Transdermal Drug Delivery System (TDDS) ppt (2)

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Transdermal Drug Delivery System (TDDS) :

Transdermal Drug Delivery System (TDDS) 1 Himanshu chauhan M.Pharm (Pharmaceutics) 2 nd semester Lovely professional university Jalandhar ( punjab )

Transdermal Drug Delivery System:

Transdermal Drug Delivery System Transdermal drug delivery system 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. A transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. 2 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.100

Advantages of transdermal drug delivery system:

Advantages of transdermal drug delivery system Avoidance of first pass metabolism, salivary metabolism and intestinal metabolism. Better patient compliance as frequent dosing avoided. Adverse affect are minimized due to a steady and optimum blood concentration. Prolonged duration of action ( ranging from few hours to one week). Daily dose of drug required is lower than that with conventional therapies. Non invasive ( no needle or injection ). Allow removal of drug source and termination of further administration, if necessary. Provides suitability of self medication. Allows effective use of drugs with short biological half-life 3 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.101 Brahmankar.M .D., Biopharmaceutics and pharmocokinetics a treatise. Vallabh prakashan , second edition, page no.496

Disadvantages of transdermal drug delivery system:

Disadvantages of transdermal drug delivery system Local irritation at site of application. Limited only to potent molecules, those requiring a daily dose of 10mg or less. Drug input is not rapid as i.v bolus, rather it is slow and sustianed . The molecular size of the drug should be reasonable that it should be absorbed percutaneously . Adhesive may not adhere well to all types of skin. Uncomfortable to wear. May not be economical . The barrier function of skin changes from one site to another on the same person, from person to person and with age. 4 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.101

Routes Of Drug Permeation :

Routes Of Drug Permeation Penetration of drug through the skin include Diffusion through the bulk stratum corneum via. Intercellular and intracellular pathway. Diffusion through the skin appendages. Sweat and hair follicles 5 Keleb.E ., Sharma.R.K ., Transdermal drug delivery system design and evaluation. International journal of advances in pharmaceutical science (2010), volume 1, page no.203 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.104-105

Kinetics Of Transdermal Permeation:

Kinetics Of Transdermal Permeation 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 6 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.107

Basic Components Of Trasdermal Drug Delivery System:

Basic Components Of Trasdermal Drug Delivery System Polymer matrix or matrices The drug Permeation enhancers Other excipients Pressure sensitive adhesives Impermeable backing membrane Release liner 7 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.107 Ashok.J ., Pallukandan.N ., Gopal.V ., Transdermal drug delivery system : An overview. International journal of pharmaceutical sciences review and research, volume 3, page no. 49

Polymer Matrix Or Mtrices:

Polymer Matrix Or Mtrices The Polymer controls the release of drug from the device. Polymer used in transdermal devices 8 Synthetic polymers Eg :- Polyvinyl alcohol, polyvinyl chloride, polyethylene, polyurea etc. Synthetic elastomers Eg : - Polybutadiene , silicone rubber, butyl rubber, neoprene etc. Natural polymers Eg : - Zein ,gelatin, shellac , waxes, protiens etc. Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.107

The Drug:

The Drug Some of the desirable properties of a drug for transdermal delivery. Molecular weight of drug < 1000 Daltons. Dose of drug < 10 mg. Water solubility of drug > 1mg/ml. Oil solubility of drug > 1mg/ml. Drug with Short half life (10 hours or less). Drug having poor oral avialibility . Drug should have low melting point ( <200°C). Non-irritating and non-sensitizing to skin. 9 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.107-108 Brahmankar.M .D., Biopharmaceutics and pharmocokinetics a treatise. Vallabh prakashan , second edition, page no.497

Permeation Enhancers:

Permeation Enhancers These are the substances, which facilitate the transport of drug molecules across skin by temporarily altering its permeability. These reduce the resistance of the skin (stratum corneum ) to diffusion of drug molecules. 10 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.108

Types of Permeation enhancers :

Types of Permeation enhancers Physical enhancers Ionotophorosis : - Delivers the charged molecules across skin by the use of small electric current. Sonophoresis : - Drug molecules migration through skin by ultrasonic energy. Electroporation : - Apply short micro to millisecond electrical pulse approx 100 – 1000 v/cm to creates temporary aqueous pore in lipid layer. 11 Chemical enhancers Solvents surfactants Physical enhancers Iontophoresis Sonophoresis Electroporation Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.108,191,208.

Chemical Enhancers:

Chemical Enhancers Solvents : - Increase penetration by swelling the polar path or by fluidising lipids. eg : - water alcohols, methyl sulfoxide , pyrrolidones , propylene glycols etc. Surfactants : - lipid fluidization or penetration of it into intracellular matrix and result in dissruption of order of corneocytes . eg : - Anionic surfactants – dicotylsulphosuccinate , sodium lauryl sulphate etc. Nonionic surfactants – pluronic F 127, pluronic F68,etc. Natural surfactant (bile salts) – sodium taurocholate , sodium tauroglycholate etc . 12 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.108-109

Other Excipients:

Other Excipients 1- Adhesives : - Serves to adhere the component of patch to skin. It should adhere with not more than applied finger pressure. It should be easily removable from the smooth surface without leaving a residue. Be aggressively and permanently tachy . Physical and compatible with the drug. Should not alter drug permeation. Should not irritate or sensitize the skin. Eg :- polyisobutylenes , acrylics and silicones. 13 Ashok.J ., Pallukandan.N ., Gopal.V ., Transdermal drug delivery system : An overview. International journal of pharmaceutical sciences review and research, volume3, page no. 49 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.109

2. Backing Membrane :-:

2. Backing Membrane :- Protect the drug in the patch from outer enviroment and also prevent leaving drug from top. Flexible Impermeable Good oxygen transmission and a high moisture vapor transmission rate. Accept printing e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate ( aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate ( aluminium foil disc) etc. 3. Release Liner :- Protect patch during storage, it is removed prior to use e.g. non-occlusive base layer (paper fabric) or occlusive ( e.g . polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon , polyester foil and metallized laminates. 14 Ashok.J ., Pallukandan.N ., Gopal.V ., Transdermal drug delivery system : An overview. International journal of pharmaceutical sciences review and research, volume 3, page no. 49 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.110

Four major transdermal system:

Four major transdermal system 1 . Polymer Membrane Permeation Controlled TDDS. 2. Polymer Matrix Diffusion Controlled TDDS. 3. Drug Reservoir Gradient Controlled TDDS/ Adhesive Dispersion Type System. 4. Microreservoir Dissolution Controlled TDDS. 15 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.110-114 Brahmankar.M .D., Biopharmaceutics and pharmocokinetics a treatise. Vallabh prakashan , second edition, page no.497

Slide 16:

Polymer Membrane Permeation Controlled TDDS. Drug Reservoir : Dispersed on solid polymer matrix e.g polyisobutylene . Suspended in unleachable viscous liquid medium eg . Silicone fluid. Dissolved in solvent. Rate controlling Membrane: Microporous , Nonporous. Eg . Ethylene-Vinyl acetate copolymer. Adhesive Layer: Thin layer, adhesive, drug compatible, hypoallergic , eg . Silicone adhesive. e.g. Estradiol releasing transdermal system Colinidine releasing transdermal patches Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.110-111 16

Polymer Membrane Permeation Controlled TDDS:

Polymer Membrane Permeation Controlled TDDS Intrinsic rate of drug release is given by :- dQ / dt - rate of drug release Cr - Drug concentration in reservior . Dm & Da - Diffusion coefficient in rate controling membrane and adhesive layer. hm & ha - Thickness of membrane and adhesive layer. K m/r & K a/m - Partition coefficient for the interfacial partioning of drug from reservior to membrane and from membrane to adhesive respctively . 17 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.110-111

Polymer Matrix Diffusion Controlled TDDS:

Polymer Matrix Diffusion Controlled TDDS Drug reservior : - Drug dispersed homogenously in a hydrophillic or lipophillic polymeric matrix. e.g. silicone elastomers,Polyurethanes , polyviny alcohols etc. Homogenously mixing drug with liquid polymer and higly viscous polymer followed by Crosslinking . At elevated temp. drug is homegenously blend with rubbery polymer. Occulusive base plate : -drug reservior containig polymer disc is pasted in it. Impermeable plastic backing Adhevise polymer : - is spread along the circumference to form a strip of adhesive rim around medicated disc. e.g. nitroglycerin release transdermal (Nitro dur ). 18 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.112-113 Brahmankar.M .D., Biopharmaceutics and pharmocokinetics a treatise. Vallabh prakashan , second edition, page no.499-500

Slide 19:

Rate of drug release from this system is : dQ / dt = [A Cp Dp /2t] A – initial drug loading dose dispersed in polymer. Cp & Cd – solubility and diffusivity of drug in the polymer respectively Advantages of matrix diffusion : - There is no dose dumping since the polymer cannot rupture Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.112-113 19

Drug Reservoir Gradient Controlled TDDS/ Adhesive Dispersion Type System:

Drug Reservoir Gradient Controlled TDDS/ Adhesive Dispersion Type System Simplified form of membrane permeation contolled system. Drug reservior : - Drug dispersed in adhesive polymer e.g. polyisobutylene , polyacrylate . Drug reservior layer :- medicated adhesive spread over a flat sheet impermeable metallic plastic backing, by solvent casting or hot melt. Rate contolling adhesive : - thin layer, non medicated, specific permeability and constant thickness applied on top of drug reservior layer to produce diffusion contolled delivery system. e.g. Isosorbide dinitrate and verapamil can be administrated by controlled manner in this adhesive dispersion type system. 20 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.111-112 Brahmankar.M .D., Biopharmaceutics and pharmocokinetics a treatise. Vallabh prakashan , second edition, page no.500

Slide 21:

Rate of drug release from adhesive dispersion type system : - dQ / dt = [ Ka/r Da /Ha(t)] A (Ha) Ka/r – is the partition coefficient for interfacial partioning of drug from the reservier layer to adhesive layer. Da - diffusion coefficient of adhesive layer. Ha (t) – thickness of adhesive layer for drug molecules to diffuse through increase with time. A (Ha) – drug loading increased with thickness of difusional path. Design of drug in adhesive type transdermal patch Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no. 111-112 21

Microreservoir Dissolution Controlled TDDS:

Microreservoir Dissolution Controlled TDDS This drug delivery system is a combination of reservior and matrix dispersion system. Drug reservior : - Drug suspended in a aqueous solution of soluble polymer. Dispersing the solution in a lipophillic polymer Thousands of unleachable , microscopic drug reserviors 22 Brahmankar.M .D., Biopharmaceutics and pharmocokinetics a treatise. Vallabh prakashan , second edition, page no.500

Slide 23:

Medicated polymer disc is coated with layer of biocompatible polymer to modify the mechanism and rate of drug release. The system is produced my positioning the medicated disc at the center and surrounding with an adhesive rim. Design of micro reservoir type transdermal patch Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no. 113 23

Evaluation Of TransdermalDrug System:

Evaluation Of TransdermalDrug System Evaluation of adhesives Peel adhesion properties. Tack properties Shear strength properties In- vitro drug release evaluation In- vivo evaluation Animal model Human model 4. Cutaneous toxicological evaluation 24 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no. 118-126

Evaluation of adhesives:

Evaluation of adhesives A Peel adhesion properties : - It is the force required to remove adhesive coating from test substrate. It is tested by measuring the force required to pull a single coated tape, applied to substrate at 180° angle. B Tack properties : - It is the ability of the polymer to adhere to substrate with little contact pressure. Thumb tack test : - The force required to remove thumb from adhesive is a measure of tack Rolling ball test : - This test involves measurement of the distance that stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the further the ball will travel . 25 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.118-121

Slide 26:

Quick stick (Peel tack) test :- The peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90◦ at the speed of 12 inch/min. Probe tack test :- Force required to pull a probe away from an adhesive at a fixed rate is recorded as tack. C 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 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.118-121 26

In Vitro Drug Release Evaluation:

In Vitro Drug Release Evaluation Franz d iffusion cell : - In this method transdermal system is placed in between receptor and donor compartment of the diffusion cell. The transdermal system faces the receptor compartment in which receptor fluid i.e., buffer is placed. The agitation speed and temperature are kept constant. The whole assembly is kept on magnetic stirrer and solution in the receiver compartment is constantly and continuously stirred throughout the experiment using magnetic beads. At predetermined time intervals, the receptor fluid is removed for analysis and is replaced with an equal volume of fresh receptor fluid. The concentration of drug is determined spectrophotometrically . 27 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition page no.121-122

Slide 28:

The pH of the dissolution medium 5 to 6 Test temperature is typically set at 32°C (even though the temperature may be higher when skin is covered). Typical agitation rate 100 rpm. The dissolution data obtained is fitted to mathematical models in order to ascertain the release mechanism. 28

In - Vivo Evaluation:

In - Vivo Evaluation Animal model The most common animal species used for evaluating transdermal drug delivery system are mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig etc. Rhesus monkey is one of the most reliable models for in Vivo evaluation of transdermal drug delivery in man. Standard radiotracer methodology is used. Application site are generally forearm or abdomen. Alternative animal models include weanling pig and human skin grafted nude mouse. 29 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no . 123

Human model:

Human model It involves collection of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. First described by ( Feldmann & Maibach ). Determination of percutaneous absortion by indirect method of measuring radioactivity in excreta followed by topical application of labbeled drug. % dose absorbed = total radioactivity excreted after topical administration divide by total radioactivity excreted after intravenous administration multiplied by 100 14C is generally used for radio- labelling . 30 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.123 - 124

Cutaneous toxicological model:

Cutaneous toxicological model Evaluation of transdermal drug delivery system to deletrious effect on skin. A – Contact dermatitis : - Irittant dermititis , due to toxic injury to cell membranes, cytoplasm or nuclei. Manefested by inflamation , erythema and itching occur from drug , enhancers , adhesive and other excipient . Animal used rabbit and guinea pig Measured by : - Primary irritaion test and Evaporative water loss measurement. Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.125 - 126 31

B- Growth of microorganism:

B- Growth of microorganism Localised superfacial infection : - Evaluation of prolification of bacteria ( S. aureus ) , fungi and yeast by quantitative bacteriological cultures of skin sites before and after use of transdermal system. Millaria (prickly heat) : - Ocuur due to sweating. This may lead to millaria rubra . 0ther evaluation : - Thickness of patch. Weight uniformity. Folding endurance. Moisture content. Water vapour permeability. Drug content. 32 Jain .N.K., Contolled and novel drug delivery. CBS publisher and distributor, first edition, page no.126 Ashok.J ., Pallukandan.N ., Gopal.V ., Transdermal drug delivery system : An overview. International journal of pharmaceutical sciences review and research, volume 3, page no. 51

Slide 33:

Thank You 33