W24 Transdermal drug delivery l, ll and lll (AM) Flashcards
What is the aim of transdermal drug delivery?
Aim is to get the drug across the stratum corneum (difficult) and viable epidermis (easier) and then be taken up by systemic circulation
Why is the transdermal route desirable? (8)
- Avoids first pass metabolism
- Controlled rate of drug delivery (avoids peaks/troughs)
- Avoids GI problems (irritancy, pH, adsorption…)
- Can be administered by the patient
- Favoured by patients
- Reduces dosage frequency = improves compliance
- Rapid identification of drug in emergencies
- Compared to depot injections, less painful and drug input readily terminated
What are the challenges to TDD? (8)
- Skin is a very effective barrier – only potent drugs suitable
- Skin is metabolically active so drugs metabolised by skin / bacterial enzymes
- Unsuitable for irritant drugs / excipients
- Pharmacokinetic limitations
- Small volume of distribution required
- Lag-time
- Tolerance induced by constant plasma levels
- Transdermal formulations more expensive to manufacture
What are some Common drugs administered by TDD?
- Hyoscine (or scopolamine) – used as an anti-emetic so need to avoid oral route – first transdermal patch launched in 1979
- Nicotine – used as a smoking cessation aid to deliver a constant amount of nicotine to the blood
- Opioids (fentanyl, buprenorphine) – not well absorbed orally. Patient may also have issues with swallowing if palliative care
Hyoscine
MW = 303 Da
Log P = 1.31
Nicotine
MW = 162 Da
Log P = 1.17
Fentanyl
MW = 336 Da
Log P = 2.9
Buprenorphine
MW = 468 Da
Log P = 3.6
- Glyceryl trinitrate (GTN, nitroglycerin) has an oral bioavailability of 1%
- Rivastigmine used in mild to moderate Alzheimer’s disease – oral route can cause nausea and vomiting
- Hormones (oestrogens, progestogens, testosterone) are used in HRT – reduced GI side-effects and blood clotting
GTN
MW = 227 Da
Log P = 2.15
Estradiol
MW = 272 Da
Log P = 2.7
Levonorgestrel
MW = 312 Da
Log P = 3.55
Rivastigmine
MW = 250 Da
Log P = 2.5
So what are the ideal properties of transdermal drugs? (7)
Molecular weight < 500 Daltons
Log P 1 to 3.5
( these 2 are most important)
Potency High – oral dose of < 20 mg / day
Drug charge =Neutral at skin pH (- 5.5)
Aqueous solubility > 100 μg/ml
Biocompatibility =Non-irritant to skin
Diffusivity= High permeability coefficient
There should also be pharmaceutical or clinical reasons for using this route
What method is used in TDD evaluation? (lab based)
What apparatus?
- In vivo is the gold standard, i.e. TDD followed by analysis of blood samples or microdialysis
- Franz-type diffusion cells are most commonly used
Structure:
* Door compartment, Sampling port, Receptor compartment, Magnetic stirring bar
* Sample quantified by HPLC, LC-MS
What are the features of a permeation profile graph?
Y axis: Cumulative amount permeated (mg/cm2)
X axis = Time (hours_
Steady state flux= Gradient (amount/area/time)
Lag time
TDD evaluation: Calculating gradient
What eq is used?
What are the units for flux?
Gradient = (y2-y1)/(x2-x1)
Flux units = mg / cm2/hours
Flux units = mg / cm2 / h
Flux units = mg cm-2 h-1
Evaluating TDD- Fick’s Law
What is Fick’s law?
What is the equation?
- Diffusion is complex but mathematical models can be used to describe/ model permeation
- Fick’s first law of diffusion can often be used to describe the passive diffusion of a permeant (drug) across skin at steady state
J=Kp xCo
Where:
J = flux of the permeant (calculated experimentally)
Kp = permeability coefficient
C0 = permeant concentration in the donor
phase (formulation) - The permeability coefficient (Kp) is an important parameter for a drug
- It has the units of distance per unit time, i.e. cm / s or cm s-1
Evaluating TDD: example question
A drug dissolved in an aqueous gel was applied to the skin over an area of 18.0 cm2. If the concentration of the drug in the solution was 250 ug cm-3 and the permeability coefficient (Kp) of the drug was 7.56 x 10-7 cm s-1, what amount of drug would have permeated the membrane over a 24 h period?
J = Kp × C0
J= 7.56 x10-7 x 250
= 1.89 x 10-4 ugcm-2s-1
Amount permeated = 1.89 × 10-4 × 18.0 × (60 × 60 × 24)
Amount permeated = 294 ug (or 0.294 mg)
Is there a way to predict the permeability coefficient? (Kp)
- Published transdermal in vitro permeation data has been used to predict the permeability coefficients (Kp) of other drugs
(mathematical models)
Predicting TDD (for info) l
- Mathematical models are often used in pharmaceutical sciences to predict physical properties (melting/ boiling points, solubilities, log P values)
- Can also be used to predict pharmacokinetic properties, e.g. absorption
- Published transdermal in vitro permeation data has been used to predict the permeability coefficients (Kp) of other drugs
- Gordon Flynn produced a dataset of drug delivery data (n=94) that had used similar experimental conditions
Predicting TDD (for info) ll
- Multiple authors have performed regression analyses on this dataset to try and predict Kp – Potts & Guy is the most well known:
log Kp = 0.71 log P – 0.0061MW – 2.74 - These are referred to as QSARs- quantitative structure activity relationships
- If we know (or can predict) the log P and MW we can also predict the Kp
- Although a wide margin of error (Potts & Guy QSAR r2 = 0.69) we can at least have an approximate idea of likely success using transdermal delivery
TDD enhancement
* To increase the number of drugs deliverable transdermally (or topically) which various enhancement techniques have been used? (3)
- (1) Formulation manipulation
- (2) Skin modification
- (3) Physical methods/ external forces (Lecture 3)
What is meant by formulation manipulation?
- Switching to an occlusive formulation or employing a cosolvent are two examples already seen
- Supersaturation is the ultimate example of increasing the drug concentration
- Although inherently unstable, formulation techniques, e.g. increased viscosity can prevent crystallisation
TDD enhancement: skin modification
What are Penetration enhancers?
- Penetration enhancers are compounds that increase the rate of diffusion of a permeant through the skin – usually act on the Stratum Corneum
What are the different ways that penetration enhancers can exert an effect?
- (1) Disruption of the highly ordered multiple lamellar lipid arrangement
- (2) Interaction with intercellular proteins
- (3) Increasing partitioning into the skin
What are the ideal properties of a penetration enhancer? (5)
- Non-toxic & non-irritant
- No pharmacological activity
- Act rapidly, reversibly and unidirectionally
- Compatible with drugs and excipients
- Cosmetically acceptable to patients
TDD enhancement: skin modification
What are examples of common penetration enhancers
What are their subsequent likely mode of action?
- Water: Swelling of corneocytes = disrupting lipid lamellar “mortar” layer
- Ethanol and other alcohol= Disrupts order of lipid lamellar layer. Possible partitioning effects
- Small aprotic molecules, e.g. DMSO: nteraction with polar head groups in lipid
lamellar layer = disrupts order - Fatty acids: Insertion into bilayers. Kinked structure disrupts packing
- Bespoke enhancers, e.g. Azon= Insertion into bilayers. Disruption at head and chain regions
- Surfactants= Depends on nature, i.e. anionic, cationic, non-ionic, but have effects on bilayers and keratin
What are the 4 elements common to all transdermal patches/ TTS
- Drug
- Adhesive
- Backing layer
- Liner
Drug:
* The amount of drug delivered can be controlled by the drug loading, i.e. concentration, in the patch and the size (area) of the patch
J = Kp × C0
Flux units = mg / cm2 / h
TTS: adhesives
* Which following requirements do they have to meet?
- The adhesive is a critical component of the TTS
- Non-toxic and non-irritant
- Keep patch in place for duration of treatment
- Compatible with drug + excipients
- Allow bathing but also removeable (painlessly)
- Pressure sensitive adhesives (PSAs), i.e. adhesion is proportional to the degree of pressure applied
- Typically acrylic or rubber based – need to consider chemical nature of the drug / excipients
TTS: backing layer
What requirements does it need to meet?
- Backing layer protects formulation before and during use:
- Needs to be strong but also permit multidirectional stretch
- Can be opaque or clear
- May be occlusive for shorter duration use (polyethylene or polyester) but permeable for longer use (PVC)
- Should not interact with the drug or other excipients
What are the 3 types of TTS?
- Drug in adhesive patch
- Drug in matrix patch
- Rate limiting membrane patch
TTS: Liner
What requirements does it need to meet?
Liner is removed, i.e. peeled away, prior to the patch being used:
- Should be easily removed by the patient
- Polymeric or aluminium foil
- Compatible with the formulation (particularly the adhesive)
- Usually occlusive to prevent loss of volatile adhesive components
What is the most common type of TTS?
TTS: drug-in-adhesive patch
* Drug is incorporated within the adhesive that attaches the patch to the skin
* The adhesive layer is crucial since it attaches the formulation to the skin and contains the drug and all the excipients
* Very widely used – particularly for nicotine and estradiol delivery
What is a Drug-in-matrix patch (TTS)
- Drug is incorporated in a separate matrix which may be in direct contact with the skin or drug may also have to permeate adhesive layer
- Can be formulated to provide controlled release
- Matrix may be polymeric or hydrogel-based
- Loading dose may be included
What is a rate-limiting membrane patch? (TTS)
- Rate-limiting membrane controls release of drug from a liquid or gel reservoir
- Membrane is usually polymeric – poly (ethylene-vinyl acetate) often used
- Addition of plasticizer alters permeability characteristics
Transdermal formulations (for info)
- TTS (transdermal patches) are useful for delivering a defined dose of drug
- Semi-solid dosage forms – often gels – are an alternative transdermal formulation that allows the dose to be varied by control the area of skin to which the semi-solid is applied
Summary (for info)
- Mathematical models constructed using in vitro permeation data have been used to predict permeability coefficients (Kp)
- Penetration enhancers can be used to increase the rate of diffusion of a permeant through the skin
- A majority of such enhancers act upon the stratum corneum –lipid or cellular domains
- There are many types of transdermal therapeutic system but they all contain: drug, adhesive, backing layer, and liner
Name the Physical methods for enhancing transdermal drug delivery? (4)
- Electroporation
- Sonophoresis
- Microneedles
- Iontophoresis
What is Electroporation?
- Technique pioneered in microbiology to create transitory pores in cell membranes
- Discovered that this approach can be applied to the stratum corneum to create pores of < 10 nm
- High voltage electrical current (10 – 1000 V/cm-1) is applied to the skin for very short periods, i.e. us to ms
- Number of pulses, duration and amplitude,
i.e. voltage, all appear to be key parameters - Delivery of high MW drugs and vaccines has
been demonstrated with electroporation
How exactly is transdermal delivery enhanced? (2) using high voltages
What are the challenges involved?
- Electrophoresis= Principal mechanism for
charged permeants –occurs during the high
voltage pulse - Molecular diffusion= Occurs during the pulse, but also continues for hours afterwards. Suggests that pores remain for an extended period
- Electroporation shown to enhance insulin transdermal delivery 20-fold
- Challenges include pain/ discomfort, skin irritation and lasting changes to the SC
What is Sonophoresis?
What are the 2 enhancement mechanisms?
- Sonophoresis (or phonophoresis) uses ultrasound to modify the SC multiple lamellar arrangement
- Low frequencies are used: 20 kHz–16 MHz
- Enhancement mechanisms rely on:
1. Thermal effects = skin temperature increases by 20 °C
2. Cavitation = cavities and bubbles are created at corneocyte-lipid interface and this disrupts the SC - Coupling medium transfers ultrasonic energy from the transducer/probe to the skin
Sonophoresis (for info)
- Significant enhancement demonstrated with many drugs (including macromolecules)
- Park et al note 46 transdermal sonophoresis studies in their 2014 review article
- Synergistic effects also shown with other techniques, e.g. iontophoresis
- Challenges include the development of small and inexpensive devices coupled with the unknown longer-term effects
What are Microneedles?
What are they produced from?
- These are needles in the micron size-range – typically between 25 um and 2000 um
- Produced as “arrays”, i.e. multiple microneedles on a single device
- Long enough to puncture the SC but not so long that they trigger nerves in the dermis
- Create channels through the SC which facilitate TDD
- Prepared from numerous materials (silicon, tungsten, glass, polymers)
Microneedles:
What are the 5 different approaches taken to microneedle design and usage?
(1) Solid microneedles- array is applied to skin for few minutes, remove
(2) Coated microneedles
(3) Hollow microneedles
- attached to drug resevoir which means drug can permeate through epidermis + dermis
(4) Dissolving microneedles
(5) Hydrogel microneedles
Features of hydrogel microneedles?
What have they been trialed to treat?
- A fifth newer microneedle design are the hydrogel microneedles – these needles are designed to swell after the array has been placed on the skin
- Successful TDD of hydrophilic and high MW substances including peptides, proteins and vaccines
- Trials have also examined topical drug delivery for treatment of plaques in psoriasis patients
What are the challenges of microneedle usage? (4)
− Microneedle geometry and physical properties (including strength)
− Challenging and (currently) expensive to produce
− Risks of long-term damage to the skin are unknown – some tips also remain
− Risk of microbiological contamination – left with a biohazard
What is Iontophoresis?
- Involves the use of (low) electric current to drive drugs across the stratum corneum
- SC has high electric resistance so drugs/ions move in the epidermis and dermis
- If the drug was anionic then it would be placed at the cathode
- Drug removed to systemic circulation before reaching the oppositely-charged electrode
Iontophoresis
- Clear how charged drugs can be delivered, but iontophoresis can also enhance delivery of neutral drugs. How?
- Convective fluid flows are caused by electroosmosis (movement of ions and H2O) and this can “drag” uncharged molecules through SC
- Transappendageal routes, e.g. sweat ducts, are believed to be important permeation pathways
- Iontophoresis more efficient for cationic drugs – the skin is negatively charged at physiological pH due to keratin
- Flux is proportional to the current that is applied (but this is limited by skin tolerance: up to 0.5 mA/cm2)
Iontophoresis: Issues around iontophoretuc devices?
- Iontophoresis can provide rapid and
controllable systemic blood levels… but - Despite showing promise there are currently no commercially available iontophoretic devices on the market
- Ionsys (fentanyl) was approved for use but
withdrawn soon afterwards due to issues
around device self-activation - Other generic challenges to iontophoresis
include device size and cost, erythema and
that electrical current can be noticeable
What is Reverse iontophoresis?
Example of device that uses this?
- Can be used to extract drugs or biomolecules (from the dermis) through the skin
- Potential for needle-free blood monitoring for diagnostic or therapeutic purposes
- Has been demonstrated for charged and uncharged (glucose) molecules
- GlucoWatch G2 Biographer was launched in 2002 and could provide real-time blood glucose levels every 10 mins
- Calibration required, so not completely needle-free
- Withdrawn in 2007 due to issues around
accuracy and skin irritation
Glucose monitoring:
How does the freestyle libre device work?
- Real-time glucose monitoring has however is now commercially successful
- FreeStyle Libre device has been recommended by NICE
- Subcutaneous rather than transdermal
-Disposable sensor with a 0.4 mm filament
which is inserted 5 mm under the skin
-Separate reader device captures the signal from the sensor
