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
