W24 Transdermal drug delivery l, ll and lll (AM)

Question 1

What is the aim of transdermal drug delivery?

Answer 1

Aim is to get the drug across the stratum corneum (difficult) and viable epidermis (easier) and then be taken up by systemic circulation

Question 2

Why is the transdermal route desirable? (8)

Answer 2

1. Avoids first pass metabolism
2. Controlled rate of drug delivery (avoids peaks/troughs)
3. Avoids GI problems (irritancy, pH, adsorption…)
4. Can be administered by the patient
5. Favoured by patients
6. Reduces dosage frequency = improves compliance
7. Rapid identification of drug in emergencies
8. Compared to depot injections, less painful and drug input readily terminated

Question 3

What are the challenges to TDD? (8)

Answer 3

• 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

Question 4

What are some Common drugs administered by TDD?

Answer 4

• 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

Question 5

So what are the ideal properties of transdermal drugs? (7)

Answer 5

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

Question 6

What method is used in TDD evaluation? (lab based)
What apparatus?

Answer 6

• 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

Question 7

What are the features of a permeation profile graph?

Answer 7

Y axis: Cumulative amount permeated (mg/cm2)
X axis = Time (hours_
Steady state flux= Gradient (amount/area/time)
Lag time

Question 8

TDD evaluation: Calculating gradient
What eq is used?
What are the units for flux?

Answer 8

Gradient = (y2-y1)/(x2-x1)
Flux units = mg / cm2/hours
Flux units = mg / cm2 / h
Flux units = mg cm-2 h-1

Question 9

Evaluating TDD- Fick’s Law
What is Fick’s law?
What is the equation?

Answer 9

• 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

Question 10

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?

Answer 10

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)

Question 11

Is there a way to predict the permeability coefficient? (Kp)

Answer 11

• Published transdermal in vitro permeation data has been used to predict the permeability coefficients (Kp) of other drugs
  (mathematical models)

Question 12

Predicting TDD (for info) l

Answer 12

• 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

Question 13

Predicting TDD (for info) ll

Answer 13

• 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

Question 14

TDD enhancement
* To increase the number of drugs deliverable transdermally (or topically) which various enhancement techniques have been used? (3)

Answer 14

• (1) Formulation manipulation
• (2) Skin modification
• (3) Physical methods/ external forces (Lecture 3)

Question 15

What is meant by formulation manipulation?

Answer 15

• 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

Question 16

TDD enhancement: skin modification
What are Penetration enhancers?

Answer 16

• Penetration enhancers are compounds that increase the rate of diffusion of a permeant through the skin – usually act on the Stratum Corneum

Question 17

What are the different ways that penetration enhancers can exert an effect?

Answer 17

• (1) Disruption of the highly ordered multiple lamellar lipid arrangement
• (2) Interaction with intercellular proteins
• (3) Increasing partitioning into the skin

Question 18

What are the ideal properties of a penetration enhancer? (5)

Answer 18

• Non-toxic & non-irritant
• No pharmacological activity
• Act rapidly, reversibly and unidirectionally
• Compatible with drugs and excipients
• Cosmetically acceptable to patients

Question 19

TDD enhancement: skin modification
What are examples of common penetration enhancers
What are their subsequent likely mode of action?

Answer 19

• 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

Question 20

What are the 4 elements common to all transdermal patches/ TTS

Answer 20

1. Drug
2. Adhesive
3. Backing layer
4. 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

Question 21

TTS: adhesives
* Which following requirements do they have to meet?

Answer 21

• 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

Question 22

TTS: backing layer
What requirements does it need to meet?

Answer 22

• 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

Question 23

What are the 3 types of TTS?

Answer 23

1. Drug in adhesive patch
2. Drug in matrix patch
3. Rate limiting membrane patch

Question 24

TTS: Liner
What requirements does it need to meet?

Answer 24

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

Question 25

What is the most common type of TTS?

Answer 25

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

Question 26

What is a Drug-in-matrix patch (TTS)

Answer 26

* 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

Question 27

What is a rate-limiting membrane patch? (TTS)

Answer 27

* 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

Question 28

Transdermal formulations (for info)

Answer 28

* 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

Question 29

Summary (for info)

Answer 29

* 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

Question 30

Name the Physical methods for enhancing transdermal drug delivery? (4)

Answer 30

- Electroporation - Sonophoresis - Microneedles - Iontophoresis

Question 31

What is Electroporation?

Answer 31

* 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

Question 32

How exactly is transdermal delivery enhanced? (2) using high voltages What are the challenges involved?

Answer 32

1. Electrophoresis= Principal mechanism for charged permeants –occurs during the high voltage pulse 2. 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

Question 33

What is Sonophoresis? What are the 2 enhancement mechanisms?

Answer 33

* 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

Question 34

Sonophoresis (for info)

Answer 34

* 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

Question 35

What are Microneedles? What are they produced from?

Answer 35

* 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)

Question 36

Microneedles: What are the 5 different approaches taken to microneedle design and usage?

Answer 36

(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

Question 37

Features of hydrogel microneedles? What have they been trialed to treat?

Answer 37

* 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**

Question 38

What are the challenges of microneedle usage? (4)

Answer 38

− 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

Question 39

What is Iontophoresis?

Answer 39

* 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

Question 40

Iontophoresis

Answer 40

* 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)

Question 41

Iontophoresis: Issues around iontophoretuc devices?

Answer 41

* 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

Question 42

What is Reverse iontophoresis? Example of device that uses this?

Answer 42

* 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

Question 43

Glucose monitoring: How does the freestyle libre device work?

Answer 43

* 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