Tdds

Transdermal drug delivery system

1. TRANSDERMAL DRUG DELIVERY SYSTEM Presented by Dasara Thanmayi

2. ABSTRACT 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. In order to deliver therapeutic agents through the human skin for systemic effects, the comprehensive morphological, biophysical and physicochemical properties of the skin are to be considered. Transdermal delivery provides a leading edge over injectables and oral routes by increasing patient compliance and avoiding first pass metabolism respectively. Transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which often causes undesirable side effects. The TDDS review articles provide valuable information regarding the transdermal drug delivery systems and its evaluation process details as a ready reference for the research scientist who is involved in TDDS.

3. INTRODUCTION Transdermal therapeutic systems are defined self contained ,self discrete dosage form ,which when controlled rate to the systemic circulation. Transdermal patch uses a special membrane to control the release rate at which the liquid drug contained patch reservoir can pass into skin and into blood stream. Transdermal delivery also allows continous input drugs with short biological half lives and eliminates pulsed delivery into systemic circulation which is responsible for undesirable side effects

4. ADVANTAGES It delivers a steady infusion of drug over an extended period of time. It increases the therapeutic value of many drugs by avoiding specific problems associated with the drug. Self medication is possible with this type of system. The drug input can be terminated at any point of time by removing the patch. It is mostly useful in patients who are nauseated or unconciousness .

5. DISADVANTAGES The drug must have desired physiochemical properties for penetration through stratum corneum . Heat, cold and sweating prevent the patch from sticking to the surface of the skin. The adhesive used may not adhere well to all types of skin. This system is may not be economical for some patients.

6. APPLICATIONS Transdermal patch of nicotine which releases nicotine in controlled dose to help with cessation of tobacco smoking. Nitroglycerine patches are also sometimes prescribed for the treatment of angina Transdermal form of the MAO selegline ,become the first transdermal delivery agent for anti depressant Transdermal delivery agent for the attention deficit hyperactivity disorder [ADHD].

7. ANATOMY OF SKIN Skin is an extensive organ of body covering an area of about 2m 2. with thickness of 1mm. The skin separates the underlying blood circulation from outside environment. Human skin consists of three layers: The stratified, vascular,cellular epidermis Underlying dermis and hypodermis

8. EPIDERMIS: It is divided into stratum corneum and stratum germinativum . Stratum corneum is outermost layer and consists of many layers of flattened, keratinized cells responsible for barrier function of skin and behaves as a primary barrier to percutaneous absorption. stratum granulosum Stratum corneum stratum lucidum stratum spinosum

9. DERMIS : It is made up of network of collagen fibers and this network or gel structure is responsible for the elastic properties of the skin. Upper portion of dermis is formed into ridges containing lymphatics and nerve endings . SUBCUTANEOUS: This is a sheet of fat containing tissue known as superficial fascia.

10. MARKETED PRODUCTS OF TRANS DERMAL DRUG DELIVERY SYSTEM S.NO PRODUCT ACTIVE DRUG TYPE OF PATCH PURPOSE 1 nitrodur nirtoglycerine matrix angina pectoris 2 deponit nirtoglycerine drug in adhesive angina pectoris 3 lidoderm lidocaine drug in adhesive anaesthetic 4 Duragesic Fentanyl Reservoir Pain relief patch 5 Transdermscop Scopolamine Matrix Motion sickness

11. BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY Polymer matrix (rate controlling polymer) The drug Permeation enhancers Adhesive Backing layer

12. POLYMER MATRIX: Rate controlling polymer is in the form of membrane or matrix It is responsible for control of release by diffusion of drug through the rate controlling membrane. Polymers used: Natural polymers: cellulose derivatives, zein , gelatin , shellac,waxes,gums and natural rubber. Synthetic elastomer : polysiloxane,silicon rubber,nitrile,acrylonitrile,butyl rubber.

13. DRUG: for successful developing of transdermal delivery drug should be chosen with great care . physicochemical properties : molecular weight less than 1000 daltons . Affinity for both lipophilic &hydrophilic phases. Drug should have low melting point. Biological properties: Half life of drug should be short. It should be potent with daily dose of few mg/day. Non irritant to skin.

14. IDEAL PROPERTIES OF DRUG USED IN TDDS PARAMETERS PROPERTIES Dose Should be low Half life 10 or less Partition coefficient <400 Log P ( octonal - water) between1-4 Skin permeability coefficient >0.5X 10 -3 cm/hr Skin reaction Non irritating and non sensitizing Oral bioavailability Low Therapeutic index Low

15. Permeation/penetration/sorption enhancers: these are the agents that interact with skin constituents to promote the drug flux/absorption. the flux J,of drugs across the skin can be written as J=D dc/ dx where D=diffusion coefficient C=concentration of diffusing species X=spatial coordinate. Solvents: methanol,ethanol,omso,dmf,glycerol . Surfactants:anionic dioctyl sulfosuccinate,sls . cationic puronic CF 127,pluronic F-68 Binary systems: propylene glycol.

16. ADHESIVES: it is an important component which is necssary for attachment of TDDS. the fastening of all transdermal devices to the skin has been done by using a pressure sensitive adhesive Adhesive systems should fulfil the following criteria Should adhere to the skin aggresively & easily removed Should not leave an unwashable residue. Should not irritate or sensitize the skin. Should have intimate contact with the skin. Permeation of the drug should not be affected. Should not effect the normal functioning of the skin.

17. BACKING MEMBRANE: It is an impermeable membrane that protects the product during the use on the skin. Prevents the drug from leaving the dosage form through top and protects the formulation throughout shelf life and during wear period. Must be compatible with the formulation. eg:metallic plastic laminate ,plastic backing with absorbent pad and occlusive base plate ( aluminium foil),adhesive foam pad (flexible polyurethane) with occulsive base plate ( aluminium foil disc) etc.

18. ROUTES OF DRUG ABSORPTION THROUGH SKIN The drug absorption through skin occurs by Transepidermal absorption Transfollicular (shunt pathway absorption) Clearance by local circulation. Transepidermal absorption: Stratum corneum is the main resistance for absorption Permeation involves partitioning of the drug into the stratum corneum Hydrophilic drug pass through cell of stratum corneum (intracellular). Non-polar drugs diffuse through non-aqueous lipid matrix between the protein filaments.

19. Transfollicular absorption: The skin’s sebaceos and eccrine (sweat)glands are considered as shunts for by passing the stratum corneum . Follicular route is important for permeation because the opening of follicular pore is large and sebum aids in diffusion of the penetrant . After partitioning into sebum,the drug diffuses the depths of epidermis. Clear by local circulation: the drugs enter into the systemic circulation from papillary plexus in upper epidermis .

20. GENERAL METHOD OF PREPERATION FOR TDDS DRUG PREPARATION DRUG/ADHESIVE SOLUTION PREPERATION RELEASE LINER DRUG/ADHESIVE COATINGS BACKING FILM LAMINATION DIE CUTTINGS SYSTEM PACKAGING FINAL PRODUCT

21. FORMULATION APPROACHES USED IN THE DEVELOPMENT OF TDDS Membrane permeation - controlled system Adhesive dispersion - type systems Matrix diffusion – contolled systems Micro reservoir type or microsealed dissolution –controlled systems.

22. MEMBRANE PERMEATION – CONTROLLED SYSTEM The drug reservoir is totally encapsulated in a shallow compartment moulded from a drug-impermeable metallic plastic laminate and a rate controlling polymeric membrane which may be microporous or non porous(ethylene vinyl acetate) Eg:nitroglycerine -releasing transdermal system( transdermal -nitro)for once a day in angina pectoris

23. The intrinsic rate of drug release from this type is , where, C r = drug concentration in the reservoir compartment p a & p m = permeability coefficient of adhesive and the rate controlling membrane respectively. for microporous membrane , p m is the sum of permeability coefficients for simultaneous penetration across the pores and polymeric material , hence d m h a

24. Preparation: these products consists of three substrates held together by two layers of drug containing adhesive Drug is processed into physical or chemical form Drug adhesive components & excipients are mixed Solvent is added to above mixture to form uniform solution These adhesive components are deposited as thin film on moving substance and dried The lamination of adhesive film and other layers is done The lamination then printed &die cut into final dosage form Packing is done in foil pouches

25. ADHESIVE DISPERSION-TYPE SYSTEM This system is simplified form of the membrane permeation controled system Prepration the drug reservoir is formulated by directly dispersing the drug in an adhesive polymer eg;poly (isobutylene)or ( acrylate )adhesive and then spreading the medicated adhesive,by solvent casting or hot melt ,onto a flatsheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer

26. On the top of the drug reservoir layer,thin layers of non- medicated,rate controlling adhesive polymer of a specific permeability and constant thickness are applied to produce an adhesive diffusion-controlled delivery system Eg:isosorbide dinitrate -releasing transdermal therapeutic system( frandol tape)for once aday in angina pectoris The rate of drug release in this system is defined by h a C R where , = partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer

27. MATRIX DIFFUSION-CONTROLLED SYSTEM The drug reservoir can be formed by dissolving drug and polymer in a common solvent folowed by solvent evaporation in a mould at an elevated temperature and vaccum The advantage of this type of system is the absence of dose dumping since polymer cannot rupture Eg:nitroglycerine -releasing transdermal therapeutic system at a daily dose of 0.5gm/cm 2 for therapy of angina pectoris The rate of drug release from this type is given by 1/2

28. Preparation the drug reservoir is prepared by homogenously dispersing drug particles in a hydrophilic or lipophilic polymer matrix Moulded into a medicated disc with a defined surface area and controlled thickness The dispersion of drug particles in the polymer matrix can be accomplished by mixing the drug particles with Liquid polymer highly viscous base polymer followed by crosslinking of the polymer chains or Blending drug solids with a rubbery polymer At an elevated temperature

29. MATRIX DIFFUSION-CONTROLLED SYSTEM

30. MICRORESERVOIR TYPE OR MICROSEALED DISSOLUTION-CONTROLLED SYSTEM This is the combination of reservoir and matrix diffusion type drug delivery systems Drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water soluble liquid polymer and then dispersing the drug suspension homogenousy in a lipophilic polymer such as silicon elastomers by high dispersion technique Eg:nitroglycerine -releasing transdermal system( nitrodisc )for once a day therapy of angina pectoris

31. EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEM Physico -chemical evaluation In –vitro evaluation In –vivo evaluation

32. PHYSICO-CHEMICAL Drug -polymer interaction studies: interaction studies were conducted on the medicated TDDS formulations by comparing them with the pure drug and placebo formulations on the basis of thermal analysis (DSC), fouriter transform infrared spectroscopy (FTIR) ,ultra violet (UV)and chromatographic techniques by comparing their physicochemical properties like assay , melting point ,wave number and absorption maxima , RF value etc.

33. Physical appearance: Patches were visually inspected for colour , clarity ,flexibility and smoothness Thickness uniformity : transdermal film is determined by travelling microscope ,dial gauge ,screw gauge or micrometer at different points of the film . Unifromity of weight: A specified area 1cm 2 of patch is to be cut in different parts of the patch and is to be dried at 60 c for 4 hours before testing and weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight

34. Drug content determination: Accurately weighed portion of film (about 100mg) is dissolved in 100ml of suitable solvent and shaken continously for 24 hrs After sonication & subsequent filteration,drug in solution is estimated against the reference solution consisting of placebo films with the suitable method(UV or HPLC technique) Surface p H : transdermal films were allowed to swell for 2 hours at 37 c on the surface of an agar plate, prepared by dissolving 2% (W/V)agar in warm isotonic phosphate buffer of p H 5.5 then the surface p H was measured by using p H paper placed on the surface of the swollen patch .after 90 sec the colour developed

35. Folding Endurance: it involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. It 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: polymeric film was determined with universal strength testing machine. The sensitivity of the machine was 1gm

36. EVALUATION OF ADHESIVE Shear adhesion test: shear adhesion strength is determined by measuring (cohesive strength of an adhesive polymer ) the time it takes to pull the tape off the plate

37. Peel adhesive test : In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion.

38. Tack properties: Rolling ball tack test :- In this test, stainless steel ball of 7/16” in diameter is released on an inclined track so that it rolls down and comes into contact with horizantal , upward facing adhesive film.

39. Quick stick ( peel-tack) test: the peel force required breaking the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90 at the speed of 12 inch/min.

40. Probe tack test: the tip of a clean probe is contact with adhesive and bond is formed between probe and adhesive. the force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams.

41. IN–VITRO EVALUATION Paddle over disc : this method the transdermal system is attached to a disc or cell resting at the bottom of the vessel which contain medium at 32 ± 5 c .

42. Cylinder modified usp basket : this method is similar to the usp basket type dissolution apparatus ,except that the system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5 c . Reciprocatingdisc :-( uspapparatus 7) in this method patches attached to holders are oscillated in small volumes of medium. Allowing the apparatus to be useful for systems delivering low concentration of drug . In addition paddle over extraction cell method may be used.

43. In-vitro skin permeation studies : the transdermal system is applied to the hydrophilic side of the membrane(donor compartment) and then mounted in the diffusion cell with lipophilic side in contact with receptor fluid (receptor compartment usually temperature 32±5 c for membrane) . In verical diffusion cell such as Franz diffusion cell or Keshary -chain (K-C)diffusion cell and is continously stirred at a constant rate.

44. IN-VIVO EVALUATION animal model: In-vivo animals models are preferred , because considerable time and resources are required to carry out studies in humans. Some of the species are used:- mouse,rat,guinea pig ,rabbit , rat,cat , dog, Human models: it is first described by fieldman and maibach . They includes determination of percutaneous absorption by an indirect method of measuring radioactivity in excreta following topical application of the label drug 14 c is generally used for radio- labelling . %dose absorbed =

45. KINETICS OF TRANSDERMAL PERMEATION Knowledge of skin permeation kinetics is vital to the successful development of transdermal therapeutic systems. Transdermal permeation of a drug involves the following steps: 1. Sorption by stratum corneum . 2. Penetration of drug through viable epidermis. 3. Uptake of the drug by the capillary network in the dermal papillary layer. The rate of permeation across the skin is given by: dQ / dt = Ps ( Cd – Cr ) --------eq.1

46. Where Cd and Cr are the concentration of the skin penetrant in the donor compartment i.e. Ps is the overall permeability coefficient of the skin tissue to the penetrant . This permeability coefficient is given by the relationship: P s = k s d ss / h s From equation (1) it is clear that a constant rate of drug permeation can be obtained only when Cd >> Cr i.e. the drug concentration at the surface of the stratum corneum Cd is consistently and substantially greater than the drug concentration in the body Cr. The equation becomes: dQ / dt = Ps Cd And the rate of skin permeation is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation

47. REFERENCES Controlled and Novel drug delivery edited by N.K.Jain reprint 2007 www.sciencedirect.com controlled drug delivery –concepts and advances –by S.P.Vyas R.K.Khar