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Due to recent advances in technology and the ability to apply the drug to the site of action without rupturing the skin membrane, transdermal route is becoming a widely accepted route of drug administration. Over the last two decades more than 35 Transdermal patch products have been approved in US. Definition: Transdermal drug delivery system can deliver the drugs through the skin portal to systemic circulation at a predetermined rate and maintain clinically the effective concentrations over a prolonged period of time. 3 10/19/2010 vikramjit singh Slide 4: Potential advantages of TDDS Avoids chemically hostile GI environment (drug degradation in acidic and basic environments is prevented). No GI distress and the factors like Gastric emptying, intestinal motility, transit time, donot effect this route as in oral route. Avoidance of significant presystemic metabolism (degradation in GIT or by the liver) and therefore need lower doses. Allows effective use of drugs with short biological half-life. Allow administration of drugs with narrow therapeutic window because drug levels are maintained within the therapeutic window for prolonged periods of time. Reduced inter and intra patient variability. 4 10/19/2010 vikramjit singh Slide 5: Enhance therapeutic efficacy, reduced fluctuations (rapid blood level spikes-low and high) due to optimization of blood concentration – time profile. Reduction of dosing frequency and enhancement of patient compliance. Provides controlled plasma levels of very potent drugs. Can provide adequate absorption of certain drugs. Avoids the risk and inconveniences of parenteral therapy (Painless method of drug administration). Drug input can be promptly interrupted simply by removal of the patch when toxicity occurs. Provides suitability of self medication. 5 10/19/2010 vikramjit singh Slide 6: Disadvantages of TDDS Drugs that require high blood levels cannot be administered – limited only to potent molecules, those requiring a daily dose of 10mg or less. Transdermal administration is not a means to achieve rapid bolus type drug input, rather it is usually designed to offer slow, sustained drug delivery. Adequate solubility of the drug in both lipophilic and aqueous environments, to reach dermal microcirculation and gain access to the systemic circulation. The molecular size of the drug should be reasonable that it should be absorbed percutaneously. 6 10/19/2010 vikramjit singh Slide 7: Tolerance inducing compounds are not an intelligent choice for this mode of administration unless an appropriate wash out period is programmed in between the dosing regimen. Difficulty of permeation of the drug through human skin –barrier function of the skin. Skin irritation or dermatitis due to excipients and enhancers of drug delivery system used for increasing percutaneous absorption is another major limitation. Adhesive may not adhere well to all types of skin. Uncomfortable to wear. May not be economical. 7 10/19/2010 vikramjit singh Cross-section of human skin : Cross-section of human skin 8 10/19/2010 vikramjit singh Slide 9: Stratum Corneum (topmost 15 μm layer) is the main barrier 9 10/19/2010 vikramjit singh 1.Through stratum corneum 2.Transfollicular 3.Through sweat gland : 1.Through stratum corneum 2.Transfollicular 3.Through sweat gland Pathways of drug penetration 10 10/19/2010 vikramjit singh Mechanisms of drug permeation : Mechanisms of drug permeation 11 Hydrophilic drugs permeates by Intercellular pathway and Lipophilic drugs permeates by Intracellular (Transcellular) mechanism. 10/19/2010 vikramjit singh Skin permeability kinetics : Skin permeability kinetics Fick’s First Law of Diffusion Percutaneous absorption of most drugs is a passive-diffusion process that can be described by Fick’s first law of diffusion dQ/dt = JT = PAΔC JT is the total flux transported through a unit area of skin per unit time in steady state (µg/hr) A is area of the skin P is the effective permeability coefficient ΔC is the drug concentration gradient across the skin 12 10/19/2010 vikramjit singh Factors affecting percutaneous absorption : Factors affecting percutaneous absorption Physicochemical factors Biological factors Formulation factors 13 10/19/2010 vikramjit singh Slide 14: Physicochemical factors of penetrant/drug Partition coefficient Solubility Ionization / pKa Molecular size and weight Stability or half-life 14 10/19/2010 vikramjit singh Slide 15: Biological factors PH of the environment Area of application Age, Sex, Race Condition of the skin Integrity and Thickness of stratum corneum Pathological conditions of skin Hydration Metabolism Temperature 15 10/19/2010 vikramjit singh Slide 16: Formulation factors Vehicle-solubility of the drug Lipophilicity of the solvent PH of the vehicle Composition of drug delivery system Surfactants 16 10/19/2010 vikramjit singh Drug properties : Drug properties Dose deliverable : ≤ 10mg/day Aqueous solubility : >1mg/ml Lipophilicity : log P (1-3) Molecular size : < 500 Daltons Melting point : < 200°C Drug should not be an irritant to skin. The drug should not stimulate an immune reaction in the skin. Along with these properties the drug should be potent, having short half life 17 10/19/2010 vikramjit singh Strategies for the enhancement of drug permeability : Strategies for the enhancement of drug permeability 18 10/19/2010 vikramjit singh Slide 19: Drug vehicle interactions 1.Prodrugs The prodrug approach has been investigated to enhance transdermal delivery of drugs with unfavourable partition coefficients. The prodrug design strategy generally involves addition of a pro-moiety to increase partition coefficient and solubility to increase the transport of the drug in the stratum corneum. Upon reaching the viable epidermis, esterases release the active drug by hydrolysis thereby optimizing concentration in the epidermis. 19 10/19/2010 vikramjit singh Slide 20: 2.Ion-pairs Charged drug molecules do not readily partition into or permeate through human skin. Formation of lipophilic ionpairs has been investigated to increase stratum corneum penetration of charged species. This strategy involves adding an oppositely charged species to the charged drug, forming an ion-pair in which the charges are neutralized so that the complex can partition into and permeate through the stratum corneum. The ion-pair then dissociates in the aqueous viable epidermis releasing the parent charged drug that can diffuse within the epidermal and dermal tissues. 20 10/19/2010 vikramjit singh Slide 21: Needle-free Jet Injectors 21 10/19/2010 vikramjit singh Advantages : Advantages Pain-free delivery — particles are too small to trigger pain receptors on the skin. Improved efficacy and bioavailability. Targeting to a specific tissue, such as a vaccine delivered to epidermal cells. Accurate dosing and Overcomes needle phobia. Safety — the device avoids skin damage or infection from needles or splash back of body fluids. The PowderJect system fires solid particles (20–100µm) through stratum corneum into lower skin layers, using a supersonic shock wave of helium gas. Intraject is a development of the vaccine gun designed to deliver liquids through skin without using needles. 22 10/19/2010 vikramjit singh 2.Chemical permeation enhancers : 2.Chemical permeation enhancers A substance that will increase the permeability of the epithelial barrier by modifying its structure also termed as accelerants or sorption promoters-can enhance drug flux. Ideal Penetration Enhancer Non-toxic, non-irritating, non-allergenic. Immediate onset of increased permeability. Immediate recovery of normal barrier properties upon removal (reversible). Physically and Chemically compatible with a wide range of drugs. 23 10/19/2010 vikramjit singh Slide 24: Solvents - Ethanol, acetone, polyethylene glycol, glycerol, propylene glycol, dimethyl sulfoxide Surfactants - Brij30, brij72, Pluronic, Sodium lauryl sulphate, Span 20, Tween 80. Azones - N- Acyl hexahydro-2-oxo-1H-azepines, N-Alkylmorpholine-2,3-diones. Terpenes - Limonene, Carvone Fatty alcohols - Lauryl alcohol, linolenyl alcohol, oleic and fatty acids acid and lauric acid. Miscellaneous - Lecithin, sodium deoxycholate, L-amino acid, acid phosphatase,phospholipase & calonase 24 10/19/2010 vikramjit singh Electrically Assisted methods : Electrically Assisted methods 1.Ultrasound (Phonophoresis / Sonophoresis) Used originally in physiotherapy and sports medicine, applies a preparation topically and massages the site with an ultrasound source. The ultrasonic energy (at low frequency) disturbs the lipid packing in stratum corneum by cavitation. Sonicators operating at frequencies in the range of 20kHz to 3MHz are available commercially and can be used for Sonophoresis. Therapeutic ultrasound (1–3MHz) - for massage, Low-frequency ultrasound (23-40kHz) - in dentistry, High-frequency ultrasound (3–10 MHz) - diagnostic purposes. 25 10/19/2010 vikramjit singh Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound. : Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound. 26 10/19/2010 vikramjit singh Slide 27: Ultrasound to Enhance Skin Permeability 27 10/19/2010 vikramjit singh 2.Iontophoresis : 2.Iontophoresis The electrical driving of charged molecules into tissue, passes a small direct current (approximately 0.5 mA/cm2) through a drug containing electrode in contact with the skin. The most popular electrodes are based on the silver/silver chloride redox couple. Three main mechanisms enhance molecular transport: Charged species are driven primarily by electrical repulsion from the driving electrode. Flow of electric current may increase the permeability of skin and Electroosmosis may affect uncharged molecules and large polar peptides. Limitations: Hair follicle damage is possible. 28 10/19/2010 vikramjit singh Slide 29: 29 10/19/2010 vikramjit singh 3.Electroporation : 3.Electroporation 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.. 30 10/19/2010 vikramjit singh Slide 31: 31 10/19/2010 vikramjit singh Slide 32: 32 10/19/2010 vikramjit singh Slide 33: 33 10/19/2010 vikramjit singh Basic components of TDDS : Basic components of TDDS Drug Polymer matrix Penetration enhancers Other Excipients Rate controlling membrane Adhesive Release liner Backing membrane 34 10/19/2010 vikramjit singh Types of Transdermal delivery devices : Types of Transdermal delivery devices 35 10/19/2010 vikramjit singh Transdermal matrix system : Transdermal matrix system 36 Rate controlling factors Drug concentration in polymer matrix Chemical nature of polymer matrix Geometry of device Polymers: PVC, PVP, Ethylene vinylacetate, microporous polypropylene. Initially the drug is released rapidly, then rate declines as matrix is depleted. Advantages: Sleeker and thinner, daily or multiple-day Applications. Appropriate for drugs that penetrate readily and/or have low dosage requirements. Transdermal reservoir system : Transdermal reservoir system 37 Rate controlling factors Membrane thickness Membrane permeability Polymers: Cellulosic esters, polyamides or PVC. Advantages: Used when matrix systems cannot penetrate skin and drugs require significant penetration enhancement and/or high dosage levels. Slide 38: Release liners Protects the skin-contacting adhesive during storage. Substrate carries a very thin release coating. Provides low energy surface for ease of removal. e.g.: polyester or polystyrene based films. Backing material Contains formulation throughout shelf life and during wear period. They have laminate structure. They must be compatible with the formulation (nonadsorptive). They are occlusive and completely water impermeable in nature. e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins. Adhesive layer Acrylic copolymers, polyisobutylene and polysiloxane. 38 10/19/2010 vikramjit singh Evaluation of TDDS : Evaluation of TDDS Content, Content uniformity. In vitro release Vs Ex vivo permeation of active and penetration enhancer – difussion cells. Residual solvent, residual monomer Release liner peel, adhesion. Mechanical properties Moisture absorption & Moisture loss Microbiology Pouch integrity 39 10/19/2010 vikramjit singh Franz Diffusion Cell : Franz Diffusion Cell 40 Skin: Rat abdominal, Rabbit, Porcine, Human cadaver 10/19/2010 vikramjit singh Mechanical properties evaluation by ultra tester : Mechanical properties evaluation by ultra tester 41 10/19/2010 vikramjit singh Moisture absorption & Moisture loss studies : Moisture absorption & Moisture loss studies Moisture absorption study: Saturated solution of Alcl3 (79.50% RH)/ 3 days. Moisture loss study: Patches were placed in a desiccator containing Cacl2 at 40oC/24 hr. 42 10/19/2010 vikramjit singh Slide 43: Transdermal patches available in the market 43 10/19/2010 vikramjit singh Slide 44: Marketed Products of Modified Transdermal Drug Delivery Technologies 44 10/19/2010 vikramjit singh Conclusion : Conclusion Transdermal drug delivery technologies are becoming one of the fastest growing sectors within the pharmaceutical industry. Advances in drug delivery systems have increasingly brought about rate controlled delivery with fewer side effects as well as increased efficacy and constant drug delivery. The market value for transdermal delivery was $12.7 billion in 2005, and is expected to increase to $21.5 billion in the year 2010 and $31.5 billion in the year 2015 – suggesting a significant growth potential over the next 10 years. 45 10/19/2010 vikramjit singh References : References Controlled drug delivery –concepts and advances – by S.P.Vyas R.K.Khar. Encyclopedia of pharmaceutical technology -third edition edited by James Swarbrick volume-4 Microsphere Technology and Applications by Diane J. Burgess and Anthony J. Hickey. Controlled and Novel drug delivery edited by N.K.Jain reprint 2007 Encyclopedia of controlled drug delivery volume 2 encyclopedia of controlled drug delivery Asian Journal of Pharmaceutical and Clinical Research transdermal drug delivery system: a review p. k.gaur,s. mishra, s. purohit, k. dave.. 46 10/19/2010 vikramjit singh Slide 47: European Journal of Pharmaceutical Sciences Review -Novel mechanisms and devices to enable successful transdermal drug delivery by B.W. Barry. Transdermal drug delivery- penetration enhancement techniques- Heather A.E. Benson. Microneedles : The option for painless delivery by Geeta M Patel. 47 10/19/2010 vikramjit singh Slide 48: 48 10/19/2010 vikramjit singh You do not have the permission to view this presentation. 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