Transdermal Drug Delivery System,seminar presentation based on M.Pharm

TRANSDERMAL DRUG DELIVERY SYSTEM : 

TRANSDERMAL DRUG DELIVERY SYSTEM PRESENTED BY :- Saundarya Kumar M. Pharm (Pharmaceutics) II sem Under the Guidance of: Mr. Vijay Singh ( Asst. Professor) Department of Pharmaceutics KNIMT, Sultanpur 6/2/2012 1

CONTENT : 

CONTENT Introduction Definition Objectives of TDDS Condition in which Transdermal patches are Used Condition in which Transdermal patches are not Used Types of TDDS Factor Influencing of TDDS General Consideration in the use of TDDs Limitations of TDDS Formulation of TDDS Methods for Preparation of TDDS Different approaches of TTDS Evaluations ofbTDDS Advantages & Disadvantage of TDDS Marketed products References 6/2/2012 2

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INTRODUCTION The first commercially available prescription patch was approved by the U.S.  Food and drug administration in December 1979, which administered scopolamine for motion sickness. 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 . The primary objective of controlled drug delivery is to ensure safety and efficacy of the drugs as well as patients compliance. 6/2/2012 3

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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 . 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. 6/2/2012 4

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Definition Transdermal drug delivery systems (patches) are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin 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. Actually, transdermal drug delivery is a transport process of drugs through a multi-laminar structure, e.g. from the patch to SC then to the viable epidermis, and finally penetrating into the blood . 6/2/2012 5

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Objectives of Rate-Controlling TDD Systems 1. Deliver the drug substances at a controlled rate, to the intact skin of patients, for absorption into the systemic circulation. 2. The system should possess the proper physicochemical characteristics to permit the ready release of the drug substance and facilitate its partition from the delivery system into the stratum corneum . 3. The system should occlude the skin to ensure the one-way flux of the drug substance. 4. The transdermal system should have a therapeutic advantage over other dosage forms and drug delivery system. 6/2/2012 6

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5. The system’s adhesive, vehicle, and active agent should be nonirritating and nonsensitizing to the skin of the patient. 6. The patch should adhere well to the patient’s skin and its physical size and appearance and placement on the body should not be a deterrent to use. 7. The system should not permit the proliferation of the skin bacteria beneath the occlusion. Objectives of Rate-Controlling TDD Systems 6/2/2012 7

Conditions in which Transdermal Patches are used : 

Transdermal patch is used when: (1) When the patient has intolerable side effects (including constipation) and who is unable to take oral medication ( dysphagia ) and is requesting an alternative method of drug delivery. (2) Where the pain control might be improved by reliable administration. This might be useful in patients with cognitive impairment or those who for other reasons are not able to self-medicate with their analgesia. (3) It can be used in combination with other enhancement strategies to produce synergistic effects . Conditions in which Transdermal Patches are used 6/2/2012 8

Conditions in which Transdermal Patches are not used : 

The use of transdermal patch is not suitable when: (1) Cure for acute pain is required. (2) Where rapid dose titration is required. (3) Where requirement of dose is equal to or less then 30 mg/24 hrs . Conditions in which Transdermal Patches are not used 6/2/2012 9

Classification of transdermal drug delivery systems: 

Transdermal drug delivery systems generally fall into the following subcategories: (1) Polymer membrane permeation-controlled (2) Polymer matrix diffusion-controlled (3) Drug reservoir gradient-controlled (4) Micro reservoir dissolution-controlled - Liquid-filled laminate structure - Peripheral-adhesive laminate structure - Solid-state laminate structure - Sub-classes of the above In terms of the drug release mechanisms, TDDS can be divided into six categories: (1) Solution in matrix (2) Suspension in continuous matrix (3) Suspension in porous matrix (4) Solution upstream of membrane (5) Suspension upstream of membrane (6) Laminated membrane downstream Classification of transdermal drug delivery systems 6/2/2012 10

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2 Basic Types Of Transdermal Dosing System Those that control the rate of drugdelivery to the skin. Those that allow the skin to control the rate of drug absorption 6/2/2012 11

Types of Transdermal Patch : 

1. Single-layer Drug-in-Adhesive The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing. 2 . Multi-layer Drug-in-Adhesive The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug. The multi-layer system is different however that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary liner-layer and a permanent backing. 3. Reservoir Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order. Types of Transdermal Patch 6/2/2012 12

Types of Transdermal Patch : 

4 . Matrix The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it. 5. Vapour Patch In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour . The vapour patches are new on the market and they release essential oils for up to 6 hours. The vapours patches release essential oils and are used in cases of decongestion mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market. Types of Transdermal Patch 6/2/2012 13

Factors influencing transdermal Delivery : 

The factors influencing transdermal permeability of stratum corneum can be classified into 3 major categories: 1 . Physicochemical properties of the penetrates. 2 . Physicochemical properties of the drug delivery systems 3. Physiological and pathological conditions of the skin (A) Physicochemical properties of the penetrates: 1. Partition coefficient - Drugs possessing both water and lipid solubility's are favorably absorbed through skin. Transdermal permeability coefficient shows in linear dependency on partition coefficient. A lipid/water partition coefficient of 1 or greater is generally required for optimal transdermal permeability. Factors influencing transdermal Delivery 6/2/2012 14

Factors influencing transdermal Delivery : 

2. pH conditions - pH conditions of skin surface and in drug delivery systems affect the extent of dissociation of ionogenic drug molecules and their transdermal permeability. 3. Penetrant concentration - Transdermal permeability across mammalian skin is a passive diffusion process thus depends on the concentration of penetrate molecules on the surface layers of the skin. (B) Physicochemical properties of drug delivery systems : 1. Release characteristics - Generally, the more easily the drug is released from the delivery system, the higher the rate of transdermal permeation .The mechanism of drug release depends on whether the drug molecules are dissolved or suspended in the delivery system and on interfacial partition coefficient of the drug from delivery system to the skin tissue. Factors influencing transdermal Delivery 6/2/2012 15

Factors influencing transdermal Delivery: 

2. Composition of drug delivery systems - The composition of drug delivery system has a great influence on percutaneous absorption of a drug molecule. It may affect not only the rate of drug release but also the permeability of stratum corneum by means of hydration, mixing with skin lipids or other sorption promoting effects. 3. Enhancement of transdermal permeation - Transdermal permeation of drugs can be improved by the addition of a sorption or permeation promoter in the drug delivery system ( a)     Organic solvents as permeation promotor - e.g. Dimethylsulfoxide (DMSO), Dimethylacetamide , Dimethylformide , Ethylene glycol, Polyethylene glycol, Ethanol (b) Surface active agent as permeation promoter- The anionic surfactants are most effective permeation promoters. e.g. Sodium lauryl sulfate, Sodium dioctyl sulfosuccinate . Factors influencing transdermal Delivery 6/2/2012 16

Factors influencing transdermal Delivery: 

(C) Physiological and pathological conditions of the skin : 1. Reservoir effect of horny layer- The horny layer especially its deeper layer can act as a depot or reservoir and modify transdermal permeation characteristics of some drug. 2. Lipid film - Lipid film on skin surface, formed by product of the excretion of sebaceous gland and epidermalcell lipid maintains the barrier function of stratum corneum . 3. Skin hydration- Hydration of stratum corneum can enhance the permeability of the skin by as much as eight fold. 4. Skin temperature- A ten fold in the skin permeation was raised from 10 0 to 37 0 C of acetyl salicylic acidand glucosteroids was noticed when the environmental temperature 7 . 5. Formulation factors include : (1) Physical chemistry of transport (2) Vehicles and membrane used (3) Penetration enhancers used (4) Method of application (5) Device used Factors influencing transdermal Delivery 6/2/2012 17

General Considerations in the use of TDD S: 

The site selected for application should be clean clean , dry, and hairless (but not shaved) Example : nitroglycerin - chest; estradiol - buttocks or 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. The patch should be removed from its protective package, being careful not to tear or cut. 4. If irritation results, patient should seek re-evaluation . General Considerations in the use of TDD S 6/2/2012 18

4. 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. 5. 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. 6. The patient should be instructed to cleanse the hands thoroughly before and after applying the patch. Care should be taken not to rub the eyes or touch the mouth during handling the patch.: 

4. 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. 5. 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. 6. The patient should be instructed to cleanse the hands thoroughly before and after applying the patch. Care should be taken not to rub the eyes or touch the mouth during handling the patch. General Considerations in the use of TDDS 6/2/2012 19

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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 6/2/2012 20

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Formulation of TDDS • In the formulation of Transdermal drug Delivery system (patches) consist of several components. Some of these are similar in both classes, while others are class-specific. Those common to both include: (1) Backing films (2) Release liners (3) Pressure-sensitive adhesives (4) Active ingredient(s) (5) Permeation enhancers (6) Other additives (7) Micro porous or semi-permeable membranes (8) Pouching materials 6/2/2012 21

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1 Backing Films- Backing films play a critical role in the TDDS (as long as they are packaged in their pouch), as well as during the use of the system. The role of such a film is to protect the active layer and safeguard the stability of the system, and to affect skin permeation and tolerance, depending on occlusion or breathability. (2) Release Liners- Generally, a release liner is a film covered with an anti- adherent coating. The role of the release liner is to protect the system as long as it is in the package, and it is removed just before the adhesion of the TDDS to the skin. 6/2/2012 22

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Release liners play a crucial role in the stability of the product and in its safe and functional use. The release liner must therefore be chosen very carefully. An incorrect release liner does not permit the easy release of the patch, and can interfere with the active(s) or other components, thereby reducing its shelf life hot melts, and silicon PSAs. (3) Pressure-Sensitive Adhesives- For both classes of TDDS, pressure-sensitive adhesives (PSAs) play a major role, serving as the matrix that carries everything active (such as additives and permeation enhancers) and the means for making the patch stick to the skin. There are three major families of PSAs: rubber-based PSAs, acrylic PSAs in the form of acrylic solutions, emulsion polymers or 6/2/2012 23

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Acrylics: 1. With or without functional groups 2. Cross-linked or not Solutions, hot melts or emulsions Silicon-Based Adhesives: 1. Standard 2. Amine-compatible Rubbers with different: 1. Tackifiers 2. Cross-linkers 3. Stabilizers and   plasticizers (4) Penetration Enhancers- This term refers to an entire family of chemically different substances that all share a common characteristic - they facilitate the permeation of the actives through the skin, increasing the permeation rate by several times. This is very important with respect to the feasibility of a system, because most of the actives do not enter the skin in the required dosage from a relatively small area. Sometimes a combination of ingredients is needed to create the correct enhancement effect. 6/2/2012 24

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Various Methods used For Preparation of TDDS: 1. Asymmetric TPX membrane method. 2. Circular teflon mould method. 3. Mercury substrate method. 4. By using “IPM membranes” method. 5. By using “EVAC membranes” method. 6. Aluminium backed adhesive film method. Methods For Preparation of TDDS: 6/2/2012 25

1. Asymmetric TPX membrane method:: 

1. Asymmetric TPX membrane method: A prototype patch can be fabricated for this a heat sealable polyester film (type 1009, 3m) with a concave of 1cm diameter will be used as the backing membrane . 6/2/2012 26

2. Circular teflon mould method:: 

2. Circular teflon mould method: 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. 6/2/2012 27

3. Mercury substrate method:: 

3. Mercury substrate method: 6/2/2012 28

4. By using “IPM membranes” method: : 

4. By using “IPM membranes” method: 6/2/2012 29

5. By using “EVAC membranes” method:: 

5. By using “EVAC membranes” method: 6/2/2012 30

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The collected powder is transferred into a glass bottle and stored at the freeze temperature until characterization . 6/2/2012 31

6. Aluminium backed adhesive film method: : 

6. Aluminium backed adhesive film method: 6/2/2012 32

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6/2/2012 33

Approaches of TDDS Various technologies have been developed to by pass 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 Various technologies have been developed to by pass 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. 6/2/2012 34

1. Physical Approaches.: 

1. 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. 6/2/2012 35

Mechanism of Iontophoresis: 

Mechanism of Iontophoresis 6/2/2012 36

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2. Electrophorasis .( Ionophoresis ) 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 . 6/2/2012 37

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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. 6/2/2012 38

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3. 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. 6/2/2012 39

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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. 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. 6/2/2012 40

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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. 6.Medicated tattoos - 6/2/2012 41

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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. 6/2/2012 42

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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. 6/2/2012 43

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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. Mechanism 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. 6/2/2012 44

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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. 6/2/2012 45

2. Chemical approaches -: 

2. 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). 6/2/2012 46

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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. 6/2/2012 47

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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. 6/2/2012 48

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Evaluation of TDDS These evaluation are predictive of transdermal dosage forms and can be classified into following types: Physicochemical evaluation In vitro evaluation In vivo evaluation 6/2/2012 49

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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: 6/2/2012 50

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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 Thicknesses of the backing membranes (before casting the drug matrix) and of whole patches (adhesive matrix with the drug plus the backing membrane) were measured at four points using digital calipers (Dogmatic Massschieber , model CD-6 CS, Mitutoyo Corp., Japan). The average thicknesses of the backing membrane and of the drug matrix with the backing membrane were determined. Thickness of the patch 6/2/2012 51

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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 6/2/2012 52

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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 6/2/2012 53

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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 6/2/2012 54

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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 6/2/2012 55

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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 6/2/2012 56

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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 endurancevalue . 6/2/2012 57

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 overa pulley. The weights are added gradually to the pan attached with the hanging end of the thread. 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 Tensile Strength : 6/2/2012 58

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. 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. Area of the patches. The diameter, D, of each patch was measured using a millimeter scale, and the area (π[ D /2] 2 ) of each patch was calculated. 6/2/2012 59

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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: 6/2/2012 60

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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 6/2/2012 61

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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 Rolling ball tack test This test measures the softness of a polymer 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 6/2/2012 62

Evaluation of adhesion (Thumb tack test): 

1. One week after the preparation of the TDDSs, a thumb tack test was performed by lightly pressing a thumb on a patch for ~5 s and then quickly removing it . 2. By varying the pressure and time of contact, and considering the difficulty of pulling the thumb from the adhesive, it was possible to guess how easily, quickly, and strongly the adhesive formed a bond with the skin. 3. The test was performed blindly on various types of formulations to determine the proper formulation for further studies. 4. The patches were applied on the forearm of 10 volunteers. After 24 h, the patches were removed to study the skin-adhesion capability and compatibilities of the formulations with the skin. Ultimate scoring of acceptability was based on result of a thumb tack test as well as skin adhesion, removal capacities, and the formulations' compatibilities with the skin. Evaluation of adhesion (Thumb tack test) 6/2/2012 63

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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 6/2/2012 64

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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 6/2/2012 65

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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 6/2/2012 66

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In vitro release Evaluation The Paddle over Disc: The Cylinder modified USP Basket : The reciprocating disc: Keshary - Chien Cell: In vitro permeation Evaluation Preparation of skin for permeation studies: Intact full thickness skin: Separation of epidermis from full thickness skin 6/2/2012 67

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In vivo Studies Animal models Human volunteers 6/2/2012 68

Advantages of TDD Systems: 

Avoids gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity, drug interactions with food, drinks, or other orally administered drugs. Substitutes for oral administration of medication when that routes is unsuitable, as in instances of vomiting and/or diarrhea. Avoids first-pass effect, that is, the initial pass of a drug substance through the systemic and portal circulation following gastrointestinal absorption (thereby possibly avoiding the drug’s deactivation by digestive and liver enzymes). Avoids the risks and inconveniences of parenteral therapy and the variable absorption and metabolism associated with oral therapy. Advantages of TDD Systems 6/2/2012 69

Advantages of TDD Systems: 

Provides the capacity for multiday therapy with a single application, thereby improving patient compliance over use of other dosage forms requiring more frequent dose administration. Extends the activity of drugs having short half-life through the reservoir of drug present in the therapeutic delivery system and its controlled release characteristics. Provides capacity to terminate drug effect rapidly (if clinically desired) by removal of drug application from the surface of the skin. Provides ease of rapid identification of the medication in emergencies (e.g. non responsive, unconscious or comatose patient) Advantages of TDD Systems 6/2/2012 70

Disadvantages of TDD Systems: 

The transdermal route administration is unsuitable for drugs that irritate or sensitize the skin. Only relative potent drugs are suitable candidates for transdermal delivery due to the natural limits of drug entry imposed by the skin’s impermeability. Technical difficulties are associated with the adhesion of the systems to different skin types and under various environment conditions, and the development of rate-controlling drug delivery features which are economically feasible and therapeutically advantageous for more than a few drug substances. Disadvantages of TDD Systems 6/2/2012 71

PowerPoint Presentation: 

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 Pharmaceutical TDDS products 6/2/2012 72

PowerPoint Presentation: 

REFERENCES Mr. Vijay Singh Asst.Professor Kamla Nehru Institute of technology & Management Faridipur , Sultanpur Uttar Pradesh. 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. Miller II KJ, Govil SK, Bhatia KS, inventors; Mylan Pharmaceuticals, Inc., assignee; Fentanyl suspense ion based silicone adhesive formulations and devices for transdermal delivery of fentanyl . US Patent 7556823, 2009. 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; 6/2/2012 73

PowerPoint Presentation: 

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. 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. 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 penetrationbenhancers on the in vitro transport of ephedrine throughb rate skin and human epidermis from matrix based Transdermal formulations. Drug. Dev. Ind. Pharm . 1993 Ryan D. Gordon, and Tim A. Peterson, transdermal drug delivery , drug Deliverytechnology ,www.drugdeliverytechnology.com77. 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 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 6/2/2012 74

THANK YOU: 

THANK YOU 6/2/2012 75