topical formulation design Flashcards
what is transdermal delivery?
Transdermal delivery is controlled systemic delivery.
how does transdermal delivery work?
Large surface area so potentially numerous sites.
Good patient compliance
Easy cessation of therapy in problematic cases
Avoidance of first pass hepatic metabolism
would higher or lower melting point be absorbed faster?
lower
is lipophilic molecules or hydrophilic molecules better delivered
lipophilic
how can you find a good candidate for topical formulation?
- From experience (and literature), want a drug with:
MW 300-500
Log P(octanol/water) 1- ~ 3.5
Aqueous solubility >100 mg/mL - estimate drug fux
- After estimating flux from equations, looking at physico-chemical properties (MW, solubility, log P, melting point), calculating dose and comparing molecule with similar ones in literature, take a reality check!
If within an order of magnitude of dose required, may have a chance of delivering to therapeutic levels in vivo (possibly using formulation strategies)
If 2 orders of magnitude, unlikely!
(unless delivery to broken skin barrier, e.g. psoriasis)
- The formulation should be designed to ensure appropriate release of the drug
Rapid release for a locally acting drug
Sustained and slow release for a 7-day patch
If the formulation contains a moderately lipophilic drug in a lipophilic oily base, the drug is less likely to partition out of the formulation and enter the lipophilic skin barrier than if it is applied from a more aqueous base.
Essentially, the vehicle should allow some solubility of the drug but should not retain the drug by being a very good solvent
- flux = conc. x permeability coefficient (Kp)
So, saturated solutions deliver most (Kp fixed for a given molecule from a given solvent).
Saturated solutions (suspensions) give maximum thermodynamic activity
So, can use a low conc. of a saturated drug to deliver drug
rule 6: occlusion helps covering the skin
Allows the SC to equilibrate with underlying (wet) epidermis
Stops Transepidermal Water Loss (TEWL)
Hydrates tissue – up to 400% water content
Promotes delivery of hydrophilic and hydrophobic compounds
Can cause irritation of underlying skin
Patches typically occlude, thus promoting drug delivery
Some preparations require occlusion to deliver the required dose to therapeutic levels, such as EMLA cream, applied as a thick layer under an occlusive dressing
Or, occlusion can also be inadvertent such as when applying hydrocortisone ointments or creams to treat nappy rash when tightly-fitting waterproof pants can occlude the area.
when is semisolid formulation used?
Semisolid formulations selected for increased residence on the skin
when is transdermal patches used?
Transdermal patches for extended drug delivery through the skin
when is liquid formulation used?
Liquid formulations for a rapid short-term drug input into the skin.
for normal to oily skin type what is preffered?
For normal to oily skin types, gels are often preferred.
for normal to dry skin types what is preffered?
For normal to dry skin types, lotions are often preferred.
for dry skin what is preferred?
cream
what vehicle should be chosen for hairy areas?
lotions, gels or sprays
what vehicle is used for intertriginous areas (sites where skin may touch or rub)
creams or lotions
what type of formulation should be used for skin lesions - wet or weeping?
aqueous based - cream, lotion or gel
what type of formulation should be used for thickened scaly lesion - dry
fatty formulation - ointments, paste
what are the rules for a topical formulation?
Normal rules apply! Must be:
Stable
Drug and excipients must be compatible
Drug must be released from the dosage form following application.
Should be cosmetically acceptable with a good skin feel, texture and fragrance
- But depends on indication!
- Alcoholic gel formulation to broken skin is unlikely to enhance patient compliance
in topical formulation how much percentage is bioavailable?
For topical products (e.g. creams and gels), typically only between 1 and 3% of the applied dose is bioavailable
what is the bioavailability of patches?
Bioavailability from patches is typically 30-70% for drugs such as buprenorphine and fentanyl.
what are enhancers?
Chemicals that interact reversibly with skin to promote drug flux
Typically disrupt stratum corneum inter-cellular lipid structure
Described in lecture 2 that lipids have to be crossed by a molecule either intercellular or transcellular pathways
May also alter intra-cellular keratin conformation
Can also change partitioning into the tissue (reservoir effect)
what is the Hawthorne effect?
We know what we should be doing… but don’t… and then “remember” just before we go to visit the doctor / dentist/ pharmacist!
what are the reasons for non-adherance?
Lack of efficacy or patient dissatisfaction with the efficacy
Side effects or fear of side effects.
The fear of side effects of topical corticosteroids may have a larger impact on adherence than actual side effects
The complexity or inconvenience of the treatment regimen
Even twice a day can be challenging!
Patches adherence better than creams / ointments
The cosmetic properties of topical agents or even the smell of the drugs may be very important factors contributing to adherence.
Permeation through human skin well know to be variable to what?
Little / no difference male:female or with age (mature skin)
Neonatal skin more permeable
Variable with skin site
Also different follicular densities (shunt routes) with skin site
Little racial variability to most drugs
Possible variations with skin treatments
Moisturisers, soaps?
Significant variations with diseased states
Psoriasis etc
Also less obvious conditions, dry skin
