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Medicine Year 3, Sem 1 - Drug Development Process > Biopharmaceutics Transdermal 1 > Flashcards

Biopharmaceutics Transdermal 1 Flashcards

1
Q

Parenteral drug delivery is any route other than…

A

GIT

This includes pulmonary, nasal, injection and transdermal

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2
Q

Parenteral drug delivery systems represent what fraction of all formulations on the market?

A

2/3

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3
Q

What is percutaneous drug delivery?

A

Through the skin i.e. injections

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4
Q

What is transdermal drug delivery?

A

Through unbroken skin, does not include injections

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5
Q

What are some of the advantages of parenteral drug delivery? (7)

A

Improved control of onset of action, serum levels, tissue concentration and elimination
Rapid action
Enhanced efficacy via local delivery or for drugs that cannot be formulated for oral admin
Ease of use
Increased compliance
Local/targeted delivery
Fall back route

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6
Q

What is one disadvantage of parenteral drug delivery?

A

Absorbance is still hampered by poor and/or variable blood flow

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7
Q

Why is transdermal delivery limited?

A

Due to the significant barrier to penetration across the skin, primarily associated with the stratum corneum (SC)

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8
Q

What is a typical daily dose that can be administered from a transdermal patch?

A

5-25mg

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9
Q

What does the typical daily dose indicate?

A

This route is only appropriate for potent drugs

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10
Q

How is maximal penetration of the SC achieved?

A

Choice of drug and formulation of delivery vehicle
Modification of the SC
Powered penetration enhancement devices

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11
Q

How can choice of drug and formulation of delivery vehicle be manipulated to achieve maximal SC penetration?

A

By choosing a very permeable drug or formulating that drug with excipients which make it more permeable

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12
Q

How can the SC be modified to achieve maximal penetration?

A

Include excipients that disrupt or damage the SC

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13
Q

What are powered penetration enhancement devices?

A

Use an electric current or sound wave to enhance penetration of drug through the outer skin barrier

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14
Q

How do powered penetration enhancement devices work? (3)

A

Iontophoresis
Phonophoresis
Electroporation

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15
Q

What are the 3 transdermal penetration routes?

A

Directly across the SC
Through the sweat ducts
Via hair follicles and sebaceous glands

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16
Q

Which of these 3 penetration routes is the most important?

A

The majority of skin penetration enhancement is focused on increasing transport across SC
The other routes comprise a very small s.a. (~0.1%) for penetration so do not contribute to the steady state flux of most drugs

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17
Q

Which penetration route is associated with iontophoretic drug delivery?

A

Uses an electric current

Primarily via sweat ducts, hair follicles and sebaceous glands as these offer the least electrical resistance

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18
Q

How can the structure of the SC be described?

A

Brick and mortar-like

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19
Q

Explain this description (B+M).

A

The bricks are 10-15 layers of keratin-rich corneocyte cells which are 0.2-1.5μm thick and 34-36μm in diameter (these cells are dead and in the process of being removed)
The mortar is an intercellular lipid matrix, extruded by keratinocytes and including long chain ceramides, free FA’s, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters

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20
Q

How thick is the SC?

A

10-15μm (dry) to 40μm (hydrated)

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21
Q

What is the function of keratin?

A

Gives the skin strength

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22
Q

Does the extruded lipid behaviour of the SC differ to that of a biomembrane?

A

Yes, biomembrane is primarily made up of phospholipids

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23
Q

How is the intercellular lipid matrix arranged?

A

Hydrocarbon chains are arranged into crystalline, lamellar gel and lamellar liquid crystal phase domains within the lipid bilayer
First few layers rearrange into broad intercellular lipid lamellae

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24
Q

What is the role of water in transdermal delivery?

A

Water is essential as a plasticiser in promoting transdermal drug delivery to prevent cracking of the SC and to maintain suppleness

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25
Q

What can happen to both drugs and excipients in the skin?

A

Hydrolysed by enzymes e.g. esterases, which can affect absorption

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26
Q

Hydrolysis of drugs and excipients may…

A

Inactivate drugs (decrease absorption) or activate a prodrug (increase absorption)

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27
Q

What are the 2 routes of skin penetration?

A

Intercellular

Transcellular

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28
Q

Intercellular penetration…

A

Is a major pathway for most drugs, drug is either soluble in lipid region or in a formulation disrupting lipid region

29
Q

Transcellular penetration…

A

Is a route for more hydrophilic drugs penetrating aqueous regions of keratin filaments, must also transverse intercellular lipid region

30
Q

How are the lipid lamellae structured?

A

Lipid lamellae are the ‘mortar’ between the corneocyte-rich ‘bricks’
The lipid lamellae have alternating layers of both aqueous and lipid-rich regions

31
Q

How does the alternating structure of the lipid lamellae impact drug delivery?

A

Means that even if drugs move by the intercellular route through the lipid-rich layer, within that layer itself it must pass through alternating aqueous and lipid-rich regions

32
Q

What causes this alternating structure?

A

The lipids forming the structure of the lipid lamellae have both hydrophobic domains, which comprise the lipid rich regions, and hydrophilic domains, where they have their charged functional groups forming the aqueous regions

33
Q

For effective penetration, a drug must be…

A

Lipid soluble enough to move through the lipid-rich regions and water soluble enough to move through the aqueous regions

34
Q

What are the physiochemical factors involved in transdermal delivery?

A 
Diffusion coefficient (D)
Diffusional path length or membrane thickness (h)
Partition coefficient (P) of the drug between the skin and the vehicle 
Drug concentration (C) (assumed to be constant)
35
Q

What equation/law relates these physiochemical factors together?

A

Fick’s Law of Diffusion

States that steady state flux (J) is related to D, h, P and C

36
Q

How does partition coefficient affect drug diffusion?

A

An ‘intermediate’ logP in octanol/water of 1-3 is ideal
Need adequate drug solubility within the lipid domains but also must be sufficiently hydrophilic to allow partitioning into tissues of the epidermis and the aqueous regions of the lipid lamellae

37
Q

What are the ideal drug properties for a transdermal patch?

A 
MW <1000 Da and preferably <500 Da
MP <200ᵒC
Log P 1-3
No or few polar centres, like carboxylate or zwitterionic structures 
Kinetic half-life of 6-8 hours 
50cm² max. size
5-25mg/day maximum feasible dosage
38
Q

Why do you want a drug to have no or few polar centres when formulating as a transdermal patch?

A

If you have charges associated with the molecule, the drug will be too hydrophilic which will significantly affect diffusion through the lipophilic areas of the skin

39
Q

Why do we want a drug to have a kinetic half-life of 6-8 hours when formulating as a transdermal patch?

A

When you put the patch on you want rapid uptake and establishment of plasma conc. but similarly, when you take the patch off you want concentrations to drop, good ‘on-off’ dosing

40
Q

Why do we want a 50cm² max. size for a transdermal patch?

A

Not feasible to ask patients to wear huge patches

41
Q

How do reusable and needle-free injectors work?

A

Some are spring powered and can be used 1000’s of times

Others use high pressure gas to force drug through the skin

42
Q

When can reusable and needle-free injectors be used?

A

For SC, IM or intradermal admin (need to be more powerful for IM or intradermal admin)

43
Q

Are reusable and needle-free injectors bioequivalent to regular needle-based injections?

A

Yes

44
Q

What is an example of a reusable and needle-free injector? How does it work?

A

Powderject (Novartis injector)
Powered by helium gas, burst of gas that is so powerful that it actually forms a physical channel in the skin
There is cell damage immediately around the site but this is not extensive
Allows penetration deep into the skin (through SC to epidermis and dendritic cells)
No inflammation, pain or swelling
Used for highly potent drugs and vaccines e.g. HepB, influenza

45
Q

What is a microneedle patch?

A

Structure is similar to a standard transdermal patch but you have microneedles on the adhesive part

46
Q

How do microneedles work?

A

SC is pierced with short needles to deliver drugs into the skin in a minimally invasive manner
Actively drive drugs into the skin during microneedle insertion (for drug-coated needles)

47
Q

What formulations are microneedles used in?

A

Used for small molecule drugs, proteins and nanoparticles to form extended release patches e.g. naltrexone, PTH, vaccines

48
Q

How do microneedles increase permeability?

A

Create micron-scale pathways in the skin

49
Q

Which layer of the skin do microneedles target?

A

SC, as this causes minimal damage and disruption, but they typically pierce across the epidermis and into the superficial dermis too

50
Q

What are some different types of microneedle? (5)

A 
Solid
Hollow 
Rapidly separating 
Drug coated 
Drug containing dissolving
51
Q

Are microneedle patches painful?

A

No, nerve endings are much lower down, you don’t feel pain as they are not stimulated

52
Q

How do drug containing dissolving needles work?

A

When needles contact fluid within the skin, they dissolve and the drug is carried into the skin

53
Q

How does a patch powered by iontophoresis work?

A

The patch has electrodes on it so you can apply an electrical current through it
Uses low-voltage current to increase the permeability of highly charged and weakly charged/uncharged drugs

54
Q

How does iontophoresis increase the permeability of highly charged drugs?

A

The charge of the electrical current moving across the skin will promote and encourage highly charged drugs to enter the skin as they follow the electric current

55
Q

How does iontophoresis increase the permeability of weakly charged/uncharged drugs?

A

By increasing the electroosmotic flow of water because of mobile cations, e.g. Na⁺, and fixed anions, e.g. keratin

56
Q

The rate of delivery by an iontophoresis powered patch…

A

Increases with electrical current

57
Q

How is the electrical current of an iontophoresis powered patch controlled?

A

Either by a microprocessor or the patient to allow for personalised delivery

58
Q

The maximum current…

A

And therefore delivery rate, is limited by skin irritation and pain

59
Q

How does iontophoresis provide control over dosing?

A

Because delivery is proportional to amount of charge i.e. it is the product of current and flow

60
Q

How does electroporation work?

A

Short, high-voltage electrical pulses reversibly disrupt the cell membrane and skin lipid lamellae in SC to create pores in the skin
The electro-pores created persist for hours and increase diffusion by orders of magnitude for drugs, peptides, proteins and DNA
SC has a higher resistance than deeper tissues, resistance drops dramatically upon application of the electrical field

61
Q

In which products is electroporation utilised?

A

Microneedle patches

62
Q

What happens over time after use of an electroporation patch?

A

The lipids spontaneously rearrange to recover their original confirmation

63
Q

Are electroporation patches painful?

A

The electrical field distributes into deeper tissues which contain sensory and motor neurons, which can cause pain and muscle stimulation

64
Q

How can the pain be avoided?

A

By using closely spaced microelectrodes that constrain the electrical field to the SC

65
Q

What is ultrasound?

A

An oscillating pressure wave at a frequency too high for humans to hear

66
Q

How do phonophoresis powered patches work?

A

Ultrasound is used to chance the skin permeability of small, lipophilic drugs by disrupting the lipid lamellae of the SC
Low frequency ultrasound causes formation, oscillation and collapse of bubbles
Cavitation energy at the site of the bubbles causes small holes to form in the skin, enhancing delivery

67
Q

What drugs are phonophoresis powered patches used for?

A

Lidocaine, insulin, heparin and tetanus toxoid vaccine

68
Q

What other mechanism can skin permeability be increased by that works by a related mechanism?

A

Pulsed lasers

Use a related/similar shockwave mechanism

Medicine Year 3, Sem 1 - Drug Development Process (8 decks)

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