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)
polymer matrices and Drug release depends on:
- Diffusion coefficient of drug
- SA
- Conc of polymer > dilute (more crosslink)
- Porosity/ tortuosity of polymer matrix
* Intramolecular interactions (crosslink, H bonds)
drug encapsulated between matrix, diffuse out slowly
permeation enhancers
- interaction with intercellular protein
- improve partition of the drug into stratum corneum
cyclodextrin
glyceryl monoleate
ethanol
propylene glycol
solvent
ethanol
propylene glycol
viscosity modifier
carboxymethyl cellulose, HPMC
hyaluronate sodium
calcium alginate
carbomer
poly(methyl vinyl ester/ maleic anhydride)
matrix polymer
glyceryl monooleate (SR agent)
carboxymethyl cellulose, HPMC
hyaluronate sodium
calcium alginate
povidone (SR)
adhesive
calcium alginate
carbomer
povidone
poly(methyl vinyl ester/ maleic anhydride)
glyceryl monooleate (bioadhesive)
silicone, rubber, adhesives
humectant
hyaluronate sodium
hydrates skin, better permeation (brick, mortar)
packaging and storage
- Patches sealed in indiv pouches
○ Plastic/ polymer lining (maintain hydration in patch)
○ Al lining (protect from light degradation) - Sealed packaging
○ Maintain integrity of adhesive
○ Maintain integrity of pdt (oxidation, reduction, temp)
○ Maintain hydration
designs of patches (3)
1) membrane patch (bulky, reservoir, matrix, adhesive separate)
2) matrix patch (drug in matrix, no reservoir)
3) drug-in-adhesive matrix patch (drug+polymer+adhesive)
- calcium alginate
- povidone
parts of a patch
- backing layer (ontop, impermeable)
- membrane (polmer matrix)
- adhesive
- liner (protects adhesive, remove just before admin)
backing layer
○ Impermeable layer (plastic/ polymer lining, additional Al lining)
○ Protects drug and contents
○ Maintain patch: hydration, stability (light, Oxidation)
○ support and protection of drug-loaded adhesive from environ
membrane, polymer layer
○ Polymer matrix
○ Release rate depends on:
* Composition/ chemistry, thickness and porosity/ tortuosity (channels in matrix)
adhesive
silicone, rubber, adhesives
permeatiion enhancers (prime skin for better permeation)
special considerations of TD patch
- release rate of drug
* toxicity/ ADR/ ineffectiveness
* temp (no heated blankets, incr SE)
* crystallinity of drug over time - strength of adhesion
* b. clothes layers, influence of sweat, hair - disposal of patch
* high conc left in patch –> needed to create a flux (release)
release rate of drug affected by
- potential for leaching, extraction of drug from backing
* drug remains in reservoir, not fluxed/ released
* substances from backing layer (may be toxic) leached - temp (not use heated blankets, incr SE)
- crystallinity of drug over time (crystal/ amorphous – melting point)
rotigotine/ neupro
- drug in adhesive
- dopamine receptor agonist (PD)
backing film, drug matrix, protective liner
admin of patch
- Apply on skin that was not used previously
○ Adhered skin is more tender, rate of drug penetration affected
○ rotate sites, not repeat in 14d
○ shave hairy site 3d before apply - Immediately apply to skin after peeling protective layer from adhesive
○ Exposed to microbials
○ Affect adhesiveness of patch - 30s Warm up area to activate adhesion
○ Better adhere to skin
rotigotine API
- MW: 315.48 g/mol
- logP: 4.7
- Hydrogen bond donor (1)
- Hydrogen bond acceptor (3)
- Ionisable –yes 3*amine & OH
○ pKa is weak, affected by pH of body + formulation
○ Usually uncharged to have higher LogP, better partition into lipo layer of skin
○ may become ionised for systemic circulation
rotigotine composition
- Ascorbyl palmitate – antioxidant
- Sodium metabisulfite – antioxidant
- DL-alpha tocopherol vit E – anti oxidant
- Povidone – polymer, SR, adhesive
- Silicone adhesive
PK/PD of rotigotine
- ~45% released in 24hrs (0.2mg/cm2)
○ Cmax dependent on patch dose - repeated daily use to maintain steady state conc
- After removing patch,
○ Plasma lvl decr with t1/2: 5-7hrs
fentanyl/ duragesic
- opioid agonist – pain relief (repeat 72h application)
- drug in membrane (bulky: reservoir, release mem, adhesive – separated)
- dose depeds on conc in patch + size of patch
backing layer, drug reservoir,mem, silicone, protective liner
- rotate sites, do not shave (clipped)
fentanyl API
- MW: 336.5g/mol
- logP: 4.05
- Hydrogen bond donor (0)
- Hydrogen bond acceptor (2)
Ionisable, +ve charged
fentanyl composition
- Alcohol *– permeation enhancer (found on adhesive)
○ Minute amounts, less irritation to skin - Ethylene-vinyl acetate copolymer – matrix
- Hydroxyethyl cellulose – matrix
- Polyester – backing layer (no water passes through)
- Silicone – adhesive
PK/PD of fentanyl
- SS plasma conc after ~ 3days
○ Large variability (pt) - Plasma conc depend on patch dose
- large conc variability even at maintenance
- After removing patch
○ t1/2 ~ 7hrs
