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2 The NDDS may involve a new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of injections. Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms. HISTORY OF TDDS:

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3 Transdermal drug delivery system was first introduced more than 20 years ago. First transdermal patch was approved in 1981 to prevent nausea and vomiting associated with motion sickness. The FDA has approved, more than 35 transdermal patch products. 3 Continued...,

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4 CONTENTS: Introduction. Advantages & Disadvantages. Structure of the skin. Permeation through skin. Factors affecting permeation. Basic components of TDDS. Advances in TDDS.

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5 INTRODUCTION: Definition: Transdermal drug delivery is defined as a self contained discrete dosage form, which when applied to the intact skin, will deliver the drug at a controlled rate to the systemic circulation.

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8 STRUCTURE OF SKIN: Epidermis: Stratum corneum (Horny cell layer) Stratum lucidum (Clear layer) Stratum granulosum ( Granular Layer) Stratum spinosum (Prickly layer) Stratum germinativum Dermis: Hypodermis or Subcutaneous layer:

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11 STRUCTURE OF SKIN: Epidermis: The outer layer of skin is made up of Stratified Squamous epithelial cells. Epidermis is thickest in palms and soles. The stratum corneum forms the outer most layer (10-15µm thick ) which consists of many layers of compacted , flattened, dehydrated keratinized cells. The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption.

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12 Continued… Water content of stratum corneum is around 20%. The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness. It consists of Cermides and neutral lipids such as Sterols, free fatty acids and triglycerides.

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13 Continued.. The composite structure of skin permeation barrier is represented by 3 layers: Stratum corneum (15µm thick) Viable epidermis (150µm thick) Papillary layer of dermis (100-200µm thick)

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15 DERMIS: The dermis is made up of regular network of robust collagen fibers of fairly uniform thickness with regularly placed cross striations . This network or the gel structure is responsible for the elastic properties of the skin. It is supplied by blood to convey nutrients, remove waste & regulate body temp. Drug is well absorbed by this route. Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings.

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16 SUBCUTANEOUS TISSUE: This is a sheet of the fat containing areolar tissue known as the superficial fascia, attaching the dermis to the underlying structures . SKIN APPENDAGES: Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies. Its function is to control heat. HAIR FOLLICLES: They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene.

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17 MECHANISM OF ABSORPTION THROUGH SKIN Mechanism involved is passive diffusion This can be expressed by FICK’s LAW of DIFFUSION dq = D K A ( c1 – c2 ) dt h dq /dt = rate of diffusion D = diffusion co-efficient K = partition co-efficient A = surface area of membrane H = thickness of membrane 17

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18 Routes of drug absorption through skin: Trans follicular route Trans epidermal route 18

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19 TRANSFOLLICULAR ROUTE: Fractional area available through this route is 0.1 % Human skin contains 40-70 hair follicles, 200 to 250 sweat glands on every of skin area. Mainly water soluble substance are diffused faster through appendages than that of other layers. Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST corneum.

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20 TRANS EPIDERMAL ROUTE Epidermal barrier function mainly resides in horny layer The viable layer may metabolize, inactivate or activate a prodrug. Dermal capillary contains many capillaries so residence time of drug is only one minute. Within stratum corneum molecule may penetrate either transcellularly or intercellularly. Intracellular region is filled with lipid rich amorphous material.

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22 Process of transdermal permeation.

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24 FACTORS AFFECTING TRANSDERMAL PERMEABILITY Physico chemical properties of parent molecule Solubility and partition co- efficient pH condition Penetrant concentration Physico chemical properties of drug delivery system Release characteristic Composition of drug delivery system Permeation enhancer used

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25 Physiological and pathological condition of skin Lipid film Skin hydration Skin temperature Effect of vehicle Pathological injury to skin Biological factors Skin age Thickness of S. Corneum Skin condition 25

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26 Solubility and partition co- efficient: Solubility of a drug influences its ability to penetrate the skin. Drug solubility determines concentration presented to absorption site which will effect rate and extent of absorption. Skin permeation can be enhanced by increasing lipophilic character of drug, so that drug penetrates through STC but not through epidermis due to decreased water solubility. Drug which is lipid & water soluble is favored.

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27 pH & penetration concentration: Moderate pH is favorable because if solutions with high or low pH will result in destruction to the skin. Higher the concentration of the drug in vehicle faster the absorption. At higher concentrations than solubility the excess solid drug will function as a reservoir and helps to maintain a constant drug constitution for prolonged period of time.

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28 28 Physico-chemical properties of drug delivery system Release characteristic Solubility of drug in vehicle determines the release rate. Composition of drug delivery system It not only effects the rate of drug release but also the permeability through STC. Example methyl salicylate is more lipophilic than its parent acid (Salicylic acid). When applied to skin from fatty vehicle methylsalicylate yielded higher absorption.

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29 29 Physiological and pathological condition of skin Lipid film: It acts as protective layer to prevent removal of moisture from skin. Deffating of this film will decrease TD absorption. Skin hydration: It can be achieved by covering skin with plastic sheeting, which leads to accumulation of sweat, condensed water vapors, increase hydration and increase porosity.

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30 30 Effect of vehicle: A vehicle can influence absorption by its effect on physical state of drug and skin. Example greases, paraffin bases are more occlusive while water in oil bases are less. Humectants in bases will dehydrate the skin and decrease percutaneous absorption.

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31 31 Biological factors: Skin age: Skin of foetus ,young ones and elders is more permeable than adult tissue. Skin metabolism: Viable epidermis is metabolically active than dermis. If topically applied drug is subjected to biotransformation during permeation local and systemic bioavailability is affected.

Basic components of Transdermal drug delivery : 

32 32 Basic components of Transdermal drug delivery BACKING MEMBRANE DRUG ADHESIVE LINER

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33 33 LIST OF POLYMERS USED NATURAL POLYMERS: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Gums & Natural rubber SYNTHETIC POLYMER Poly vinyl alcohol, Poly vinyl chloride, Polyethylene, Poly propylene, Poly urea, Pvp

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34 34 DRUG For successful developing transdermal delivery, drug should be chosen with great care, Physicochemical properties: Mol. wt. less than 400 Daltons 2)Affinity for both lipophilic & hydrophilic phase 3)Drug should have low melting point

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35 Ideal properties of drug candidate

Schematic Skin absorption of drug : 

36 Schematic Skin absorption of drug 36

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37 37 Hypothetical blood level pattern from a conventional multiple dosing schedule, and an ideal pattern from a transdermal delivery system.

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38 Fig. 3. Types of transdermal delivery devices.

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39 Polymer membrane permeation controlled tdds Transderm scop Transderm nitro Catapres Adhesive polymer dispersion tdds Deponit Frandol type Nitro dur II Recent Developments

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40 Cont.., Non adhesive polymer dispersion tdds Nitro-dur system NTS system Micro-reservoir dissolution controlled tdds Nitro disc system Transdermal contraceptive system

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41 Table 1 Transdermal Controlled-Release Products and Devices

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42 More than 35 TDD products have now been approved for sale in the US & approximately 16 active ingredients are approved for use in TDD products globally.

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43 43 DRUG APPLICATION Commercial success

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44 Review article from IJPS TDDS though expensive alternative to conventional formulation are becoming popular because of some unique advantages like : controlled zero order absorption. Simple administration mode. Easy removal in case of adverse manifestations.

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45 Article from aaps Pharmsci Tech Comparison studies were carried out between oral carvedilol dosage form & carvedilol transdermal patch. Oral carvedilol acted quickly & drastically but later its effect dropped off. But the patches did not greatly decrease the BP in the initial phase when compared with the oral form. The effect of oral carvedilol started declining after 6 hrs due to its short half life. Since the administration of carvedilol through patches resulted in sustained and continued drug release for 24 hours, the patches were able to control the hypertension throughout the period.

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46 References Y. W. Chien, Novel drug delivery systems, 2nd edition, Revised & expanded, Marcel Dekker, Inc., New York, 1992. N. K. Jain, Controlled & Novel drug delivery, CBS Publishers & Distributors, New Delhi, First edition, 1997. Controlled drug delivery devices by Pravin Tyle, Marcel Dekker, Inc., New York, 1992, pg. no. 406 – 408. Mechanisms of Transdermal drug delivery system by Y. W. Chien, Marcel Dekker, Inc., New York. Journal of aaps pharmscitech, jan 19, 2007 Indian journal of pharmaceutical sciences september-october 2008 pg-556 to 560

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