NDDS Transdermal Drug Delivery System.pptx

Transdermal Drug Delivery System

1. Transdermal Drug Delivery System Ms. Shubhangi B Khade Assistant Professor Department of Pharmaceutics Sanjivani College of Pharmaceutical Education & Research(Autonomous), Kopargaon, Ahmednagar, Maharashtra

2. CONTENTS Introduction Permeation through skin Factors affecting permeation permeation enhancers basic components of TDDS Formulation approaches

3. History The first transdermal patch was approved in 1981 to prevent motion sickness. The FDA has approved till 2003, more than 35 Transdermal patch products, spanning 13 molecules . Throughout the past 20 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over the other dosage forms.

4. Introduction Definition : Transdermal therapeutic systems are defined as self contained discrete dosage forms, which when applied to intact skin , will deliver the drug at a controlled rate to systemic circulation.

5. Advantages Easy to use Avoid GIT absorption problems for drugs Avoids First pass metabolism of drugs More improved and convenient patient compliance. Rapid termination of therapy is possible in case of toxicity. Self medication is possible Reduces frequency of dosing Maintains therapeutic levels for 1 to 7 days. Controlled delivery resulting in more reliable and predictable blood levels.

6. Disadvantages Daily dose of more then 10 mg is not possible. Drug must have some desirable physicochemical properties to penetrate through skin. Local irritation is a major problem Uncomfortable to wear May not be economical barrier function changes from person to person Rapid onset of action is not possible Heat, cold, sweat, and showering causes patch fall off.

7. Structure Of Skin Anatomically skin has many histological layers but it is divided into 3 main layers, Epidermis Dermis Subcutaneous tissue (Hypodermis)

8. Epidermis epidermis further divided into five anatomical layers with approximately 100-150 micrometres thick Stratum Corneum (Horny Cell layer) Stratum lucidum ( Clear layer) Stratum Granulosum (Granular layer) Stratum Spinosum ( Prickly layer) Stratum germinativum

9. The outer layer of skin is made up of stratified squamous epithelial cells . The stratum corneum forms the outer most layer ( 10 to 15 Um thick) which consists of many layers of compacted, flattened, dehydrated, keratinized cells. Keratinocytes change their shape, size and physical properties when migrating to the skin surface . Water content of stratum corneum is about 20%. The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption.

10. Dermis Dermis consists of extensive microvasculature network structures like sweat glands, hair follicles , and the smaller blood vessels. Therefore, in order to have drug delivery via the skin, the drug must pass through the epidermis into the dermis where it can be absorbed by capillaries into the circulatory system . Inner and larger (90%) skin layer comprises primarily of cone ctive tissue and provides supports to the epidermis layer of the skin. The boundary between dermis and epidermis layer is called Dermal- Epidermal junction which provides a physical barrier for the large molecules of drug and cells.

11. Dermis can be divided into two anatomical region ; papillary dermis Reticular dermis. Papillary is the thinner outermost portion of the dermis Collagen and elastin fibres are mostly vertically oriented in the papillary region and connected with the dermal-epidermal junction .

12. Hypodermis Subcutaneous, or hypodermis in histology, is the third layer beneath the dermis . Subcutaneous is an elastic layer and includes a large amount of fat cells that work as a shock absorber for blood vessels and nerve endings. The thickness of this layer is on average .

13. Permeation through skin The permeation through skin occurs by the following routes Trans epidermal absorption Trans follicular ( shunt pathway absorption) Clearance by local circulation

14. Pathways of permeation through skin

15. The main route of transport for water-soluble molecules is paracellular . It involves the passage through the cytoplasm of corneocytes and lipid arrangement of the stratum corneum. The pathway of transport for lipid soluble molecules is transcellular ; it implicates the passage apparently through the endogenous lipid within the stratum corneum . The trans cellular and intercellular route is collectively known as trans-epidermal route. Transcellular and intercellular permeation requires diffusion through epidermis and dermis.

16. Transepidermal Absorption Stratum corneum is the main resistance for absorption through this route. Transepidermal pathway is responsible for drug diffusion across skin. Permeation involves partitioning of the drug into the stratum corneum. Permeation through the skin depends upon the O/W distribution tendencies of the drug. Extremely hydrophilic and extremely hydrophobic have difficulty in passing through viable epidermis. Lipophilic drug concentrate in and diffuse with relative ease.

17. Transfollicular Absorption The skin appendages (sebaceous) are considered as shunts for by passing the stratum corneum . Follicular route is important for permeation because the opening of the follicular pore is large and sebum aids in the diffusion of penetrant. Human skin contains 40- 70 hair follicles , 200- 250 sweat glands on every sq. cm of skin area. Mainly water soluble substance are diffused faster through appendages than that of other layers.

18. Once the dosage form is applied topically, the percutaneous absorption or transdermal permeation can be visualized as a composite of a series of steps. a. Adsorption of a penetrant molecule onto the surface layers of SC. b. Diffusion through SC and through viable epidermis

19. Principle involved in drug permeation through skin, Expressed by Ficks First law of diffusion. And given by Dq / dt = DKA (c1-c2)/h where dq / dt = rate of diffusion D= diffusion coefficient K= partition coefficient A= surface area of membrane H= thickness of membrane

20. The permeability coefficient at steady state ( Pss ) of the skin tissue to the drug is given by , Pss = Ks. Dss / Hs Where Ks= partition coefficient of drug into stratum corneum Dss = apparent diffusivity for the steady state diffusion of the drug Hs = overall thickness of skin tissue. The flux ( Jss ) of the penetrating drug is given by Jss = Pss.Cveh Where Jss = steady state flux Cveh = concentration of drug in vehicle/ formulation

21. Factors affecting permeation The factors that affect the permeability of the skin are classified into following three categories : A. Physicochemical properties of the permeate molecule B. Physicochemical properties of the drug delivery system C. Physiological and pathological condition of the skin

22. A. Physicochemical properties of the permeate molecule Partition co-efficient Molecular size Solubility Ionization of the drug Melting point Lipophilicity B. Physicochemical properties of the drug delivery system The affinity of the vehicle for the drug molecules Composition of drug delivery system Enhancement of transdermal permeation

23. C. Physiological and pathological condition of the skin Skin age Lipid film Skin hydration Skin temperature Cutaneous drug metabolism Species differences Pathological injury to the skin

24. Permeation Enhancers These are compounds that promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. Penetration enhancers are incorporated into a formulation to improve the diffusivity and solubility of drugs through the skin that would reversibly reduce the barrier resistance of the skin . Thus allows the drug to penetrate to the viable tissues and enter the systemic circulation . The flux J of drug across the skin can be written as J= D[dc/dx] Where J= The flux, D= diffusion coefficient, C= Concentration of diffusing species, X= spatial Coordinate.

25. The methods employed for modifying the barrier properties of the SC to enhance the drug penetration (and absorption) through the skin can be categorized as, A. Chemical method of enhancement B. Physical Method of enhancement A. Chemical method/ Chemical enhancers Substances that temporarily diminish the barrier property of the skin known as accelerants or absorption enhancers, can enhance the drug flux.

26. Chemical permeation enhancers can work by one or more of the following three principle mechanisms : Relaxation of the extremely ordered lipid structure of the stratum corneum . Interacting with aqueous domain of bilayer of lipid. Enhanced partition of the drug, by addition of co-enhancer or solvent into the stratum corneum . Promoting penetration and establishing drugs reservoir in the stratum corneum . Chemical permeation enhancers exert their effect through above modifications in the skin structure .

27. Activity of penetration enhancers Interaction with the polar head groups of lipid via hydrogen and ionic bonding Change in the hydration sphere of lipids and affect the packing of head region. Increase volume of the aqueous layer swelling and hydration. Protein modification – opens up the dense keratin structure and make it more permeable. Some of the most widely studied permeation enhancers are di- methylsulfoxide (DMSO), di- methylacetamide (DMA), an diethyltoluamide (DEET ), propylene glycol (PG ). The penetration enhancers, such as DMSO , urea and surfactants, can also interact with the keratin filaments present in corneocytes which leads to disruption within the cell thereby increasing diffusion coefficient and permeability

28. Physical method of enhancement/ Enhancers Electroporation Electroporation involves the application of high voltage pulses to induce skin perturbation. High voltages (≥100 V) and short treatment durations (milliseconds ) are most frequently employed . The technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size (i.e., small molecules , proteins, peptides, and oligonucleotides ). 2. Iontophoresis This method involves enhancing the permeation of a topically applied therapeutic agent by the application of a low-level electric current , either directly to the skin or indirectly via the dosage form.

29. 3. Ultrasound Ultrasound involves the use of ultrasonic energy to enhance the transdermal delivery of solutes either simultaneously or through pretreatment, and is frequently referred to as sonophoresis . The proposed mechanism behind the increase in skin permeability is attributed to the formation of gaseous cavities within the intercellular lipids on exposure to ultrasound, resulting in disruption of the stratum corneum 4. Magnetophoresis This method involves the application of a magnetic field that acts as an external driving force to enhance the diffusion of a diamagnetic solute across the skin.

30. 5. Thermophoresis The skin surface temperature is usually maintained at 32°C in humans by a range of homeostatic controls. 6. Microneedle -based devices One of the first patents ever filed for a drug delivery device for the percutaneous administration of drugs is based on this method. These micro-needles of length 50 to 110 mm will penetrate the stratum corneum and epidermis to deliver the drug from the reservoir 7. Needleless injection Needleless injection is reported to involve a pain-free method of administering drugs to the skin.

31. Ideal properties of penetration enhancer It should be pharmacologically inert. It is should be nontoxic, nonirritating, and non-allergenic to the skin. It should produce rapid onset of action; predictable and suitable duration of action for the drug used Following removal of the enhancer, the stratum corneum should immediately and fully recover its normal barrier property. The barrier function of the skin should decrease in one direction only i.e., they should permit therapeutic agents into the body and efflux of endogenous materials should not occur.

32. It should be chemically and physically compatible with the delivery system. It should be non-damaging to viable cells. They should be Inexpensive and cosmetically acceptable. The Penetration enhancer used should be economical.

33. Basic Components of TDDS: Polymer Matrix Drug Permeation Enhancers Pressure sensitive adhesives (PSA ) Backings Laminates Release Liner Other Excipients

34. Polymer Matrix

35. Drug For successful development of TDDS following are the desirable properties of drug Must be non ionic Low molecular weight. (less than 1000Da) Adequate solubility in oil and water Low melting point (less than 200 o C) Dose should be less than 10 mg/day

36. Permeation Enhancers : Penetration enhancers are incorporated into a formulation to improve the diffusivity and solubility of drugs through the skin that would reversibly reduce the barrier resistance of the skin . Ex. Water , pyrolidones , fatty acids and alcohols, zone and its derivatives, alcohol and glycols, essential oils , terpenes and derivatives , sulfoxides like DMSO and their derivatives, urea and surfactant . Pressure sensitive adhesives (PSA ) These provide good adhenrence and help to secure the transdermal device on the skin for long period of time. Should not irritate the skin Should not adhere to skin aggressively Should be easily removed.

37. Should not leave an unwashable residue on skin. Should be compatible with drug, excipients, and permeation enhancers. The major classes of PSA are Polyisobutylene based adhesives These are elastomeric polymers commonly used as primary base polymer and tackifiers . Acrylic adhesives These are produced by co polymerization of acrylic esters with acrylic acid and other functional monomers. These are used as matrix adhesives and dominate the medical market.

38. Silicon based adhesives These are composed of PDMS( poly dimethyl siloxane ) and benzene soluble silicate resin. They possess excellent chemical stability, low toxicity and skin compatibility.

39. Backings Laminates Backings laminates are selected for appearance, flexibility and provide good bond to the drug reservoir. Ex. polyester film, polyethylene film and polyolefin film, and aluminum vapor coated layer . Release Liner During storage the patch is covered by a protective liner that is removed and discarded before the application of the patch to the skin. Ex. Polyesters and metal foils

40. Formulation Approaches of TDDS Polymer membrane permeation controlled TDD system Polymer matrix diffusion controlled TDD system Adhesive Dispersion – Type Systems Microreservoir dissolution controlled TDD system

41. Polymer membrane permeation controlled TDD system Drug reservoir sandwiched/ encapsulated between drug impermeable backing laminate and rate controlling polymeric membrane. In drug reservoir compartment drug is dispersed in the solid polymeric matrix ( e.g. polyisobutylene ) or suspended in an unleachable , viscous liquid medium ( e.g. silicon fluid) to form a paste like suspension. A layer of adhesive polymer is applied on the membrane to help secure the device onto skin surface.

42. Ex. Nitroglycerine releasing TDDS for once a day medication for angina Scopolamine releasing TDDS for 72 hrs for motion sickness. Estradiol releasing TDDS for menopausal syndrome. Clonidine releasing TDDS for 7 day for hypertension.

43. The intrinsic rate of drug release from this type of drug delivery system is defined by Dq = C R 1/pm +1/pa dt Where CR = Concentration of drug in reservoir, Pa = permeation coefficient of adhesive layer Pm = permeation coefficient of rate controlling membrane For any micro porous rate – controlling membrane, Pm approximately represents the sum of permeability co-efficient across the pores and polymeric material . Pa and Pm may be separately defined as Pa Pa= Ka / m.Da /ha

44. Pm=Km/ r.Dm / hm Where, Da = Diffusion Co-efficient of an derive layer Dm =Diffusion Co-efficient of rate – controlling membrane Ka /m = Partition Co-efficient for interfacial partitioning of drug from rate controlling membrane to adhesive layer Km/r =Partition Co-efficient for interfacial partitioning of drug from reservoir to rate controlling membrane hm = Thickness of rate = Controlling membrane. Ha = Thickness of adhesive layer

45. Polymer matrix diffusion controlled TDD system In this the drug reservoir is prepared by homogeneously dispersing drug particles in a hydrophilic (or) lipophilic polymer matrix . The resulting polymer matrix is then moulded into discs with defined surface area and controlled thickness . The medicated disc is then moulded onto an occlusive base plate in a compartment made up of a drug impermeable backing. Finally adhesive polymer is spread along the circumference of the film .

46. Rate of drug release in this system is given by the equation dq / dt = { ACpDp /2t}1/2 Where, A= Initial drug loading dose dispersed in polymer matrix Cp = Solubility of drug in Polymer Dp = Diffusivity of drug in Polymer since Cp is equal to Cr

47. Adhesive Dispersion – Type Systems In this system, drug and other selected excipients are directly incorporated into the adhesive solution . They are then mixed and casted as thin films and finally the solvent is evaporated by drying the film The drug reservoir (film) is the then sandwiched between the backing laminate and rate –controlling adhesive polymer membrane . Ex. Isosorbide dinitrate Releasing TDDS for Once a day medication

48. The rate of drug release from this system is given by , dq / dt = Cr.Ka /r . Da/ha Where Ka /r = Partition co-efficient for interfacial partitioning of drug from reservoir layer to adhesive layer CR = Concentration of drug in reservoir , Da = Diffusion Co-efficient of an derive layer Ha = Thickness of adhesive layer

49. Microreservoir dissolution controlled TDD system It is considered as the hybrid system of reservoir and matrix dispersion type drug delivery The drug reservoir is formed by suspension of drug into aqueous solution of water soluble liquid polymer. Homogenously dispersing of drug suspenson in a lipophilic polymer. As a result unleachable microscopic spheres of drug reservoir is formed which is stabilized by cross linking. Medicated polymer is moulded into a medicated discs of desired surface and thickness. Depending upon property of drug the disc is coated by bio compatible polymer.

50. Ex. Nitro glycerine releasing TDDS for angina pectoris .

51. Evaluation OF TDDS Physical evaluation Film thickness Tensile strength Weight variation Drug content % moisture content Adhesive evaluation Peel adhesion test Tack properties- 1. thumb tack test. 2. rolling ball tack test. 3. quick stick/ peel – tack test,. 4. probe tack test In viro drug release/ skin permeation test

52. Physical Evaluation Film thickness By electronic verniercallipiers . Tensile strength By modified pulley system. Measure force require to break system

53. Adhesion evaluation Peel adhesion test It is tested by force required to pull a single coated tape applied to a substrate at 180 ° angle. Higher value indicated greater strength.

54. Tack properties Thumb tack test Done by briefly pressing thumb on adhesive. Rolling ball tack test Measurement of distance that a stainless steel ball travels along upward facing adhesive.

55. In vitro Test Franz diffusion cell Keshary chien cell ( K- C cell) Valia chien cell ( V- C ) Ghannam chien permeation cell Jhawar rod rotating disc cell