transdermal drug delivery

Question 1

what are the advantages of parental drug delivery?

Answer 1

• Improved control of onset of action, serum levels, tissue concentration, elimination
• Rapidity of action e.g. via IV administration. Fastest way to admin drugs so they work immediately
• Enhanced efficacy: via local delivery or for drugs that cannot adequately be formulated for oral administration. Drug delivered to the site
• Ease of use: can be administered to unconscious or uncooperative patients
• Increased compliance e.g. via depot injections or patches for contraceptives, mental health- daily tablets, can change to depot injections – a single administration can last a longer period of time so people are more likely to use them- weeks/ months
• 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 wherever the drug may be injected or a cream applied

Question 2

what is intravenous drug delivery?

Answer 2

• Formulation: sterile solutions, suspensions, emulsions and reconstituted solids
• Usually administered in aqueous buffers at neutral pH e.g. citrate, phosphate, acetate, glutamate (exceptionally pH 3-10.5)
• Drug must be completely solubilised so they can act– solubility affects volume administered. If your drug doesn’t solubilise well, you’ll need to inject more to have an effect.
– Co-solvents may be added to improve solubility or stability e.g. glycerin, ethanol, propylene glycol, polyethylene glycol
• No particulate matter should be present- don’t want to block vessels, except for some nutritional lipids e.g. egg yolk phospholipid in oil (< 1 micron diameter)
• Hypertonic solutions can be used with slow administration
– NaCl, KCl, dextrose often added for tonicity adjustment

Question 3

what is intramuscular drug delivery?

Answer 3

• Less rapid onset of action than with IV; more rapid than sub-cutaneous injection as the muscles are more highly vascularised
• Can achieve prolonged release of oily and particulate doses e.g. poorly soluble drugs which will sit in the muscle and slowly dissolve
• Excipients must maintain an appropriate viscosity and avoid aggregation; may include wetting agents
• Dissolution is affected by solubility in biological fluids at the injection site; partition coefficient of the drug is also important
• The higher the blood flow to the tissue, the higher the absorption

Question 4

what is sc drug delivery?

Answer 4

– Rapid and predictable absorption; slower than IM
– Often used for self-medication
– 0.5 - 1.5ml injection volume into abdomen, arms, hips, upper back
– Drugs are typically water-soluble and non-irritant
– Poorly-absorbed and unstable drugs can be administered this way e.g. insulin

Question 5

what is IP drug delivery?

Answer 5

– Chemotherapy for abdominal tumours; peritoneal dialysis in renal failure; diagnostic imaging agents
– Major route of absorption is the portal circulation, leading to 1st pass metabolism
– Larger water-soluble drugs are absorbed more slowly than smaller, lipid soluble drugs
– Avoid bowel puncture, avoid causing haemorrhage- these are risks

Question 6

Transdermal drug delivery has various possible benefits for drugs with poor oral bioavailability. Which one of the following statements is NOT consistent with transdermal drug delivery?
A: Avoids first pass metabolism
B: Avoids food effects
C: Compensates for rapid clearance – rapid uptake of the drug, skin is permeable so you get faster affects in transdermal delivery
D: Achieves sustained drug concentrations in blood
E: Avoids the effects of variable blood flow – will affect drug absorption from partitioning

Answer 6

E

Question 7

why is transdermal drug delivery limited?

Answer 7

due to the significant barrier to penetration across the skin, which is associated primarily with the outermost stratum corneum (SC) layer of the epidermis- prevents drug penetration. This is to try and prevent bacterial infections happening more commonly making it harder to them to enter

Question 8

what is the typical drug dose which can ve delivereeyd through a transdermal patch?

Answer 8

5-25mg

limiting this route to potent drugs at low doses

Question 9

how is maximal penetration of drugs via s/c achieved?

Answer 9

• choice of drug and formulation or delivery vehicle to promote absorption
  - modification of the stratum corneum – modify enhancers
• choose the potent drug which allow it to penetrate

Question 10

what the 3 main transdermal penetration routes?

Answer 10

1) Directly across the stratum corneum – major route
2) Through the sweat ducts
3) Via the hair follicles and sebaceous glands

Question 11

what is the stratum corneum?

Answer 11

Bricks and mortar-like structure, cells are the bricks and the mortar is a lipid rich matrix that sits between the layers of cells; thickness: 10-15 µm (when dry) to 40µm (hydrated)- swells
• Cells: 10-15 layers of keratin-rich corneocytes, these are dead: polygonal “bricks” 0.2-1.5µm thick, 34-46µm in diameter.
• Mortar: intercellular lipid matrix extruded by keratinocytes and includes long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters
Extruded lipid phase behaviour is different to that of bio-membranes which contains lots of phospholipid:
• Hydrocarbon chains arranged into crystalline, lamellar gel and lamellar liquid crystal phase domains within lipid bilayers
• First few layers rearrange into broad intercellular lipid lamellae – you get layers of lipids sat between the cells

Question 12

why is the intercellular route a major pathway for most drugs?

Answer 12

soluble in the lipid regions or in formulation disrupting the lipid regions
Drugs pass through spaces between the cells – this is where the lipid matrix is.
The lipid matrix regions are shown in the middle diagram – alternate layers of aqueous regions and lipid regions – lipid lamellae.

Question 13

what is the molecular weight needed for a transdermal patch?

Answer 13

<1000 daltons

Question 14

what should the melting point be for a transdermal patch?

Answer 14

<200 degrees

Question 15

what should the log P be for a transdermal patch?

Answer 15

between 1 and 3

they need to be able to pass through both the lipid and aqeuous phase

Question 16

can a transdermal patch have polar centres?

Answer 16

no

or if it does very few as this would affect the solubility in lipophilic regions so they wont be able to pass through

Question 17

what should the kinetic half life be of a transdermal patch?

Answer 17

<6-8 hours
needs to mimic i/v delivery and maintain the therapeutic conc of drugs with short half lives
need a rapid onset of action

Question 18

what is the maximum patch size/

Answer 18

50cm2

Question 19

what is the maximum feasible dose of a transdermal patch?

Answer 19

5-20mg a day

Question 20

what do you need to think about when thinking of the drug vehicle?

Answer 20

• drug selection
• prd drug ester to redcue the number of charged centres
• ion pairs and complexes, you can make a pair to reduce the number of charged centres
• chemical potential
• eutectic systems promotes permeation through the skin
• liposome or vesicle based fromulation allows you to control the size to increase permeation
• lower mw for higher diffustion

Question 21

In a design for an occlusive skin patch for effective systemic delivery of a 600 Dalton, relatively high melting point, ester of a weak acid drug of LogP ~2 formulated with fatty acids, which of the following effects is least likely to have a significant effect on skin penetration the drug?
A: Swelling of the stratum corneum – enhances penertration, if you add skin the cells swell and this aid penetration – more route for drug to pass through
B: Formulating a eutectic mixture, lowering the melting point of the drug – aid permeation, lower MP better it permeates
C: Disruption of the stratum corneum lipid lamellae – anything that disrupts layers aids permeation
D: Formation of an ion pair increasing the lipid solubility of the drug – cannotbe an ion pair as it isn’t chared
E: Hydrolysis by enzymes in the epidermis – hydrolysis of the ester and resulting products will have charges which will have an effect on penetration – changes the nature of the drug and how it will move through

Answer 21

D

Question 22

how is the maximum skin penetration rate achieved?

Answer 22

drug has the highest thermodynamic activity when at highest conc, the drug on skin and in the tissue has a steep conc gradient so there is rapid movement into the tussues

Question 23

what is supersaturation?

Answer 23

eveporation of solvent from warm surface of the skin and occurs when it is topicalluy applied to the skin.
same amount od drug is dissolved in less vehicle

Question 24

what is a eutectic mixture?

Answer 24

two components that at a certain ratio, inhibit crystallisation of each other this means the melting point of both components is decreased.

Question 25

what is the enhancement ratio?

Answer 25

drug permeability coefficient before enhancer treatment

Question 26

how is the ER achieved?

Answer 26

• Disruption of the intercellular lipid lamellar structure- fluidising them and making it easier for the drugs to diffuse through
• Interactions with intracellular proteins of the stratum corneum to disrupt the structure
• Improvement of partitioning of a drug, with a co-enhancer or co-solvent penetrating the stratum corneum

Question 27

what is the role of hydration in the stratum corenum?

Answer 27

increases skin penetration of hydrophilic and lipophilic agents
• increase drug solubility and favours partitioning
• Increases skin hydration, swelling and opening of the SC structure, leading to increased penetration
• Diffusion coefficients of alcohols are 10x higher following hydration- so formulations with alcohol will work much better in hydrated skin compared to dry skin

Question 28

what is the water content of the SC?

Answer 28

15-20%

Question 29

what do liposomes do?

Answer 29

they hydrate or alter lipid layers, especially when lipids are similar to the SC lipids
they can readily enter and fuse with the sc lipids

Question 30

what are lipid nanoparticles?

Answer 30

consist of an almost perfect, solid lipid matrix. The drug molecules are mostly distributed around the edge of the SLN

Question 31

what are nanostructured lipid carriers?

Answer 31

composed of solid lipid matrix immersed in liquid lipid (oil) droplets- mixture of solid lipid crystals immersed in liquid lipid or oil. Part solid part liquid properties- therefore the drug is more uniformly distributed through the NLC

Question 32

Identify the permeation-enhancing excipients and describe how they may alter skin permeation. Why might there be differences between the gel and the cream?

Answer 32

-proponal is an alcohol – disrupts the lipids and aids permeation
• Triglyceride are lipid base so can alter the arrangement of lipid in the skin, these are not as effective but are still permeation enhancers
• Water – hydrate the skin, separate the layers and help the enhance the drug
• Dimethyl isosorbide – acts a solvent and dissolves the lipids
• Lavender oil – small amounts but will interact with the skin and aid permeation as they fus and dissolve or could alter the lipid layer
• Poloxamer – surfactants properties and will have some effect on helping penetration of the skin

Question 33

Explain the differences in short and long term permeation between the formulations

Answer 33

• Initially and subsequently higher permeation from the cream, due to better skin permeating excipients and a more lipophilic formulation
• Sustained effect from additional lipidic excipients in the cream formulation
• An increase in permeation from the gel after 1st hour, presumably due to the gel permeation enhancers (solvent, surfactants poloxamer) but after a few hours, the permeation rate of the gel product declined relative to cream
• The cream developed 2-3 times higher permeation than the gel longer term ( up to 28 hours)- due to greater permeabilization from lipids and surfactants and water donation.

Question 34

How would you explain the differences in:
(i) Recovery of the ibuprofen on permeation through skin?
(ii) Skin absorption of ibuprofen?
How do you think the differences in permeation and absorption may be useful in the usage of topical ibuprofen treatments?

Answer 34

• Highest ibuprofen reservoir (skin absorption) when treated with the solution, closely followed by the gel, because ibuprofen is poorly soluble and lipophilic log P3.7 so its partially retained in the lipid lamellae.
• The cream contains more effective permeation enhancers, which shortern the onset of action and increase drug recovery/permeation by modifying the skin lipids and reducing drug interactions with the skin.
• Ibuprofen taken for rapid pain relief, so highest permeation should result in higher pain benefit (cream), whereas exteneded release may also benefit treatment of inflammation.
• Higher skin absorption (retention) by the gel (and solution) may provide longer term benefit

Question 35

Which ONE of the following statements is NOT consistent with delivery of drugs through skin by modifying the stratum corneum with a microemulsion?
A: Reduced drug absorption in the skin increases the level in the blood – if you have less drug getting stuck in lamellae you will have more in blood
B: Oil absorption in the skin increases drug permeability
C: Water absorption in the skin increases drug permeability – hydration of layers helps permeation
D: Increased melting point of the lipid lamellae increases drug permeability – need a decreased in melting point to promote permeability
E: Allergic and inflammatory reactions may arise – anything you put on skin may cause an issue

Answer 35

D