TRANSDERMAL DRUG DELIVERY SYSTEM

TRANSDERMAL DRUG DELIVERY SYSTEM

1. TRANSDERMAL DRUG DELIVERY SYSTEM PRESENTED BY: HARI.P 1 ST M.PHARM PHARMACEUTICS 1

2. INTRODUCTION TDDS are topically administered medicaments in the form of patches that deliver drugs for systemic effects at predetermined and controlled rate. Transdermal patch is an adhesive patch, that has a coating of medicine (drug), that is placed on the skin to deliver specific dose of the medicine, into the blood over a period of time. 2

3. ADVANTAGES OF TDDS 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. Improve physiological and pharmacological responses. Reduction of fluctuations in plasma levels of drugs. Allow easy termination. Reduction of dosing frequency and patient compliance. 3

4. DISADVANTAGES OF TDDS TDDS cannot deliver ionic drugs. TDDS cannot achieve high drug levels in blood/plasma. Cannot develop TDDS for drugs of large molecular size. Cannot develop TDDS, if drug or formulation causes irritation to skin. 4

5. ANATOMY AND PHYSIOLOGY OF SKIN Skin is the part of Integrated system i.e. it helps to maintain body temperature and protect It from surrounding environment. It covers an area of about 2m 2 and 4.5-5 kg i.e. about 16% of total body weight in adults. Thickness is in range of 0.5mm (on eyelids ) to 4.0mm ( on heels ) . 5

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7. EPIDERMIS Stratum Corneum- consists of 25 to 30 layers of flattened dead keratinocytes. Which makes it water repellent. Stratum Granulosm- consists of 3 to 5 layers and under goes Apoptosis. It contains granules known as Keratohyalin. These granules release Lipid rich secretion, which acts as the water repellent. Stratum Spinosum- contains 8 to 10 layers of cells and it is closely arranged. Stratum Basal- consists of single layer of cubical or columnar keratinocytes. 7

8. DERMIS Composed of strong connective tissue containing collagen and elastic fibers, hence it can easily stretch and recoil easily. Blood vessel, nerves gland and hair follicles are embedded in this layer. 8

9. SUBCUTANEOUS LAYER It is also called as Hypodermis . It is made up of loose connective tissue, including Adipose tissue. This helps to insulate the body by monitoring heat gain and heat loss. The dermis is the layer of tissue that is Deeper and Thicker than epidermis. 9

10. ROUTES OF PENETRATION To penetrate a molecule in the normal human intact skin there are two diffusion pathways: Trans appendageal and Transepidermal pathway. TRANSAPPENDAGEAL The trans appendageal route is for ions and large polar molecules Mainly water soluble substance are diffused faster through appendages than that of other layers. Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST corneum. 10

11. TRANSEPIDERMAL ROUTE Trans epidermal route is for the unionized molecules which can cross the intact layer. Stratum corneum is the main resistance for absorption through this route . Permeation involves partitioning of the drug into the stratum corneum. Permeation through the skin depends upon the o/w distribution tendencies of the drug. Lipophilic drug concentrate in and diffuse with relative ease . Permeation through the dermis is through the interlocking channels of the ground substance 11

12. COMPONENTS OF TDDS components of the transdermal drug delivery system include – Polymer matrix / Drug reservoir Drug Permeation enhancers Pressure sensitive adhesive (PSA) Backing laminates Release liner Other excipients like plasticizers 12

13. POLYMER MATRIX 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 enhancer. Additionally they should provide consistent and effective delivery of a drug throughout the product’s intended shelf life and should be of safe status. 13

14. EXAMPLES Natural Polymers: e.g. cellulose derivatives, zein , gelatin, shellac, waxes, gums, natural rubber and chitosan etc . Synthetic Elastomers: e.g. poly butadiene, hydrin rubber, polyisobutylene, silicon  rubber, nitrile, acrylonitrile, neoprene, butyl rubber etc . Synthetic Polymers: e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene, polyacrylate, polyamide ,polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc . 14

15. DRUG 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). 15

16. 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, non irritating, nonallergic, odourless, tasteless, colourless, 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 ( N –methyl pyrrolidone). Terpenes (limonene). Sulfoxides (dimethyl sulfoxide) Esters(isopropyl myristate). 16

17. 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 . Enhancing solubility and Increasing partitioning into the stratum corneum. Interaction with intercellular protein, and keratin denaturation . 17

18. Classification of Permeation enhancers:- a. Solvents b. Surfactants i ) Anionic surfactants: Dioctyl sulphosuccinate, Sodium lauryl sulphate. ii) Non-ionic surfactants: Pluronic F127, Pluronic F68 iii) Bile salts : Sodium taurocholate ,Sodium deoxycholate. c. Binary systems : Propylene glycol, oleic acid d. Miscellaneous chemicals : Urea.. 18

19. PRESSURE SENSITIVE ADHESIONS 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. . 19

20. BACKING LAMINATES While designing a backing layer, the consideration of chemical resistance of the material is most important. 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. Hold and protect the drug reservoir from exposure to atmosphere. Avoid loss of drug Accept printing High flexibility Examples : vinyl, polyethylene and polyester films. 20

21. 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 21

22. Other excipients Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir . 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. 22

23. Different approaches of TDDS systems Membrane permeation-controlled TDDS - Transderm-Scop , Duragesic, Clonidine-TDS Drug in adhesive-type TDDS - Daytrana , Climara , Habitrol , Nicoderm , Exelon Matrix diffusion controlled TDDS- NitroDur Micro reservoir dissolution controlled TDDS Androderm 23

24. Polymer membrane permeation-controlled TDDS In this type of systems, the drug reservoir is sandwiched between a drug-impermeable backing laminate and a rate controlling polymeric membrane. The drug is allowed to permeate only through the rate controlling membrane. The drug solids are homogeneously dispersed in a solid polymer matrix, suspended in an unleachable , viscous liquid medium e.g. silicone fluid to form a paste like suspension or dissolved in a releasable solvent e.g. alkyl alcohol to form a clear drug solution. The rate controlling membrane can be either a micro porous or a nonporous polymeric membrane e.g. ethylene-vinyl acetate copolymer, with specific drug permeability 24

25. On the external surface of the polymeric membrane a thin layer of drug-compatible, hypoallergenic pressure sensitive adhesive polymer e.g. Silicone- adhesive may be applied to provide intimate contact of TDDS with the skin surface. Varying the composition of drug reservoir formulation, the permeability coefficient and thickness of rate controlling membrane can alter the drug release rate. e.g. Scopolamine releasing Transderm system and nitro glycerine releasing Transderm -nitro system 25

26. Adhesive diffusion controlled TDDS This is a system in which the drug is incorporated directly into the adhesive, rather than into a separate layer, it is usually used for smaller molecular weight compounds. These can be either a single layer or multi-layer. Sometimes referred to as the “matrix type patch”. e.g. Deponit (Nitroglycerine) for once a day medication of angina pectoris. 26

27. Matrix diffusion controlled TDDS In this system, the drug reservoir is formed by homogeneously dispersing the drug solids in a hydrophilic or lipophilic polymer matrix and then the medicated polymer formed is molded into medicated disks with defined surface area and thickness. This drug reservoir containing polymer disk is then mounted on occlusive base plate in a compartment fabricated from a drug-impermeable plastic backing. Instead of coating adhesive polymer directly on the surface of medicated disk, it is applied along the circumference of the patch to form a strip of adhesive rim surrounding the medicated disk e.g. Nitro- Dur system and Minitran system for angina pectoris. 27

28. Alternately, the polymer matrix drug dispersion type TDDS can be fabricated by directly dispersing drug in a pressure-sensitive adhesive polyacrylate and then coating the drug-dispersed adhesive polymer by solvent casting or hot melt onto a flat sheet of drug-impermeable backing laminate to form a single layer of drug reservoir, this yields a thinner patch . 28

29. Micro reservoir controlled TDDS This thermodynamically unstable system is quickly stabilized by immediately cross-linking the polymer chains which produces a medicated polymer disk with a constant surface area and a fixed thickness. Medicated disk is mounted at the center of an adhesive pad. e.g. Nitrodisk system for angina pectoris. 29

30. Factors influence transdermal delivery Biological factors – Skin condition Skin age Blood flow Regional skin sites Skin metabolism Species differences 30

31. Physicochemical factors – Skin hydration Temperature and pH Diffusion coefficient Drug concentration Partition coefficient Molecular shape and size 31

32. Evaluation Parameter for Transdermal Patches Physicochemical evaluation In vitro drug release In-vivo evaluation 32

33. PHYSICOCHEMICAL EVALUATION Drug content determination Uniformity of weight Moisture content Flatness Tensile Strength Thickness Folding Endurance Adhesive studies 33

34. Thickness of the patch The thickness of the 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 patch. 34

35. Drug content determination An accurately weighed portion of film (above 100 mg) is dissolved in 100mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 hrs in shaker incubator. Then the whole solution is sonicated . After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution. Moisture content The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 hrs. 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 35

36. Moisture Uptake Weighed films are kept in a desiccators at room temperature for 24 hrs. 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. Then % moisture uptake is calculated as given below. Final weight – Initial weight % moisture uptake = ------------------------------------- X100 Initial weight 36

37. 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. 37

38. Folding endurance Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value. Tensile Strength : To determine tensile strength, polymeric films are sandwiched separately by corked linear iron plates. One end of the films is kept fixed with the help of an iron screen and other end is connected to a freely movable thread over a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. 38

39. Adhesive studies: 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. 39

40. 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 180°C angle, and the force required for tape removed is measured. 40

41. 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 resins in polymer. Thumb tack test The force required to remove thumb from adhesive is a measure of tack. Rolling ball tack test 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. 41

42. 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 and recorded as tack value, which is expressed in ounces or grams per inch width. 42

43. 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. The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams. 43

44. 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 44

45. In vitro DRUG RELEASE In vitro drug release testing was performed using a Franz diffusion cell for the transdermal drug delivery system. This testing was conducted at a rotating speed of 50 rpm. The dissolution medium was purified water which was maintained at a temperature of 32˚C. A sample was taken through a 0.8 μ m filter at the predetermined sampling times and replaced with an equal volume of purified water. The drug release was analyzed by a HPLC / UV method. 45

46. 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 (50cm²) of the rabbit is to be cleaned and hairs are removed from the clean dorsal surface by shaving and then the surface was cleaned by using rectified spirit and then the representative formulations can be applied over the skin. The patch is to be removed after 24 hrs and the skin is to be observed and classified into 5 grades on the basis of the severity of skin injury. 46

47. TDDS Products Product name Drug Manufacturer Indication Alora Estradiol TheraTech/ Proctol and Gamble Postmenstrual syndrome Androderm Testosterone TheraTech/GlaxoSmithKline Hypogonadism in males Catapres-TTS Clonidine Alza/ Boehinger Ingelheim Hypertension Climaderm Estradiol Ethical Holdings/ Wyeth- Ayerest Postmenstrual syndrome Climara Estradiol 3M Pharmaceuticals/ Berlex Labs Postmenstrual syndrome CombiPatch Estradiol/ Norethindrone Noven , Inc./Aventis Hormone replacement therapy Deponit Nitroglycerin Angina pectoris Duragesic Fentanyl Alza / Janssen Pharmaceutica 47

48. The US food and drug administration (FDA) has approved asenapine (SEUCADO) the only transdermal patch to treat adults with schizophrenia. 48

49. CONCLUSION As we know, the basic functions of the skin is protection and hence it is difficult to target the skin for drug delivery. Because skin having numerous layers. But using novel techniques in TDDS we have successfully penetrate the drug into systemic circulation. 49

50. REFERENCES Brahmankar D. M., Jaiswal Sunil B.(2009) Biopharmaceutics and Pharmacotherapeutics -A Treatise , 2 nd edition, pp-495-501. Chien Yie W.(2002), Novel Drug Delivery Systems , Marcel Dekkar , Inc Publication, volume-50, 2 nd edition, pp-301. Jain, N.K. (1997) Controlled and novel drug delivery . 1 st ed. New Delhi: CBS publishers and distributors, pp. 100- 127. 50

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