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transdermal drug delivery Flashcards

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1
Q

define transdermal drug delivery

A

Delivery of a drug across the stratum corneum

and into the systemic circulation

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2
Q

define topical delivery

A

Delivery of a drug across the stratum corneum and

into the deeper skin layers for local action

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3
Q

what are the advantages of transdermal delivery systems?

A 
• Controlled release of drug into 
systemic circulation
• Decrease in dosage frequency
• Avoidance of liver metabolism
• Increased bioavailability, 
administration of a lower dose
• Safer –no G.I. side effects
• Patient compliance
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4
Q

what are the limitations of transdermal drug delivery?

A 
• Permeability barrier
– Only small, lipophilic molecules 
can permeate through the skin
• Low dose delivery
– Potent molecule
• Inter- and intra-patient 
variability in skin permeability
– Wide therapeutic window
• Skin irritation
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5
Q

what are the 3 tissue layers of the skin?

A

epidermis, dermis, subcutaneous fat tissue

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6
Q

what is the multicomponent organ the skin comprised of?

A

▪ Three tissue layers: epidermis, dermis, subcutaneous fat tissue
▪ Skin appendages: hair follicles, sweat glands
▪ Epidermal enzyme systems: e.g. esterases

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7
Q

what is the stratum corneum?

A

the main barrier to drug transport across the skin

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8
Q

how is drug removed in the skin?

A

• Drug removed from blood supply in dermis
▪ Concentration gradient between drug on skin surface and the dermal
vasculature –sink conditions
▪ Driving force for diffusion across the skin membrane

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9
Q

how does drug delivery occur in the skin?

A

Multi-step process of alternating partition and diffusion
▪ Dissolved drug molecules diffuse along the vehicle, towards the vehicle/skin interface
▪ Partitioning of drug from vehicle into the SC, diffusion through SC
▪ Partitioning from SC into viable epidermis, diffusion through viable epidermis (aqueous)
▪ Partition from epidermis into dermis, diffusion through dermal tissue
▪ Partition into capillaries and removal by systemic circulation

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10
Q

what are the other potential dates of drug delivery in the skin?

A

▪ “Reservoir effect” = drug binds to keratins in SC
▪ Enzymatic metabolism = drug degradation or activation (pro-drug) by skin enzymes in viable epidermis
▪ Partitioning into subcutaneous fatty layers

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11
Q

how does permeation occur through the stratum corneum?

A

“Brick and mortar” structure of stratum corneum
▪ “Bricks”: corneocytes (terminally differentiated keratinocytes)
▪ “Mortar”: intercellular lipid domain (ceramides, fatty acids, cholesterol)

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12
Q

what is the intrercellular pathway of the SC?

A

▪ Diffusion via the intercellular lipid domain
▪ Main pathway for small, uncharged, lipophilic molecules
▪ Pathlength of permeation (~ 500 μm)&raquo_space; thickness of SC

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13
Q

what is the intracellular pathway of the SC?

A

▪ Sequential partition and diffusion across the corneocytes

▪ Pathlength of permeation ~ thickness of SC ~ 20 μm

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14
Q

what is appendageal transport?

A

▪ Significant in vivo contribution
▪ Important route for large, polar molecules and ions e.g. iontophoresis, and
vesicular structures

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15
Q

how do the pathways of the SC operate?

A

can operate concomitantly

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16
Q

what is the mathematical description of passive transdermal delivery?

A

▪ Significant in vivo contribution
▪ Important route for large, polar molecules and ions e.g. iontophoresis, and
vesicular structures

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17
Q

what does the diffusion coefficient D measure?

A

measures the diffusion speed of a molecule

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18
Q

what does the diffusion coefficient depend on?

A

▪ The viscosity of the diffusional pathlength (η)
▪ Size (radius) of diffusing molecule (r)
▪ Temperature of the skin (T)

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19
Q

what are the ideal therapeutic properties of a drug for passive transdermal delivery?

A
  1. Therapeutic properties
    • Low daily dose (<10 mg/day)
    • Short half-life (t1/2 ≤ 10 hours)
    • Non-irritating or sensitizing to skin
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20
Q

what are the ideal physiochemical properties for transdermal drug delivery?

A

Low molecular weight (< 500 Daltons)
▪ D is inversely proportional to molecular size of drug
• Aqueous solubility
▪ > 1 mg/ml to be removed by blood supply
• Optimal partition coefficient K (log Ko/w = 1 to 3)
▪ Lipid solubility to diffuse across SC
• Low melting point (< 200 °C)

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21
Q

what are methods to increase drug diffusion via the skin?

A

• Alteration of K, D, Cv variables
– Increase Ksc/v of drug
– Increase D of drug across SC
– Increase Cs of drug in the vehicle

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22
Q

how do you make a hydrophilic drug into a lipophilic prodrug?

A

Attach a lipophilic functional group e.g. ester group
– Prodrug has optimal K
– Prodrug is converted to active drug by enzymes in viable
epidermis

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23
Q

what is cmax?

A

maximum solubility of drug in vehicle = saturation concentration of drug
in vehicle i.e. dissolved drug molecules are in equilibrium with solid drug

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24
Q

what is the purpose of chemical enhancers?

A

Diffuse into the skin and reversibly alter the properties of the
stratum corneum

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25
what do chemical enhancers do?
• Increase D: disrupt the packing of the lipid bilayers Accumulate within SC lipids Aqueous channel formation e.g. oleic acid, surfactants, sulphoxides (DMSO), azone, alcohols • Increase D: disrupt protein structure Alter keratin conformation Proteins embedded in lipid bilayers e.g. ionic surfactants, sulphoxides (DMSO, DMF, DMA) • Alter K: change the solvent nature of stratum corneum Pyrrolidones, propylene glycol, water, ethanol
26
what are the ideal properties with chemical enhancers?
– Pharmacologically inactive, non toxic/allergenic, compatible with drug – Immediate & reversible effect – Unidirectional action
27
what is the problem with chemical enhacners?
safety issues
28
what is an eutectic mixture?
Mixture of the drug with another component at a certain ratio where they inhibit crystallisation of each other
29
what properties does an eutectic mixture have?
– Stable formulation | – Eutectic system has a lower melting point than either of the two components
30
what is the ideal solution therapy?
– “thelower the melting point of the drug the higher its solubility in the stratum corneum lipids”
31
why us mp suppression, using eutectic mixture at or below 32 degrease desirable?
because it results in a liquid eutectic mixture
32
give examples of eutectic mixtures
Ibuprofen-thymol, | lidocaine-menthol, testosterone-menthol, lidocaine-prilocaine (EMLA cream)
33
what are liposomes?
Definition: Phospholipid vesicles – Modify lipid component to imitate stratum corneum lipids (e.g.ceramides): “Cerasomes” – Topical delivery- reservoir formation in stratum corneum – Not effective for transdermal delivery
34
what are ethosomes?
– Liposomes with 30% ethanol | – Enhance transdermal delivery
35
what are transfersomes?
– Elastic liposomes: phospholipid + surfactant + ethanol – Squeeze through pores in stratum corneum – Hydration gradient –non-occlusive vehicle
36
define transdermal drug delivery patches?
Flexible pharmaceutical preparations containing one or more active substances, intended to be applied on unbroken skin in order to deliver the active substance(s) to the systemic circulation after passing through the skin barrier”
37
how long should you apply transdermal patches for?
1-7 days, depending on the medication
38
what are the main patch components?
backing layer liner adhesive
39
what is the backing layer responsible for?
•Protects patch components from environment throughout application –Occlusive (low water vapor transmission) –Flexibility
40
what is the liner responsible for?
* Polymer material that covers the adhesive * Removed to allow patch application on the skin * Occlusive, to minimise loss of volatile patch components
41
what is the adhesive responsible for?
* Attaches patch to skin * Polymer: acrylic, polyisobutylene (PIB), silicone * Visco-elastic material * May contain the drug and excipients
42
what are the two optional patch components?
membrane | matrix polymer
43
what is the purpose of the membrane?
Moderates the rate of drug release from drug reservoir into the adhesive layer • Steady-state drug release
44
what is the purpose of the matrix polymer?
Layer containing drug dispersed or dissolved in a polymer matrix
45
what does QC testing test for?
* Uniformity of dosage units BP * Uniformity of content BP * Dissolution BP * Adhesive performance
46
what release patters does a resevoir( membrane controlled) system follow?
steady state release
47
what factors should be present in the BP dissolution for transdermal patches?
– Temperature of dissolution medium: 32 ±0.5C | – pH of dissolution medium ~ 5
48
how do you test adhesive performance?
* Peel test * Tack test * Rheological criteria for adhesive performance
49
how does active transdermal delivery work?
– Increasing the energy of drug molecules - Iontophoresis, Electroporation, Sonophoresis – Bypassing or removing skin barrier - Stratum corneum bypass or removal
50
what is iontophoresis?
Movement of molecules across the skin under the influence | of an electric field
51
what would be the ideal properties dor iontophoresis?
broad range of drugs, ideally charged mol
52
what voltage is ued in iontophoresis?
use low voltage electric current <1V
53
how can drug transport rate be monitored in iontophoresis?
by adjusting the | electrical current
54
what are the properties of the drug resevoir in the iontophoretic patch?
– Aqueous, biocompatible gel – pH to optimize iontophoretic delivery and skin tolerance – +ve drug at anode, -ve drug at cathode
55
what is the purpose of the return resevoir in the iontophoretic patch?
Saline and charged molecules to complete circuit
56
what mechanisms does the ionotropic drug transport work by?
Electrophoretic mechanism – Transport of molecules under direct interaction with electric field – Charged molecules of low MW • Electro-osmotic mechanism – Transport of molecules under the influence of the electrically induced solvent flow – Solvent flow: Flux of skin cations from anode to cathode – Uncharged, large molecules e.g. peptides, or +ve drug molecules
57
how does an E-trans fentanyl system work?
* 24-hour system, administration up to 6 times/hour | * Pain relief within a few minutes after pressing button
58
what is electroporation?
Formation of transient aqueous pores in the skin by short | electrical pulses of high voltage
59
what volts is used in electroporation?
100 -1000 Volts
60
what does electroporation disrupt?
Disruption of lipid structure of stratum corneum
61
how long does it take for electroporation effect to be reversed?
seconds to hours
62
what is sonophoresis?
Low frequency ultrasonic energy (~ 20 kHz) | • Thermal effect by absorption of ultrasound
63
how does microneedles work?
Array of m silicon needles or biodegradable needles • Microneedles do not reach dermis: pain-free drug delivery • Pre-treatment of skin or drug administration device • Microneedles can be either drug-coated or drug-loaded
64
how does powderject system work?
Supersonic wave of helium gas | • Solid drug particles (20-100 μm) fired into lower skin layers
65
what does the laser alblation do?
Partial or complete removal of stratum corneum • Has been used for cosmetic resurfacing of skin • Requires specialised practitioner • Reversible technique- skin regeneration

PHA 333 (42 decks)

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