Permeation enhancement through skin

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  • 1. Presented by Guided by Mr.Thakur Rohit.G Dr.Kokare C.R.Sem-II(Pharmaceutics)4/27/2012 1
  • 2. Introduction Transdermal DDS Structure of Skin Transport across Skin Barriers Factors Penetration enhancement References4/27/2012 2
  • 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”.4/27/2012 3
  • 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.4/27/2012 4
  • 5. Fig-1 Skin and its appendages4/27/2012 5
  • 6. Figure-2 Cross-section of human skin4/27/2012 6
  • 7. Figure-3 Barrier properties of skin4/27/2012 7
  • 8. Fig-4 Transport across skin4/27/2012 8
  • 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.4/27/2012 9
  • 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 surfactants4/27/2012 10
  • 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.4/27/2012 11
  • 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 assisted4/27/2012 12
  • 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.4/27/2012 13
  • 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.4/27/2012 14
  • 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. 4/27/2012 15
  • 16. Fig-5 Mode of action of penetration enhancers4/27/2012 16
  • 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.4/27/2012 17
  • 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)Azones4/27/2012 18
  • 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 permeants4/27/2012 19
  • 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.4/27/2012 20
  • 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.4/27/2012 21
  • 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.4/27/2012 22
  • 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.4/27/2012 23
  • 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.4/27/2012 24
  • 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.4/27/2012 25
  • 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.4/27/2012 26
  • 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.4/27/2012 27
  • 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.4/27/2012 28
  • 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.4/27/2012 29
  • 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.4/27/2012 30
  • 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.4/27/2012 31
  • 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.4/27/2012 32
  • 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.4/27/2012 33
  • 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.4/27/2012 34
  • 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 acids4/27/2012 35
  • 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).4/27/2012 36
  • 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 Microneedles4/27/2012 38
  • 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 III4/27/2012 39
  • 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.4/27/2012 40
  • 41. Fig-8 Electroporation4/27/2012 41
  • 42. Ultrasound pulses are passed through the probe into the skin fluidizing the lipid bilayers by the formation of bubbles caused by Fig-9 Sonophoresis4/27/2012 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.4/27/2012 43
  • 44. Fig-10 Photomechanical Wave Generator4/27/2012 44
  • 45. Enhancement of skin permeability by applying a magnetic field to therapeutic molecules that are dimagnetic or paramagnetic. LEDDTTM Fig-11 Laser Assisted Penetration4/27/2012 45
  • 46. Fig-12 Needle Free Jet Injectors4/27/2012 Penetration enhancement through skin 46 46
  • 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.4/27/2012 47
  • 48. Ethosomes- (“soft vesicles”) Ethosomes are soft, malleable vesicles composed mainly of phospholipids, ethanol (relatively high concentration) and water. Ethosomes improving the drugs 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 patch4/27/2012 48
  • 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.4/27/2012 49
  • 50. SALIENT FEATURES High Deformability High Penetration Ability Across the Skin  High Entrapment Efficiency  Suitable for Both High As Well As Low Molecular Weight drugs4/27/2012 50
  • 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.4/27/2012 52
  • 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 names4/27/2012 53
  • 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 drugdelivery. 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. 4/27/2012 55
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