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MALLIKARJUNAYADAV
MPHARM(PHARMACEUTICS)VAGDEVI COLLEGE OF PHARMACY,
NELLORE
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To understand the skin structure & its barrier function.
To study factor affecting penetration through skin.
To study various approaches to enhance drug
penetration through skin, including
1. Type
2. Need
3. Mode of action.
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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.04/10/23PENETRATION ENHANCERS 4
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A diagrammatical cross-section through human skin
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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It involves passive diffusion of substance through skin. Transcorneal penetration:
Intra cellular penetration. Inter cellular penetration.
Transappendegeal Penetration.
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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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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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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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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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Fick’s 2nd Law of diffusion
dC/ dt = D d2C/dx2 ---------- (1) Where, C = Conc. Of drug x = space co-ordinate D = Diffusion coefficient t = Time
Under steady state condition,
dm / dt = D C0 / h ----------------(2) Where, m= cumulative mass of drug that passes per unit area of membrane in time t C0 = Conc. of diffusant in the first layer of membrane at
the skin surface
h = Membrane thickness
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C0 = P C’0 ---------- (3)
where, P = Partition coefficientSubstituting eq. (3) in eq. (2) gives
dm / dt = D C’0 P / h ----------- (4)
From equation it can be seen that : 1. Diffusion coefficient of drug in stratum
corneum. 2. Dissolved effective conc. of drug in the vehicle. 3.Partition coefficient of drug between the
formulation & stratum corneum. 4. Membrane thickness.
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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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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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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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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 permeants04/10/23PENETRATION ENHANCERS 20
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.04/10/23PENETRATION ENHANCERS 21
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.04/10/23PENETRATION ENHANCERS 22
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.
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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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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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.04/10/23PENETRATION ENHANCERS 27
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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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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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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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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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 delivery.
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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.04/10/23PENETRATION ENHANCERS 33
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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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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NEEDLE-FREE JET INJECTORS
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Basic principle of phonophoresis. Ultrasound pulses are passed through the probe into the skin fluidizing the lipid bilayers by the formation of bubbles
caused by cavitation
PHONOPHORESIS
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Ultrasound to Enhance Skin Permeability
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IONTOPHORESIS
Basic principle of iontophoresis. A current passed between the active electrode and the indifferent electrode repelling drug away from the active electrode and into the skin,
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• Skin electroporation (electropermeabilization) creates transient aqueous pores in the lipid by application of high voltage of electrical pulses of approximately 100–1000 V/Cm for short time(milliseconds). These pores provide pathways for drug penetration that travel straight through the horny layer.
• This technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size including biopharmaceuticals with molecular weights
greater that 7kDA..
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Basic principle of electroporation. High voltage current is applied to the skin producing hydrophilic pores in the intercellular bilayers via
momentary realignment of lipids
ELECTROPORATION
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Basic design of microneedle delivery system devices. Needles with or without hollow
centre channels are placed onto the skin surface so that they penetrate the SC and epidermis without reaching the nerve endings present in the
upper epidermis.
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IN VITRO EVALUATION OF IN VITRO EVALUATION OF
PENETRATIONPENETRATION
Skin: Rat abdominal, Rabbit, Porcine,
Human cadaver
Temp.: 32 +/- 1°C. Media: Simulated
Fluid.PH : 6.8
FRANZ DIFFUSION CELLFRANZ DIFFUSION CELL
SR. NO.
NAME OF DRUG
CPE’s USED INVESTIGATORS
JOURNAL
1 5-FUSesquiterpe
ne(40 fold )
P. A. Cornwell J Pharm Pharmacol
2 Naloxone Lauric acid Bruce J. Aungst J Pharm Pharmacol
3 Acyclovir Azone Mohsen I. Afouna
International Journal of Pharmaceutics
4 CaffeineDimethyl
Formamide(12 fold )
Southwell D.Journal of Biomedical
Optics
5 Levonorgestrel Alcohols David Friend
Journal of Controlled Release
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Remington: The Science & Practice of Pharmacy, 21st edition, Vol. 2, Lippicott, Williams & Wilkins, 2006,p.n. 959.
Jain N.K; Controlled and Novel Drug delivery, CBS Publishers & Distributors, first edition, page no-100.
Williams A. C. , Barry B. W. ; Penetration enhancers; Advanced Drug Delivery Reviews ,56, 603– 618(2004) .
Heather A.E. Benson; Transdermal Drug Delivery: Penetration Enhancement Techniques; Current Drug Delivery; Bentham Science Publishers Ltd.;, 2, 23-33(2005).
Pathan I. B. , Setty C M. ; Chemical Penetration Enhancers for Transdermal Drug Delivery Systems; Tropical Journal of Pharmaceutical Research, 8 ,173-179(2009) .
Friend D. , Catz P. , Heller J. , Reid J. , Baker R. , Transdermal delivery of levonorgestrel I. Alkanols as permeation enhancers, J. Control. Release 7 (1988) 243– 250.
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Sinha V. R. , Kaur M. P. ; Permeation Enhancers for Transdermal Drug Delivery; Drug Development and Industrial Pharmacy, 26(11), 1131–1140 (2000).
Shembale A. I. , Borole D. K. , Lohiya R. T. ; Useful Permeation Enhancers For Transdermal Drug Delivery: A Review; International Journal of Pharmaceutical Research & Development – Online(IJPRD); 5(2), 1-6(2010).
Aungst B.J. , Rogers N.J., Shefter E. , Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides, Int. J. Pharm. 33 225– 234(1986) .
Cornwell P.A. , Barry B.W., Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil, J. Pharm. Pharmacol. , 46, 261– 269(1994).
Southwell D. , Barry B.W. , Penetration enhancers for human skin: mode of action of 2-pyrrolidone and dimethylformamide on partition and diffusion of model compounds water, n-alcohols and caffeine, J. Invest. Dermatol., 80, 507– 515(1983) .
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