drug delivery to skin

Question 1

what is transdermal drug delivery

Answer 1

delivery of drugs to systemic circulation through skin or using target that’s on/within skin

Question 2

why is transdermal drug delivery useful

Answer 2

avoids GIT, controlled rate of drug delivery so its at steady state

Question 3

limitations of TDD

Answer 3

only a few drugs can cross skin

Question 4

name 3 pathways to penetrate through the strum corneum

Answer 4

transappendageal- hair follicles, sweat ducts offer pores to dermis

transcellular- polar route for hydrophilic molecules, unfavourable as drug needs to partition into lipid bilayers between cells

intercellular- less polar route for hydrophobic molecules, favourable as its a continuous pathway

Question 5

ways to delivery drugs transdermally

Answer 5

gels/creams/ointments- no control on amount applied and rate of drug release

transdermal patches- easy to apply, can control dose and rate, occlusive leading to increase skin hydration, different designs available

Question 6

describe 3 main designs of transdermal patches and draw diagrams

Answer 6

drug in adhesive, drug in matrix, drug in reservoir

Question 7

why is TDD challenging

Answer 7

lag time- cant be used for rapid delivery

high temperature increases release

importance of solvent- rapidly permeates through skin, permeation enhancement, drag effect

constant rate over application period- works if excess drug in vehicle

rate controlled by affinity for matrix/adhesive or by semi permeable membrane

Question 8

how are drug candidates selected for TDD

Answer 8

1, suitable physiochemical properties- MW 300 to 500 Da, Log P (octanol/water):1-3.5, solubility >100 ug/ml, neutral at skin pH (~5)

2. potent-patch surface area around 10cm^2, realistic dose delivered 10 mg/day
3. optimisation of pharmacokinetic profile
4. effectiveness at constant plasma levels
5. tolerance at constant plasma levels
6. irritancy, skin allergy issues

Question 9

how to make drugs more suitable for TDD/drug enhancement

Answer 9

-modification of physiochemical properties of drug (make into prodrug)
-optimisation of vehicle (highly deformable liposomes)
-avoidance/alteration of stratum corneum (microneedles, sonophoresis, iontophoresis)

Question 10

ways to avoid/alter stratum corneum

Answer 10

microneedles, sonophoresis, iontophoresis

Question 11

what are prodrugs and their limitations

Answer 11

attachment of lipophilic moieties to increase partitioning into stratum corneum

limitations=prodrugs are new, strategy not used a lot in industry

Question 12

what are highly deformable liposomes made of, what is their driving force and how do they work

Answer 12

-made of phospholipids and a surfactant
-driving force is xerophobia/fear of dryness
-vesicles are pulled through skin pores towards the more hydrated deep layers, more effective under non occlusive conditions

Question 13

what are microneedles, name the types and the materials theyre made from

Answer 13

use of arrays of microscopic needles to create micron scale holes in the skin

types- plain, hollow
materials- silicon, metal, polymers

Question 14

advantages and limitations of microneedles

Answer 14

advantages- painless, can delivery small and large molecules

limitations- correct geometry and physical properties for insertion into skin, can break upon insertion, blockage of hollow microneedles, challenging and expensive to produce, risk of microbiological contamination, only small doses can be delivered

Question 15

what is sonophoresis

Answer 15

use of low frequency ultrasounds to enhance skin permeability, requires a coupling medium (solution, gel, cream) to transfer ultra sounds from transducer to skin

Question 16

what is high, mid and low frequency sonophoresis used for

Answer 16

high=diagnostic
mid=treatment
low=transdermal

Question 17

describe the 2 approaches to sonophoresis

Answer 17

simultaneous- drug and ultrasound applied simultaneously, drug must not be degraded by us

pre treatment- US applied for 20-30 minutes before drug delivery, skin remains permeable for several hours, degree of permeabilisation must be controlled

Question 18

how does sonophoresis work

Answer 18

cavitation (rapid transformation and collapse of gas bubbles in coupling medium), production of shock waves and liquid microjets which disrupt lipid bilayer, heat produced increases the fluidity of lipid bilayers

Question 19

limitations of sonophoresis

Answer 19

parameters affecting skin permeation nut fully understood (US frequency, intensity, duration), long term skin damage, reversibility of technique, effect of endogenous proteins, might not be broadly applicable

Question 20

what is iontophoresis

Answer 20

application of low intensity current to drive molecules through skin, uses power supply and anode and cathode

Question 21

name and describe the 2 mechanisms of iontophoresis

Answer 21

electromigration- charged molecules driven through skin by charge repulsion
-more efficient for cations, isoelectric point of keratin ~3-4, skin negatively charged at physiological pH, cations attracted towards skin, anions must overcome electrostatic repulsion

electroosmosis- small cations present in anode compartment and skin are attracted to cathode, they drag water molecules with them
-(non charged molecules), convective fluid flows are created which entrain neutral molecules and some anionic drugs, involved in migration of large cations

Question 22

advantages and limitations of iontophoresis

Answer 22

advantages- minimally invasive, blood levels rapidly achieved, delivery terminated by stopping current, control over drug kinetics, potential for customised therapies

limitations- causes erythema, electrical discharge noticeable, expensive devices, disposal of miniaturised system

Question 23

what does narrow therapeutic window mean

Answer 23

small differences in doses/blood conc may lead to serious therapeutic failures or life threatening side reactions

Question 24

transdermal delivery of macromolecules

Answer 24

patches- no
microneedles- yes if its potent, low MW, slow release
sonophoresis- no
iontophoresis- yes if low MW, positively charged, hydrophilic

Question 25

what are combination strategies

Answer 25

using two enhancement techniques to obtain synergistic effects

-synergy if 2 different enhancement mechanisms, first one to permeabilise skin and second to provide driving forcfe