Transdermal (IC18) Flashcards
1
Q
Skin anatomy
A
- Stratum corneum
- Epidermis
- Dermis
2
Q
Physiology: Stratum corneum
A
- Top 10um of skin
- 10-20 layers of flattened, stratified, fully keratinized dead cells
- Squamous cells and keratinocytes
- Primary barrier to drug crossing the skin
- pH ~5
3
Q
Physiology: Epidermis
A
- Divided into various morphologically and compositionally different layers, cells become notably flatter and more keratinized moving up through layers
4
Q
Physiology: Dermis
A
- Blood vessels, macrophages, mast cells
- Sebaceous gland, hair follicle roots
5
Q
Drug transport across stratum corneum
A
Brick and mortar structure:
- ordered, rigid bilayer structure
- access primarily via intercellular lipidic domains (lipids, cholesterol, fatty acid, ceramides), navigate around the corneocytes
- some access via ‘appendages’: sweat ducts, hair follicles
6
Q
Topical VS Transdermal
A
Topical:
- Shallow skin penetration up to epidermis only
- Local delivery: antiseptic, anti-inflammatories, cosmetics
Transdermal:
- Deep skin penetration, into dermis and blood vessels
- Systemic delivery
7
Q
Advantages of transdermal delivery
A
- Controlled release (reservoirs, duration of contact, dcr dosing frequency)
- No GI degradation/irriation
- Bypass hepatic first pass effect
- Easy termination of input (remove patch)
- Non-invasive
8
Q
Disadvantages and barriers of transdermal delivery
A
- Variability b/w people and location of administration on body
- Stratum corneum serves as a physiological barrier to slow absorption
- Skin irritation (interactions and removal)
- Could be removed by patient
- Presence of metabolic enzymes on the skin
- Still need to permeate the blood brain barrier for CNS delivery
- Systemic side effects as drug enters blood circulation
9
Q
Factors that affect delivery:
A
- Skin condition: age, disease, injury, site
- Skin thickness: thickness of diffusion layer
- Hydration of the skin: hydration widens the gaps between cells and increases drug absorption through the stratum corneum
- Stimulation of the skin: phonophoresis/ultrasound, iontophoresis, heat
- Physicochemical properties: lipophilicity, diffusion coefficient
- Permeation enhancers: reversible reduction in the barrier resistance of the stratum corneum w/o damaging viable cells
- Concentration gradient
- Area of contact b/w formulation and skin
10
Q
Ideal drug candidates for transdermal delivery
lipinski rule of 5 modified for TD
A
MW: <500Da
Hydrogen bond donors: =<5
Hydrogen bond acceptors: =<10
LogP 1-3 (vs <5)
Ionisation state: unionized
11
Q
Delivery systems (formulations) for topical and transdermal
A
Topical: gel, creams, ointments
Transdermal: patches (solutions/suspensions in reservoirs, polymer matrix)
12
Q
What are some examples of transdermal patches on the market?
A
- Rotigotine: PD
- Fentanyl: pain relief
- Estrogen: HRT
- Nicotine: nicotine replacement therapy for smoking cessation
13
Q
What excipients are required in transdermal patch?
A
- Preservatives
- Solvents/cosolvents
- Viscosity modifiers => rheology, flow, affect stability, affect drug release from polymer matrix
- Permeation enhancers => affect brick and mortar structurm of stratum corneum, to allow drug penetration
- Adhesives
14
Q
[Excipients for Transdermal Patch]
Permeation enhancers
A
- Cyclodextrin
- Glyceryl monooleate (can be bioadhesive, sustained release agent - forms intricate structure and complex matrix to slow down drug release)
- Ethanol (can be solvent as well)
- Propylene glycol (can be solvent as well)
15
Q
[Excipients for Transdermal Patch]
Viscosity modifiers
A
- Carboxymethylcellulose, hydroxypropyl methyl cellulose
- Hyaluronate sodium
- Calcium alginate
- Carbomer
- Poly(methyl vinyl ether/maleic anhydride)
16
Q
[Excipients for Transdermal Patch]
Matrix polymer - can form sustained release matrix
A
- Carboxymethylcellulose, hydroxypropyl methyl cellulose
- Hyaluronate sodium (also a humectant, hydrates the skin)
- Calcium alginate
17
Q
[Excipients for Transdermal Patch]
Adhesive
A
- Calcium alginate
- Carbomer
- Poly(methyl vinyl ether/maleic anhydride)
18
Q
Polymer matrices
- drug release from matrix is dependent on:
A
- diffusion coefficient of the drug
- surface area
- concentration (high conc of polymer increases cross-linking of polymer matrix thereby making it more sustained release)
- porosity/tortuosity of polymer matrix (determined by intramolecular interactions - crosslinking, H-bonding)
19
Q
Packaging and storage of transdermal patches
A
Patches sealed in individual pouches (plastic/polymer lining, aluminium lining if sensitive to light)
- maintain the integrity of the adhesive
- maintain the integrity of the product
- maintain hydration within the patches
20
Q
What are the 3 different design of transdermal patches?
A
- Membrane
- drug dispersed in separate depot
- rate-controlling membrane limits the amount of drug release over time (this membrane can contain polymers)
- components: backing layer, drug reservoir, rate controlling membrane, adhesive
- Matrix
- drug incorporated in a polymer matrix, separate to the adhesive layer
- components: backing layer, rate-controlling polymer matrix containing the drug, adhesive
- Drug-in-adhesive matrix
- Drug combined with adhesive and released from this matrix
- components: backing layer, drug-in-adhesive matrix
21
Q
Function of backing layer
A
- inert backing layer, typically impermeable plastic/aluminium
- protect drug and contents from exposure to light/air
- structural support
22
Q
Function of membrane
A
- polymer matrix
- composition/chemistry, thickness and porosity/tortuosity determines its release
23
Q
Function of adhesive
A
- silicone and rubber commonly used as adhesives
- may include permeation enhancers
24
Q
Function of liner
A
- protects the adhesive
- e.g., transparent fluoropolymer-coated polyester film
25
Special considerations for transdermal patches:
- release rate of drug from patch
- strength of adhesion
- disposal
Release rate of drug from patch
- potential for leaching and extraction of drug into backing/other layers
- **temperature** (e.g., heating may incr release of drug from the patch)
- crystallinity of drug over time
Strength of adhesion
- between layers, influence of sweat, hair etc.
- e.g., shave the area before using patch
Disposal
- high concentration patches such as fentanyl patches - fold and flush down toilet
26
[Rotigotine/Neupro]
- Application
- switch sites to prevent skin irritation
- apply and hold for 30s to ensure adhesion
27
[Rotigotine/Neupro]
Function of excipients:
- Ascorbyl palmitate
- Povidone
- Silicone
- Sodium metabisulfite
- DL-alpha-tocopherol
- Ascorbyl palmitate (antioxidant)
- Povidone (polymer matrix, adhesive)
- Silicone adhesive (adhesive)
- Sodium metabisulfite (antioxidant)
- DL-alpha-tocopherol (antioxidant)
28
[Rotigotine/Neupro]
PK
45% released in 24h
*the remaining % maintains the concentration gradient
*Cmax is dependent on patch dose
*removal of patch: plasma levels decreased with a terminal half-life of 5-7h
29
[Fentanyl/Duragesic]
Function of excipients:
- Alcohol
- Ethylene-vinyl acetate copolymer
- Hydroxyethyl cellulose
- Polyester
- Silicone
- Minute amounts of alcohol (permeation enhancer)
- Ethylene-vinyl acetate copolymer (polymer matrix in the release membrane)
- Hydroxyethyl cellulose (viscosity modifier + matrix in the drug reservoir)
- Polyester ( backing layer)
- Silicone (adhesive)
30
[Fentanyl/Duragesic]
Where each excipient is in the patch design
1) a backing layer of polyester film
2) a drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl cellulose
3) an ethylene-vinyl acetate copolymer membrane that controls the rate of fentanyl delivery to the skin surface
4) a fentanyl containing silicone adhesive. Before use, a protective liner covering the adhesive layer is removed and discarded.
31
[Fentanyl/Duragesic]
PK
Steady state plasma conc. after 3 days (72h patch)
Plasma conc. dependent on patch dosage
Half-life ~7h after patch removal
