DDS: Transdermal Flashcards
What are the functions of the skin?
- Largest organ of body (by weight) @ 2 m2
Functions:
- Protection from environment (physical, chemical, microbiological)
- Maintain temp., electrolyte & fluid balance
- Component of immune, nervous & endocrine systems
- Synthesis, processing and metabolism of proteins, lipids, glycans, signaling molecules
Why are chemicals applied to the skin?
- Cleanse skin
- Improve or restore barrier
- Enhance beauty and slow ageing – cosmetic/cosmeceutical
- Treat disease associated with skin and underlying tissues
- Systemic absorption (TDD)
- Accident
What are drugs used in the following;
A) superficial
B) appendaegeal
C) epidermal/dermal
D) systemic
E) deeper tissue
A)
Sunscreens, cosmetics, insect repellents, barrier products
B)
Anti-acne, anti-infectives
C)
Antihistamines, anaesthetics, antimitotics, scopolamine
D)
Nitroglycerin, nicotine, hormone replacement therpay
E)
Analgesics and antiinflammatories
What are the advantages of TDD (transdermal drug delivery)
- Convenience and accessibility of skin
- Avoid G.I. tract – stability, irritation, variability
- Avoid 1st pass metabolism
- Constant & continuous drug input
- Prolonged application time
- Rapid termination of drug input - safety
What are the disadvantages/limitations of TDD?
- Not suitable for immediate/rapid effect
- Depends on skin permeability
- Depends on physicochemical properties of drugs
- Limited PK clearance range
- Potential for metabolism in skin
- Potential for development of tolerance
- Skin irritancy/allergic reactions
What makes up the below antaomy of the skin
A) Epidermis
B) Dermis (1-2 mm)
C) Hypodermis and subcutaneous tissue (1-2mm)
A)
- Stratum corneum or horny layer (10-20μm)
- Viable epidermis (50-100 μm)
B)
- Connective tissue, nerve, lymphatic & vascular vessels; appendages
C)
- N/A
What is the process of how a drug enters the skin and is/isn’t systematically absorbed?
The drug initially penetrates through the stratum corneum and then passes through the deeper epidermis and dermis without drug accumulation in the dermal layer.
- When drug reaches the dermal layer, it becomes available for systemic absorption via the dermal microcirculation
What is the main barrier to penetration?
Stratum corneum
What some non-invasive in vivo assessment methods for skin penetration?
- Skin blanching assay: vasoconstrictors
- TiVi image analysis (Wheels Bridge): vasodilators
- Dermainspect: multiphoton microscopy: fluorescence lifetime imaging (MPM-FLIM)
- Real-time imaging of penetration of fluorescent molecule within the epidermis
What does ‘flux mean’? (Fick’s law of diffusion)
In delivery systems involving transdermal patches, the drug is stored in a reservoir (reservoir type) or drug dissolved in a liquid or gel-based reservoir (matrix type).
- The starting point for the evaluation of the kinetics of drug release from a transdermal patch is an estimation of the drug compound’s maximum flux across the skin (flux (J))
When does maximum flux occur?
(skin penetration: passive diffusion)
Maximum flux occurs when capp = solubility limit of drug in applied formulation
capp = conc of permeant in applied vehcile
What are some factors influencing skin penetration?
- Age – pre-term infants
- Condition – injury or disease
- anatomical site
- blood flow
- skin metabolism
- Species – animal v human
What happens to the skin in atopic dermatitis?
Increased transepidermal water loss (TEWL)
- stratum corneum lipids are modified
Rank in order of rabit,rat,pig,monkey human the relative in vivo absorption of different chemicals
Most to least:
rabbit>rat>pig>monkey>human
What are two types of enzymes involved in skin metabolism? Give examples for each one.
Endogenous enzymes
- Hormones, steroids, inflammatory mediators
Exogenous enzymes
- drugs, pesticides, environmental & industrial chemicals
Metabolising potential estimated about 2% of the liver
What are examples of skin metabolism?
- Polycyclic aromatic hydrocarbons (in soot) – relatively harmless but activated in skin to DNA binding chemicals – scrotal CANCER in chimney sweeps
- Activation of inactive pro-drugs eg. Steroid esters
What are the effects of vehicle in TDD?
- Hydration by occlusion
- Release & absorption according to type of formulation
- Vehicle components biologically inert?
- Vehicle components affect skin permeability?
- Enhancement of flux or sustained release
What can the vehicle influence in TDD? Include positive and negatives.
- Solubility of penetrant (thermodynamic activity/concentration) in vehicle
- Partitioning – from vehicle to skin
Positive
Enhancement in:
- Increase solubility in skin
- Modify the barrier – increase diffusion coefficient
Negative
- Damage the stratum corneum or skin integrity
> disrupt lipid structure
> dentaure proteins
What are some drug properties that can affect skin permeation?
- Molecular weight/volume
- Melting point
- Partition coefficient – vehicle/stratum corneum & stratum corneum/stratum granulosum
- Solubility in oil and water
- Hydrogen bonding groups
How does TDD delivery rate relate to molecular weight and melting point?
Lower molecular weight (between 100 and 200 DA) and lower melting point =increased delivery rate
What log P value is good from NSAID and Salicylate POV for skin permeation
NSAID: LogP between 2 and 5
Salicylate: LogP between 1 and 4
What are the factors that affect selection of drug candidates for TDD?
- Daily dose and potency – limit few mg/day
- Clearance kinetics: t½, Vd
- Physicochemical properties
> Partition coefficient
> Molecular weight
> Solubility in water and oils
> Melting point
- Tolerance, allergy, irritancy – any predictable problems?
What is the effect of half-life on the predicted plasma levels for a drug delivered transdermally?
Longer half life = increased plasma levels for a longer period of time
What are some indications for TDD patches? Include the drug names.
- Hormone replacement (testosterone, estrogens, progestogens)
- Angina (nitroglycerin)
- Pain relief (fentanyl, buprenorphine)
- Hypertension (clonidine)
- Motion sickness (scopolamine) –
- Smoking cessation (nicotine)
- Treat overactive bladder (oxybutinin)
- Depression (selegilene)
- ADHD (methylphenidate)
What are the types of transdermal delivery devices (passive systems)? What do all the devices have in common?
All devices are diffusion-controlled release
- Reservoir systems
- Matrix or drug-in-adhesive matrix systems
> TDD next generation e.g. Patchless patch system (Acrux, Melbourne)
For a TDD reservoir system;
A) What does it consist of?
B) How does it allow for constant release?
original TDD system design
A)
- Impermeable backing
- Reservoir of gel containing drug, solvent, enhancers, ant-irritants, gelling agent
- Release membrane controlling rate of delivery
- Adhesive
B)
Drug from reservoir slowly partitions into membrane and adhesive –> constant release
For TDD matrix/adhesive system;
A) What three layers is it composed of?
B) Initially what happens?
C) How does it compare to TDD matrix device?
A)
- Impermeable backing
- Core polymer matrix containing drug and penetration enhancer
- Release liner
B)
- Initial rapid drug release, slows as drug in matrix depletes
C)
- Sleeker and thinner than reservoir type
Provide examples of the following options for skin penetration enhancement
A) Formulation
B) Physical
C) Chemical
E) Penetration retarders
A)
Hydration/occlusion – Supersaturation – Ion-pair – Lipidation – Eutectic mixtures – Vesicles – Chaperons – Nanotechnology
B)
*Iontophoresis – Jet propulsion – Ablation – *Sonophoresis – *Microneedles – *Magnetophoresis – *Elongated microparticles
C)
Organic solvents – Azone – *Fatty acids, alcohols & glycols – *Surfactants – *Terpenes
D)
Barrier creams – Chemicals eg. N-0915
What are the main mechnanisms of actions of chemical skin penetration enhancers? Give examples of these drugs.
Increase diffusion coefficient
- Disorder the stratum corneum lipids eg. Azone, oleic acid, DMSO, terpenes, surfactants
- Extraction of stratum corneum lipids eg. ethanol, acetone, surfactants
- Denature protein in corneocytes
Increase drug solubility in skin
- eg. propylene glycol, ethanol, transcutol, N-methyl pyrrolidone
What is the influence of propylene glycol (drug solubility enhancer) on the permeation of ibuprofen from saturated solutions through rat skin
Increased flux
What is iontophoresis (electrical method)? what does it involve? Why is it used? AE?
small electric current (0.5 mA/cm2) applied to drug reservoir on skin surface
- Same charged electrode as solute to produce repulsion effect
- Drives solute away from electrode into skin; also electroosmosis effect – water movement
Why
- Numerous research applications – small drugs, peptides and proteins
AE
- Local erythema at site is common – release of cytokine, prostaglandin & other mediators, vasodilatation
What is an example of drugs and devcies used in iontophoresis?
- idoSite™ (Vyteris Inc.): lidocaine HCl and epinidrione –> 10 min application to reduce needle pain
- Ionsys™ (Alza è Incline Therapeutics Inc) –> Fentanyl for patient controlled analgesia (withdrawn due to corrosion)
- Zecuity™ (NuPathe Inc.): sumatriptan for migraine–> 6.5 mg sumatriptan delivered over 4 h
What is an example of drug and device used in sonophoresis?
- Sonoprep™ (Sontra) –> Lidocaine to reduce needle pain
- Prelude™ Skin Prep System
- Symphony™ CGM System
What is magnetophoresis? What is an example?
Application of magnetic energy
- Murthy et al – 10mT stationary magnet field
- Benson et al – time varied magnetic field with average 0.25mT (Dermaportation)
- OBJ Pty Ltd, Perth
> Pulsed electromagnetic field (Dermaportation: e- Skin™)
> Magnetic micro-array (ETP)
> Field in motion magnetic micro-array (FIM)
> Pharmaceutical, cosmetic, personal care, infection control/hygiene
How are micoroneedles/microarrays use for TDD?
Create physical pathway through the upper epidermis
- ≈600 μm length; ≈80 μm width at base
- Array of ≈3x3 mm
- Various microneedle designs
- Depth of insertion less than cutaneous nerves
> Potential for large proteins & peptides including vaccines
What are the types of microneedles/microarrays?
- Solid microneedles
- Coated microneedles
- Dissolvable microneedles
- Hollow microneedles
What are some other delivery systems?
- Nano-needles (nano patch) –> array of 1000s of vaccine coated microprojections
- Elongate microparticles (EMP: Foroderm)
