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Medicine Y3 Semester 1 > Biopharmaceutics of transdermal drug delivery > Flashcards

Biopharmaceutics of transdermal drug delivery Flashcards

1
Q

What does para enteron mean?

A

Avoids the intestines

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2
Q

Parenteral formulations represents ___ of all formulations

A

2/3

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3
Q

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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4
Q

Examples of percutaneous drug delivery:

A

IM, iV, SC and ID

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5
Q

Why are hypertonic formulations generally avoided?

A

due to osmotic effect

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6
Q

IV drug delivery formulations:

A

sterile solutions, suspensions, emulsions and reconstituted solids.

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7
Q

What pH are IV drugs usually administered?

A

Usually administered in aqueous buffers at neutral pH e.g. citrate, phosphate, acetate, glutamate (exceptionally pH 3-10.5)

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8
Q

Do drugs need to be completely solubilised In iv drug delivery?

A

rug must be completely solubilised – solubility affects volume administered
– Co-solvents may be added to improve solubility or stability e.g. glycerin, ethanol, propylene glycol, polyethylene glycol

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9
Q

When can hypertonic solutions be used?

A

• Hypertonic solutions can be used with slow administration

– NaCl, KCl, dextrose often added for tonicity adjustment

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10
Q

IM drug delivery characteristics:

A

• Less rapid onset of action than with IV; more rapid than sub-cutaneous injection
• Can achieve prolonged release of oily and particulate doses e.g. poorly soluble drugs
• Excipients must maintain an appropriate viscosity and avoid aggregation; may include wetting agents
• The higher the blood flow, the higher the absorption:
– Deltoid arm muscles (2ml max injection volume) provide better absorption than the buttock (5ml max volume) or thigh
– Age and disease affect blood flow
– Local environment will influence degradation e.g. proteases affecting protein drugs
• Must avoid local blood vessels when injecting

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11
Q

Subcut and intra peritoneal drug delivery:

A

– 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
– IP: into a cavity or organ e.g. liver, kidney, bladder
– Chemotherapy for abdominal tumours; 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

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12
Q

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
D: Achieves sustained drug concentrations in blood
E: Avoids the effects of variable blood flow

A

C: Compensates for rapid clearance

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13
Q

Transdermal delivery is limited due to:

A
  • the significant barrier to penetration across the skin, which is associated primarily with the outermost stratum corneum (SC) layer of the epidermis (significant barrier)
    • A daily dose of drug that can be delivered from a transdermal patch is typically 5-25 mg, limiting this route of administration to potent drugs with transdermal route
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14
Q

Maximal penetration of drugs into the SC is achieved by:

A
  • choice of drug and formulation or delivery vehicle
  • modification of the stratum corneum

Powered penetration enhancement devices are also used e.g. iontophoresis, phonophoresis and electroporation patches

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15
Q

Transdermal penetration routes include:

A

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

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16
Q

Where is the majority of skin penetration enhance focused and why?

A

On increasing transport across the stratum corneum

The other routes comprise a very small surface area (~0.1%) for permeation so do not contribute to the steady state flux of most drugs (most drugs pass throught)

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17
Q

Where does iontophoretic drug delivery focus?

A

iontophoretic drug delivery (electric current through skin )is primarily via sweat ducts and hair follicles as these offer less electrical resistance

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18
Q

Describe the structure of the stratum corner?

A

Bricks (cells) and mortar-like (lipid) structure; thickness: 10-15 µm (when dry) to 40µm (hydrated)
• Cells: 10-15 layers of keratin-rich corneocytes: polygonal “bricks” 0.2-1.5µm thick, 34-46µm in diameter. These are dead cells.
• 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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19
Q

Extruded lipid phase behaviour is different to that of biomembranes:

A
  • 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
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20
Q

Use of water in the SC

A

Water is essential as a plasticiser to prevent cracking of the SC and to maintain suppleness
Both drugs and excipients may be hydrolysed by enzymes in the skin e.g. esterases, which can affect absorption

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21
Q

Intercellular or transcellualr penetration:

A

Intercellular route major pathway for most drugs, soluble in the lipid regions or in formulations disrupting the lipid regions.

Transcellular route - more hydrophilic drugs penetrating aq regions of keratin filaments but must also traverse intercellular lipid region.

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22
Q

Fick’s law of diffusion states that steady state flux (J) (permeation/uptake) is related to:

A
  • the diffusion coefficient (D) of the drug
  • the diffusional path length or membrane thickness (h)
  • the partition coefficient (P) of the drug between the skin and vehicle
  • the drug concentration (C) applied (assumed to be constant)
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23
Q

Both solubility and partition coefficient affect drug diffusion:

A
  • an “intermediate” log P in octanol/water of 1 – 3 is ideal
  • adequate drug solubility within the lipid domains of the stratum corneum is required to permit diffusion through this region
  • the drug must also be sufficiently hydrophilic to allow partitioning into the tissues of the epidermis
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24
Q

Characteristics of a typical transdermal patch:

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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25
Q

Compare plasma concentrations of fentanyl and buprenorphine over time and explain how the differences in molecular weight, Log P, solubility and melting point may have contributed to the differing profiles over time

A
  • The low molecular weight (<500) increases the rate of diffusion and partitioning through skin
  • The log P is between 1-3, suggesting good lipid partition and suitability for transdermal delivery
  • The doses required are in the microgram range, which should be achievable via transdermal delivery
  • Poor solubility in water may impair partitioning through the stratum corneum, so an alternative solvent should be considered
26
Q

Skin permeation enhancement

Drug/vehicle:

A
  • Drug selection that has the requirements for TDDD
  • Pro-drug – ester, introduce lipophilic regions etc
  • Ion pairs, complexes
  • Chemical potential (thermodynamic methods)
  • Eutectic systems – helps promote permeation through skin
  • Liposome or vesicle-based formulations
  • Optimal permeability: low MW for higher diffusion; low MP
27
Q

Skin permeation enhancement

Stratum corneum:

A 
When a drug does not possess the ideal physicochemical properties, manipulation of the SC to enhance diffusion is necessary
•	Hydration
•	Lipid fluidisation
•	Powered electrical devices:
- iontophoresis
- phonophoresis
- electroporation
28
Q

In a design for an occlusive skin patch for effective systemic delivery of a 600 Dalton, relatively high melting point, weak acid ester 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
B: Formulating a eutectic mixture, lowering the melting point of the drug
C: Disruption of the stratum corneum lipid lamellae
D: Formation of an ion pair increasing the lipid solubility of the drug
E: Hydrolysis by enzymes in the epidermis

A

D) Formation of an ion pair increasing the lipid solubility of the drug

Esters are not charged, so won’t form an ion pair

General reminder: charged molecules are not able to pass through lipids because they are not soluble in a hydrophobic environment and are not able to partition

29
Q

The maximum skin penetration rate is achieved when:

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 (steep conc gradient)

30
Q

Most common mechanism of supersaturation:

A

Most common mechanism seen clinically: evaporation of solvent from the warm surface of the skin, resulting in supersaturation; this occurs in many topically applied formulations

31
Q

Are supersaturated systems stable?

A
  • Supersaturated systems are inherently unstable and require the incorporation of anti-nucleating agents e.g. fatty acids to improve stability
  • Complex mixtures of fatty acids, cholesterol, ceramides in the stratum corneum may provide an anti-nucleating effect, thereby stabilising the supersaturated drug formulation
32
Q

What is a eutectic system?

A
  • Eutectic mixture: two components that at a certain ratio, inhibit crystallisation of each other, thus the melting point of both components is decreased
  • In a crystal – highly organised structure and a lot of energy is needed to disrupt it, if you inhibit crystallisation, less energy is needed for the drug to undergo a phase change therefore mpt is decreased.
33
Q

Melting point influences solubility and therefore skin penetration :
The lower the drug’s melting point, the ______ the solubility in a given organic solvent, including skin lipids

A

GREATER

– Melting points can be reduced to below or around skin temperature to enhance drug solubility

34
Q

Various eutectic systems also contain a:

A

a penetration enhancer as the second component (disrupt lamellae)
–e.g. ibuprofen with terpenes, methyl nicotinate with menthol, propranolol with fatty acids, lignocaine with menthol

35
Q

Penetration enhancer activity is expressed as enhancement ratio (ER)

A

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

36
Q

Enhancement ratio is achieved by?

A
  • Disruption of the intercellular lipid lamellar structure
  • Interactions with intracellular proteins of the stratum corneum
  • Improvement of partitioning of a drug, with a co-enhancer or co-solvent penetrating the stratum corneum
37
Q

Use of water to increase skin penetration:

A
  • Alters drug solubility and partitioning
  • Increases skin hydration, swelling and opening of the SC structure, leading to increased penetration (more routes)
  • Diffusion coefficients of alcohols are 10x higher following hydration
38
Q

The water content of the SC is 15-20% of the dry weight, but hydration varies with external environment, including medications by:

A
  • Occlusion with transdermal patches, plastic films, paraffins, oils or waxes as components of ointments and water-in-oil emulsions that prevent transdermal water loss
  • Oil-in-water emulsions that can donate water into the skin
39
Q

Use of liposomes:

A

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

Their small size aids their penetration

40
Q

What are deformable liposomes or transfersomes:

A
  • contain 10-25% surfactant (e.g. sodium cholate) with 3 -10% ethanol
  • act as “edge activators”, conferring deformability and allowing them to squeeze through channels less than one-tenth the diameter of the transfersome
41
Q

Use of ethosomes:

A

their high alcohol content fluidises lipids

42
Q

Use of Niosomes:

A

vesicles composed of non-ionic surfactants

43
Q

What are solid lipid nanoparticles?

A

carriers for enhanced skin delivery of sunscreens, vitamins A and E, triptolide, glucocorticoids

• Solid lipid nanoparticles (SLN) consist of an almost perfect, solid lipid matrix

44
Q

Use of the solid lipid in SLNS?

A

In SLNs, the solid lipid matrix is almost perfect, forcing encapsulated drugs to the surface of the particle.

45
Q

What are NLC’s?

A
  • Nanostructured lipid carriers (NLCs) are composed of solid lipid matrix immersed in liquid lipid (oil) droplets
  • 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
  • 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
46
Q

Skin permeability can be increased by disrupting the structure of the SC:
Keratin can be disrupted by:

A

using decylmethylsulphoxide, urea or surfactants

47
Q

Skin permeability can be increased by disrupting the structure of the SC:
Lipids can be fluidised using:

A

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 concentrations, excipients pool within the lipid domains to create permeable pores that provide less resistance for polar molecules

48
Q

Problems with penetration enhancers:

A

cause skin irritation/immune response/ damage

49
Q

Ibuprofen mode of action:

A
  • Ibuprofen inhibits cyclooxygenase-mediated conversion of fatty acids into prostaglandins, providing analgesic & anti-inflammatory action
  • It is rapidly metabolised and eliminated in urine
50
Q

Types of permeation enhancer:

A
  • Water: hydration enhances permeation
  • Oils/lipids: fluidise skin lipids to aid permeation by fusing with, dissolving and/or altering lipid layers
  • Surfactants: disrupt lipid structure to aid permeation
  • Alcohols: fluidise skin lipids to aid permeation
51
Q

Explain the differences in short and long term permeation between the gel and cream formulations:

A
  • Initially and subsequently higher permeation from the cream, due to better skin permeating excipients and a more lipophilic formulation
  • Sustained effect from the additional lipidic excipients in the cream formulation
  • An increase in permeation from the gel after ~1 hour, presumably due to the gel permeation enhancers (solvent, surfactant poloxamer) but after a few hours, the permeation rate of the gel product declined relative to the cream
  • The cream developed 2-3 times higher permeation than the gel longer term (up to 28 hours) – due to greater permeabilisation from lipids & surfactants and water donation.
52
Q

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
B: Oil absorption in the skin increases drug permeability
C: Water absorption in the skin increases drug permeability
D: Increased melting point of the lipid lamellae increases drug permeability
E: Allergic and inflammatory reactions may arise

A

D: Increased melting point of the lipid lamellae increases drug permeability

53
Q

Rotigotine patches (2 - 8mg per 24h) are recommended as monotherapy for early phase Parkinson’s Disease / dementia, or in the later stages in combination with oral levodopa. The drug is poorly absorbed orally and extensively hepatically metabolised, with variable oral bioavailability (~1%).

It has a MW of 325, a LogP of 4.3 and is a moderately weak base (pKa 10.9), which is poorly soluble and lipophilic at intestinal and skin pH.

A: The excipients partitioning into lipid lamella improve the permeability of the drug through the skin
B: Hydrolysis of ester excipients into acids by skin esterases improves the solubility and permeation of the drug in the aqueous regions of skin
C: Improved hydration underneath the patch may reduce the permeability of this lipophilic drug through skin
D: Patches avoid dose adjustments associated with variation in drug metabolism
E: Patches avoid dysphagia issues, improve patient compliance and are preferred by health professionals

Which one of the following statements LEAST applies to rotigotine patches?

A

C: Improved hydration underneath the patch may reduce the permeability of this lipophilic drug through skin

54
Q

Use of painless and needle free injectors:

A
  • Some are spring powered and can be used 1000s of times; others use high pressure gas to force drug through the skin
  • Spring powered.
  • Can be used for SC, IM or intradermal administration
  • Bioequivalent to regular needle-based injections
  • Many different devices are available
55
Q

What is the powderject (Novartis injector)

A

Helium gas powered

56
Q

How does the powderject (Novartis injector) work?

A

Gas burst acceleration of powdered drug particles to supersonic speeds:

  • Gas sequentially bursts diaphragms bearing drug powder (0.5-5mg)
  • Used for highly potent drugs, vaccines e.g hep b, influenza
57
Q

Describe 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:
    (i) increase skin permeability by creating micron-scale pathways in skin
    (ii) actively drive drugs into the skin during microneedles insertion
    (iii) target the stratum corneum, although microneedles typically pierce across the epidermis and into the superficial dermis too.
    Examples: naltrexone, parathyroid hormone, vaccines
58
Q

Types of micro needles:

A

Needle types: solid microneedles, hollow microneedles, rapidly separating microneedles, drug-coated microneedles, dissolving microneedles containing drug

59
Q

Powered patches: iontophoresis mechanism:

A

Iontophoresis uses low-voltage current to increase permeability of:
• Charged drugs
• 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

60
Q

How does the rate of delivery increase in powered patches?

A

The rate of delivery increases with electrical current, which is controlled by a microprocessor or the patient, to enable personalised delivery
• The maximum current, and therefore delivery rate, is limited by skin irritation and pain
• 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.

61
Q

what is electroporation:

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.
62
Q

Powered patches: Describe phonophoresis

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

Medicine Y3 Semester 1 (8 decks)

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