Skin structure, varios mechanisms of drug absorption. classification of penetration enhancers and their mode of action

1. PENETRATION
ENHANCERS
Naresh gorantla M.pharm, (Ph.D)
BALAJI COLLEGE OF PHARMACY,
ANANTAPUR
4/24/2020 1

2.  The aim of drug administration via skin can be either
the local therapy or the transdermal drug delivery of
the systemic circulation.
 Transdermal system delivers medications through the
skin direct into the blood stream.
 One long standing approach to increase the range of
drugs that can effectively delivered via this route has
been to use penetration enhancers: chemicals that
interact with skin constituents to promote drug flux.
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A diagrammatical cross-section through human
skin

4.  Weight of skin: 8 pounds
 Surface Area: 20,000 sq. cm.
 Three layers:
 Epidermis (Stratum corneum):dead keratinized
cells, density 1.55,
palms& soles : 100 micrometer.
Other portions: 10 micrometer in dry state & 40 to
50 micrometer in hydrated state.
Dermis: consists of proteins in a matrix of muco
polysaccharide, blood vessels, lymphatics, nerves,
hair follicles, sebaceous & sweat glands.
Subcutaneous layer
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5.  It involves passive diffusion of substance through skin.
 Transcorneal penetration:
 Intra cellular penetration.
 Inter cellular penetration.
 Transappendegeal Penetration.
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6.  Solubility in stratum corneum
 Diffusion through stratum corneum
 Partitioning
 Diffusion through viable skin tissue
 Condition of skin
 Effect of moisture
 Effect of vehicles
 Effect of concentration of medicament
 Effect of surfactant
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7.  Skin penetration enhancement technique have been
developed to improve bioavailability & increase the range of
drugs for which topical & transdermal delivery.
 Penetration enhancers penetrates through skin to decrease
the barrier resistance.
 Alternatively, physical mechanism such as iontophoresis &
phonophoresis can be used for certain cases of drugs.
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8.  Chemical enhancers or penetration enhancers or absorption
promoters are the agents that interact with skin constituents
to promote the drug flux.
 Many agent have studied & evaluated for enhancement
properties.
 Yet their inclusion in skin formulation is limited due to
unknown mechanism & toxicity.
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9.  Non toxic, non irritating, non allergic.
 Ideally work rapidly.
 Pharmacologically inert.
 Its duration of action should be predictable & reproducible.
 Should work unidirectionally.
 When removed from skin barrier properties should return
both rapidly & fully.
 Cosmetically acceptable.
 Compatible with both excipients & drug.
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10. 1. By increasing the diffusion coefficient of the drug.
2. By increasing the effective concentration of the drug in the
vehicle.
3. By improving partitioning between the formulation and the
stratum corneum.
4. By decreasing the skin thickness.
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11. 1. Surfactants :
a) Ionic: SLS, Na laureate, etc.
b) Non ionic : Tween 80, Polysorbates, etc.
2. Bile Salts & Derivatives :
E.g.. Na glyacolate, Na deoxycholate
3. Fatty Acid & Derivatives :
E.g.. Oleic acid, Caprylic acid, etc.
4. Chelating Agents :
E.g.. EDTA, Citric acid, etc.
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12. 5. Sulphoxide :
E.g.. DMSO, DMA, DMF, etc.
6. Polyols :
E.g. : PG, PEG, Glycerol, etc.
7. Monohydric Alcohols :
E.g. : Ethanol, 2- Propanol, etc.
8. Miscellaneous :
E.g. : a) Urea & its derivatives
b) Terpenes & Terpenoids
c) Phospholipids
d) Water
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14.  The water content of human stratum corneum is
typically around 15-20% of tissue dry weight.
 Soaking the skin in water, exposing the membrane to
high humidities or, occluding allow the stratum
corneum to reach water contents in equilibrium with
underlying epidermal skin cells.
 Water content increases to 400%
 In general, increased tissue hydration appears to
increase transdermal delivery of both hydrophilic &
lipophilic permeants
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15.  Water present in stratum corneum is in two form, bound
& free,
 Free form act as solvent for polar permeants to diffuse.
 MOA:
- free water act as solvent & alter solubility of permeants
& so its partitioning. .
- The corneocytes take up water and swell, such swelling
of cells would impact upon the lipid structure between
the corneocytes causing some disruption to the bilayer
packing.
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16.  Dimethyl sulphoxide(DMSO), aprotic solvent which form
hydrogen bond with itself rather than with water.
 used in many areas of pharmaceutical sciences as a
‘‘universal solvent’’.
 Promotes both hydrophilic & hydrophobic permeants.
 Effect is concentration dependent(> 60% needed for
optimum action).
 At high concentration – erythema & whales, may
denature proteins.
 Metabolite dimethyl sulfide produces foul odor on
breath.
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17.  To avoid above side effects researchers have
investigated chemically related materials – DMAC &
DMF
 MOA:
- denature protein, changes the keratin confirmation
from α - helical to β – sheet.
- interacts with the head groups of some bilayer
lipids to distort to the packing geometry.
- also may facilitate drug partitioning from formulation
to this universal solvent.
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 First chemically design molecule as penetration enhancer.
 Promote flux both hydrophilic & lipophilic permeants.
 Highly lipophilic with Log o/w =6.2.
 Effective at low concentration(0.1 – 5%).
 Soluble in & compatible with most organic solvents.
 Enhances permeation of steroids, antiviral & antibiotics.
 MOA:
- Interact with the lipid domains of the stratum corneum.
- Partition into the lipid bilayer to disrupt their packing
arrangement.

19.  Mostly used member : 2- Pyrrolidone(2P) & N- Methyl -2-
Pyrrolidone(NMP).
 NMP & 2P are miscible with most organic solvents.
 Used for numerous molecules including hydrophilic (e.g.
mannitol, & 5-FU) and lipophilic ( hydrocortisone and
progesterone) permeants.
 Greater effect on hydrophilic drugs.
 MOA:
- may act by altering the solvent nature of the membrane and
pyrrolidones have been used to generate ‘reservoirs’ within
skin membranes.
- Such a reservoir effect offers potential for sustained release
of a permeant.
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20.  Oleic acid & other long chain fatty acid are used.
 Effective at low concentration(<10%)
 Used both for hydrophilic & lipophilic drugs.
 Saturated alkyl chain lengths of around C10–C12 attached
to a polar head group yields a potent enhancer.
 In unsaturated compounds, the bent cis configuration is
expected to disturb intercellular lipid packing more than
trans.
 Used for estradiol, acyclovir, 5 FU, Salicylic acid.
 MOA:
- Interacts with & modifies the lipid domains of stratum
corneum discrete lipid domains is induced within stratum
corneum bilayer lipid on exposure to oleic acid.
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21.  Ethanol is used most commonly in patches.
 Used for levonorgestrol, estrdiol, 5 FU, etc.
 Its effect is concentration dependent, at high
concentration causes dehydration of biological
membrane & decreases the permeation.
 Applied in concentration range from 1 – 10%.
 Branched alkanols lower activity
 1- Butanol most effective.
 1-octanol and 1-propranolol to be effective enhancers
for salicylic acid and nicotinamide.
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22.  MOA:
- Act as solvent.
- alter solubility property of tissue leads to improvement in
drug partitioning.
- volatile nature of ethanol help in modifying thermodynamic
activity of drug.
- due to evaporation of ethanol drug concentration increases
providing supersaturated state with greater driving force
- Solvent drag may carry permeant into the tissue.
- As volatile solvent may extract lipid fraction from skin.
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23.  Are made up of alkyl or aryl side chain with polar head
group.
 Have potential to damage human skin.
 Both anionic & cationic surfactant can be used, but non
ionic surfactant are safe.
 Non ionic – minor effect, anionic – pronounced effect.
 MOA:
- Solubalise the lipophilic active ingredient & also have
potential to solubalise lipids within the stratum corneum.
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24.  Used as medicines, flavoring and fragrance agents.
 Hydrocarbon terpenes less potent, alcohol/ ketone
containing terpenes moderate and oxide & terpenoid
shows greatest enhancement .
 Smaller terpenes are more active than larger.
 Non polar(limonene) agents active for lipophilic drugs &
polar(menthol) for hydrophilic drugs.
 MOA:
- Modify the solvent nature of the stratum corneum,
improving drug partitioning.
- Alters thermodynamic activity of the permeant.
- Terpenes may also modify drug diffusivity through the
membrane.
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25.  Hydrating agent, have been used in scaling conditions
such as psoriasis & other skin conditions.
 It produces significant stratum corneum hydration,
produces hydrophilic diffusion channels.
 Has keratolytic properties, usually when used in
combination with salicylic acid for keratolysis.
 Urea itself possesses only marginal penetration
enhancing activity.
 Cyclic urea analogues and found them to be as potent
as Azone for promoting indomethacin.
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26.  Generally employed as vesicles (liposomes) to carry drugs.
 In a non-vesicular form as penetration enhancers.
 Phosphatidylcholine & hydrogenated soya bean
phospholipids have been reported to enhance penetration
of theophylline & diclofenac respectively.
 MOA:
- occlude the skin surface & thus increase tissue hydration.
- phospholipids fuse with stratum corneum lipids.
- this collapse of structure liberates permeant into the
vehicle where drug is poorly soluble and hence
thermodynamic activity could be raised so facilitating drug
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27.  It is difficult to select rationally a penetration enhancer
for a given permeant.
 Penetration enhancers tend to work well with co-
solvents such as PG or ethanol.
 Most penetration enhancers have a complex
concentration dependent effect.
 Permeation through animal skins & rodent skins are
generally considerably greater than those obtained with
human skin.
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28. 1. Act on the stratum corneum intracellular keratin,
denature it or modify its conformation.
2. Affect the desmosomes that maintain cohesion
between corneocytes.
3. Modify the intercellular lipid domains to reduce the
barrier resistance of the bilayer lipids.
4. Alter the solvent nature of the stratum corneum to
modify partitioning of the drug.
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29. 1. Modification of thermodynamic activity of the vehicle.
2. Solvent permeating through the membrane could
‘drag’ the permeant with it.
3. Solubalising the permeant in the donor, especially
where solubility is very low so that can reduce
depletion effects and prolong drug permeation.
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