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PHA333 > transdermal drug delivery > Flashcards

transdermal drug delivery Flashcards

1
Q

What is transdermal delivery?

A

delivery of drug across the stratum corneum and into the systemic circulation

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2
Q

What is topical drug delivery?

A

delivery of a drug across the stratum corneum and into the deeper skin skin layers for local action

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3
Q

advantages of transdermal route vs oral/IV route

A
  • controlled release of drug into systemic circulation (dec dose frequency)
  • avoidance of liver metabolism (inc bioavailability, admin of a lower dose)
  • safer (no GI s/e)
  • patient compliane
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4
Q

limitations of transdermal route vs oral/IV route

A
  • permeability barrier (only small, lipophilic molecules can permeate through skin)
  • low dose delivery (potent molecules)
  • inter and intra patient variability (wide therapeutic window)
  • skin irritation
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5
Q

3 layers of skin

A

epidermis
dermis
subcutaneous fat tissue

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6
Q

main barrier to drug transport across the skin

A

stratum corneum (SC)

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7
Q

How are drugs removed from the skin?

A

blood supply in dermis

  • conc gradient between drug on skin surface and the dermal vasculature
  • driving force for diffusion across the skin membrane
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8
Q

steps for drug delivery via the skin

A
  • dissolved drug molecules diffuse along the vehicle towards the vehicle/skin interface
  • partitioning of drug from vehicle into 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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9
Q

other fates of drug delivery via skin

A
  1. '’reservoir effect’’ - drug binds to keratins in SC
  2. enzymatic metabolism - drug degradation or activation (pro-drug) by skin enzymes in viable epidermis
  3. partitioning into subcutaneous fatty layers
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10
Q

structure of stratum corneum

A
  1. corneocytes - differentiated keratinocytes
  2. intercellular lipid domain - ceramides, FAs, cholesterol
  • > no phospholipids, ceramides insetad
  • > ceramined only in lipids in skin, no where else in body
  • > '’brick and mortar’’ structure
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11
Q

intercellular pathway through stratum corneum

A
  • diffusion via the intercellular lipid domain
  • main pathway for small, uncharged, lipophilic molecules
  • pathlength of permentation 500 microm > thickness of SC
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12
Q

intracellular/transcellular pathway through stratum corneum

A
  • sequential partition and diffusion across the corneocytes

- pathlength of permeation = thickness of SC (20 microm)

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13
Q

appendageal transport in stratum corneum (hair follicles, sweat/oil glands)

A
  • significant in vivo contribution

- important for large, polar molecules and ions

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14
Q

What is diffusion of a drug in transdermal delivery?

A

spontaneous flow of molecules across an area

from a region of high concentration to a region of lower concentration, driven by a concentration gradient

slow, random movement - Brownian motion

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15
Q

Mr of a drug and its diffusion through SC

A

larger = slower diffusion through SC

smaller = higher diffusion coefficient, faster

-> low Mr drugs best for transdermal dosage forms

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16
Q

temperature and diffusion coefficient of drug transdermally

A

higher/inc T of skin = higher/inc diffusion coefficient, quicker drug release

  • > can casue s/e if it exceeds MSC
    eg. fentanyl patches, inc skin temp will inc diffusion of drug and can cause side effects
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17
Q

ideal properties of a drug for passive transdermal delivery

A
  1. therapeutic properties

2. physiochemical properties

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18
Q

therapeutic properties of drug for passive transdermal delivery

A

low daily dose (<10mg/day)

short half life (<10hrs)

non-irritating/sensitising to skin

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19
Q

physiochemical properties of drug for passive transdermal delivery

A 
low Mr (<500 Da)
- D (diff coeff) inversely proportional to molecular size of drug

aqueous solubility
- needs >1mg/ml to be removed by blood supply

optimal partition coefficient K

  • lipid solubility to diffuse across SC
  • logK o/w = 1-3

low melting point (<200 degC)

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20
Q

methods to increase drug diffusion via skin

A
  1. prodrug
  2. super-saturation
  3. chemical enhancers
  4. eutectic mixtures
  5. colloidal drug cerrier systems
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21
Q

prodrug approach

A

hydrophilic drugs to lipophilic prodrug

  • attach lipophilic fxn group (ester group)
  • prodrug has optimal K
  • prodrug converted to active drug by enzymes in viable epidermis
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22
Q

examples of prodrug approach

A

topical anti-inflammatory steroids

  • betamethasone 17 valerate
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23
Q

problem with using prodrug approach

A

needs extra toxicological studies - new chemical entity being made

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24
Q

super-saturation approach

A

max flux (Jmax) when Cv = Cmax

Cmax = max sol of drug vehicle = saturation conc of a drug in vehicle (dissolved drug molecules are in equilibrium with solid drug

but will create an unasable formulation, high tendency to crystlalise
-> add anti-nucleating excipients to prevent drug crystallisation

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25
Q

use of chemical enhancers

A

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

inc D

  • disrupt packing of the lipid bilayers
  • disrupt protein structure

alter K
- change the solvent nature of stratum corneum

26
Q

ideal properties of chemical enhancers

A
  • pharmacologically inactive, non-toxic/allergenic, compatible with drug
  • immediate and reversible effect
  • unidirectional action
27
Q

problems with chemical enhancers

A

safety issues

can be toxic, need to use in low concs for formulation

28
Q

What is a eutectic mixture?

A

mixture of drug with another component at a certain ratio where they inhibit crystallisation of each other

  • stable formulation
  • eutectic system has a lower MP than either of the 2 components
29
Q

'’ideal solution theory’’

A

the lower the MP of the drug the higher its solubility in the stratum corneum lipids

30
Q

MP for drugs for eutectic mixtures

A

< 200 degC

using eutectis mixture at or below 32 degC (skin temp) is desirable because it results in a liquid eutectis mixture

31
Q

examples of eutectic mixtures

A

ibuprofen-thymol
lidocaine-menthol
testosterone-menthol
lidocaine-prilocaine (EMLA cream)

32
Q

3 types of colloidal drug carrier systems

A
  1. liposomes
  2. ethosomes
  3. transfersomes
33
Q

liposomes for colloidal drug carrier systems

A

modify lipid component to imitate stratum corneum lipids - ceramides (‘cerasomes’)

topical delivery - reservoir formation in stratum corneum

not effective for transdermal delivery

34
Q

ethosomes in colloidal drug carrier systems

A

liposomes with 30% ethanol

enhance transdermal delivery

35
Q

transdersomes for colloidal drug carrier systems

A

elastic liposomes - phospholioid + surfactant + ethanol

squeeze through pores in stratum corneum

move across hydration gradient - non occlusive vehicle
(move from dry to moist surface)

36
Q

What are transdermal drug delivery patches?

A

flexible pharmaceutical preparations containing one or more active substances, intended to be applied on unbroken skin in order to deliver the active substances to the systemic circulation after passing through the skin barrier

forumlated med deviced that allow controlled release of drug from intact skin surface into systemic circulation

applied for 1-7 days

37
Q

patch components

A

backing layer
liner
adhesive (pressure sensitive adhesive)

optional:
membrane
matrix polymer

38
Q

backing layer of a patch

A

protects patch components from environment throughout application

  • occlusive (low water vapour transmission)
  • flexibility
39
Q

liner of a patch

A
  • polymer material, covers adhesive
  • removed to allow patch application onto skin
  • occlusive, min loss of volatile patch components
40
Q

adhesive of a patch

A
  • attaches patch to skin
  • common polyers - acrylic, polyisobutylene, silicone
  • visco-elastic material
  • may contain the drug and excipients
41
Q

membrane of patch (optional)

A
  • reservoir patch design
  • moderates the rate of drug release from drug reservoir into the adhesive layer
  • steady state drug release
42
Q

matrix polymer of a patch (optional)

A

layer containing drug dispersed or dissolved in a polymer matrix

43
Q

QC tests

A
  • uniformity of dosage units
  • uniformity of content
  • dissolution
  • adhesive performance
44
Q

drug release patterns of transdermal delivery

A
  1. reservoir (membrane controlled system)
    - steady state release
  2. drug in adhesive and matrix systems
    - Higuchi sq root of time fxn, assuming drug in suspension
45
Q

When to use diffusion cells (Franz cells)?

A

for in vitro drug release studies

46
Q

How do diffusion/Franz cells work?

A
  • dosage form applied on donor compartment
  • membrane can be artificial or human/animal skin
  • samples are collected for analysis at regular intervals
47
Q

tests for adhesive performance

A

peel test
tack test
rheological criteria for adhesive performance

48
Q

Why to use active transdermal drug delivery?

A
  • drugs that can’t be delivered by passive diffusion

- increase the drug transoport rate

49
Q

How to create active transport drug delivery?

A
  • increasing the energy of drug molecules -> iontophoresis, electroporation, sonophoresis
  • bypassing or removing skin barrier -> stratum corneum bypass or removal
50
Q

iontophoresis

A
  • movement of molecules across the skin under the influence of an electrical field
  • broad range of drugs, ideally charged molecules
  • use of low voltage electrical current <1V
  • ionophoretic drug transport rate > passive transport rate
  • drug transport rate can be monitored by adjusting the electrical current
51
Q

3 parts to iontophoretic patch

A
  1. drug reservoir
    - aqueous, biocompatible gel
    - pH to optimise iontophoretic delivery and skin tolerance
    - +ve drug at anode, -ve drug at cathode
  2. return reservoir
    - saline and charged molecules to complete circuit
  3. electronic controller
    - battery and monitor
52
Q

2 methods of iontophoretic drug transport

A
  1. electrophoretic mechanism

2. electro-osmotic mechanism

53
Q

electrophoretic mechanism of iontophoretic drug transport

A

transport of molecules under direct interaction with electric firle

charged molecules of low MW

54
Q

electro-osmotic mechanism of iontophoretic drug transport

A

transport of molecules under the influence of the electrically induced solvent flow

solvent flow - flux of skin caitons from anode to cathode

uncharged, large molecules
eg. peptides, +ve charged drug molecules

55
Q

E-TRANS Fentanyl system

A

24hr administration up to 6 times/hr

pain relief within a few mins after pressing button

56
Q

electroporation

A

formation of transient aqueous pores in the skin by short electrical pulses of high voltage

electrical currents 100-1000 volts

electric field within the stratum corneun - pain free

disrutpion of lipid structure of stratum corneum

reversibility of effect from seconds to hrs

possible skin damage

57
Q

sonophoresis

A

low frequency ultrasonic energy (20 kHz)

thermal effect by absorption of ultrasound

‘fluid velocity’ - acoustic streaming

disruption of lipid packing by cavitation

deactivation of skin enzymes

safety and effectiveness issues

58
Q

microneedles

A

micrometer silicon needles or biodegradable needles

don’t reach dermis - pain free

pre-treatment of skin/drug admin device

needles can be drug coated OR drug loaded

59
Q

Macroflux microneedle system

A

needles drug coated

can use any type of drug

60
Q

PowderJect system

A

supersonic wave of helium gas

solid drug particles (20-100um, micronised) fired into lower skin layers

into systemic circulation

61
Q

laser ablation

A

partial/complete removal of stratum corneum

used for cosmetic resurfacing of skin

specialist practitioner

reversile technique - skin regeneration

62
Q

combination strategies

A

active with passive transport enhancement

synergistic effect

PHA333 (27 decks)

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