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MAXIMIZING THEBIOAVAILABILITY OF
DRUGS APPLIED TO SKIN
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Drug or prodrug selection
Log P obat penting??
initial concentration in the first layer ofmembrane
Log P
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Chemical potential adjustment
The maximum skin penetration rate obtained when a drug is at its highestthermodynamic act. (supersaturated sol.)
Supersaturated solutions can occur due toevaporation of solvent/mixing of cosolvents
They suggested that the complex mixture offatty acids, cholesterol, ceramides, etc. in the
stratum corneum may provide anantinucleating effect thereby stabilizing thesupersaturated system.
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Hydration
Water content of the s.c. is 15 to 20% of the dryweight but can vary according to humidity of theexternal environment
Water opens up the compact layer of the horny
layer swell and open the structure of the s.cleading to an increase in penetration.
Alter permeant solubility and thereby modifypartitioning from the vehicle into the membrane.
Moisturizing factors, occlusive films, hydrophobicointments and transdermal patchesenhance skin bioavailability
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Ultrasound (phonophoresis)
The ultrasonic energy disturbs the lipid packing inthe intercellular spaces of the s.c by:
a. heatingincrease the fluidity of the stratum corneum lipidsas well directly increase the diffusivity ofmolecules through the skin barrier
b. cavitationthe formation and subsequent collapse of gasbubbles in a liquid effects
enhances drug penetration into the tissue
ultrasound can push particles through by pressureincrease in the skin, although only slightly
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Phonophoresis
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Iontophoresis
A small electric current is applied to the skinenable penetration of charged molecules intothe skin
A drug reservoir is placed on the skin under
the active electrode with the same charge as thedrug
A grounding electrode is positioned elsewhereon the body
The active electrode effectively repels the activesubstance and forces it into the skin
Transport is driven by electrical repulsion fromdriving electrode
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Contrary to iontophoresis, electroosmosis can be
used to transport uncharged and largermolecules
When an electric field is applied to a charged
skin membrane and causes a solvent flowacross this membrane
This stream of solvent carries along with it
dissolved molecules
Enhances the penetration of neutral and especially
polar substances
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Iontophoresis
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IontophoresisIonsysTM
(Fentanyl)
Vyteris Lidosite
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ElectroporationRequires a large voltage treatment for a short
period of 10 s to 100 ms
Produces transient hydrophilic pores (aqueous
pathways on the lipid bilayers) across the skin
barrierFlux increases of up to 10 000-fold have been
obtained for charged molecules
Electroporation may combine with iontophoresisto enhance the permeation of peptides such as
vasopressin, LHRH (luteinizing hormone-
releasing hormone), neurotensin and calcitonin
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Electroporation
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Needle array
The s.c can be simply bypassed by an injection,and one development of this approach is a deviceconsisting of 400 microneedles to insert drug just
below the barrier. The feel to the skin is rather
like a cat's tongue, or sharkskin The solid silicon needles (coated with drug) or
hollow metal needles (filled with drug solution)penetrate the horny layer without breaking and
without stimulating nerves in the deeper tissues
The technique may also be combined withiontophoresis.
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g. It should be compatible with a wide range of
drugs and excipients
h. The substance should be a good solvent fordrugs
i. The material should be cosmeticallyacceptable (good spreadability and skin'feel').
j. The chemical should formulate into all the
variety of preparations used topically.k. It should be odourless, tasteless, colourless
and inexpensive.
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Water
Sulphoxides (especiallydimethylsulphoxide) and their analogues
Pyrrolidones
Fatty acids and alcohols
Azone and its derivatives
Surfactants - anionic, cationic and non-ionic
Urea and its derivatives
Alcohols and glycols
Essential oils, terpenes and derivatives
Synergistic mixtures.
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Complexes
Complexation of drugs with cyclodextrins has been
used to enhance aqueous solubility and drugstability.
Cyclodextrins of pharmaceutical relevance contain 6,
7 or 8 dextrose molecules (a-, b-, g-cyclodextrin)bound in a 1,4- configuration to form rings of
various diameters
The ring has a hydrophilic exterior and lipophilic
core in which appropriately sized organic molecules
can form non-covalent inclusion complexes resulting
in increased aqueous solubility and chemical stability
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Liposomes and transfersomes
Liposomes are colloidal particles formed as
concentric biomolecular layers that are capable
of encapsulating drugsconsisting of
phospholipids and cholesterol For example, the flux of oestradiol has been
increased 20-fold using a variety of liposomes.
The same vesicles increased 10-fold the
deposition of this hormone within the stratumcorneum.
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Transfersomes are vesicles composed ofphospholipids as their main ingredient with 10-
25% surfactant (such as sodium cholate) and 3-
10% ethanol.
The surfactant molecules act as edge
activators, conferring ultradeformability on the
transfersomes, which reportedly allows them to
squeeze through channels in the stratumcorneum that are less than one-tenth the
diameter of the transfersome
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liposomes are too large to pass through poresof less than 50 nm in size, transfersomes upto 500 nm can squeeze through to penetrate
the stratum corneum barrier spontaneously Data indicate that as much as 50% of a
topical dose of a protein or peptide (such asinsulin) penetrates the skin in vivo in 30minutes.