Types and mechanism of chemical penetration enhancers

1. PENETRATION ENHANCER FOR TDDS
Presented by-
Shubham N. Gharat
M.pharm
Department of Pharmaceutics
Guided by-
Prof. A. D. Savkare
Department of Pharmaceutics
M.V.P’s College of Pharmacy Nashik-2
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2. Introduction:
• Most drug don’t have ability to penetrate stratum corneum so skin penetration
enhancer used.
• The success of penetration enhancer depends upon on the ability of the drug to
penetrate through skin in sufficient quantities to achieve the desire therapeutic
effect.
• These are the chemical which interact with skin constituents and promote the drug
flux.
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3. Skin
• The outermost layer of skin is
SC which act as a barrier.
• Bilayer lipids and surrounding
corneocytes produce Brick and
Mortar model.
Layers:
• Stratum Corneum
• Epidermis
• Dermis
• Subcutaneous tissue
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4. Penetration Enhancer:
• Penetration enhancer is a substance which used to promote the drug
transport across the skin barrier.
• It temporarily diminishing the barrier of the skin.
• It also known as accelerants and sorption promoters can enhance drug
flux.
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5. Routes of penetration enhancer:
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1. through the sweat ducts 2. directly across the stratum corneum 3. via the hair follicles

6. Factor Affecting Skin Penetration:
• pH
• Temperature
• Molecular Weight
• Partition Coefficient
• Age
• Gender
• Body site
• Skin Exposure
• Blood flow
• Skin Condition
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7. Ideal Characteristics:
• It should reduce the barrier resistance of the stratum corneum without damaging
the cells.
• It should be non-toxic , non-irritating and non-allergic.
• It should work rapidly , the activity and duration of effect should be both
predictable and reproducible.
• It should cosmetically acceptable with an appropriate skin feel.
• The penetration enhancer should work unidirectionally.
• When penetration enhancer remove from skin , barrier properties should return
both rapidly and fully to normal.
• The substance should be an excellent solvent for drugs.
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8. Types Of Penetration Enhancer:
Drug Vehicle Based:
• Drug Selection
• Vesicles and Particles
• Prodrug and ion pairs
• Chemical potential of Drug
• Eutectic System
• Complexes
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9. Chemical Penetration Enhancer:
Solvents:
• Alcohols
• Water
• Sulfoxides
• Pyrrolidones
• Azone
• Miscellaneous solvent
Surfactants:
• Anionic surfactants
• Cationic surfactants
• Non-ionic surfactants
• Fatty acid and alcoholes
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10. Miscellaneous Chemicals:
• Urea
• N, N-diethyl-m-toluamide
• Calcium thioglycolate
• Anticholinergic agents
• Miscellaneous
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11. Physical Methods:
• Iontophoresis
• Ultrasound
• Magnetophoresis
• Electroporation
• Radio frequency
• Thermophoresis
• Microneedle array
• Skin stretching
• Skin abrasion
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12. Mechanism Of Penetration Enhancer:
Lipid Disruption (Disruption of highly ordered SC)
Protein Modification (Interaction with intercellular protein)
Partitioning Promotion
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13. Contd.
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14. Chemical penetration enhancer: Solvents
Alcohol :
Ethanol and Methanol
Mode of Action:
• Removal of lipids from stratum corneum results in loss of partitioning
influence on permeability.
• And large increase in the permeation rate of both polar and nonpolar
permeates.
Ex. Estradiol and Nitroglycerine
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15. Water
Hydration of the stratum corneum will decrease in barrier function.
Hydration increase transdermal delivery of both hydrophilic and hydrophobic drug.
Mode of action:
• Water act as solvent and alter solubility of permeants and so its partitioning.
• Also on hydration corneocytes may swell and open the structure of the stratum
corneum leading to increase in permeation.
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16. Sulfoxide
Dimethyl sulfoxide, Dimethyl acetamide, Dimethyl formamide
Mode of action :
• Extraction of stratum corneum lipids and lipoproteins.
• Interaction with the head group of bilayer lipids to distort the packing geometry.
• Delamination of horny layer(SC)
Ex. Griseofulvin, lidocaine
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17. Pyrrolidones
Sodium pyrrolidone carboxylate, 2-pyrrolidone and N-methyl-2-pyrrolidone
Mode of action :
• Act by altering solvent nature of membrane and Pyrrolidones used to generate
reservoirs with in skin membrane.
• Such reservoir effect offers potential for sustain release of permeant.
Ex. Captopril , Caffeine , Ibuprofen
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18. Amide
Azone
• Effective enhancer for both hydrophilic and hydrophobic drug.
• Increase in effectiveness by adding cosolvent ex. PG
Mode of action:
• Mechanisms yet unresolved
• But alterations in SC detected by DSC and FTIR.
• Azone probably act by disrupting horney layer lipid structure
Ex. Antibiotic: Clindamycin, erythromycin , Steroids: amcinonide, Indomethacin
and Naloxone.
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19. Surfactants
Anionic surfactants:
It can penetrate and destroy the integrity of SC within hours.
Ex. Sodium Lauryl Sulphate
MOA:
• It induced swelling of SC and viable epidermis.
• The hydrophobic interaction of the alkyl chains with the substrate leaves the negative
end group of the surfactant exposed, creating additional anionic sites in the
membrane.
• This results in development of repulsive forces which separate the protein matrix,
uncoil the filaments and expose more water-binding sites.
Ex. Naproxen, Chloramphenicol
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20. Cationic surfactant:
Alkyl amines
MOA:
• At the outer skin surface the amine has the capacity to form an ion pair with the
drug.
• The ion pair have high solubility in skin than parent anion which diffuses through
own concentration gradient to the inner sc .
• Then amine deprotonates and liberate the anion after that the amine free to travel
back to the skin surface.
• Only small amount of amine required for this carrier mechanism.
Ex. Na and K ion, Naloxone
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21. Non-ionic surfactants:
Span 80, Tween 80
MOA:
• Increase fluidity in lipid phase of stratum corneum region which reduces
diffusional resistance.
Ex. Hydrocortisone, Lidocaine
Fatty Acid and Alcohols
MOA:
• Act as solvent and alter solubility properties of tissue leads to improve
partitioning.
• Evaporation of solvent increase drug concentration.
Ex. Acyclovir, Mannitol
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22. Miscellaneous Chemicals:
Urea
MOA:
• It increase the hydration of SC and it also have keratolytic effects .
Ex. Hydrocortisone
N, N-Dimethyl-m-Toluamide
MOA:
• In this MOA is needs more study and usefulness on human skin is sparse.
Ex. Mosquito repellent
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23. Calcium Thioglycolate
MOA:
• It probably involve the reduction of cystine links leading to disruption of a keratin
matrix.
Ex. Theophylline
Anticholinergic Agents
MOA:
• These agent have antisecretory effect but insufficient to cause systemic effect.
• Because API hindered by outflow of perspiration and formation of aqueous layer
on skin.
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24. Conclusion:
• Chemical penetration enhancer are not only specific toward stratum corneum ,
they also penetrate into deeper layers of the skin to viable epidermal cells and
induce skin irritation responses.
• Penetration enhancer increase the permeation of drug but also the other
formulation excipients.
• This may lead to serious toxicological effect i.e irritation.
• Irritation produced by occlusive nature leading to accumulation of sweat and
increase in subpatch microbial growth.
• Enhancer should evaluate for irritancy under condition of long term occlusion.
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25. References:
• Pathan IB, Setty CM. Chemical Penetration Enhancers for Transdermal Drug
Delivery. Trop J Res 2009;8(2):173-8.
• Singla V, Saini S, Sing G, Rana AC, Joshi B. Penetration Enhancers: A Novel
Strategy for Enhancing Transdermal Drug Delivery. IRJP 2011;2(12):32-6.
• Walters KA. Penetration Enhancer and Their Use in Transdermal Therapeutic
Systems. In: Hadgraft J, Guy RH, editor. Transdermal Drug Delivery
Development Issues and Research Initiatives, Vol-35, 1st ed. New York: Marcel
Dekker, Inc: p. 197-232.
• Mathur, V., Satrawala, Y. and Rajput, M.S., 2014. Physical and chemical
penetration enhancers in transdermal drug delivery system. Asian Journal of
Pharmaceutics (AJP): Free full text articles from Asian J Pharm, 4(3).
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