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Pharmaceutics > Biopharmaceutics Transdermal > Flashcards

Biopharmaceutics Transdermal Flashcards

1
Q

What is parenteral?

A
  • any other route of administration other than oral

- 2/3rds of the pharmaceutical market

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2
Q

What are the advantages of parenteral drug administration?

A
  • improved control
  • rapidity of action
  • enhanced efficacy (local effects)
  • ease of use (unconscious/uncooperative)
  • increased compliance (don’t need to remember to take tablets multiple times a day)
  • local/targeted drug delivery
  • fall back route (unconscious)
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3
Q

What is the main disadvantage of parenteral drug administration?

A

absorbance is hampered by poor and/or variable blood flow

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4
Q

What is the main limitation for transdermal drug delivery?

A
  • the stratum corneum skin barrier (the outermost layer)

- prevents drug penetration into the vasculature that sits below the skin

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5
Q

How is maximal penetration of the stratum corneum achieved?

A
  • choice of drug (with appropriate properties)
  • formulation/delivery vehicle
  • powered penetration enhancement devices
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6
Q

What are the three main transdermal penetration routes?

A
  • directly across the stratum corneum (major route)
  • through sweat ducts
  • through hair follicles and sebaceous glands

2 & 3 make up a very small surface area (0.1%) and don’t contribute to the steady state flux of most drugs
- but this is where powered delivery devices work as there is less electrical resistance here than in the stratum corneum

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7
Q

What is the general structure of the stratum corneum?

A

bricks & mortar (cells & lipid matrix)

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8
Q

How thick is the stratum corneum?

A

10 - 15 um when dry

40 um when hydrated from swelling

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9
Q

What is the structure and characteristics of the cells of the stratum corneum?

A
  • cells that make up the SC are the corneocytes
  • corneocytes are largely made up of keratin
  • 10 - 15 layers of these cells in the SC
  • 0.2 - 1.5 um thick, 34 - 46um diameter
  • these cells are the dead cells that are ‘sloughing off’
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10
Q

What is the structure and characteristics of the lipid matrix of the stratum corneum?

A
  • lipid matrix is expelled by keratinocytes as they move up the dermis layer
  • composition of the lipids is different to normal cells (which usually contain a lot of phospholipids)
  • this expelled lipid phase behaves very different to that of normal biomembranes
  • made up of: ceramides, fatty acids and cholesterol
  • the hydrocarbon chains arrange into: crystalline, lammellar gel and lamellar liquid crystal within the bilayers
  • first few layers are broad intercellular lipid lamellae
  • lipid lamellae: alternate regions of aqueous and lipid regions
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11
Q

Why is water essential to the skin?

A
  • acts as a plasticiser to prevent the SC from cracking

- maintains suppleness

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12
Q

What are the enzymes found in the skin?

A
  • esterases

- drugs and excipients may be hydrolysed by these

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13
Q

What are the two major routes for penetrating the stratum corneum?

A
  • intercellular route - pass between the cells, through the lipid matrix (this is the MAJOR route for most drugs)
  • transcellular route - pass through the corneocytes
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14
Q

What type of drugs typically penetrate via the intercellular route?

A
  • lipid soluble drugs

- formulations that can disrupt the lipid regions

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15
Q

What type of drugs typically penetrate via the transcellular route?

A
  • more hydrophilic drug (penetrating the keratin filaments within the corneyocytes)
  • but still has to move across the intercellular lipid region
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16
Q

What are the physiochemical factors that govern drug permeation?

A

steady state flux (permeation/uptake of drugs) based on:

  • diffusion coefficient of the drug (D)
  • diffusional path length or membrane thickness (h)
  • partition coefficient (P) of the drug
  • drug concentration (C)
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17
Q

What is the ideal Log P of a drug for transdermal drug diffusion?

A

1 - 3

  • want it to be lipid soluble enough to pass through the lipid domains of the SC
  • want it hydrophilic enough so that it partitions into the tissues of the epidermis

a higher log P may result in a depot effect as there is high lipid association

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18
Q

What are the ideal drug characteristics for transdermal delivery?

A
  • MW < 1000 Da, and preferable less than 500Da
  • Melting point < 200 degrees (influences solubility and therefore skin penetration)
  • Log P 1 - 3
  • No/few polar centres (no charge or will impair lipid solubility)
  • Half Life < 6 - 8 hours, rapidly absorbed and rapidly metabolised (transdermal delivery has continuous delivery of a drug)
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19
Q

What are the ideal characteristics of a patch for transdermal delivery?

A
  • 50cm2 maximum patch size

- 5 - 20mg max daily dose (potent drug)

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20
Q

What are the main structures of a transdermal patch?

A
  • outer plastic covering
  • drug reservoir
  • membrane (controls the drug release)
  • adhesive contact
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21
Q

How is skin permeation enhanced by the drug/vehicle?

A
  • drug selection
  • pro-drug (reduce the number of charged centres)
  • ion pairs/complexes (reduce the number of charges)
  • chemical potential
  • eutectic systems
  • liposome/vehicle based formulations
  • optimal permeability
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22
Q

How is skin permeation enhanced by manipulating the SC?

A
  • hydration (layers will separate to form a channel)
  • lipid fluidisation
  • powered electrical devices
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23
Q

What are the different types of powered electrical devices?

A
  • iontophoresis
  • phonophoresis
  • electroporation
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24
Q

How do saturated/supersaturated drug solutions maximise skin penetration?

A
  • maximum rate of skin penetration
  • changes the chemical potential of the system
  • drug then has its highest thermodynamic activity
    (produces a high drug concentration reservoir, forming a concentration gradient for rapid uptake)
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25
Q

How are supersaturated/saturated drug solutions formed?

A
  • evaporation of the solvent
  • mixing co-solvents

so that the same concentration of drug is in less and less of the solvent, so that it is more concentrated

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26
Q

What common mechanism of supersaturation drug solutions is seen for topically applied formulations?

A

evaporation of the solvent occurs by the warm surface of the skin so that the drug then becomes super saturated

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27
Q

What happens when water is absorbed into the supersaturated vehicle of the drug?

A
  • water from the skin absorbed into the vehicle
  • acts as an anti solvent
  • increases the thermodynamic activity of the drug 5-10 x
  • increases the flow of the drug
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28
Q

Supersaturated systems are stable, true or false?

A

FALSE

  • they are unstable
  • require the incorporation of anti-nucleating agents to stabilise
  • ceramides, cholesterol and fatty acids do provide and contribute to this effect
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29
Q

What is a eutectic systems/mixture?

A
  • made up of two components
  • inhibit the crystallisation of each other
  • this decreases the melting point
  • many have a penetration enhancer as the second component (fluidises the lipid lamellae)

crystals - highly organised structures that require more energy to break, and therefore have higher melting points

inhibit crystallisation = decrease energy

30
Q

How does melting points of drugs affect skin permeation?

A
  • lower melting points = better solubility
  • solubility then enhances the skin permeation
  • MPs below or around skin temperature can enhance drug solubility
31
Q

Examples of permeation enhancers

A
  • ibuprofen & terpenes
  • methyl nicotinate & menthol
  • propranolol & fatty acids
  • lignocaine & menthol
32
Q

How is the effectiveness of a permeation enhancer measured?

A
  • the enhancement ratio (ER)

ER = drug permeability coefficient after enhancer treatment/drug permeability coefficient before enhancer

33
Q

How is the stratum corneum modified?

A
  • disruption of the lipid lamellae (fluidising)
  • interactions with intracellular proteins of the SC
  • improvement of partitioning of drug (with co-solvent/co-enhancer)
34
Q

What are the different formulations available to modify the stratum corneum?

A
  • needles/skin roller (puncture holes in the skin)
  • micro needle based patches
  • molecules (chemically alter skin)
35
Q

What is the most widely used and safest method for increasing skin penetration of both lipophilic and hydrophilic drugs?

A

water

36
Q

How does water increase skin penetration?

A
  • alters drug solubility and partitioning
  • increases hydration and therefore swelling, opening of the SC
  • provides more channels and routes for the diffusion of drugs
37
Q

Alcohol diffusion coefficients are higher in dry skin, true or false?

A

FALSE

  • formulations with high levels of alcohols will improve with HYDRATED skin
  • diffusion coefficient is 10x higher
38
Q

What is the water content of the stratum corneum?

A

15-20% of the dry weight

- varies with the external environment

39
Q

How do you improve the hydration of the SC with formulations?

A

OCCLUSION - prevent water evaporation/loss

  • transdermal pathces
  • plastic films
  • paraffins/oils/waxes for ointments
  • water in oil emulsions
  • oil in water emulsions that can donate water to the skin
40
Q

How do liposomes/other lipid nanoparticles aid penetration through the SC?

A

small size aids their penetration

41
Q

What are the different types of lipid nanoparticles?

A
  • liposomes
  • deformable liposomes (transfersomes)
  • ethosomes
  • niosomes
  • solid lipid nanoparticles
42
Q

How do LIPOSOMES aid penetration through the SC?

A
  • hydrate and/or alter lipid layers
  • if the lipids used are similar to the lipids of the SC, can readily enter/fuse with lipids of the SC
  • exchange of lipids = fluidisation and fusion
43
Q

What are deformable liposomes made up of?

A
  • 10 - 25% surfactant
  • 3 - 10% ethanol
  • lipids

they become flexible and fluid, easily deformable so that they can squeeze through channels in the SC (that are less than 1/10 of the diameter of the transferosome itself)

44
Q

What are ethosomes?

A
  • high alcohol content liposomes

- fluidises lipids & makes them more flexible

45
Q

What are niosomes?

A
  • vesicles composed of non-ionic surfactants
46
Q

What are solid lipid nanoparticles (SLN)?

A

carriers for enhanced delivery of

  • suncscreens
  • vitamins A & E
  • triptolide
  • glucocorticoids
47
Q

What is an SLN and an NLC?

A
  • solid lipid nanoparticle

- nanostructure lipid carrier

48
Q

What is the structure of an SLN?

A

perfect solid matrix

this forces the encapsulated drug molecules to the surface of the particle
= rapid release of the drug from the surface of the particle

49
Q

What is the structure of an NLC?

A
  • solid lipid matrix immersed in oil droplets
    = imperfect liquid crystal lattice

solid lipid matrix - immobilises the drug and stops nanoparticles from coalescing

liquid lipid - increases the drug loading capacity
= no rapid release of drugs from the surface of the particle

50
Q

What excipients can cause keratin fibres to be disrupted?

A
  • decylmethylsulphoxide
  • urea
  • surfactants
51
Q

What excipients can cause the lipids in the lamellae to be fluidised?

A
  • DMSO
  • alcohols
  • fatty acids
  • terpenes
52
Q

What are the different mechanisms of the excipients to cause keratin and lipid disruption?

A
  • excipients MIX homogeneously with skin lipid
    = fluidises the lipids and changes drug solubility
  • excipients EXTRACT skin lipids
    = disrupts the structure, leaving aqueous channels/microcavities
  • excipients POOL with lipid domains (only at high conc)
    = creates permeable pores that provide less resistance to polar molecules
53
Q

What factors of the permeating agents affect the permeation of the skin?

A
  • chain length
  • polarity
  • unsaturation
  • functional groups
54
Q

What is the optimal factors for a permeating agent to increase their effect?

A

SATURATED

  • chain length C10 - 12
  • attached to a polar head group

UNSATURATED
- chain length C18

55
Q

What is the main disadvantage of penetration enhancers?

A

skin irritation

significant disruption to keratin/lipids may cause an immune response and cause damage

56
Q

What is the meaning of recovery in relation to permeation of the skin?

A
  • how much of the drug has passed THROUGH the skin barrier to reach systemic circulation
57
Q

What is the meaning of absorption in relation to permeation of the skin?

A
  • how much of the drug has been STUCK in the lamellae and hasn’t partitioned into the blood
58
Q

Painless and Needle Free Injectors

A
  • spring powered/high pressure gas
  • reusable
  • subcutaneous, IM or intradermal
  • bioequivalent to normal needle injections
59
Q

What are painless and needle free injectors used for?

A
  • vaccines

e. g. powderject
- uses helium gas to create holes in the tissue to form a channel
- forces drug through at supersonic speeds
- causes cell death on entry BUT
- has limited damage and pain

60
Q

Microneedle Patches

A
  • stratum corner pierced with needles (minimally invasive)
  • delivery of small molecues/proteins/nanoparticles
  • create micron scale pathways in the skin (channels)
  • actively drive drugs through the skin, insertion
  • targets the stratum corneum, but can target further down with longer needles
61
Q

What are the different types of microneedle?

A
  • solid microneedles
  • hollow microneedles
  • rapidly separating microneedles
  • drug coated microneedles (metal)
  • dissolving microneedles (biodegradeable polymer, limited disruption to the skin)
62
Q

Powered Patches: Ionophoresis

A

uses low-voltage current to increase the permeability of charged and uncharged drugs

63
Q

How does ionophoresis enhance permeation of CHARGED drugs?

A
  • 2 electrodes on the patch will encourage the movement of charged drugs from the patch to the skin
64
Q

How does ionophoresis enhance permeation of UNCHARGED/WEAKLY CHARGED drugs?

A

by changing the electroosmotic flow of water:

  • electrical current moves cations (Na+) into the skin
  • keratin is negatively charged and is fixed
  • flow of the cations creates an osmotic imbalance
  • water from the patch then flow into the skin
  • the drug then moves with the water
65
Q

Rate of delivery of drugs is proportional to the electrical current in ionophoresis, true or false?

A

TRUE - proportional to the charge

- so you can personalise dosing according to a patient by increasing/decreasing the electrical current

66
Q

What is the maximum delivery rate in ionophoresis?

A
  • maximum delivery rate is the maximum current the patient can tolerate
  • this is the rate limiting step
  • electrical current will reach underlying nerve tissue which can cause skin damage
67
Q

Powered Patches: Electroporation

A

electric current & microneedles

  • short, high voltage pulses disrupts the cell membranes and lipid lamellae
  • creates electropores that can last hours (reversible disruption)
  • stratum corneum has higher resistance than the deeper tissues - this decreases on application of the electrical filed
68
Q

What is the rate limiting step of electroporation?

A

electrical field distributes to deeper tissues which contain sensory and motor neurons:
- muscle twitching and pain

avoid/minimise this using closely spaced micro electrodes that constrain the strength of the electrical field just to the stratum corneum

69
Q

Power Patches: Phonophoresis

A

ultrasound - an oscillating pressure wave at a frequency too high for humans to hear
- for small lipophilic compounds
- disrupts the lipid structure of the stratum corneum
- low-freuqency ultrasound causes formation, oscillation and collapse of bubbles
- bubbles collapse, release energy and disrupts the lipids around the bubbles
= causes small holes in the skin

70
Q

What are the advantages of phonophoresis?

A
  • no electric current so no pain issues

- enhances delivery of lidocaine, insulin, heparin, tetanus vaccine

Pharmaceutics (6 decks)

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