This document discusses transdermal drug delivery and penetration enhancement techniques. It begins with an introduction to transdermal drug delivery and the barriers of the skin. It then discusses various penetration enhancement techniques including chemical agents, physical methods, vesicles and prodrugs. Specific penetration enhancers are explained such as surfactants, fatty acids, DMSO, alcohols and terpenes. The mechanisms of these enhancers are also summarized. The document concludes with a discussion of other approaches like supersaturated solutions, eutectic mixtures, complexes, microneedles and iontophoresis. Overall, the document provides an overview of strategies to enhance drug permeation across the skin for transdermal drug delivery.

1. Presented by Guided by
Mr.Thakur Rohit.G Dr.Kokare C.R.
Sem-II(Pharmaceutics)
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2. Introduction Transdermal DDS Structure of Skin Transport across Skin
Barriers Factors Penetration enhancement References
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3.  The aim of drug administration via skin can be either the local therapy or
the transdermal drug delivery to the systemic circulation.
 Skin presents number of barriers for transport of drug through it.
 To enhance the transport of the drug through the skin various techniques
are applied called as penetration enhancement techniques and the agents
utilized in it are “PENETRATION ENHANCERS”.
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4.  Benefits of i.v. infusion can be closely duplicated without its
hassles by using skin as the port of entry of drugs.
 Adverse effects or therapeutic failures frequently associated
with intermittent dosing can also be avoided.
 Improved patient compliance.
 Self administrable & drug input can be terminated at any
point of time.
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5. Fig-1 Skin and its appendages
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6. Figure-2 Cross-section of human skin
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7. Figure-3 Barrier properties of skin
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8. Fig-4 Transport across skin
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9. Stratum Corneum
High density of skin
Low hydration of skin
Low area for solute transport (Because most
solute enter through the 0.1 micron
intercellular space.
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10. Diffusion through stratum corneum
Solubility in the stratum corneum
Partitioning
Conditions of the skin
Effect of moisture
Effect of vehicles
Effect of concentration of medicament
Effect of surfactants
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11. Skin penetration enhancement techniques have been
developed to improve bioavailability and increase the range of
drugs for topical and transdermal delivery.
Penetration enhancers (sorption promoters or accelerants)
which penetrate into skin to decrease the barrier resistance.
Alternatively, physical mechanism such as iontophoresis and
sonophoresis can be used for certain cases of drugs.
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12. Chemical Physical Vesicles
Prodrugs Iontophoresis Liposomes
Sonophoresis Transferosomes
Chemical Ethosomes
agents Magnetophoresis SLN
Ion pairs Electroporation
Microneedles
Supersaturated
solutions
Needle-free
injection
Complexes
Photomechanical
Waves
Eutectic
Systems Laser assisted
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13.  Chemical enhancers or penetration enhancers or absorption
promoters are the agents that interact with skin constituents to
promote the drug flux.
 Many agents have been studied & evaluated for enhancement
properties.
 Yet their inclusion in skin formulation is limited due to
unknown mechanism & toxicity.
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14. Non toxic, non
irritating, non
allergic
Compatible with
Ideally work
both excipients &
drug rapidly
Ideal
Cosmetically Penetration
Pharmacologically
acceptable. Enhancers inert.
Skin barrier Predictable &
properties should reproducible
return both rapidly duration of
& fully. action.
Should work
unidirectionally.
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15. 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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16. Fig-5 Mode of action of penetration enhancers
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17. 1. Surfactants :
a) Ionic: SLS, Na laurate, etc.
b) Non ionic : Tween 80, Polysorbates, etc.
2. Bile Salts & Derivatives :
e.g.. Na glycocholate, 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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18. 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
e)Azones
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19. 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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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.
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21.  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:
Solubilise the lipophilic active ingredient & also have potential
to solubilise lipids within the stratum corneum.
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22.  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 are induced within stratum corneum bilayer lipid on exposure
to oleic acid.
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23.  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 & wheal, may denature
proteins.
 Metabolite dimethyl sulfide produces foul odor on breath.
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24.  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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25.  Ethanol is used most commonly in patches.
 Used for levonorgestrol, estradiol, 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 show lower activity.
 1- Butanol most effective.
 1-octanol and 1-propranolol to be effective enhancers for salicylic
acid and nicotinamide.
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26. 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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27.  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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28.  Used as medicines, flavoring and fragrance agents.
 Hydrocarbon terpenes are 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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29.  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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30.  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.
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31.  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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32.  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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33.  Drugs with unfavourable partition coefficients.
 Prodrug approach increases the partition coefficient, hence solubility
and transport.
 Esterases in viable epidermis releases the moiety from Prodrug,
e.g.. 5-flurouacil solubility increases 25 times by use of N-acyl
derivative.
 Very polar 6-mercaptopurine was increased up to 240 times using 6-
acyloxymethyl and 9 dialkylaminomethyl promoieties.
 Lipophilic ion pair concept. eg. Ibuprofen ion pair.
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34. Supersaturated solution of drug, where high thermodynamic
activity and high penetration power.
Supersaturated solutions obtained due to evaporation of
solvent or by mixing of cosolvents.
Water is imbibed from the skin in to vehicle, thermodynamic
activity of the permeant would increase.
Increase in the flux of estradiol about 10 to 15 times have
been reported.
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35. The melting point of a drug delivery system can be lowered by formation
of a eutectic mixture, a mixture of two components which, at a certain ratio,
inhibit the crystalline process of each other.
The melting point of a drug influences solubility and hence skin
penetration.
A good eg. is cream formulation of lignocaine and prilocaine applied
under an occlusive film.
A number of eutectic systems containing a penetration enhancer as the
second component have been reported, for example: ibuprofen with
terpenes , menthol and methyl nicotinate ; propranolol with fatty acids
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36. COMPLEXES
 Cyclodextrin complexes enhance aqueous solubility and drug stability.
The CDs are relatively large molecules, and consequently both they and
their complexes are not able to permeate through intact skin easily.
Lipophilic CDs (as DM-β-CD and RM-β-CD) are absorbed to a greater
extent.
Enhance the drug thermodynamic activity.
 The enhancement of drug release from vehicles by improving the drug
availability at the lipophilic absorptive barrier surface (i.e. Skin).
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37. 4/27/2012 37

38. MICRONEEDLES
Needles with or without hollow centre channels are placed on to the skin
surface so that they penetrate the SC and the epidermis without reaching
the nerve endings present in the upper epidermis
Fig- 6 Microneedles
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39. Principle: A current passed between the active electrode and the
LidositeTM
indifferent electrode repelling drug away from the active electrode
Fig-7 Iontophoresis and into the skin. E-TRANS – In Phase III
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40. Skin electroporation (electropermeabilization) creates transient
aqueous pores in the lipid by application of high voltage of
electric pulses of approximately of 100 to 1000V/cm for short
time(milliseconds).These pores provide pathways for drug
penetration that travel straight to the horny layer.
This technology has been used successfully to enhance the skin
permeability of molecules with varying lipophilicity and size
including biopharmaceuticals with molecular weights greater than
7kDA.
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41. Fig-8 Electroporation
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42. Ultrasound pulses are passed through the probe into the skin
fluidizing the lipid bilayers by the formation of bubbles caused by
Fig-9 Sonophoresis
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cavitation 42

43. Also known as laser generated stress waves.
There is pressure pulse generated by ablation of target material
(polystyrene), MOA is unclear but it is believed that it leads to change in
the lacunar system within stratum corneum.
Experimental study on rats shows that reductions in blood glucose of
around 80 3%, and was maintained below 200mg/dl for more than 3 hr.
Hand held portable laser device.( Norrwood abbey ltd. Australia) of local
anesthetic lidocaine.
Not much of attention is paid on this technique, as it is new and due to
lack of clinical data.
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44. Fig-10 Photomechanical Wave Generator
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45. Enhancement of skin permeability by applying a magnetic
field to therapeutic molecules that are dimagnetic or
paramagnetic.
LEDDTTM
Fig-11 Laser Assisted Penetration
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46. Fig-12 Needle Free Jet Injectors
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47. Liposome-
Liposomes are colloidal particles formed as concentric bimolecular layers
that are capable of encapsulating drugs.
Amphiphilic, higher diffusivity, high biocompatibility, longer release
time, greater stability, improved penetration and controlled degradation.
MOA-
Phospholipids in liposomal systems can disrupt the bilayer fluidity in the
SC.
Used for high molecular weight and low solubility drug.
Creating a lipid-enriched environment.
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48. Ethosomes- (“soft vesicles”)
Ethosomes are soft, malleable vesicles composed mainly of phospholipids, ethanol
(relatively high concentration) and water.
Ethosomes improving the drug's efficacy, enhancing patient compliance and
comfort and reducing the total cost of treatment.
MOA-
Ethanol effect- ethanol disturbance of skin lipid bilayer, partial extraction of SC
lipids and decreases density.
Due to ethanol concentration, the lipid membrane is packed less tightly than
conventional vesicles, improves drug distribution.
e.g. Testosom patch
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49. Transfersomes-
 These are specially designed lipid surfactant vesicles
for transdermal or topical delivery of bioactive molecules.
Phospholipids, 10-25% surfactant, and 3-10% ethanol.
Ultra deformable carrier system.
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50. SALIENT FEATURES
High Deformability
High Penetration Ability Across the Skin
 High Entrapment Efficiency
 Suitable for Both High As Well As Low Molecular Weight
drugs
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51. Solid lipid nanoparticles-
Spherical, with average diameters between 50 to 500nm, Solid
lipid nanoparticles possess a solid lipid core matrix that can
solubilize lipophilic molecules.
4/27/2012 Fig-13 Solid Lipid Nanoparticles 51

52. Melting point must exceed body temperature.
Triacylglycerols (triglycerides), acylglycerols, fatty acids,
steroids, waxes.
Surfactants include lecithin, bile salts such as sodium
taurocholate, biocompatible nonionics such as ethylene
oxide/propylene oxide copolymers, sorbitan esters.
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53. MOA-
Occlusion can enhance the penetration of drugs through the stratum
corneum by increased hydration.
Due to hydration pore size will increase.
Nanoparticles have high adhesion to the stratum corneum due to their
small particle size.
 SLN of Vitamin A in gel.
TransoPlex®, AlphaRx(USA) is developing Vancomycin - Vansolin™ and
Gentamycin -Zysolin™ trade names
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54. Williams A.C, Barry B.W,2004. Penetration enhancers. Adv. Drug Deliv Rev. 56, 603-
618.
Pathan I.B, Setty C.M,2009. Chemical Penetration Enhancers for Transdermal Drug
Delivery Systems. Tropical Journal of Pharmaceutical Research. 8, 173-179.
 Baheti S.R et al., 2011. A recent approach towards Transdermal Drug delivery by
Physical and Chemical Techniques. Internationale Pharmaceutica Sciencia. 1, 42-53.
Yiping Wang et al., 2005. Transdermal iontophoresis:combination strategies to improve
transdermal iontophoretic drug delivery. Eur. J. Pharmaceut Biopharmaceut. 60, 179-191
Dhamecha D.L et al., 2009. Drug vehicle based approaches of penetration enhancement.
International Journal of Pharmacy and Pharmaceutical Sciences. 1, 24-46.
Subramony A.J et al.,2006. Microprocessor controlled transdermal drug delivery. Int. J.
Pharm. 317, 1-6.
4/27/2012 54

55. Barry B.W.,2001. Novel mechanisms and devices to enable successful transdermal drug
delivery. Eur. J. Pharm. Sci. 14, 101-114.
L Machet, A. Boucaud,2002. Phonophoresis: efficiency, mechanisms and skin tolerance. Int.
J. Pharm. 243, 1-15
Remington,2006. The Science & Practice of Pharmacy,Twenty-oneth ed. Vol.
2, Lippincott, Williams & Wilkins, pp. 959.
Jain N.K.,1997. Controlled and Novel Drug delivery, First ed. CBS Publishers &
Distributors, pp.100.
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57. 4/27/2012 57