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Drug Delivery > Transdermal > Flashcards

Transdermal Flashcards

1
Q

What are the benefits of orally administering a compound?

A 
Fast onset. 
Patient acceptance. 
Easy to manufacture. 
Large surface area. 
Rich blood supply.
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2
Q

What are the drawbacks of orally administering a compound?

A

Variability of absorption.
Adverse reactions.
Patient compliance issues from multiple daily dosing.
Peaks and toughs.
Side effects due to peaks, sub-therapeutic effect due to troughs,

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3
Q

How does oral and transdermal drug delivery differ in terms of the biological carrier?

A

GIT vs stratum corneum.
Low barrier resistance vs highly impermeable barrier.
Variable pH bs acidic lipid barrier.

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4
Q

How does oral and transdermal drug delivery differ in terms of the formulation/delivery technology?

A

Tablets, capsules vs patches,
Powder technology vs polymer science.
Compression and coating methods vs films, webs, adhesives.

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5
Q

How does oral and transdermal drug delivery differ in terms of drug delivery efficiency and timing?

A

Payload completely delivered (ideally) vs typically less then 50% delivered by TDD.
6-18hr release/delivery vs. 0.5-7 days.
Variable surface area vs fixed area of delivery.

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6
Q

What are the benefits of transdermal drug administration? [8]

A
  1. Blood level plasma profiles are distinct from oral dosing: avoidance of “peaks and valleys”
  2. Different patch technologies are capable of equivalent and effective drug delivery.
  3. Dose titration is possible by changing patch area.
  4. 1st pass effect avoidance leads to altered metabolite levels etc.
  5. Application to diverse therapeutic areas.
  6. sustained delivery from 0.5-7 days.
  7. Can be used to deliver difficult to formulate drugs;
  8. Improved patient compliance and drug utilisation (reduced multiple daily dosing etc.)
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7
Q

What is an adhesive transdermal patch?

A

Simply a backing layer over a layer containing a mixture of adhesive compounds and the drug itself.

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8
Q

What is a layered patch?

A

Backing layer.
Polymer/Drug matrix layer.
Adhesive/Drug layer.

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9
Q

What is a reservoir patch?

A

Backing layer.
Drug reservoir.
Rate controlling membrane.
Adhesive/drug layer.

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10
Q

What is flip-flop kinetics?

A

Iv infusion: when pump is stopped the only process controlling drug elimination is the rate of systemic clearance.

For patches, absorption across the skin is the rate-limiting step and therefore even though the patch has been removed there is still drug being absorbed across the skin into the plasma.

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11
Q

What is the greatest limitation of transdermal drug delivery?

A

The potency of the drug.

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12
Q

What are 4 reasons we may wish to use topical drug delivery?

A
  1. Modulate barrier function.
  2. Treat disease states in the epidermis and dermis.
  3. Alleviate local pain/inflammation in subcutaneous tissues.
  4. Elicit systemic pharmacological effect.
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13
Q

What are the sequential steps in the percutaneous absorption of a drug? [3]

A
  1. Drug is applied in vehicle/formulation in which it must diffuse to the skin surface, be released and partition across the SC.
  2. Drug diffuses across SC, reaching interface with the underlying viable epidermis where the drug must partition into this more aqueous in nature tissue.
  3. The drug diffuses through the viable skin until encountering the microcirculation where it is resorbed into the blood and eventually conveyed to the central compartment.
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14
Q

Why do lipophilic drugs penetrate the skin relatively poorly?

A

Lipophilic drugs partition avidly into the SC they then leave this ‘sympathetic’ environment for the more aqueous in nature viable epidermis only reluctantly. The ‘phase transfer’ from the SC into epidermis becomes the rate-limiting step for these drugs.

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15
Q

Which part of the skin represents the principal barrier to topical and transdermal drug delivery?

A

The stratum corneum

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16
Q

Describe the composition of the stratum corneum.

A

Bricks (dead-keratin filled cells) + mortar (complex lipid mixture: ceramides, cholesterol, free fatty acids).
Rivets in the mortar which hold corneocytes together are specialised protein structures known as corneodesmosomes.

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17
Q

What are corneodesmosomes.

A

Rivets in the mortar which hold corneocytes together are specialised protein structures known as corneodesmosomes.
They are the major structures to be degraded during desquamation of the skin.

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18
Q

What is the ‘mortar’ in the SC composed of?

A

Complex mixture of lipids: ceramides, free fatty acids, cholesterol.

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19
Q

How thick is the SC? What impact does this have on drug transit?

A

~10micometers.
Not that much of an impact as the principal route of drug transit is inter/paracellularly so the pathlength is much greater than SC thickness.

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20
Q

What is the rationale behind using topical drug delivery to treat local, subcutaneous pain and inflammation?

A
  1. ‘outside-in’ is at least as effective as ‘inside-out’.
  2. Significantly less systemic exposure and GI disturbances.
  3. Similar if not better plasma profiles achieved.
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21
Q

What are the two parameters that can be varied by a formulation scientist to maximise topical flux?

A

Drug concentration in the vehicle.

Partition coefficient of the drug between the SC and the vehicle.

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22
Q

Why is the drug concentration in the vehicle important to flux?

A

A higher concentration gradient implies higher flux across the skin.

23
Q

Why is the partition coefficient of the drug between the SC and the vehicle important to flux?

A

The higher the partition coefficient in Fick’s 1st law then the higher the resulting flux will be.

24
Q

What does drug administration from the skin depend on? [3]

A
  1. Physiochemical properties of the drug.
  2. Interactions of the drug with the vehicle or delivery system and with the skin.
  3. The pathology of the skin.
25
Q

What is PG and why is it used?

A

Propylene glycol is a co-solvent which is used to increase drug solubility in the vehicle at the cost of decreasing the rate of drug partitioning out of the vehicle into SC.

26
Q

Why are esters good candidates for Transdermal Drug Delivery?

A
  1. Less polar, higher flux across skin.
  2. Higher concentrations are possible before a suspension forms.
  3. Less water soluble so reach maximum flux at lower concentrations.
27
Q

How can we measure topical BA? [3]

A
  1. In vitro: using methodology + data analysis, permeability coefficient measurement, %dose absorbed.
  2. In silico: permeability coefficient, maximum flux calculation.
  3. In vivo, SC tape stripping. DPK: dermatopharmacokinetics, microdialysis.
28
Q

What is the predominant rate-determining step to transdermal drug transit?

A
  1. The SC.
  2. Except in instances when the drug is very lipophilic and rapidly partitions into the SC from the vehicle. In these circumstances the rate-limiting process becomes the phase transfer of a drug out of the SC into the more Aq viable epidermis beneath.
29
Q

What effect does the pH of the skin have on drug absorption?

A

Skin pH: 4-5.5. Acidic.

Therefore unionised drugs will be best absorbed.

30
Q

What is RT, the total resistance, a function of?

A

RT: sum of Ri = Rsc + Red.

Sum of the resistance in SC and resistance in the epidermis.

31
Q

What is the lag-time of a drug delivered transdermally?

A

Tlag = h2/6D.
At ss, flux across the membrane is constant but ss is not attained immediately. The amount of drug arriving downstream increases linearly with time. Time is required to achieve this linear concentration gradient. This is the lag time.

32
Q

What types of drug are (generally) formulated for transdermal delivery?

A

Old, well-known/studied, very potent. Oral and/or parenteral forms will exist.
For new drugs: those that suffer extensive metabolism or degradation via oral route.

33
Q

What are the limitations of transdermal delivery?

A
  1. potent molecules only, daily dose of
34
Q

What are some examples of drugs that are used topically?

A 
Scopalamine. 
Nitroglycerin. 
Clonidine. 
Estradiol. 
Fentanyl. 
Nicotine. 
Testosterone. 
Oxybutin.
Selegiline. 
Methylphenidate. 
Buprenorphine. 
Rotigotine. 
Rivastigmine.
35
Q

What types of polymers can be found in patches? [3]

A
  1. Pressure sensitive adhesives: acrylates, silicones, rubber-based.
  2. Release liners: silicones, polyesters, polycarbonates.
  3. Backings and laminates: ethylene vinyl acetate, polypropylene, polyester, PVC.
36
Q

What polymers can be used as pressure sensitive adhesives?

A

Acrylates
Silicones
Rubber-based ones.

37
Q

What polymers can be used as release liners in transdermal patches?

A

Silicones.
Polyesters.
Polycarbonates.

38
Q

The backings of transdermal patches are typically composed of:

A

Ethylene vinyl acetate.
Polypropylene,
Polyester.
PVC.

39
Q

What is iontophoresis?

A

A technique of introducing ionic medicinal compounds into the body through the skin by applying a local electric current.

It’s usually used to treat excessive sweating. However, it can also be used to treat sports injuries by delivering anti-inflammatory medications directly into the skin.

40
Q

For what disorders is iontophoresis used to treat?

A

Hyperhidrosis of the hands, feet, underarms etc.

It’s usually used to treat excessive sweating. However, it can also be used to treat sports injuries by delivering anti-inflammatory medications directly into the skin.

41
Q

How does iontophoresis work?

A

Small electric current is applied to an iontophoretic chamber placed on the skin, containing a charged active agent and its solvent vehicle. another chamber or a skin electrode carries the return current.

42
Q

What iontophoretic patches are available?

A

Two iontophoretic patches have recently been approved for vaso-active therapeutic use by the FDA - Zecuity (2013) - containing the migraine drug sumatriptan - and Ionsys (2015), indicated for moderate-to-severe acute post-operative pain, delivering a therapeutic dose of the powerful opioid, fentanyl, on-demand.

The entry of iontophoretic devices into the therapeutic mainstream will be followed with interest.

43
Q

Pilocarpine iontophoresis is often used to stimulate sweat secretion, as part diagnosis of what condition?

A

Cystic fibrosis

44
Q

The spectrum of diseases treated by transdermal administration is large, what is the sole common link between the drugs delivered in this way?

A

Their potency.

45
Q

What was the first new chemical entity developed ab initio for transdermal delivery?

A

Rotigotine

46
Q

How can drug delivery via the transdermal route be enhanced?

A
  1. Formulations which include a chemical penetration enhancer
  2. Physical action on the drug itself e.g. iontophoresis
  3. Physical and or mechanical energy applied to the barrier: ultrasound, microneedles, thermal poration.
47
Q

What is the most common side effect of penetration enhancer use?

A

There is a direct correlation between the efficacy of an enhancer to improve drug
permeation and its inherent ability to elicit irritation; thus, the better the enhancer,
the worse the irritation observed.

48
Q

What challenges exist to the use of iontophoresis?

A
  1. The ionised drug is only one of several available charge carriers in the
    system: for example, there may be ions of the same charge in the background
    electrolyte, and these can compete with the drug to carry charge into the skin.
  2. Ions of opposite charge within the body are able to transport charge in
    the opposite direction. Iontophoresis efficiency, therefore, is always less than
    100% and is often very small.
49
Q

How can iontophoresis be used in diabetes management?

A

The electrical current ‘pulls’ glucose across the skin from the extracellular fluid inside
the body to the surface, where it is analyzed in situ and the result translated into a
measurement of glycaemia via a prior calibration.

50
Q

What methods currently exist of skin ‘poration’?

A

Mechanical means: microneedle arrays or high-velocity particles.
Physical energy: ultrasound (sonophoresis) or heat/lasers (thermal poration)

51
Q

In what ways can microneedle arrays be used to deliver drugs transdermally?

A

Insertion followed by immediate removal.
Patch
Biodegradable microneedle arrays
Micro-projections coated with, a vaccine.

52
Q

The creation of micron-sized portals through the skin using thermal energy
may be accomplished by what?

A

Heated microfilament array

Use of radio frequency micro-ablation.

53
Q

Why is thermal poration an attractive technique?

A

The depth of the
pores induced ensures access to the viable tissue and that the conduits then
become filled quickly with extracellular fluid. In this way, it becomes possible to
deliver therapeutic doses of normally skin-impermeable drugs (e.g., the salt of an
active species which has much greater stability than the corresponding unionised
species) across rather small areas of skin. The thermal ablation of the SC causes
the membrane’s impedance to fall dramatically, providing an opportunity for
feedback control of the energy pulse delivered to the skin.

Because of the
dimensions of the pores, as with microneedles, the transdermal delivery of proteins
such as insulin, human growth hormone and alpha-interferon has been
possible.

Drug Delivery (11 decks)

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