Transdermal drug delivery Flashcards
What are the advantages and disadvantages of transdermal drug delivery
Advantages:
-Avoids hepatic first pass metabolism – !Skin Metabolism!
-Avoids pain associated with injections
- Continuous “Sustained Release” drug delivery with infrequent dosing
- Permits self-administration – Vaccines
- Non-invasive (no needles or injections) – Needle injuries /contamination
- Improves patient compliance
- Reduces side effects
- Allows removal of drug source
Patient preferred
Disadvantages
- Potent drugs only (few mg/24 hours)
- Lag Time (not good for acute conditions)
- Development of tolerance
- Poor diffusion of large molecules
- Allergic and Irritant reactions
What are the routes of transdermal drug absorption
Transcellular:
>Water soluble
> 25m diffusion path lenght
>Delivered through lipid structure of SC and corneocytes
Intercellular:
>Lipid-soluble drugs
>0.70% of relative surface are 350 m diffusion path length
>Drug diffuses through endogenous lipid within SC
Trans follicular:
>Via the pores
>0.10% of relative surface are 200 m diffusion path length
What are the formulation principles
Select a suitable drug
Release the drug
>Vehicle should not retain drug
>Appropriate release
>If lipophilic drug in lipophilic base then drug will stay in formulation, aqueous base more suitable
Use thermodynamics
> concentration gradient in favour of the drug -Near saturated solution
>
Alcohol can help
>Partitions into skin and provides transient reservoir for the drug
>Good solvent but evaporates from skin
Occlusion
>cover skin by blocking trans epidermal water loss
Fundamentals of skin permeation
passive diffusion process that can be described by the Fick’s law of diffusion (conc gradient)
What is fick’s first law
J = { DP / h} Cv = kp Cv
J = flux
D = apparent diffusivity in stratum corneum
P = SC / formulation partition coefficient
h = thickness of the barrier
Cv = Concentration in vehicle (donor solution)
kp = Drug’s permeability coefficient across the skin
(is formulation dependant)
What is lag time
The time period that is required to reach therapeutic level
LT=h2/ 6D
What is a steady state flux
It determines whether therapeutic levels can be reached
Examples of transdermal drugs
Buprenorphine
Fentanyl
Nicotine
Ethinyl
What are the general formulation options for transdermal formulation
general
>Semi-solid formulation: Increase residence time
> Patch: extend drug delivery through skin
> Liquid formation: Rapid short term input to permeate the skin
Skin type >Normal to oily: gels >Normal to dry: lotions >dry skin: creams >Skin site -Hairy: lotions, gels, and sprays
What are the clinical rationales that dictate topical choice and what are those choices ?
Wet, vesicular or weeping lesions: Aqueous base formulations
- Hydrophilic drugs: include water and a co-solvent but avoid alcohols - Hydrophobic drug: Mineral oil or aqueous co-solvent but avoid alcohol
Dry, thickened scaly lesions: fatty formulations such as ointments or pastes
-Oil and waxes which include surfactants and glycol depending on formulation and drug solubility
For delivery to the skin what are the formulation options
Aqueous or oil based: isopropyl myristate, propylene glycol
For delivery through the skin what are the formulation options
Aqueous or oil based formulation: alcohols, glycols, oleic acid (can be a combination)
Combination of solvents
Alcohol may enhance delivery
How can transdermal drug delivery be enhanced
increase flux
>Skin barrier properties: increase diffusivity
>Nature of permeant to increase partition
> increase conc. of the drug in the vehicle/ formulation
>Select thin skin to put the patch on
When is maximum flu achieved
At saturation
what does it mean to be super saturation
Supersaturated solution is where drug is present in excess of solubility
How can a formulation be manipulated to enhance it’s uptake
-Partitioning can be encouraged into the SC by using a vehicle in which drug is only moderately soluble
- Active should have appropriate physicochemical properties
>Enhances partitioning in lipophilic SC
>Ester-linked fatty acids can help and link can be cleaved in skin by esterases liberating the active
-Control over pH can ensure that neutral compounds are maintained that permeate better
>Ion-pairing agents can also assist
What is an adhesive patch
- It is one layer of drug contained in an adhesive polymer
- Has a reservoir of high loading capacity
- Degree of control is small and the ultimate control barrier is the stratum corneum
What are layered patches and how do they work
- They have a different polymer composition/different polymer to provide drug containing matrix
- Made of one or more sub-layers
- can increase drug content in the system or control drug release for longer delivery
-Main drawback is the area of contact between patch and skin is larger than the active area
What is a reservoir patch and how does it work
- it is pioneered from Alza
- A reservoir of the drug in a lipid state and a polymer membrane separating the reservoir form the adhesive tape
- the membrane acts a rate-controlled element
- Patch should be a reasonable size
What are the component in a patch
- Release liner
- Adhesive
- Backing layer
- Matrix/reservoir
- Rate-limiting membrane
-Release liner properties
- Temporarily covers adhesive layer and is removed
- Made from polymers: Ethylene vinyl acetate, aluminium foil
- Must easily peel away but bond firmly to prevent accidental removal
- Prevent loss of volatile component
Adhesive components properties
- Crucial to TDDS
- Pressure sensitive adhesive used: Acrylates, polyisobutylene, polyoxane
They must:
- Stick to the skin for the patches lifetime
- Non-irritating and non-allergenic
- Compatible with drug and to other excipients
- Presence of drug can affect properties and is only seen in vivo
Backing layers properties
There are many materials depending on design, size and length of use
Relatively short use small patches- occlusive backing layer
> Hydrates skin, improve drug absorption (polyethylene or polyester films)
Larger longer use patch may allow vapour transmission - polyvinylchloride films
Backing layer should allow multidirectional stretch, pliable to move with the skin
Matrix/reservoir properties
- prepped by dissolving drug and polymer in common solvent before adding plasticizer
- Viscosity modified by conc of polymer or by cross-linking chains in matrix.
- Reservoir have viscous liquid: silicone or co-solvents system occasionally with ethanol
Rate limiting membrane properties
- Transdermal patches were originally designed to control rate of delivery of active ingredient
- Membrane must be compatible with the drug, non-toxic, stable and pliable
- separate reservoirs from underlying adhesive or multiple drug-in adhesive- layers
Examples of rate controlled transdermal delivery
Clonidine
>Potent anti-hypertensive , well absorbed in GI tract, long half-life, modest clearance
>Induces immunological skin reaction
>Transdermal patch to reduce side effects and patient compliance
>Reservoir type
Oestradiol
>High hepatic first-pass effect results to an unfavourable ratio of estrone to the drug itself
>Sustained plasma concentrations with transdermal application
>First patch a reservoir worn for 3 up to 4 days
What determine the rate control of transdermal ddrugs
determined by the area of contact between patch and skin
Factors of rate control in transdermal delivery
> Transdermal delivery can be achieved by adjusting the size of the system
delivery is not so sensitive to the loading of the patch especially when the input rate is controlled by the skin
design of a patch does not guarantee that it will control the delivery rate
Advantages of transdermal opioid therapy
> Peaks and troughs avoided which would lead to side effects
reduced need for dosage administration
Fentanyl and buprenorphine unsuitable for the treatment of acute pain
Fentanyl TDDS
- Soluble in both fat and water with low MW and high potency
- Designed at 4 constant rates
- steady-state serum concentration is reached after 24 h and maintained as long as the patch is renewed.
- Durogesic® reservoir patch is mostly phased out and replaced with Durogesic® Dtrans®—a matrix design
Skin modifications done to enhance penetration
Penetration enhancers disrupt the highly organised lipid layer by:
> Interacting with cellular proteins
Increasing partitioning into the membrane
Penetration enhancers should be
- Pharmacologically inert
- Modify skin barrier in a reversible manner
- Non-toxic
- Non- irritating
- Compatible with drugs and excipients
- Acceptable to patients (good skin feel, odourless, colourless etc
What are chemical permeation enhancement
Compounds that promote skin permeability by altering the skin structure
mode of actions of chemical permeation enhancement
- Increasing the fluidity of the SC lipid bilayer
- Interaction with intercellular proteins
- Disruption or extraction of intercellular lipids
4 .Increasing the drug thermodynamic activity - Increasing the SC hydration
List the some examples of chemical permeation enhancement
Solvents alkyl-esters, dimethyl sulfoxide, pyrrolidine
Surfactants- sodium lauryl sulfate, SDS
Fatty acids-oleic acid, undecanoic acid, linoleic acid
Alcohols-octanol, nonanol
Terpenes-menthol, limonene, thymol
Lactam-laurocapram (Azone)
Chemical permeation enhancement
Water: safest and most widely used
Transdermal flux in most through hydrated skin compared to dry tissue
Occlusion is an effective means to increase permeability
Ethanol and other low MW alcohols:
Ethanol can disrupt the intercellular lipid packing and increase diffusivity but can also diffuse into membrane act as solvent within SC into which drugs can easily partition
Dimethyl sulfoxide (DMSO): can interact with lipid bilayer head groups and disrupt close packing
Fatty acids e.g. oleic acid: insert along the SC lipid chains to disrupt packing
Azone: posesses and bulky polar head group and lipid chain
Can insert with in the lipid lamellae and disrupt at both head groups and chains
Terpenes (fragrance agent) and surfactant
What is a jet injector
What is microporation
It is a way to overcome the skin barrier and is based on the formation of the micropores into the stratum corneum
Microchannels forms by external means: Microneedles, ultrasound, Electroporation, radiofrequency and lasers
What are the mechanical approaches to transdermal drug delivery
Tape striping: Remove stratum corneum using single adhesive tape
Microneedles: Multiple microscopy projections on one side of the patch
>Length: 25-200 um
>Based width: 50-250 um
>Tip diameter: 1-25 um
What are microneedles
They are needles that are painless, and are strong dermal permeabilization
They are long enough to perforate top layer of the epidermis but too short to activate nerve endings
Skin recovers barriers within 3-4 hours
Examples of microneedle medications
Naltrexone which are administered to avoid first pass metabolism
What are other available microporation techniques available
> Sonoporation (low frequency ultrasound cavitation):
Thermal ablation: (Heating sources such as laser, radiofrequency)
Iontophoresis (application of electrical currents)
Electroporation (high voltage pulse)
- human growth hormones (radiofrequency),
- gene transfer (laser), insulins (sonoporation, electroporation, laser),
- vaccine (sonoporation, electroporation).
Describe the process of iontophoresis
Skin patches that use 0.1-1mA /cm Squared of electrical currents for mins - hours
Increases speed / rate of delivery
>Lidocaine, fentanyl, migraine drugs
Rate = applied constant current
amount of drug delivered is determined by the maximal current applied before the pain level is reached.
NOT USED FOR LARGE MOLECULES
Examples of iontophoresis
Glucowatch: Reverse iontophersis
ALZA E-TRANS: fentanyl
Describe Electroporation
Pores are formedthrough the application of short and high voltages, 50-500 volts
proper designed systems can minimise sensation for the voltage pulse and facilitate drug delivery,especially of hydrophilic and charged molecules into the skin
Small and higher MW can be delivered
what is a disadvantage/draw back of electroporation
Main drawbacks are the lack of quantitative delivery,cell death with damage of proteinsand, thus, the bioactivity
Describe sonophoresis
Ultrasound is an oscillation sound pressure waveand can be used to transport drugs across the skin.
>include thermal effects, as well as cavitation effects
20 kilohertz to 60 megahertz
Delivery of drugs independently of charge and size
High-intensity ultrasounds can cause second-degree burns,limiting the delivery of many macromolecules
What is the thermal approach to transdermal drug delivery
stratum corneum is selectively depletedat the site of heating without deeper tissue damage
> Short exposure prevents damage
