maximizing bioav

8/2/2019 Maximizing Bioav.

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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.

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