Transdermal drug delievery system


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A concept clearing and detail ppt of tdds .


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INTRODUCTION Transdermal drug delivery is hardly an old technology, since 1800’s and the technology is no longer just adhesive patches. 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 . 4/15/2012 vikramjit singh 2

General Considerations in the use of TDD Systems:

General Considerations in the use of TDD Systems The site selected for application should be clean clean , dry. Example: nitroglycerin - chest; estradiol - abdoment ; scopolamine - behind the ear; nicotine – upper trunk or upper outer arm. The transdermal patch should not be applied to skin that is oily, irritated, cut, or abraded. This is to assure the intended amount and rate of transdermal drug delivery and absorption. 4/15/2012 vikramjit singh 3

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The patch should be removed from its protective package, being careful not to tear or cut. The patch should be worn for the period of time stated in the product’s instructions. Following period, the patch should be removed and a fresh patch applied as directed . Patches generally may be left on when showering, bathing, or swimming. Should a patch premature dislodge, an attempt may be made to reapply it, or it may be replaced with a fresh patch-- the latter being worn for a full time period before it is replaced. 4/15/2012 vikramjit singh 4

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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 . 4/15/2012 vikramjit singh 5

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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. 4/15/2012 vikramjit singh 6

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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. 4/15/2012 vikramjit singh 7

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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. 4/15/2012 vikramjit singh 8

Cross-section of human skin:

Cross-section of human skin 4/15/2012 vikramjit singh 9

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Stratum Corneum (topmost 15 μ m layer) is the main barrier 4/15/2012 vikramjit singh 10


Pathways of drug penetration 4/15/2012 vikramjit singh 11

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1.Through stratum corneum 2.Transfollicular 3.Through sweat gland 4/15/2012 vikramjit singh 12

Mechanisms of drug permeation:

Mechanisms of drug permeation 4/15/2012 vikramjit singh 13 Hydrophilic drugs permeates by Intercellular pathway and Lipophilic drugs permeates by Intracellular (Transcellular) mechanism.

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 = J T = PA Δ C J T 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 4/15/2012 vikramjit singh 14

Factors affecting percutaneous absorption:

Factors affecting percutaneous absorption Physicochemical factors Biological factors Formulation factors 4/15/2012 vikramjit singh 15

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Physicochemical factors of penetrant/drug Partition coefficient Solubility Ionization / p Ka Molecular size and weight Stability or half-life 4/15/2012 vikramjit singh 16

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Biological factors P H 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 4/15/2012 vikramjit singh 17

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Formulation factors Vehicle-solubility of the drug Lipophilicity of the solvent P H of the vehicle Composition of drug delivery system Surfactants 4/15/2012 vikramjit singh 18

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 4/15/2012 vikramjit singh 19

Basic components of TDDS :

Basic components of TDDS Drug Polymer matrix Penetration enhancers Other Excipients Rate controlling membrane Adhesive Release liner Backing membrane 4/15/2012 vikramjit singh 20


APPROACHES OF TDDS 4/15/2012 vikramjit singh 22

Transdermal matrix system :

Transdermal matrix system 23 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 25 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.

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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. 4/15/2012 vikramjit singh 27

Strategies for the enhancement of drug permeability:

Strategies for the enhancement of drug permeability 4/15/2012 vikramjit singh 28

Mechanism Of Action For Percutaneous Absorption Enhancers :

Mechanism Of Action For Percutaneous Absorption Enhancers 1. Reduction of the resistance of the stratum corneum by altering its physicochemical properties 2. Alteration of the hydration of the stratum corneum 3. Effecting a change in the structure of the lipids and lipoproteins in the cellular channels, through solvent action or denaturation 4. Carrier mechanism in the transport of ionizable drugs. 4/15/2012 vikramjit singh 29

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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. 4/15/2012 vikramjit singh 30

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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. 4/15/2012 vikramjit singh 31

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. 4/15/2012 vikramjit singh 32

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. 4/15/2012 vikramjit singh 33

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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 4/15/2012 vikramjit singh 34

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. 4/15/2012 vikramjit singh 35

Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound. :

Enhanced Transdermal Permeation by Cavitation of stratum corneum upon application of Ultrasound. 4/15/2012 vikramjit singh 36

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Ultrasound to Enhance Skin Permeability 4/15/2012 vikramjit singh 37

2.Iontophoresis :

2.Iontophoresis The electrical driving of charged molecules into tissue, passes a small direct current (approximately 0.5 mA/cm 2 ) 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. 4/15/2012 vikramjit singh 38

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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.. 4/15/2012 vikramjit singh 40

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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 4/15/2012 vikramjit singh 44

Franz Diffusion Cell :

Franz Diffusion Cell 4/15/2012 vikramjit singh 45 Skin: Rat abdominal, Rabbit, Porcine, Human cadaver

Mechanical properties evaluation by ultra tester :

Mechanical properties evaluation by ultra tester 4/15/2012 vikramjit singh 46

Moisture absorption & Moisture loss studies :

Moisture absorption & Moisture loss studies Moisture absorption study: Saturated solution of Alcl 3 (79.50% RH)/ 3 days. Moisture loss study: Patches were placed in a desiccator containing Cacl 2 at 40 o C/24 hr. 4/15/2012 vikramjit singh 47

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Transdermal patches available in the market 4/15/2012 vikramjit singh 48

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Marketed Products of Modified Transdermal Drug Delivery Technologies 4/15/2012 vikramjit singh 49

Examples Of TDD Systems :

Examples Of TDD Systems Clonidine - Catapress –TTS Four-layered patch: backing layer of pigmented polyester film (2) drug reservoir of clonidine , mineral oil, polyisobutylene , and colloidal silicon dioxide, (3) a microporous polypropylene membrane controlling the rate of drug delivery, and (4) an adhesive formulation of agents Uses: antihypertensive clonidine at a constant rate for 7 days , once a week dosing in the upper arm or torso.

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2 . Estradiol - Estraderm Four layered patch: (1) transparent polyester film, (2) drug reservoir of estradiol and alcohol gelled with hydroxypropyl cellulose, (3) an ethylenevinyl acetate copolymer membrane, and (4) an adhesive formulation of light mineral and polyisobutylene. Uses: design to release 17 B-estradiol continuously. Applied twice weekly over a cycle of 3 weeks. The patch is generally applied to the abdomen, altering sites with each application.

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3. Nicotine - Nicotrol Multi-layered rectangular patch: (1)outer backing of laminated polyester film, (2) rate-controlling adhesive, nonwoven material, and nicotine, (3) disposable liner removed prior to use - Aid in smoking cessation programs

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4. Nitroglycerin - Deponit Nitroglycerin in a matrix of lactose, plasticizer, polyisobutylene, and aluminized plastic Use: to provide controlled release of nitroglycerin continuously for a 24 hour period. Patches are applied to inner part of upper arm, shoulders, or chest. 5. Nitroglycerin - Nitro - Dur Nitroglycerin in a gel like matrix composed of glycerin, water, lactose, polyvinyl alcohol, povidone and sodium citrate sealed in a polyester foil polyethylene laminate.

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6 . Scopolamine - Transderm - Scop Four layered patch: (1) backing layer of aluminized polyester film, (2) drug reservoir of scopolamine, mineral oil, and polyisobutylene, (3) a microporous polypropylene membrane for rate delivery of scopolamine, and (4) adhesive of polyisobutylene, mineral oil, and scopolamine Use: for continuous release of scopolamine over a 3-day period as required for the prevention of nausea and vomiting associated with motion sickness. The patch is placed behind the ear . When repeated administration is desired, the first patch is removed and the second patch placed behind the other ear

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Nitro-Dur This contains nitroglycerin which is a type of vasodilator. This is used to prevent chest pain caused by angina. It will not help to stop an episode of chest pain.

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Nicotine Patch It is used as a temporary aid for smoking-cessation programs. It helps to control the symptoms of nicotine withdrawal (irritability, headache, fatigue, insomnia) and thus helps you to concentrate on overcoming the psychological and behavioral aspects of your smoking habit.

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Denti Patch This is a band-aid-like patch inserted on your gum to numb it before an injection

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Neupro This is a skin patch designed to treat symptoms of early Parkinson's disease.

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VIVELLE-DOT This contains estradiol in a multipolymeric adhesive that helps in the development and maintenance of the female reproductive system and secondary sexual characteristics.

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Daytrana This is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children six to 12 years of age.

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Ortho- Evra It is a contraceptive used by women to prevent pregnancy

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Mylan Estradiol Patch This patch is designed to release Estradiol continuously upon application to intact skin for the treatment of moderate to severe vasomotor and vulvovaginal symptoms associated with menopause, and for prevention of postmenopausal osteoporosis

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This contains a low dose of nicotine that is intended to help quit smoking by reducing the unpleasant nicotine withdrawal effects Nicorette Patch

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This patch contains estradiol that is a form of estrogen in female sex hormone the regulates many processes in the body. Estraderm Patch

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This helps avoid the discomfort of nicotine withdrawal symptoms when you quit smoking by giving you a controlled, sustained dose of nicotine

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. 4/15/2012 vikramjit singh 66

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4/15/2012 vikramjit singh 67 THANK YOU

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