Biopharmaceutics of transdermal drug delivery Flashcards
What are the advantages of parenteral drug delivery?
- Improved control of onset of action, serum levels, tissue concentration, elimination
- Rapidity of action e.g. via IV administration
- Enhanced efficacy: via local delivery or for drugs that cannot adequately be formulated for oral administration
- Ease of use: can be administered to unconscious or uncooperative patients
- Increased compliance e.g. via depot injections or patches for contraceptives, mental health
- Local/targeted drug delivery can be achieved e.g. by creams, inhaler, local injection of anaesthetic
- Fall back route when oral route is not possible e.g. unconscious patient
- However, absorbance is still hampered by poor and/or variable blood flow
What is percutaneous drug delivery?
‘through the skin’: IM, IV, SC, ID
Which routes is volume limited for?
IM, SC and ID routes (can have larger volume for IV)
What does hypertonic mean?
Concentrated
Why are hypertonic formulations generally avoided for percutaneous drug delivery?
They will have as osmotic effect and draw water into the area (do not want this)
How is transdermal delivery limitied?
Due to the barrier to penetration across the skin, the stratum corneum layer of the epidermis (preventing drug penetration into vasculature)
What is a typical daily dose that can be delivered from a transdermal patch?
5-25 mg - limiting this route to potent drugs
How is maximal penetration of drugs into the SC achieved?
- choice of drug and formulation or delivery vehicle (potent)
- modification of the stratum corneum (penetration enhancers)
What powered penetration enhancement devices can be used?
iontophoresis (electric current through skin), phonophoresis and electroporation patches
What are the different routes of penetration for transdermal delivery?
o Directly across the stratum corneum (major route)
o Through the sweat ducts
o Via the hair follicles and sebaceous glands
- Routes 2 and 3 only 0.1% due to a very small surface area. They use iontophoretic drug delivery as these routes offer less electrical resistance than SC
What is the thickness of the Stratum Corneum (SC)?
10-15 µm (when dry) to 40µm (hydrated – swells in the presence of water)
What is the SC layer made up of?
o Cells: 10-15 layers of keratin-rich corneocytes: polygonal “bricks” 0.2-1.5µm thick, 34-46µm in diameter
o Mortar: intercellular lipid matrix extruded by keratinocytes and includes long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters
How are hydrocarbon chains arranged in the SC?
o Hydrocarbon chains arranged into crystalline, lamellar gel and lamellar liquid crystal phase domains within lipid bilayers
o First few layers rearrange into broad intercellular lipid lamellae
What is essential to prevent cracking of the SC?
Water is essential as a plasticiser
What can drugs and excipients be hydrolysed by?
enzymes in the skin e.g. esterases, which can affect absorption
Which route has the majority of absorption?
Intercellular route
What characteristics does the intercellular route have?
- Lipid matrix made up of alternate regions of lipid and aqueous layers (lipid lamella)
- Drug must be lipid soluble - or formulated as such
What is the transcellular route?
More hydrophilic drugs penetrating aqueous regions of keratin filaments, BUT must also traverse intercellular lipid region
What is Fick’s law of diffusion?
J= (DC0P)/h
o J is steady state flux
o the diffusion coefficient (D) of the drug
o the diffusional path length or membrane thickness (h)
o the partition coefficient (P) of the drug between the skin and vehicle
o the drug concentration (C) applied (assumed to be constant)
What is an ideal logP in octanol/water?
1-3
What characteristics does a typical transdermal patch include? (7)
- Drug: molecular weight < 1000 Daltons & preferably less than 500 Da
- Melting point < 200oC
- Log P between 1 and 3
- No or few polar centres, like carboxylate or zwitterionic structures
- Kinetic half-life < 6-8 hours (transdermal delivery device mimics IV drip, maintains therapeutic concentrations of drug with a short half-life)
- 50 cm2 maximum patch size
- 5-20 mg per day usually maximum feasible dosage
What can be done to the drug/vehicle to enhance permeation?
o Pro-drug – e.g. esters: reducing amount of charged centres, introducing lipophilic groups that enhance permeation through the skin
o Ion pairs, complexes – 2 molecules with charged centres: create ion pair to reduce charge associated
o Chemical potential (thermodynamic methods)
o Eutectic systems – promotes permeation
o Liposome or vesicle-based formulations
o Optimal permeability: low MW for higher diffusion; low MP
o E.g. nicotine, nitroglycerine
How can the SC be manipulated to enhance permeation?
o Hydration – as more water is applied toe the skin, more stratum corneum layers swell up and separate, enhancing drug delivery
o Lipid fluidisation – fluidise lipid lammalae
o Powered electrical devices:
- iontophoresis
- phonophoresis
- electroporation
When is maximum skin penetration rate achieved?
When the drug has the highest thermodynamic activity e.g. when in a supersaturated solution, produced by evaporation of solvent or by mixing co-solvents
- highly concentrated
- supersaturates - same amount of drug dissolved in less solution
What is the most common mechanism seen clinically for supersaturation?
evaporation of solvent from the warm surface of the skin, resulting in supersaturation; this occurs in many topically applied formulations
How can we get the thermodynamic activity of the drug to increase by 5-10 times?
If water is absorbed from the skin into the vehicle and acts as an anti-solvent, the thermodynamic activity of the drug increases flux by 5-10 times
Are supersaturated systems stable?
NO - inherently unstable and require the incorporation of anti-nucleating agents to improve stability. (lipids already present in the SC, contribute towards anti-nucleating effects)
What can provide an anti-nucleating effect?
Complex mixtures of fatty acids, cholesterol, ceramides in the stratum corneum may provide an anti-nucleating effect, thereby stabilising the supersaturated drug formulation
What is a Eutectic mixture?
2 components that at a certain ratio, inhibit cystallisation of each other, thus the melting point of both components is decreased
What is the structure of a crystal and what impact does this have on melting point?
In a crystal, there is a highly organised structure, therefore a lot of energy needed to disrupt the structure so a drug with a crystalline structure would have a high melting point
What will happen if you inhibit the crystalline structure?
If you inhibit the crystalline structure, less energy is needed for the drug to undergo a phase change – and therefore will have a lower melting point
What relationship is there between melting point and solubility?
The lower the drug’s melting point, the greater the solubility in a given organic solvent, including skin lipids - melting points can be reduced to below or around skin temperature to enhance drug solubility and penetration through the skin
What do various eutectic systems contain as the second component?
A penetration enhancer to interact with the SC lipids - e.g. ibuprofen formulated with terpenes (penetration enhancer that fluidises the lipids), methyl nicotinate with menthol, propranolol with fatty acids, lignocaine with menthol
What is penetration enhancer activity expressed as?
Enhancement ratio (ER)
ER = (drug permeability coefficient after enhancer treatment) / (drug permeability coefficient before enhancer treatment)
How is ER achieved?
o Disruption of the intercellular lipid lamellar structure (fluidising and making easier for drugs to diffuse through)
o Interactions with intracellular proteins of the stratum corneum
o Improvement of partitioning of a drug, with a co-enhancer or co-solvent penetrating the stratum corneum
What is used to increase skin penetration of hydrophilic and lipophilic compounds, and how does it do that?
Water:
o Alters drug solubility and partitioning
o Increases skin hydration, swelling and opening of the SC structure, leading to increased penetration (more channels and routes available)
o Diffusion coefficients of alcohols are 10x higher following hydration
What is the water content of the SC dry weight?
15-20%, varies with external environment including medications by:
o Occlusion with transdermal patches, plastic films, paraffins, oils or waxes as components of ointments and water-in-oil emulsions that prevent transdermal water loss
o Oil-in-water emulsions that can donate water into the skin
How is hydration achieved?
o Donating water to skin (o/w emulsions)
o OR Preventing water from evaporating off the skin (transdermal patches or films or w/o emulsions – creating a barrier to trap water in and maintain hydration)
What aids lipid nanoparticle penetration through the SC
Their small size
What can hydrate and/or alter lipid layers?
Liposomes, especially when lipids are similar to SC lipids: they can readily enter and fuse with SC lipids
o triamcinolone acetonide liposomal lotion penetrates 4 - 5X more effectively than the ointment formulation
What do deformable liposomes or transfersomes contain?
contain 10-25% surfactant (e.g. sodium cholate) with 3 -10% ethanol (combination of both makes very fluid and can squeeze through small gaps in the SC)
What do deformable liposomes or transfersomes act as?
act as “edge activators”, conferring deformability and allowing them to squeeze through channels less than one-tenth the diameter of the transfersome
What are Ethosomes ?
their high alcohol content fluidises lipids
What are Niosomes?
vesicles composed of non-ionic surfactants
What are solid lipid nanoparticles (SLNs)?
carriers for enhanced skin delivery of sunscreens, vitamins A and E, triptolide, glucocorticoids - consist of an almost perfect, solid lipid matrix (more rapid release) - forces encapsulated drugs to the surface of the particle
What are nanostructured lipid carriers (NLCs)?
composed of solid lipid matrix immersed in liquid lipid (oil) droplets (more sustained release)
What does the SLN act as as apposed to the liquid NLC?
The solid lipid acts as a matrix to immobilize the drug and prevent nanoparticles from coalescing, whereas the liquid lipid component increases the drug loading capacity
What drug release is observed in NLCs?
- Rapid drug release from the surface of the particles is therefore observed In NLCs, the mixture of lipids of different phases forms an imperfect lipid crystal lattice
- Thus, more drugs can be encapsulated and rapid surface release is prevented
How can skin permeability be increased?
By disrupting the structure of the SC?
How can keratin in the SC be disrupted?
Keratin can be disrupted using decylmethylsulphoxide, urea or surfactants
How can lipids in the SC be fluidised?
o Lipids can be fluidised using DMSO, alcohols, fatty acids, terpenes
Excipients can mix homogeneously with skin lipids, changing drug solubility
Excipients can extract skin lipids, leaving aqueous channels or microcavities within the lipids e.g. oleic acid and terpenes
At a high concentration, excipients pool within the lipid domains to create permeable pores that provide less resistance for polar molecules
What is optimal penetration enhancement achieved with?
optimal penetration enhancement is obtained with saturated alkyl chain lengths of C10 to C12 attached to a polar head group, or C18 for unsaturated alkyl chains
What is a disadvantage of penetration enhancers?
Many cause skin irritation
What is Powderject?
Needle-free injector:
- gas burst acceleration of powdered drug particles to supersonic speeds
- used for highly potent drugs (e.g. HepB)
- uses helium gas to propel drug particles through the skin
What are microneedle patches?
• The stratum corneum is pierced with short needles to deliver drugs into the skin in a minimally invasive manner
• Drugs include small molecules, proteins and nanoparticles, released from extended-release patches
• Microneedles:
o increase skin permeability by creating micron-scale pathways in skin (physical damage)
o force of needle entering the skin, actively drive drugs into the skin during microneedles insertion
o target the stratum corneum, although microneedles typically pierce across the epidermis and into the superficial dermis too.
• Examples: naltrexone, parathyroid hormone, vaccines
What are the different types of microneedle?
- solid microneedles
- hollow microneedles
- rapidly separating microneedles
- drug-coated microneedles (then pierce skin)
- dissolving microneedles containing drug (made from biodegradable polymer – pierce skin and when in contact with biological fluids in which they dissolve. Polymeric – will cause minimal skin irritation)
Explain Iontophersis (powered patch)
• Iontophoresis uses low-voltage current to increase permeability of:
o Charged drugs
o Weakly charged and uncharged drugs, by increasing the electrosmotic flow of water, because of mobile cations e.g. Na+ and fixed anions e.g. keratin
• The rate of delivery increases with electrical current, which is controlled by a microprocessor or the patient, to enable personalised delivery
o The maximum current, and therefore delivery rate, is limited by skin irritation and pain
o Iontophoresis provides control over drug dosing, because delivery is proportional to the amount of charge i.e. it is the product of current and time.
Explain electroporation (powered patch)
- Electroporation is used with microneedle patches
- Short, high-voltage electrical pulses reversibly disrupt cell membranes and skin lipid lamellae in the stratum corneum (SC)
- The electro-pores created persist for hours and increase diffusion by orders of magnitude for drugs, peptides, protein, DNA.
- The SC has a higher resistance than the deeper tissues; resistance drops dramatically upon application of the electrical field
- The electrical field distribute into the deeper tissues which contain sensory and motor neurons
- Associated pain and muscle stimulation are avoided by using closely spaced microelectrodes, that constrain the electrical field to the SC.
Explain phonophoresis (powered patch)
- Ultrasound: an oscillating pressure wave at a frequency too high for humans to hear
- It can be used to enhances skin permeability to small, lipophilic compounds by disrupting the lipid structure of the stratum corneum
- Low-frequency ultrasound causes formation, oscillation and collapse of bubbles
- Cavitation energy at the site of bubbles causes small holes to form in the skin; this enhances delivery of lidocaine, insulin, heparin and tetanus toxoid vaccine through the skin
- Pulsed lasers can also increase skin permeability using a related shockwave mechanism
