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CONTENT Introduction Advantages and disadvantages of TDDS Structure of human skin. Barrier property. Factor affecting percutaneous absorption of drug. Penetration enhancement. Principle of penetration through skin Penetration enhancement technique. 2


objectives Study transdermal drug delivery system. Understand the skin structure and its barrier function. Study factor affecting penetration through skin. Study various approaches to enhance drug penetration through skin , including types, need and mode of action of various penetration enhancement techniqs. 3


INTRODUCTION The aim of drug administration via skin can be either the local therapy or the transdermal delivery of drug for the systemic circulation. Transdermal system delivers medications through the skin direct into the bloodstream. One long-standing approach to increase the range of drugs that can be effectively delivered via this route has been to use penetration enhancers; chemicals that interact with skin constituents to promote drug flux. 4


ADVANTAGES. Avoid gastrointestinal drug absorption difficulties. Substitute for oral administration of medication. First-pass metabolism. Extended therapy with a single application. Rapid termination of therapy. Therapeutic agent delivered at controlled rate through skin into systematic circulation. Maintain efficacious plasma levels of drug from 1 to 7 days. More convenient and improved patient compliance dosing regimen. 5


DISADVANTAGES The limitations of transdermal drug delivery are mainly associated with barrier function of skin , so it is limited to potent drug molecules. Skin irritation or contact dermatitis due to drug, excipient and enhancers is another limitation. The use of transdermal delivery may be uneconomic Limited to potent drug molecules. 6



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Barrier property :

Barrier property High density Low hydration Low surface area for solute transport. Because most solute enter through the 0.1 micron intercellular space. 10

factors affecting percutaneous absorption:

factors affecting percutaneous absorption Solubility in the stratum corneum Diffusion through the stratum corneum Partitioning. Diffusion through the viable tissue Condition of the skin Effect of moisture Effect of vehicles Effect of concentration of medicament Effect of surfactants. 11

Penetration enhancement:

Penetration enhancement “Our insides in and the outsides out” Skin penetration enhancement techniques have been developed to improve bioavailability and increase the range of drugs for which topical and transdermal delivery. Penetration enhancers (sorption promoters or accelerants) which penetrate into skin to decrease the barrier resistance. Alternately, physical mechanism such as iontophorosis and phonophoresis can be used for certain cases of drug. 12

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Chemical enhancement Physical enhancement Pro-drugs Ion pairs Chemical enhancers Supersaturation Complexes Vesicles Liposomes Transfersomes Niosomes Ethosomes Solid lipid nanoparticles Iontophoresis Magnetophoresis Electroporation Heat assisted delivery Microneedles Needle-free injection Acoustical methods Ultrasound Short-duration shock wave Chemical skin abrasion 13

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Chemical enhancers:

Chemical enhancers Chemical enhancer or penetration enhancers are the agents that interact with the skin constituents to promote the drug flux. Many agent have studied and evaluated for enhancement property. Yet their inclusion in skin formulation is limited due to unknown mechanism and toxicity. Ideal properties Non toxic, non irritating, non allergic . Ideally work rapidly. Its duration of effect should be predictable and reproducible. Should work unidirectional. When remove from skin barrier properties should return both rapidly and fully. cosmetically acceptable. 15


DIFFUSION THROUGH SKIN Diffusion through stratum corneum can be regarded as diffusion through passive membrane. Steady state flux (j) of drug by Fick's second law of diffusion With skin permeation study, with steady state diffusion across the membrane , the above equation can be simplified as, dm/ dt =DC0/h, Where m= cumulative mass of permeant, C0= conc in first layer of membrane, h= thickness, C0=pC’0 Where p = partition coefficient dm/ dt =D C’0p/h 16

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Hence flux is govern by diffusion coefficient of the drug in stratum corneum, From the equation it is clear that effective penetration enhancer increases the diffusion coefficient of drug in stratum corneum, It may act to increase the effective concentration of the drug in to the vehicle, Or could improve the partitioning between the formulation and stratum corneum. Or less likely by decreasing the skin thickness. (shortcut). 17



Chemical enhancers:

Chemical enhancers Water Sulfoxide and similar chemicals Azons Pyrrolidons Fatty acids Alcohols, fatty alcohols ,glycols Surfactant Urea Essential oils, terpens, terpenoids 19


water The water content of human stratum corneum is typically around 15–20% of the tissue dry weight. Occlusion. In general, increased tissue hydration appears to increase transdermal delivery of both hydrophilic and lipophilic permeants. Water present in stratum corneum is in 2 form, bound and free, which acts as solvent and increasing partitioning NMF( natural moisturizing factor) 20


SULPHOXIDE AND SIMILAR COMPOUND DMSO dimethyl suphoxide, aprotic solvent which form hydrogen bond with itself rather than with water Both hydrophilic and hydrophobic. Effect is concentration dependant Metabolite dimethyl sulfide adverse effect so similar type of compound have been used. E.g. dimethyl lactamide, dimethyl formamide. MOA- denature protein ,changes the keratin confirmation from B-helix to alpha- helix , it interacts with polar heads of lipid domain of stratum corneum at disort geometry. And being polar facilate the partitioning within the tissue. 21


AZONS First chemically design molecule as penetration enhancer, it a hybrid of cyclic amide Both hydrophilic and lipophilic. Lipophilic. Log o/w-6.2 . Effective at low concentration MOA- same as previous. PYRROLIDONES Greater effect on hydrophilic drug, e.g. 2-pyrrolodone MOA- they well partition into human stratum corneum, and alter the solvent nature of the membrane, they generates reservoir within skin and offer sustain release of drug. Eg .captopril matrix type transdermal patch. 22


FATTY ACIDS Oleic acid, long chain fatty acid. Both hydrophilic and lipophilic MOA- modify lipid domain of the stratum corneum. ALCOHOLS, FATTY ALCOHOLS,GLYCOLS Ethanol is used most commonly in patches, its used as a cosolvent with water in penetration study have reported. Its effect is concentration dependant, at high concentration causes dehydration of biological membrane. And decreases the permeation MOA-1) Solvent, 2) Permeation into stratum corneum solubility property of tissue leads to improvement in partitioning 3) volatile nature of ethanol help in modifying thermodynamic activity of drug, due to evaporation of ethanol drug conc. Increases providing supersaturated state with greater driving force. 23


SURFACTANT Surfactant made of lipophilic alkyl or aryl side chain with polar head group. Both anionic and cationic surfactant can be used, but non ionic are surfactant are safe. MOA- Solubilise the lipophilic active ingredient, and also have potential to solubilise lipids within the stratum corneum. Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc. Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc. Bile Salts: e.g. Sodium taurocholate, Sodium deoxycholate, UREA Hydrating agent, have been used in scaling condition such as psoriasis, and other skin condition. It produces significant stratum corneum hydration, produces hydrophilic diffusion channels. 24

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Prodrug and ion pair:

Prodrug and ion pair 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. Iboprofen ion pair. 26

Saturated and unsaturated solutions:

Saturated and unsaturated solutions 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. 27

Eutectic Systems:

Eutectic Systems 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 28


complexes Cyclodextrin complexes. Enhance aqueous solubility and drug stability. Inclusion complexation. 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) Nitroglycerine vehicle, CD, sustain effect. 29

Carrier and vesicles :

Liposomes - 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. 30 Carrier and vesicles

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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- 1) ethenol 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. 2) ethosom effect. E.g. Testosom patch 31

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Microemulsion- Microemulsions are isotropic, thermodynamically stable solutions in which substantial amounts of two immiscible liquids are brought into a single phase by means of an appropriate surfactant or surfactant mixture. MOA- 1)Provide large concentration gradient. Interact with the rigid lipid bilayer structure and acts as a chemical enhancer. Transfersomes- Transfersomes 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. 32

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SALIENT FEATURES High Deformability High Penetration Ability Across the Skin High Entrapment Efficiency Suitable for Both High As Well As Low Molecular Weight Drugs 33 Lipid bilayer Aquous cavity

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Solid lipid nanoparticals- Spherical, with average diameters between 50 to 500nm, Solid lipid nanoparticles possess a solid lipid core matrix that can solubilize lipophilic molecules. 34

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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. MOA- Occlusion can enhance the penetration of drugs through the stratum corneum by increased hydration. Due to hydration pore size will be increases. Nanoparticles high adhesion to the stratum corneum due to its small particle size. SLN of Vitamin A in gel. TransoPlex ®, AlphaRx(USA) is developing vancomycin Vansolin™ and Zysolin™ trade names 35

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ELECTRICAL TECHNIQUES Iontophorosis- Ionised solutes, with inherently low partition coefficients due to their charged state, across tissue membranes. Application of current 0.5mA/ drug reservoir on the skin. The same charged electrode as the solute of interest, repulsion effect that effectively drives solute molecules away from the electrode and into the skin. Electroosmosis, elecropertubation. Technique have some problem such as skin burn, irritation, erythema. Effectively used in protein and peptide delivery Phoresor , E- TRANS,Vyteris . 38

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Electroporation- The process involves the application of large transmembrane voltages caused by electrical pulses (10μs–100ms) , leads of transient pores in the membrane via a combination of possible processes including diffusion, local electrophoresis and/or electroosmosis. Concentration, pulse. Increase in transdermal drug delivery up to 104-fold have been reported in-vitro for various sizes of molecules. Some muscle contractions with electrical pulse and around mild muscle fatigue after treatment. These side-effects, even if considered safe. Invivo biomedical corporation. 40

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Ultrasound (Sonophoresis) It is also a important technique tried to enhance the drug penetration in TDDS, but more traditionaly in physiotherapy, sport medicine. Ultrasound produces thermal and non-thermal effects, out of this nonthermal effect is responsible for drug delivery. Cavitation principle. 20kHz to168 kHz, Due to this principle there is formation of defects in stratum corneum of size 20 micron , But ultrasound-facilitated transdermal delivery has not yet been tried and tested in the clinical field. Sonoprep ( Sontra medical corporation). Local anasthetic. 42

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Photomechanical Waves 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) local anasthetic lidocain. But there is no that much of attention on this technique, as it is new and no clinical data available. 44

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STRUCTURE-BASED TECHNIQUES Microneedles- Microneedles are a relatively new delivery technique, first patented drug delivery device. Individual silicon needles measuring approximately 150μm in length and 80μm base diameter are fabricated onto arrays of approximately 3 x 3 mm (approximately 400 needles). There is hollow bore of about 7-40 micron for drug delivery. Microneedle arrays are pierce the upper epidermis (which contains no nerves). Problem associated with this technique is breakage on needle in to the skin. Microflux, microprojection array( ALZA Corporation) 46

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VELOCITY-BASED TECHNIQUES Jet-Propelled Particles- The transdermal jet-injectors propel drug molecules into the skin by production of a high-velocity jet (>100m/s) of compressed gas (usually helium) that accelerates through the nozzle of the injector device, carrying with it drug particles. Particle size, velocity of carrier gas, discharge pressure, are important point to be considered for penetration. Insulin is 1 st . It is used to delivery off DNA, protein vaccine, 48



Examples for commercially available transdermal patches:

Examples for commercially available transdermal patches 50 Active ingredient Trade name System type Wearing time Clinical indication Patch size ( cm 2 ) Buprenorphin Transtec® PRO Matrix 3 days Analgesia 25 - 50 Clonidine Catapres-TTS® Reservoir 7 days Hypertension 20 Estradiol Estraderm® Reservoir 3 - 4 days HRT1 5 - 20 Fentanyl Durogesic® Reservoir 3 days Analgesia 10.5 - 42 Lidocaine Lidoderm® Matrix 12 hours Post-herpetic neuralgia 140 Methylphenidate Daytrana® Matrix 9 hours ADHD2 12.5 – 37.5 Nicotine Nicorette® Matrix 1day(16 hours) Smoking cessation 10 - 30 Nitroglycerin Nitro-Dura® Matrix 12– 14 hours Angina 5 - 40


REFERENCES 1) B.W. Barry, Dermatological Formulations: Percutaneous Absorption, Marcel Dekker, New York, 1983, 612-617. 2) Xiaoling Li, Bhaskaara R. Jasti,Design of Controlled Release Drug Delivery Systems, McGraw-Hill publication, 62-28. 3) Jain. N.K, Controlled and novel drug delivery ,first edition, CBS publishers and distributors, New Delhi.1997. 4) Tapash K. Ghosh, Bhaskara R. Jasti, theory and practice of contemporary pharmaceutics, CRC press, 423-439. 5) Adrian C. Williams, Brian W. Barry, Penetration enhancers, Advanced Drug Delivery Reviews 56 (2004) 603– 618. 6) S.E. Cross and M.S. Roberts, Physical Enhancement of Transdermal Drug Application: Is Delivery Technology Keeping up with Pharmaceutical Development? Current Drug Delivery, 2004, 1, 81-92. 7) Heather A.E. Benson, Transdermal Drug Delivery: Penetration Enhancement Techniques, Current Drug Delivery, 2005, 2, 23-33. 51

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8) Banker G. S and Rhodes C. T, Modern pharmaceutics, third edition, New York, Marcel Dekker, inc,. 1990. 9)Inayat Bashir Pathan1*, C Mallikarjuna Setty2, Chemical Penetration Enhancers for Transdermal Drug Delivery Systems, Tropical Journal of Pharmaceutical Research, April 2009; 8 (2): 173-179. 10)Jain A K, Thomas NS, Panchagnula R. Transdermal drug delivery of imipramine hydrochloride. I. Effect of terpenes. J Control Rel 2002; 79: 93- 101. 52



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