W24 Topical drug delivery (AM) Flashcards
In terms of physiochemical properties of the drug, what factors should be considered?
- The drug needs to have an intermediate partition coefficient, i.e. not too polar, not too non-polar (higher log Ps acceptable for
targeting the outer layers of skin) - If a weak acid or a weak base, then should be in the unionised form
- Low molecular weight (<500 Daltons)
Difference between topical and transdermal delivery?
Topical= Drug is applied to treat local inflammation, local effect
Transdermal= Drug is administered below the Dermis and is absorbed into the bloodstream, systemic effect ( Goes past the Stratum corneum, Viable epidermis then Dermis)
How do drugs permeate the skin?
- The most obvious route would appear to be via the sweat ducts and hair follicles / sebaceous glands – this is not the case
- Permeation occurs directly across the stratum corneum, which is also the main barrier to drug delivery via this route
Bricks and mortar model:
Goes through Corneocycytes- “bricks” (hydrophilic)
and Lipids- “mortar” (hydrophobic)
How do drugs permeate the skin:
What is the barrier?
- There is a ceramide-rich lipid region that is complex and consists of a multiple lamellar structure presenting alternating hydrophilic/hydrophobic regions
- This ordered lipid domain presents a barrier to permeating drug molecules
- Once the stratum corneum has been crossed the permeated drug molecule is then presented with the more hydrophilic viable epidermis and then dermis.
What sites are we trying to target?
(5)
- Skin surface
Condition: UV radiation, Biting insects, e.g. mosquito
Example drugs: Chemical & physical
sunscreens (PABA/ZnO) Repellents (DEET) - Stratum corneum
Condition: Bacterial, fungal infections, Parasitic infestations
Example drugs: Antimicrobials, Anti-infectives (permethrin) - Viable epidermis
Condition: Keratinocytes, Atopic dermatitis Psoriasis, Skin cancer
Example drugs: Corticosteroids, Keratolytics (salicylic acid), 5-fluorouracil
T-cells Atopic dermatitis Tacrolimus
Melanocytes Hyperpigmentation
Vitiligo
Whitening agents (melanostatin)
Repigmentation (psoralen) - Dermis Nerve endings Local pain management Anaesthetics (lidocaine)
- Appendages Hair follicles, Eccrine glands
Acne, Hyperhidrosis
Example drugs: Topical antibiotics (erythromycin), Antiperspirants (aluminium salts)
What are the main dosage forms in topical drug delivery? (2)
- Liquid dosage forms (solutions, emulsions, suspensions)
- Semi-solid dosage forms (creams, ointments, gels, pastes)
Others: Sprays, Dusting powders, Patches/plasters
Dosage forms in topical drug delivery:
What are typical liquid dosage forms? (3)
Do they have a short/long residence time?
- Topical liquid dosage forms
− Solutions: could be simple aqueous solution, e.g. chlorhexidine gluconate +/- cosolvents (ethanol)
− Emulsions: oil or insoluble liquid drug, e.g. benzyl benzoate emulsion
− Suspensions: contain undissolved solids, e.g. calamine lotion - Liquid dosage forms will have a short residence time, i.e. they will run off → limited drug delivery to tissue
- Solvent may also evaporate leaving a more concentrated solution – this increases thermodynamic activity (more later)
Zineryt is a solution which must be mixed in the pharmacy before supplying
Dosage forms in topical drug delivery
What are typical semi-solid dosage forms?
- Semi-solid dosage forms are the dominant formulation used for topical delivery
− Creams: typically o/w or w/o formulations with the latter being more greasy. Water content necessitates a preservative.
− Ointments: usually lipophilic (oily) formulations in which a drug has been dissolved or suspended. Often viscous with lower spreadability and also “occlusive”
− Gels: aqueous formulations (+/- cosolvents) that have been thickened containing dissolved/suspended drug.
− Pastes: ointments containing high proportions of undissolved solids – very viscous, useful if spreading undesirable,
e.g. keratolytic agents harmful to health skin (psoriasis)
Ointments are typically more viscous than creams, gels
What are examples of some other dosage forms?
(not liquid or semi-solid)
− Sprays: useful for difficult to reach areas, e.g. back (sunscreen) or for depositing powders to skin surface.
− Dusting powders: absorb moisture (talc/starch) which reduces friction and can be mixed with drug, e.g. tolnaftate for athlete’s foot
− Patches/plasters: analogous with transdermal patches, i.e. drug often incorporated in a matrix. Ensure delivery to a specific area, e.g. medicated corn plaster
What is occlusivity?
What could provide this occlusivity?
- The stratum corneum is the principal barrier to water loss from the skin
- Water lost through the SC quickly evaporates – but what if that is prevented?
SC (specifically the corneocytes) absorbs water and expands – integrity of SC reduced due to lipid disordering → enhanced drug delivery
What could provide this occlusivity?
* Hydrophobic polymer, e.g. in a patch or plaster
* Ointment if oil-based (white soft paraffin)
* w/o cream, i.e. where the oil is the continuous phase l
=leading to more of the drug being absorbed (greater topical effect)
Evaluation of topical drug delivery (for info)
- Evaluation of topical drug delivery can be carried out through multiple methods (which overlap with transdermal testing)
- First question is in vitro or in vivo?
- Whilst in vivo techniques are considered the gold standard they are quite invasive if investigating topical delivery – we want to know
what’s in the skin not what has passed through it
In vivo techniques:
What is microdialysis?
− Involves insertion of dialysis tubing
into the skin (dermis)
− Perfusate pump through tubing
− Drug molecules enter perfusate
− Analysis (typically HPLC)
In vivo techniques:
What is tape stripping?
Way of quantifying the depth that a topical drug has permeated into the stratum.
− Layers of the skin (primarily stratum corneum) are successively removed using adhesive tape or specialist products, e.g. D-Squame tape
− Relatively painless technique
− Drug on tape strips removed with solvent and quantified
− Tape strips can also be examined under a microscope as a diagnosis aid for skin conditions
- Strips of tape successively removed with force
- Depth profile of drug in the skin layers can be “mapped
In vivo techniques:
What is a skin biopsy?
− More invasive than tape stripping – biopsies could be of the viable epidermis, dermis or subcutaneous fat
− Potentially painful due to neuronal network in the dermis
− Punch biopsy could be used to quantify drug concentration in different skin layers
In vivo techniques:
What is testing for physiological response?
− Relies upon the drug having some form of
physiological effect that can be observed, e.g. vasodilation → skin reddening
− Analogous with “patch testing”
− Laser doppler velocimetry used to monitor blood flow
