Penetration enhancers Used in transdermal drug delivry

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Penetration enhancers Used in transdermal drug delivry

  1. 1. MALLIKARJUNAYADAV MPHARM(PHARMACEUTICS)VAGDEVI COLLEGE OF PHARMACY, NELLORE 10/10/12 1
  2. 2. PENETRATION ENHANCERS 10/10/12 2
  3. 3.  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. PENETRATION ENHANCERS 10/10/12 3
  4. 4.  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. PENETRATION ENHANCERS 10/10/12 4
  5. 5. A diagrammatical cross-section through human skin PENETRATION ENHANCERS 10/10/12 5
  6. 6.  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 PENETRATION ENHANCERS 10/10/12 6
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  9. 9.  It involves passive diffusion of substance through skin. Transcorneal penetration:  Intra cellular penetration.  Inter cellular penetration. Transappendegeal Penetration. PENETRATION ENHANCERS 10/10/12 9
  10. 10.  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 PENETRATION ENHANCERS 10/10/12 10
  11. 11.  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. PENETRATION ENHANCERS 10/10/12 11
  12. 12.  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. PENETRATION ENHANCERS 10/10/12 12
  13. 13.  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. PENETRATION ENHANCERS 10/10/12 13
  14. 14.  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 = TimeUnder 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 PENETRATION ENHANCERS 10/10/12 14
  15. 15. 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. PENETRATION ENHANCERS 10/10/12 15
  16. 16. 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. PENETRATION ENHANCERS 10/10/12 16
  17. 17. 1. Surfactants : a) Ionic: SLS, Na laureate, etc. b) Non ionic : Tween 80, Polysorbates, etc.2. Bile Salts & Derivatives : E.g.. Na glyacolate, Na deoxycholate3. Fatty Acid & Derivatives : E.g.. Oleic acid, Caprylic acid, etc.4. Chelating Agents : E.g.. EDTA, Citric acid, etc. PENETRATION ENHANCERS 10/10/12 17
  18. 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 PENETRATION ENHANCERS 10/10/12 18
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  20. 20.  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 PENETRATION ENHANCERS 10/10/12 20
  21. 21.  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. PENETRATION ENHANCERS 10/10/12 21
  22. 22.  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. PENETRATION ENHANCERS 10/10/12 22
  23. 23.  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. PENETRATION ENHANCERS 10/10/12 23
  24. 24.  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. PENETRATION ENHANCERS 10/10/12 24
  25. 25.  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. PENETRATION ENHANCERS 10/10/12 25
  26. 26.  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. PENETRATION ENHANCERS 10/10/12 26
  27. 27.  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. PENETRATION ENHANCERS 10/10/12 27
  28. 28.  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. PENETRATION ENHANCERS 10/10/12 28
  29. 29.  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. PENETRATION ENHANCERS 10/10/12 29
  30. 30.  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. PENETRATION ENHANCERS 10/10/12 30
  31. 31.  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. PENETRATION ENHANCERS 10/10/12 31
  32. 32.  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 32 10/10/12
  33. 33.  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. PENETRATION ENHANCERS 10/10/12 33
  34. 34. 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. PENETRATION ENHANCERS 10/10/12 34
  35. 35. 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. PENETRATION ENHANCERS 10/10/12 35
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  37. 37. NEEDLE-FREE JETINJECTORS PENETRATION ENHANCERS 10/10/12 37
  38. 38. PHONOPHORESISBasic 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 PENETRATION ENHANCERS 10/10/12 38
  39. 39. Ultrasound to Enhance Skin Permeability PENETRATION ENHANCERS 10/10/12 39
  40. 40. IONTOPHORESISBasic principle of iontophoresis. A current passed between the active electrode and theindifferent electrode repelling drug away from the active electrode and into the skin, PENETRATION ENHANCERS 10/10/12 40
  41. 41. • 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.. PENETRATION ENHANCERS 10/10/12 41
  42. 42. ELECTROPORATIONBasic principle of electroporation. High voltage current is applied to the skin producing hydrophilic pores in the intercellular bilayers via momentary realignment of lipids PENETRATION ENHANCERS 10/10/12 42
  43. 43. 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. PENETRATION ENHANCERS 10/10/12 43
  44. 44. IN VITRO EVALUATION OF PENETRATION Skin: Rat abdominal, Rabbit, Porcine, Human cadaver Temp.: 32 +/- 1°C. Media: Simulated Fluid. PH : 6.8 FRANZ DIFFUSION CELL PENETRATION ENHANCERS 10/10/12 44
  45. 45. SR. NAME OF CPE’s USED INVESTIGATORS JOURNALNO. DRUG Sesquiterpene 1 5-FU (40 fold ) P. A. Cornwell J Pharm Pharmacol 2 Naloxone Lauric acid Bruce J. Aungst J Pharm Pharmacol International Journal of 3 Acyclovir Azone Mohsen I. Afouna Pharmaceutics Dimethyl Journal of Biomedical 4 Caffeine Formamide Southwell D. Optics (12 fold ) 5 Levo Journal of Controlled norgestrel Alcohols David Friend Release PENETRATION ENHANCERS 10/10/12 45
  46. 46.  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. PENETRATION ENHANCERS 10/10/12 46
  47. 47.  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.,10/10/12 507– 515(1983) . PENETRATION ENHANCERS 80, 47
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