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CONTENT Introduction Trasdemal permeation Advantages of TDDS Limitations of TDDS Basic components of TDDS Different approches of TTDS Evaluations Marketed products Conclusion

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INTRODUCTION Transdermal drug delivery systems (TDDS), also known as ‘‘patches,’’ are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin . An ideal dosage form would be maintaining the drug concentration in the blood at a constant level nearly coinciding with the Minimum Effective Concentration (MEC) of drug throughout the treatment period. This leads to the concept of the controlled drug delivery. The primary objective of controlled drug delivery is to ensure safety and efficacy of the drugs as well as patients compliance.

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To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and polymer are required. TDDS a realistic practical application as the next generation of drug delivery The future of transdermal drug delivery is the development of skin pretreatment methods & combination devices .

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Transdermal Permeation Skin is the most intensive and readily accessible organ of the body as only a fraction of millimeter of tissue separates its surface from the underlying capillary network. The various steps involved in transport of drug from patch to systemic circulation are as follows: Diffusion of drug from drug reservoir to the rate controlling membrane. Diffusion of drug from rate limiting membrane to stratum corneum. Sorption by stratum corneum and penetration through viable epidermis. Uptake of drug by capillary network in the dermal papillary layer. Effect on target organ.

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Permeability Coefficient Is the Critical Predictor of Transdermal Delivery Transport = Flux = (mg/cm 2 /sec) = J=P x A x (C d – C r ) Permeability Coefficient = P = D x K (cm/sec) h Where A = Surface area of patch D = Diffusivity of drug in membrane (skin) K = Partition coefficient (patch/skin) C = Concentration in donor or receptor patch or skin) h = Thickness of membrane (skin)

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Advantages of TDD Systems Reduces first-pass effect and GI incompatibility Sustains therapeutic drug levels Permits self-administration Non-invasive (no needles or injections) Improves patient compliance Reduces side effects Allows removal of drug source & Termination of further administration, if necessary Administration of drugs with: - A very short half-life - Narrow therapeutic window - Poor oral absorption

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Limitations of TDD Systems Poor diffusion of large molecules. Skin irritation Limited By: Dose of the drug. Molecular weight of drug. Crystalline state. Melting point

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Basic Components of TDDS • Polymer matrix / Drug reservoir • Drug • Permeation enhancers • Pressure sensitive adhesive (PSA) • Backing laminates • Release liner • Other excipients like plasticizers and solvents

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Different approaches of TDDS systems Membrane permeation-controlled TDDS - Transderm-Scop, Duragesic, Clonidine-TTS Drug in adhesive-type TDDS - Daytrana, Climara, Habitrol, Nicoderm, Exelon Matrix diffusion controlled TDDS- NitroDur Microreservoir dissolution controlled TDDS- Androderm

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Polymer membrane permeation-controlled TDDS Figure: 1 Polymer membrane permeation-controlled TDDS TransdermScop (Scopolamine) for 3 days protection of motion sickness and TransdermNitr( Nitroglycerine ) for once a day medication of angina pectoris .

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Adhesive diffusion controlled TDDS Figure: 2 Adhesive diffusion controlled TDDS Deponit (Nitroglycerine) for once a day medication of angina pectoris.

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Matrix diffusion controlled TDDS Figure: 3 Matrix diffusion controlled TDDS Nitro Dur (Nitroglycerine) used for once a day medication of angina pectoris.

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Microreservoir controlled TDDS Figure 4: Microreservoir controlled TDDS Nitro- dur ® System (Nitroglycerin) for once a day treatment of angina pectoris.

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These studies are predictive of transdermal dosage forms and can be classified into following types: • Physicochemical evaluation • In vitro evaluation • In vivo evaluation

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Physicochemical Evaluation : Thickness : Uniformity of weight Drug content determination : Moisture content : Flatness: Folding Endurance: Tensile Strength: Water vapour transmission studies (WVT): Microscopic studies:

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Thickness of the patch The thickness of the drug prepared patch is measured by using a digital micrometer at different point of patch and determines the average thickness and standard deviation for the same to ensure the thickness of the prepared patch

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Content uniformity test 10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 85% to 115% of the specified value and one has content not less than 75% to 125% of the specified value , then transdermal patches pass the test of content uniformity. But if 3 patches have content in the range of 75% to 125%,then additional 20 patches are tested for drug content. If these 20 patches have range from 85% to 115%, then the transdermal patches pass the test

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Drug content determination An accurately weighed portion of film (above 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the wholesolution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution

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Moisture content: The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula. Initial weight – Final weight % Moisture content = ---------------------------------X100 Final weight

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Moisture Uptake: Weighed film sare kept in a desiccator at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below. Final weight – Initial weight % moisture uptake =---------------------------------- X 100 Initial weight

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Flatness: A transdermal patch should possess a smooth surface and should not constrict with time. This can be demonstrated with flatness study. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent

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Folding Endurance : Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding . Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value. Tensile Strength : To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over

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Tensile strength=F/a . b (1+L/l) (2) F is the force required to break; a is width of film; b is thickness of film; L is length of film; l is elongation of film at break point. Water vapour transmission studies (WVT): For the determination of WVT, weighed one gram of calcium chloride and placed it in previously dried empty vials having equal diameter.

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Peel Adhesion properties Tack properties Thumb tack test Rolling ball test Quick stick (Peel tack) test Probe tack test Shear strength properties or creep resistance Adhesive studies :

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In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion. Molecular weight of adhesive polymer, the type and amount of additives are the variables that determined the peel adhesion properties. A single tape is applied to a stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180°C angle, and the force required for tape removed is measured Peel Adhesion test: Figure: 1 Peel Adhesion test

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Tack properties : It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer Thumb tack test The force required to remove thumb from adhesive is a measure of tack. Rolling ball tack test This test measures the softness of a polymer

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In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing adhesive (Figure-2). The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch Figure: 2 Rolling ball tack test

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Quick stick (peel-tack) test In this test, the tape is pulled away from the substrate at 90ºC at a speed of 12 inches/min. The peel force required breaking the bond between adhesive and substrate is measured (Figure-3) and recorded as tack value, which is expressed in ounces or grams per inch width . Figure: 3 Quick stick (peel-tack) test

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Shear strength properties or creep resistance Shear strength is the measurement of the cohesive strength of an adhesive polymer i.e., device should not slip on application determined by measuring the time it takes to pull an adhesive coated tape off a stainless plate Figure: Shear strength properties or creep resistance

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Probe Tack test In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it (Figure-4). The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams Figure: 4 Probe Tack test

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In vitro release studies The Paddle over Disc: The Cylinder modified USP Basket : The reciprocating disc: Keshary- Chien Cell: In vitro permeation studies : Preparation of skin for permeation studies: Intact full thickness skin: Separation of epidermis from full thickness skin

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In vivo Studies Animal models Human volunteers

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Product name Drug Manufacturer Indication Alora Estradiol TheraTech/ Proctol and Gamble Postmenstrual syndrome Androderm Testosterone TheraTech/GlaxoSmithKline Hypogonadism in males Catapres-TTS Clonidine Alza/ Boehinger Ingelheim Hypertension Climaderm Estradiol Ethical Holdings/ Wyeth- Ayerest Postmenstrual syndrome Climara Estradiol 3M Pharmaceuticals/ Berlex Labs Postmenstrual syndrome CombiPatch Estradiol/ Norethindrone Noven , Inc./Aventis Hormone replacement therapy Deponit Nitroglycerin Angina pectoris Duragesic Fentanyl Alza / Janssen Pharmaceutica TDDS products

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CONCLUSION Due to the recent advances in technology and the incorporation of the drug to the site of action without rupturing the skin membrane transdermal route is becoming the most widely accepted route of drug administration. The foregoing shows that TDDS have great potentials, being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and polymer are required.

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TDDS facilitate the passage of therapeutics quantities of drug substances through the skin and into general circulation for their systemic effects. TDDS is one of the systems lying under the category of controlled drug delivery, in which the aim is to delivery the drug through skin in predetermined and controlled rate.

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REFERENCES Gondaliya D, Pundarikakshudu K. Studies in formulation and pharmacotechnical evaluation of controlled release transdermal delivery system of bupropion. AAPS. Pharm. Sci. Tech. 2003; 4: Article3. Swarbrick J, Boylan J. Encyclopedia of Pharmaceutical Technology: “Transdermal drug delivery devices: system design and composition”: 309-37. Singh J, Tripathi KT, Sakia TR. Effect of penetration enhancers on the in vitro transport of ephedrine through rate

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Miller II KJ, Govil SK, Bhatia KS, inventors; Mylan Pharmaceuticals, Inc., assignee; Fentanyl suspension based silicone adhesive formulations and devices for transdermal delivery of fentanyl. US Patent 7556823, 2009. skin and human epidermis from matrix based Transdermal formulations. Drug. Dev. Ind. Pharm. 1993; 19: 1623-8. Aarti N, Louk ARMP, Russsel OP, Richard HG. Mechanism of oleic acid induced skin permeation enhancement in vivo in humans. Jour. control. Release. 1995; 37: 299-306

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Wade A, Weller PJ. Handbook of pharmaceutical Excipients. Washington, DC: American Pharmaceutical Publishing Association; 1994. p.362-366. Reddy RK, Muttalik S, Reddy S. Once daily sustainedrelease matrix tablets of nicorandil: formulation and in vitro evaluation. AAPS. Pharm. Sci. Tech. 2003; 4: 4. Shaila L, Pandey S, Udupa N. Design and evaluation of matrix type membrane controlled Transdermal drug delivery system of nicotin suitable for use in smoking cessation. Indian. Journ . Pharm. Sci. 2006; 68: 179-84.

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Lec ST, Yac SH, Kim SW, Berner B. One way membrane for transdermal drug delivery systems / system optimization. Int. J. Pharm. 1991; 77: 231-7. Singh J, Tripathi KT, Sakia TR. Effect of penetration enhancers on the in vitro transport of ephedrine through rate skin and human epidermis from matrix based Transdermal formulations. Drug. Dev. Ind. Pharm . 1993; 19: 1623-8. . .

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Costa P, Ferreria DC , Morgado R, Sousa Lobo JM. Design and evaluation of a lorazepam transdermal delivery system, Drug Dev Ind Pharm 1997, 23, 939-944 Bagyalakshmi J, Vamsikrishna RP, Manavalan R, Ravi TK, Manna PK.Formulation development and in vitro and in vivo evaluation of membranemoderated transdermal systems ofampicilline sodium in ethanol: pH 4.7 buffer solvent system AAPS PharmSciTec. 2007, 8, Article 7 Minghetti P, Cilurzo F, Tosi L, Casiraghi A, Montanari L. Design of a new water soluble pressure sensitive adhesive for patch preparation, AAPS PharmSciTech 2003, 4, Article 8

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Ryan D. Gordon, and Tim A. Peterson, transdermal drug delivery , drug Delivery technology ,www.drugdeliverytechnolo gy.com77.



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