)
○ P-gP, BCRP (breast cancer resistance protein), MRP (multi-drug resistance protein)
2) Endocytosis mediated transporters (INTO by Specific molecules/ functional grp binding)
○ Carrier-mediated transporters (LAT1, GLUT1, MCT1, OCTN2)
○ Receptor-mediated transporters (IR, TfR)
TD drug candidate lipinski
- logP 1-3
if too hydrophobic: repelled, still needs to be transported systemically - unionised
TD formulations
- Topical: gel, creams (w-based/ oil-based), ointment
- TD: patches
○ Sol/ susp in reservoirs
○ Polymer matrix
TD excipients
- Preservatives - reduce microbial growth
- Solvent, co-solv - dissolve drug
- Viscosity modifier - flow of formulation in reservoir
- Permeation enhancer - in contact w/ SC
○ Bioadhesive (stick to mucus layer)
○ SR agent (complex matrix) - Adhesives - stick to skin
○ May have properties: viscosity enhancers, matrix polymer - Polymer matrices (SR)
