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Y3 Med Pharmaceutics sem 1 > Biopharmaceutics of transdermal drug delivery > Flashcards

Biopharmaceutics of transdermal drug delivery Flashcards

1
Q

What are the advantages of parenteral drug delivery?

A
  • Improved control of onset of action, serum levels, tissue concentration, elimination
  • Rapidity of action e.g. via IV administration
  • Enhanced efficacy: via local delivery or for drugs that cannot adequately be formulated for oral administration
  • Ease of use: can be administered to unconscious or uncooperative patients
  • Increased compliance e.g. via depot injections or patches for contraceptives, mental health
  • 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
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2
Q

What is percutaneous drug delivery?

A

‘through the skin’: IM, IV, SC, ID

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3
Q

Which routes is volume limited for?

A

IM, SC and ID routes (can have larger volume for IV)

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4
Q

What does hypertonic mean?

A

Concentrated

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5
Q

Why are hypertonic formulations generally avoided for percutaneous drug delivery?

A

They will have as osmotic effect and draw water into the area (do not want this)

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6
Q

How is transdermal delivery limitied?

A

Due to the barrier to penetration across the skin, the stratum corneum layer of the epidermis (preventing drug penetration into vasculature)

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7
Q

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

A

5-25 mg - limiting this route to potent drugs

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8
Q

How is maximal penetration of drugs into the SC achieved?

A
  • choice of drug and formulation or delivery vehicle (potent)
  • modification of the stratum corneum (penetration enhancers)
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9
Q

What powered penetration enhancement devices can be used?

A

iontophoresis (electric current through skin), phonophoresis and electroporation patches

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10
Q

What are the different routes of penetration for transdermal delivery?

A

o Directly across the stratum corneum (major route)
o Through the sweat ducts
o Via the hair follicles and sebaceous glands
- Routes 2 and 3 only 0.1% due to a very small surface area. They use iontophoretic drug delivery as these routes offer less electrical resistance than SC

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11
Q

What is the thickness of the Stratum Corneum (SC)?

A

10-15 µm (when dry) to 40µm (hydrated – swells in the presence of water)

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12
Q

What is the SC layer made up of?

A

o Cells: 10-15 layers of keratin-rich corneocytes: polygonal “bricks” 0.2-1.5µm thick, 34-46µm in diameter
o Mortar: intercellular lipid matrix extruded by keratinocytes and includes long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters

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13
Q

How are hydrocarbon chains arranged in the SC?

A

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

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14
Q

What is essential to prevent cracking of the SC?

A

Water is essential as a plasticiser

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15
Q

What can drugs and excipients be hydrolysed by?

A

enzymes in the skin e.g. esterases, which can affect absorption

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16
Q

Which route has the majority of absorption?

A

Intercellular route

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17
Q

What characteristics does the intercellular route have?

A
  • Lipid matrix made up of alternate regions of lipid and aqueous layers (lipid lamella)
  • Drug must be lipid soluble - or formulated as such
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18
Q

What is the transcellular route?

A

More hydrophilic drugs penetrating aqueous regions of keratin filaments, BUT must also traverse intercellular lipid region

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19
Q

What is Fick’s law of diffusion?

A

J= (DC0P)/h
o J is steady state flux
o the diffusion coefficient (D) of the drug
o the diffusional path length or membrane thickness (h)
o the partition coefficient (P) of the drug between the skin and vehicle
o the drug concentration (C) applied (assumed to be constant)

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20
Q

What is an ideal logP in octanol/water?

A

1-3

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21
Q

What characteristics does a typical transdermal patch include? (7)

A
  1. Drug: molecular weight < 1000 Daltons & preferably less than 500 Da
  2. Melting point < 200oC
  3. Log P between 1 and 3
  4. No or few polar centres, like carboxylate or zwitterionic structures
  5. Kinetic half-life < 6-8 hours (transdermal delivery device mimics IV drip, maintains therapeutic concentrations of drug with a short half-life)
  6. 50 cm2 maximum patch size
  7. 5-20 mg per day usually maximum feasible dosage
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22
Q

What can be done to the drug/vehicle to enhance permeation?

A

o Pro-drug – e.g. esters: reducing amount of charged centres, introducing lipophilic groups that enhance permeation through the skin
o Ion pairs, complexes – 2 molecules with charged centres: create ion pair to reduce charge associated
o Chemical potential (thermodynamic methods)
o Eutectic systems – promotes permeation
o Liposome or vesicle-based formulations
o Optimal permeability: low MW for higher diffusion; low MP
o E.g. nicotine, nitroglycerine

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23
Q

How can the SC be manipulated to enhance permeation?

A

o Hydration – as more water is applied toe the skin, more stratum corneum layers swell up and separate, enhancing drug delivery
o Lipid fluidisation – fluidise lipid lammalae
o Powered electrical devices:
- iontophoresis
- phonophoresis
- electroporation

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24
Q

When is maximum skin penetration rate achieved?

A

When the drug has the highest thermodynamic activity e.g. when in a supersaturated solution, produced by evaporation of solvent or by mixing co-solvents

  • highly concentrated
  • supersaturates - same amount of drug dissolved in less solution
25
Q

What is the most common mechanism seen clinically for supersaturation?

A

evaporation of solvent from the warm surface of the skin, resulting in supersaturation; this occurs in many topically applied formulations

26
Q

How can we get the thermodynamic activity of the drug to increase by 5-10 times?

A

If water is absorbed from the skin into the vehicle and acts as an anti-solvent, the thermodynamic activity of the drug increases flux by 5-10 times

27
Q

Are supersaturated systems stable?

A

NO - inherently unstable and require the incorporation of anti-nucleating agents to improve stability. (lipids already present in the SC, contribute towards anti-nucleating effects)

28
Q

What can provide an anti-nucleating effect?

A

Complex mixtures of fatty acids, cholesterol, ceramides in the stratum corneum may provide an anti-nucleating effect, thereby stabilising the supersaturated drug formulation

29
Q

What is a Eutectic mixture?

A

2 components that at a certain ratio, inhibit cystallisation of each other, thus the melting point of both components is decreased

30
Q

What is the structure of a crystal and what impact does this have on melting point?

A

In a crystal, there is a highly organised structure, therefore a lot of energy needed to disrupt the structure so a drug with a crystalline structure would have a high melting point

31
Q

What will happen if you inhibit the crystalline structure?

A

If you inhibit the crystalline structure, less energy is needed for the drug to undergo a phase change – and therefore will have a lower melting point

32
Q

What relationship is there between melting point and solubility?

A

The lower the drug’s melting point, the greater the solubility in a given organic solvent, including skin lipids - melting points can be reduced to below or around skin temperature to enhance drug solubility and penetration through the skin

33
Q

What do various eutectic systems contain as the second component?

A

A penetration enhancer to interact with the SC lipids - e.g. ibuprofen formulated with terpenes (penetration enhancer that fluidises the lipids), methyl nicotinate with menthol, propranolol with fatty acids, lignocaine with menthol

34
Q

What is penetration enhancer activity expressed as?

A

Enhancement ratio (ER)

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

35
Q

How is ER achieved?

A

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

36
Q

What is used to increase skin penetration of hydrophilic and lipophilic compounds, and how does it do that?

A

Water:
o Alters drug solubility and partitioning
o Increases skin hydration, swelling and opening of the SC structure, leading to increased penetration (more channels and routes available)
o Diffusion coefficients of alcohols are 10x higher following hydration

37
Q

What is the water content of the SC dry weight?

A

15-20%, varies with external environment including medications by:
o Occlusion with transdermal patches, plastic films, paraffins, oils or waxes as components of ointments and water-in-oil emulsions that prevent transdermal water loss
o Oil-in-water emulsions that can donate water into the skin

38
Q

How is hydration achieved?

A

o Donating water to skin (o/w emulsions)
o OR Preventing water from evaporating off the skin (transdermal patches or films or w/o emulsions – creating a barrier to trap water in and maintain hydration)

39
Q

What aids lipid nanoparticle penetration through the SC

A

Their small size

40
Q

What can hydrate and/or alter lipid layers?

A

Liposomes, especially when lipids are similar to SC lipids: they can readily enter and fuse with SC lipids
o triamcinolone acetonide liposomal lotion penetrates 4 - 5X more effectively than the ointment formulation

41
Q

What do deformable liposomes or transfersomes contain?

A

contain 10-25% surfactant (e.g. sodium cholate) with 3 -10% ethanol (combination of both makes very fluid and can squeeze through small gaps in the SC)

42
Q

What do deformable liposomes or transfersomes act as?

A

act as “edge activators”, conferring deformability and allowing them to squeeze through channels less than one-tenth the diameter of the transfersome

43
Q

What are Ethosomes ?

A

their high alcohol content fluidises lipids

44
Q

What are Niosomes?

A

vesicles composed of non-ionic surfactants

45
Q

What are solid lipid nanoparticles (SLNs)?

A

carriers for enhanced skin delivery of sunscreens, vitamins A and E, triptolide, glucocorticoids - consist of an almost perfect, solid lipid matrix (more rapid release) - forces encapsulated drugs to the surface of the particle

46
Q

What are nanostructured lipid carriers (NLCs)?

A

composed of solid lipid matrix immersed in liquid lipid (oil) droplets (more sustained release)

47
Q

What does the SLN act as as apposed to the liquid NLC?

A

The solid lipid acts as a matrix to immobilize the drug and prevent nanoparticles from coalescing, whereas the liquid lipid component increases the drug loading capacity

48
Q

What drug release is observed in NLCs?

A
  • Rapid drug release from the surface of the particles is therefore observed In NLCs, the mixture of lipids of different phases forms an imperfect lipid crystal lattice
  • Thus, more drugs can be encapsulated and rapid surface release is prevented
49
Q

How can skin permeability be increased?

A

By disrupting the structure of the SC?

50
Q

How can keratin in the SC be disrupted?

A

Keratin can be disrupted using decylmethylsulphoxide, urea or surfactants

51
Q

How can lipids in the SC be fluidised?

A

o Lipids can be fluidised using DMSO, alcohols, fatty acids, terpenes
 Excipients can mix homogeneously with skin lipids, changing drug solubility
 Excipients can extract skin lipids, leaving aqueous channels or microcavities within the lipids e.g. oleic acid and terpenes
 At a high concentration, excipients pool within the lipid domains to create permeable pores that provide less resistance for polar molecules

52
Q

What is optimal penetration enhancement achieved with?

A

optimal penetration enhancement is obtained with saturated alkyl chain lengths of C10 to C12 attached to a polar head group, or C18 for unsaturated alkyl chains

53
Q

What is a disadvantage of penetration enhancers?

A

Many cause skin irritation

54
Q

What is Powderject?

A

Needle-free injector:

  • gas burst acceleration of powdered drug particles to supersonic speeds
  • used for highly potent drugs (e.g. HepB)
  • uses helium gas to propel drug particles through the skin
55
Q

What are microneedle patches?

A

• The stratum corneum is pierced with short needles to deliver drugs into the skin in a minimally invasive manner
• Drugs include small molecules, proteins and nanoparticles, released from extended-release patches
• Microneedles:
o increase skin permeability by creating micron-scale pathways in skin (physical damage)
o force of needle entering the skin, actively drive drugs into the skin during microneedles insertion
o target the stratum corneum, although microneedles typically pierce across the epidermis and into the superficial dermis too.
• Examples: naltrexone, parathyroid hormone, vaccines

56
Q

What are the different types of microneedle?

A
  • solid microneedles
  • hollow microneedles
  • rapidly separating microneedles
  • drug-coated microneedles (then pierce skin)
  • dissolving microneedles containing drug (made from biodegradable polymer – pierce skin and when in contact with biological fluids in which they dissolve. Polymeric – will cause minimal skin irritation)
57
Q

Explain Iontophersis (powered patch)

A

• Iontophoresis uses low-voltage current to increase permeability of:
o Charged drugs
o Weakly charged and uncharged drugs, by increasing the electrosmotic flow of water, because of mobile cations e.g. Na+ and fixed anions e.g. keratin

• The rate of delivery increases with electrical current, which is controlled by a microprocessor or the patient, to enable personalised delivery
o The maximum current, and therefore delivery rate, is limited by skin irritation and pain
o Iontophoresis provides control over drug dosing, because delivery is proportional to the amount of charge i.e. it is the product of current and time.

58
Q

Explain electroporation (powered patch)

A
  • Electroporation is used with microneedle patches
  • Short, high-voltage electrical pulses reversibly disrupt cell membranes and skin lipid lamellae in the stratum corneum (SC)
  • The electro-pores created persist for hours and increase diffusion by orders of magnitude for drugs, peptides, protein, DNA.
  • The SC has a higher resistance than the deeper tissues; resistance drops dramatically upon application of the electrical field
  • The electrical field distribute into the deeper tissues which contain sensory and motor neurons
  • Associated pain and muscle stimulation are avoided by using closely spaced microelectrodes, that constrain the electrical field to the SC.
59
Q

Explain phonophoresis (powered patch)

A
  • Ultrasound: an oscillating pressure wave at a frequency too high for humans to hear
  • It can be used to enhances skin permeability to small, lipophilic compounds by disrupting the lipid structure of the stratum corneum
  • Low-frequency ultrasound causes formation, oscillation and collapse of bubbles
  • Cavitation energy at the site of bubbles causes small holes to form in the skin; this enhances delivery of lidocaine, insulin, heparin and tetanus toxoid vaccine through the skin
  • Pulsed lasers can also increase skin permeability using a related shockwave mechanism

Y3 Med Pharmaceutics sem 1 (5 decks)

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