Transdermal drug delivery system

Transdermal drug delivery system: 

Transdermal drug delivery system Prepared by - Mitesh P. Sonawane . Under guidance of - Ms. M. R. Narkhede M.G.V.Pharmacy College, Panchavati,Nashik-03,Nashik .

Introduction1,2 -: 

Introduction 1,2 - The use of the transdermal route has been well established since the1800s. There is considerable interest in the skin as a site of drug application both for local and systemic effects. Transdermal drug delivery systems allow delivery of a drug into the systemic circulation via permeation through skin layers at a controlled rate. The skin poses an extremely good barrier to drug penetration and it is usually necessary to employ enhancement strategies. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles, and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly, transdermal dosage forms in clinical practice. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 2

Objective - : 

Objective - To explore skin as a site for drug administration. To identify physicochemical properties of drug required in development of TDDs. To study various methods for preparation of TDDs. To study various methods for evaluation of TDDs. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 3

Advantages of TDDS2 - : 

Advantages of TDDS 2 - Avoids the risk and inconvenience of intravenous therapy. Usually provides less chance of an overdose or under dose. Permit both local and systemic effects . Reduces dosing frequency. Avoids hepatic first pass elimination and gastrointestinal irritation. Non-invasive drug delivery system. Improve physiological and pharmacological responses. Reduction of fluctuations in plasma levels of drugs. Allow easy termination. Utilization of drug candidates with short half-life and low therapeutic index. Reduction of dosing frequency and patient compliance. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 4

Disadvantages of TDDS7 - : 

Disadvantages of TDDS 7 - TDDS cannot deliver ionic drugs. TDDS cannot achieve high drug levels in blood/plasma. Cannot develop TDDS for drugs of large molecular size. TDDS cannot deliver drugs in a pulsatile fashion. Cannot develop TDDS, if drug or formulation causes irritation to skin. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 5

PERCUTANEOUS ABSORPTION7 - : 

PERCUTANEOUS ABSORPTION 7 - Percutaneous absorption is defined as penetration of substances into various layers of skin and permeation across the skin into systemic circulations. The percutaneous absorption is a step-wise process and can be divided into three parts: Penetration : is the entry of a substance into a particular layer. Permeation : is the penetration from one layer into another, and is different both functionally and structurally from the first layer. Absorption : is the uptake of a substance into systemic circulation. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 6

Anatomy of skin along with routes of penetration2 - : 

Anatomy of skin along with routes of penetration 2 - Fig1: Anatomy of skin. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 7

Anatomy of skin cont…: 

Anatomy of skin cont… Drug molecules in contact with skin surface can penetrated by three potential pathways, through *sweat ducts, *via the hair follicles and *sebaceous glands. *Stratum corneum. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 8

Ideal properties of drug used for TDDS1: 

Ideal properties of drug used for TDDS 1 Parameter Dose Half life in ‘h’ Molecular weight Partition coefficient Skin permeability coefficient Skin reaction Oral bioavailability Therapeutic index Properties Should be low (>20 mg/day) 10 or less <400 Log P (octanol-water) between 1-4 >0.5 10 -3 cm/hr Non irritating and non sensitizing Low Low 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 9

Approaches of TDDS3,4,6,7. Various technologies have been developed to bypass or modulate the barrier function of the skin and to allow easier passage of drugs into the dermal microcirculation; these can be categorized into physical and chemical.: 

Approaches of TDDS 3,4,6,7 . Various technologies have been developed to bypass or modulate the barrier function of the skin and to allow easier passage of drugs into the dermal microcirculation; these can be categorized into physical and chemica l . Physical Approaches Iontophoresis . Electroporation . Microporation. Heat. Needless injection. Medicated tattos. Sonophoresis. Pressure valve Radio Frequency. Magnetophoresis Chemical Approaches . prodrug approaches. penetration Enhancer. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 10

Physical Approaches.: 

Physical Approaches . 1. Iontophoresis- Iontophoresis is the process of enhancing the permeation of topically applied therapeutic agents. The drug is applied under an electrode of the same charge as the drug, and an indifferent counter electrode is positioned elsewhere on the body. The active electrode effectively repels the active substance and forces it into the skin and rough the skin by the application of electric current. Mechanisms. First mechanism proposes that the drug is forced across the skin by simple electronic repulsion of similar charges. Anionic drugs can cross the skin by using a negatively charged working electrode. Similarly, cationic drugs can cross the skin when a positively charged electrode is used. The second the electric current enhances the permeation by inhibiting the skin's ability to perform its protective barrier function. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 11

Mechanism of Iontophoresis: 

Mechanism of Iontophoresis 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 12

Slide 13: 

2. Electroporation. Electroporation is another electrical enhancement method which involves the application of short (microsecond or millisecond), high voltage (50-1000 volts) pulses to the skin. Larger macromolecules have also been delivered by electroporation, including insulin, vaccines, oligonucleotides, and microparticles. A few model compounds such as calcein and LHRH drugs have also been studied for increased transdermal absorption by electroporation. Mechanism. The mechanism of penetration is the formation of transient pores due to electric pulses that subsequently allow the passage of macromolecules from the outside of the cell to the intracellular space via a combination of processes such as diffusion and electrophoresis . 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 13

: 

3. Microporation - Microporation involves the use of microneedles that are applied to the skin so that they pierce only the stratum corneum and increase skin permeability. Microneedles are needles that are 10 to 200 µm in height and 10 to 50 µm in width. Microneedles do not stimulate the nerves, so the patient does not experience pain or discomfort. They are usually drug coated projections of solid silicon or hollow, drug filled metal needles. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 14

: 

4 . Heat - Heat enhances the skin permeation of drugs by increasing body fluid circulation, blood vessel wall permeability, rate-limiting membrane permeability, and drug solubility, thus facilitating drug transfer to the systemic circulation. Example: The effect of temperature on in vitro transdermal fentanyl flux was estimated at temperatures of 32 ° and 37 ° C. Drug flux approximately doubled over this 5 ° range. Heat may also cause changes in physiochemical properties of patches, sweating, and increased hydration of skin, thus increasing the permeation of drugs. Mechanism : When heat is applied, the kinetic energy of drug molecules, proteins, lipids, and carbohydrates is known to increase in the cell membrane. Also, drug solubility both in the patch and within the skin may increase with a rise in temperature. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 15

: 

Needleless injection involves a pain-free method of administration of drugs to the skin. This technique involves firing the liquid or solid particles at supersonic speeds through the stratum corneum. Problems with this technique include the high developmental cost for both the device and dosage form and the inability to program or control drug delivery to compensate for intersubject differences in skin permeability. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 16 5.Needleless injection - Mechanism The mechanism involves forcing compressed gas such as helium or nitrogen through the nozzle with the resultant drug particles entrained within the jet flow, reportedly traveling at sufficient velocity for skin penetration.

: 

Medicated tattoos are a modification of temporary tattoos which contain an active drug medicament for transdermal delivery. They are very attractive and fun to wear and are applied by wetting with water and pressing against the skin. The tattoo contains a drug layer, a colour design layer, and an adhesive layer that binds to the skin. There is no predetermined duration of therapy. The manufacturer provides a colours chart that can be compared to the colours of the patient's tattoo to determine when the tattoo should be removed. It gives a visual indication as the drug is absorbed into the skin. Upon absorption, the tattoo gradually fades away and is painless to remove with a simple astringent wash containing isopropyl alcohol. The drugs used in medicated tattoos prototypes include acetaminophen, vitamin C etc. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 17 6.Medicated tattoos -

Slide 18: 

7.Pressure waves - Pressure waves generated by intense laser radiation, can permeabilize the stratum corneum as well as the cell membrane. PW is only applied for a very short time (100ns-1µs). It is thought that the pressure waves form a continuous or hydrophilic pathway across the skin due to expansion of lacunae domains in the stratum corneum.A single pressure wave is sufficient to permeabilize the stratum corneum and allow the transport of macromolecules into the epidermis and dermis. In addition, the drug delivered into the epidermis can enter the vasculature and produce a systemic effect. Example: Insulin delivered by pressure waves resulted in reducing the blood glucose level over many hours. The application of pressure waves does not cause any pain or discomfort and the barrier function of the stratum corneum always recovers. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 18

: 

8.Sonophoresis - Sonophoresis is a technique which involves the use of ultrasonic energy to enhance skin penetration of active substances. Transdermal enhancement is particularly significant at low frequency regimes (20 KHz < f <100 KHz) than when induced by high frequency ultrasound. Ultrasound parameters such as treatment duration, intensity, pulse length, and frequency are all known to affect percutaneous absorption with frequency being the most important. Example: Sonophoresis of hypotensive agents and papain has been used in the treatment of eye diseases. Several antibiotics including tetracycline, biomycin, and penicillin have been sonophoretically administered for the therapy of skin diseases. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 19

Slide 20: 

The mechanism of transdermal skin permeation involves the disruption of the stratum corneum lipids by the formation of gaseous cavities, thus allowing the drug to pass through the skin. Mechanism 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 20

: 

9.Magnetophoresis - The term, "magnetophoresis" was used to indicate application of a magnetic field and acts as an external driving force to enhance drug delivery across the skin. It induces alteration in the skin's structure that could contribute to an increase in permeability. Magnetoliposomes consist of magnetic nanoparticles wrapped by a phospholipid bilayer which can be successfully applied for drug delivery systems, magnetic resonance imaging markers for cancer diagnosis, and thermal cancer therapy. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 21

: 

10.Radiofrequency - Radiofrequency involves exposure of the skin to a high frequency alternating current of 100 KHz that results in the formation of heat-induced microchannels in the cell membrane. The drug delivery rate is controlled by the number and depth of microchannels formed, which depends on the properties of the microelectrodes in contact with the skin during treatment. Skin delivery of testosterone and human growth hormone are in progress by use of this method. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 22

Chemical approaches -: 

Chemical approaches - 1. Penetration enhancer - Incorporation of penetration enhancers facilitates the absorption of drugs by altering the barrier property of the stratum corneum. A permeation enhancer should be pharmacologically inert, nontoxic, nonirritating, nonallergic, odorless, tasteless, colorless, compatible with most drug and excipients, inexpensive, and have good solvent properties. Different classes of penetration enhancers includes: Alcohols and polyols (ethanol, propylene glycol). Surfactants (Tween, Span, SLS). Fatty acids (Oleic acid). Amines and amides (Azone, N -methylpyrrolidone). Terpenes (limonene). Sulfoxides (dimethylsulfoxide) Esters(isopropylmyristate). 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 23

Slide 24: 

Mechanism: Permeation enhancers can enhance the skin permeability by a variety of mechanisms, including Interaction with intercellular lipids leading to disruption of their organization and increasing their fluidity. Extraction of lipids from the stratum corneum. Displacement of bound water, Loosening of horny cells, Delamination of stratum corneum. Enhancing solubility and Increasing partitioning into the stratum corneum, Interaction with intercellular protein, and keratin denaturation. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 24

Slide 25: 

2.Prodrug - Prodrugs are therapeutically inactive derivatives of therapeutically active drugs. A prodrug undergoes metabolism to produce the therapeutically active drug. A prodrug is more lipophilic than the parent drug and has different physicochemical properties. Different prodrugs were developed for estradiol and "Transdermal Bioactive Hormone Delivery" devices were developed based on the results. The release rate of estradiol from Transdermal Bioactive Hormone Delivery is dependent on the chain length of the ester group at the 17 th position. Alkyl ester prodrugs of ketorolac having optimum lipophilicity could improve the transdermal delivery of ketorolac. Also, the prodrug approach is a very feasible way to increase the skin permeation of protein/peptide drugs. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 25

Slide 26: 

Fig. Schematic representation of pro-drug approach to increase drug penetration across skin 7 . 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 26

Formulation aspects1:: 

Formulation aspects 1 : 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 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 27

Polymer matrix / Drug reservoir -: 

Polymer matrix / Drug reservoir - Polymers are the backbone of TDDS, which control the release of the drug from the device. Polymer matrix can be prepared by dispersion of drug in liquid or solid state synthetic polymer base. Polymers used in TDDS should have biocompatibility and chemical compatibility with the drug and other components of the system such as penetration enhancers and PSAs. Additionally they should provide consistent and effective delivery of a drug throughout the product’s intended shelf life and should be of safe status. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 28

Slide 29: 

Examples: Natural Polymers: e.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural rubber and chitosan etc . Synthetic Elastomers: e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon  rubber, nitrile, acrylonitrile, neoprene, butylrubber etc . Synthetic Polymers: e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc . 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 29

Drug:: 

Drug: The transdermal route is an extremely attractive option for the drugs with appropriate pharmacology and physical chemistry. Transdermal patches offer much to drugs which undergo extensive first pass metabolism, drugs with narrow therapeutic window, or drugs with short half life which causes non- compliance due to frequent dosing. The foremost requirement of TDDS is that the drug possesses the right mix of physicochemical and biological properties for transdermal drug delivery. It is generally accepted that the best drug candidates for passive adhesive transdermal patches must be; non ionic, of low molecular weight (less than 500 Daltons), have adequate solubility in oil and water (log P in the range of 1-3), a low melting point (less than 200°C) potent (dose in mg per day). 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 30

Permeation Enhancers: : 

Permeation Enhancers: These are the chemical compounds that increase permeability of stratum corneum so as to attain higher therapeutic levels of the drug candidate. Penetration enhancers interact with structural components of stratum corneum i.e., proteins or lipids. They alter the protein and lipid packaging of stratum corneum, thus chemically modifying the barrier functions leading to increased permeability . Over the last 20 years, a tremendous amount of work has been directed towards the search for specific chemicals, combination of chemicals, which can act as penetration enhancers. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 31

Pressure sensitive adhesives: : 

Pressure sensitive adhesives: A PSA is a material that helps in maintaining an intimate contact between transdermal system and the skin surface. It should adhere with not more than applied finger pressure, be aggressively and permanently tachy, exert a strong holding force. Additionally, it should be removable from the smooth surface without leaving a residue. Polyacrylates, polyisobutylene and silicon based adhesives are widely used in TDDSs. The selection of an adhesive is based on numerous factors, including the patch design and drug formulation. For matrix systems with a peripheral adhesive, an incidental contact between the adhesive and the drug and penetration enhancer should not cause instability of the drug, penetration enhancer or the adhesive. In case of reservoir systems that include a face adhesive, the diffusing drug must not affect the adhesive. In case of drug-in-adhesive matrix systems, the selection will be based on the rate at which the drug and the penetration enhancer will diffuse through the adhesive. Ideally, PSA should be physicochemically and biologically compatible and should not alter drug release. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 32

Backing Laminate: : 

Backing Laminate : While designing a backing layer, the consideration of chemical resistance of the material is most important. Excipient compatibility should also be considered because the prolonged contact between the backing layer and the excipients may cause the additives to leach out of the backing layer or may lead to diffusion of excipients, drug or penetration enhancer through the layer. However, an overemphasis on the chemical resistance may lead to stiffness and high occlusivity to moisture vapor and air, causing patches to lift and possibly irritate the skin during long wear. The most comfortable backing will be the one that exhibits lowest modulus or high flexibility, good oxygen transmission and a high moisture vapor transmission rate. Examples : vinyl, polyethylene and polyester films. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 33

Release Liner: : 

Release Liner: During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to skin. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug. However, as the liner is in intimate contact with the delivery system, it should comply with specific requirements regarding chemical inertness and permeation to the drug, penetration enhancer and water. Typically, release liner is composed of a base layer which may be non-occlusive ( e.g . paper fabric) or occlusive ( e.g . polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon. Other materials used for TDDS release liner include polyester foil and metallized laminates. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 34

Other excipients: : 

Other excipients : Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir . In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 35

VARIOUS METHODS FOR PREPARATION TDDS4: : 

VARIOUS METHODS FOR PREPARATION TDDS 4 : a. Asymmetric TPX membrane method. b. Circular teflon mould method. c. Mercury substrate method. d. By using “IPM membranes” method. e. By using “EVAC membranes” method. f. Aluminium backed adhesive film method. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 36

Asymmetric TPX membrane method:: 

Asymmetric TPX membrane method: A prototype patch can be fabricated for this a heat sealable polyester film (type 1009, 3 m) with a concave of 1cm diameter will be used as the backing membrane. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 37

Circular teflon mould method:: 

Circular teflon mould method: 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 38 The solvent is allowed to evaporate for 24 hrs. The dried films are to be stored for another 24hrs at 25±0.5°C in a desiccators containing silica gel before evaluation to eliminate aging effects. The type films are to be evaluated within one week of their preparation.

Mercury substrate method:: 

Mercury substrate method: 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 39

By using “IPM membranes” method:: 

By using “IPM membranes” method: 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 40

By using “EVAC membranes” method:: 

By using “EVAC membranes” method: 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 41

Slide 42: 

8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 42

Slide 43: 

8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 43

Aluminium backed adhesive film method:: 

Aluminium backed adhesive film method: 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 44

Slide 45: 

8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 45

Evaluation1,4,7:: 

Evaluation 1,4,7 : 1. Interaction studies: 11. Peel Adhesion test: 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 46 2. Thickness of the patch: 3. Weight uniformity: 4. Folding endurance: 5. Percentage Moisture content: 6. Percentage Moisture uptake: 7. Drug content: 8. Water vapour permeability (WVP) evaluation: 9. Uniformity of dosage unit test: 10. Shear Adhesion test: 12. Flatness test: 13. Percentage Elongation break test: 14. Rolling ball tack test: 15. Quick Stick (peel-tack) test: 16. Skin Irritation study: 17. In vitro drug release studies: 18. In vitro skin permeation studies: 19. Stability studies:

1. Interaction studies:: 

1. Interaction studies: Excipients are integral components of almost all pharmaceutical dosage forms. The stability of a formulation amongst other factors depends on the compatibility of the drug with the excipients. The drug and the excipients must be compatible with one another to produce a product that is stable, thus it is mandatory to detect any possible physical or chemical interaction as it can affect the bioavailability and stability of the drug. If the excipients are new and have not been used in formulations containing the active substance, the compatibility studies play an important role in formulation development. Interaction studies are commonly carried out in Thermal analysis, FT-IR, UV and chromatographic techniques by comparing their physicochemical characters such as assay, melting endotherms, characteristic wave numbers, absorption maxima etc., 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 47

2. Thickness of the patch:: 

2. Thickness of the patch: The thickness of the drug loaded patch is measured in different points by using a digital micrometer and determines the average thickness and standard deviation for the same to ensure the thickness of the prepared patch. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 48 3. Weight uniformity: The prepared patches are to be dried at 60°c for 4hrs before testing. A specified area of patch is to be cut in different parts of the patch and weigh in digital balance. The average weight and standard deviation values are to be calculated from the individual weights.

4. Folding endurance:: 

4. Folding endurance: A strip of specific are is to be cut evenly and repeatedly folded at the same place till it broke. The number of times the film could be folded at the same place without breaking gave the value of the folding endurance. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 49 5. Percentage Moisture content : The prepared films are to be weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature for 24 hrs. After 24 hrs the films are to be reweighed and determine the percentage moisture content from the below mentioned formula. Percentage moisture content = [Initial weight- Final weight/ Final weight] ×100.

6. Percentage Moisture uptake:: 

6. Percentage Moisture uptake: The weighed films are to be kept in a desiccator at room temperature for 24 hrs containing saturated solution of potassium chloride in order to maintain 84% RH. After 24 hrs the films are to be reweighed and determine the percentage moisture uptake from the below mentioned formula. Percentage moisture uptake = [Final weight- Initial weight/ initial weight] ×100. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 50 7 . Drug content: A specified area of patch is to be dissolved in a suitable solvent in specific volume. Then the solution is to be filtered through a filter medium and analyse the drug contain with the suitable method (UV or HPLC technique). Each value represents average of three different samples.

8. Water vapour permeability (WVP) evaluation:: 

8. Water vapour permeability (WVP) evaluation: The WVP can be determined by the following formula Water vapour permeability can be determined with foam dressing method the air forced oven is replaced by a natural air circulation oven. WVP=W/A Where, WVP is expressed in gm/m 2 per 24hrs, W is the amount of vapour permeated through the patch expressed in gm/24hrs and A is the surface area of the exposure samples expressed in m 2 . 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 51

9. Uniformity of dosage unit test:: 

9. Uniformity of dosage unit test: An accurately weighed portion of the patch is to be cut into small pieces and transferred to a specific volume volumetric flask, dissolved in a suitable solvent and sonicate for complete extraction of drug from the patch and made up to the mark with same. The resulting solution was allowed to settle for about an hour, and the supernatant was suitably diluted to give the desired concentration with suitable solvent. The solution was filtered using 0.2m membrane filter and analysed by suitable analytical technique (UV or HPLC) and the drug content per piece will be calculated. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 52

10. Shear Adhesion test:: 

10. Shear Adhesion test: This test is to be performed for the measurement of the cohesive strength of an adhesive polymer. It can be influenced by the molecular weight, the degree of crosslinking and the composition of polymer, type and the amount of tackifier added. An adhesive coated tape is applied onto a stainless steel plate; a specified weight is hung from the tape, to affect it pulling in a direction parallel to the plate. Shear adhesion strength is determined by measuring the time it takes to pull the tape off the plate. The longer the time take for removal, greater is the shear strength. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 53

11. Peel Adhesion test:: 

11. Peel Adhesion test: 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 180º angle, and the force required for tape removed is measured. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 54 12. Flatness test: Three longitudinal strips are to be cut from each film at different portion like one from the center, other one from the left side, and another one from the right side. The length of each strip was measured and the variation in length because of non-uniformity in flatness was measured by determining percent constriction, with 0% constriction equivalent to 100% flatness.

13. Percentage Elongation break test:: 

13. Percentage Elongation break test: The percentage elongation break is to be determined by noting the length just before the break point, the percentage elongation can be determined from the below mentioned formula. Elongation percentage = L 1 -L 2 ×100 L 2 Where, L1is the final length of each strip and L2 is the initial length of each strip. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 55 14. Rolling ball tack test: This test measures the softness of a polymer that relates to talk. 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. The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch.

15. Quick Stick (peel-tack) test:: 

15. 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 to break the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces or grams per inch width. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 56 16. Skin Irritation study: Skin irritation and sensitization testing can be performed on healthy rabbits (average weight 1.2 to 1.5 kg). The dorsal surface (50cm 2 ) of the rabbit is to be cleaned and remove the hair from the clean dorsal surface by shaving and clean the surface by using rectified spirit and the representative formulations can be applied over the skin. The patch is to be removed after 24 hr and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury.

17. In vitro drug release studies:: 

17. In vitro drug release studies: The paddle over disc method (USP apparatus V) can be employed for assessment of the release of the drug from the prepared patches. Dry films of known thickness is to be cut into definite shape, weighed, and fixed over a glass plate with an adhesive. The glass plate was then placed in a 500-ml of the dissolution medium or phosphate buffer (pH 7.4), and the apparatus was equilibrated to 32± 0.5°C. The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 50 rpm. Samples (5- ml aliquots) can be withdrawn at appropriate time intervals up to 24 h and analyzed by UV spectrophotometer or HPLC. The experiment is to be performed in triplicate and the mean value can be calculated. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 57

18. In vitro skin permeation studies:: 

18. In vitro skin permeation studies: An in vitro permeation study can be carried out by using diffusion cell. Full thickness abdominal skin of male Wistar rats weighing 200 to 250g. Hair from the abdominal region is to be removed carefully by using a electric clipper; the dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels, equilibrated for an hour in dissolution medium or phosphate buffer pH 7.4 before starting the experiment and was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the diffusant. The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically controlled heater. The isolated rat skin piece is to be mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample volume of definite volume is to be removed from the receptor compartment at regular intervals, and an equal volume of fresh medium is to be replaced. Samples are to be filtered through filtering medium and can be analyzed spectrophotometrically or HPLC. Flux can be determined directly as the slope of the curve between the steady-state values of the amount of drug permeated (mg cm 2 ) vs. time in hours and permeability coefficients were deduced by dividing the flux by the initial drug load (mg cm 2 ). 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 58

19. Stability studies:: 

19. Stability studies: Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°c and 75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug content. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 59

Conclusion -: 

Conclusion - Transdermal drug delivery system has been recognized as a potential delivery system in spite of its limitation. Essentially this drug delivery system brings ratecontrolled delivery with fewer side effects , increased efficacy and constant delivery. The skin has an extremely good barrier function and to improve the penetration of active ingredients it is frequently necessary to employ enhancement strategies. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 60

References -: 

References - Geeta Agrawal,Dr.Sanjiv Dhawan,Development fabrication and evaluation of TDDS, Review,Vol.7 Issue 5-2010 Pharmainfo.net A. E. Benson TDDS Penetration enhancement Technology 2005 bentham Science Publisher limited. Bharkatya M,Neema RK,Skin Penetration Enhancement Technique,J Young Pharmacist 2009;110-5. J Ashok Kumar , Nikhila pullakandan , S. Lakshamana prabu,V.Gopal,Faculty Of Pharmacist,PRIST University, Thanjavur , Tamilnadu-614904. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 61

Slide 62: 

Indian Journal Of Pharmaceutical Sciences, Review Article, Year-2008,Volume-70,Issue-1,Page no-5-10. Swati Rawat, Sudha Vengurlekar,B.Rakesh,S.Jain,G.Srikarti,Smriti College Of Pharmaceutical Education Indore-452010,India Mathur et al Enhancer in TDDS,Asian Journal Of Pharmaceutical Sciences, nov-2010. Ramesh Panchagnula,Transdermal Delivery of drug Indian Journal of Pharmacology July-1997. 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 62

THANK YOU: 

THANK YOU 8/22/2011 TRANSDERMAL DRUG DELIVERY SYSTEM 63