Transdermal Drug Delivery System

Structure of skin and barriers, Penetration enhancers, Transdermal Drug Delivery Systems, Formulation and Evaluation

1. TRANSDERMAL DRUG DELIVERY SYSTEM By I.Silambarasan M pharm (pharmaceutics) Mtpg & rihs

2. INTRODUCTION Now a day about 74% of drugs are taken orally and are found not to be as effective as desired either due to bioavailability problems or degradation of drug in acidic pH of stomach. To resolve such problems, transdermal drug delivery system (TDDS) was emerged. Transdermal drug delivery systems, also known as ‘‘patches ”

3. HISTORY Medicated plasters – are first TDDS (External application) China – Chinese medicated plaster Japan - Cataplasms & salonpas England – Allcock’s porous plaster Germany – ABC (arnica/belladonna/capsicum) USA - Belladonna plaster Mustard plaster Salicylic acid plaster

4. INITIAL DEVELOPMENT D e velopment of female syndrome in male operator working in the estrogen containing pharmaceutical company. Challange the old theory-”Skin is impermeable barrier”. To develop patch type Drug delivery system for rate controlled drug delivery system for system delivery of drug.

5. MARKETED FORMULATION S NO DRUG BRAND NAME TREATMENT 1 Scopalamine Transderm-scop 72 hrs for motion induced nausea 2 Nitroglycerine Nitrodisc,Nitrodur Angina pectoris 3 Isosorbide Dinitrate Frandol tape Once a day medication for angina pectoris 4 Clonidine Catapress-TDDS Weekly theraphy-Angina pectoris 5 Estradiol Estraderm Twice a week- postmenoposal syndrome 6 Fentanyl Duragesic Twice a week-Analgesic for cance patients

6. OBJECTIVES OF TDDS To maintain a constant, prolonged and therapeutically effective drug levels in the body To by pass first pass metabolism To reduce systemic side effects To improve efficacy to have a better patient’s compliance

7. DEFINITION Transdermal drug delivery is defined as self contained discrete dosage form,which when applied to intact skin will deliver the drug at a controlled rate to systemic circulation. A simple patch that stick on to your skin like an adhesive bandages,which use passive diffusion for delivery mechanism.

8. ADVANTAGES Minimize fluctuation in pharmacological response. Avoids FP hepatic metabolism of drugs. Rapid termination in case of toxicity is possible. Self medication is possible. Reduces frequency of dosing and enhance patient compliance. Maintains therapeutic level for 1 to 7 days Drug canditate with short biological half life can be utilized

9. DISADVANTAGES Daily dose of more than 20mg is not possible. Local irritation is a major problem. Drugs with high molecular weight (> 500 Da ) are difficult to penetrate the stratum corneum Drug with long half life can not be formulated in TDDS. May not be economical. Barrier function changes from person to person and within the same person. Heat, cold, sweating (perspiring) and showering prevent the patch from sticking to the surface of the skin for more than one day. A new patch has to be applied daily.

10. COMPARISON BETWEEN IV,ORAL, TDDS ADVANTAGES IV ORAL TDDS Avoid hepatic first pass effects YES NO YES Constant drug levels YES NO YES Self administration NO YES YES Termination of theraphy NO YES YES

11. HUMAN SKIN Skin is the largest organ in the body. It covers entire body suface and has surace area of 2 sq meter. Weighs 4.5-5.0 kg i.e 16 % total body weight in adults. Receives 1/3 of blood circulate through body. Elastic ,Rugged ,Self regenarative. Barrier against physial and chemical attack and protect from microoraganism from environment.

12. ANATOMY OF SKIN

13. L AYERS OF SKIN Epidermis Stratum corneum (Horny cell layer) Stratum germinativum Stratum Lucidum (Clear layer) Stratum Granulosum ( Granular Layer) Stratum Spinosum (Prickly layer) Dermis Hypodermis or Subcutaneous layer

14. EPIDERMIS O utermost layer,composed of stratified squamous epithelial cells. Epithelial cells are held together by interlocking bridges, which is responsible for integrity of skin. Epidermis is thickest in palm and soles . T hinnest in ventral surface of trunk .

15. MICROSCOPIC SECTION OF EPIDERMIS Two layers: 1)Stratum corneum 2)Stratum Germinativum

16. STRATUM CORNEUM It is outermost layer of epidermis It is formed and continuosly replinished by slow upward movement of cells produced by stratum Germinativum. Regeneration takes place fror every 2 weeks in mature adults. Water content of Stratum corneum =20% Water content for Stratum Germinativum=70% Below 10 % water content in sc called “DRY SKIN”

17. C ont, The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption. Thickness of skin is mainly by stimulation of skin and bearing of weight.

18. The stratum corneum is the outermost layer of the epidermis and is composed mainly of dead cells that lack nuclei. These are sloughed off during the day and replaced by new cells from the stratum germinativum.

19. C ont, In the process of degenaration granules of ketohyalin appear in the cells W hen ketohyalin convert to keratin ,stratum lucidum is formed. Removal of the layer causes water loss and enhancement of permeability.

20. DERMIS The dermis is made up of regular network of robust collagen fibers of fairly uniform thickness with regularly placed cross striations . This network or the gel structure is responsible for the elastic properties of the skin. It is supplied by blood to convey nutrients, remove waste & regulate body temp. Drug is well absorbed by this route. Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings.

21. C ont, SUBCUTANEOUS TISSUE: This is a sheet of the fat containing areolar tissue known as the superficial fascia attaching the dermis to the underlying structures . SKIN APPENDAGES: Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies. Its function is to control heat. HAIR FOLLICLES They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene

22. Mechanism of absorption through skin Mechanism involved is passive diffusion This can be expressed by FICK’s LAW of DIFFUSION dq = D A K (C1-C2) dt h dq / dt = rate of diffusion D = diffusion co-efficient K = partition co- efficient A = surface area of membrane h = thickness of membrane

23. STRATUM CAORNEUM AS SKIN PERMEATION BARRIER THREE LAYER’S 1)Stratum Corneum (15 µm thick) 2)Viable Epidermis(150 µm thick) 3)Papillary layer of dermis(100-200 µm thick) These structure is pierced in various places by two shunts, 1)Hair Follicles 2)Sweat Glands

24. Routes of drug absorption through skin 2 Ways 1)Trans follicular absorption 2)Trans epidermal absorption -Intercellular diffusion -Transcellular diffusion

25. TRANSFOLLICULAR DIFFUSION Skin appendages occupy 1% of total human skin surface. 40-70 hair follicles and 200-250 sweat ducts in every sq.cm of skin area. Mainly water soluble substance are diffused faster through appendages . Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST corneum.

26. TRANSEPIDERMAL DIFFUSION 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.

27. INTERCULLAR AND TRANSCELLULAR ROUTE

28. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY Physico chemical properties of parent molecule Solubility pH condition Penetrant concentration Physico chemical properties of drug delivery system Release characteristic Composition of drug delivery system Permeation enhancer used

29. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY Physiological and pathological condition of skin Lipid film Skin hydration Skin temperature Effect of vehicle Pathological injury to skin Biological factors Skin age Thickness of S. Corneum Skin condition

30. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY Solubility and partition co- efficient: Solubility of a drug influences its ability to penetrate the skin. pKa is index of solubility of drug in vehicle and ST corneum has influence on transfer of drug from vehicle to skin. Skin permeation can be enhanced by increasing lipophilic character of drug. Drug which is lipid & water soluble is favored.

31. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY pH & Concentration: Moderate pH is favorable because high or low pH will result in destruction of the skin. Higher the concentration of the drug in vehicle faster the absorption.

32. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY Release characteristic Solubility of drug in vehicle determines the release rate. Composition of drug delivery system It not only effects the rate of drug release but also the permeability of STC by means of hydration mixing with skin lipids. Example methyl salicylate is more lipophilic than its parent acid (Salicylic acid). When applied to skin from fatty vehicle methylsalicylate yielded higher absorption.

33. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY Lipid film: It acts as protective layer to prevent removal of moisture from skin. Removal of this film will decrease TD absorption. Skin hydration: It can be achieved by covering skin with plastic sheeting, which leads to accumulation of sweat, condensed water vapors, increase hydration and increase porosity.

34. FACTOR’S AFFECTING TRANSDERMAL PERMEABILITY Skin age: Skin of foetus , young ones and elders is more permeable than adult tissue. Skin metabolism : Viable epidermis is metabolically active than dermis.

35. BASIC COMPONENTS OF TDDS Polymer matrix / Drug reservoir Drug Permeation enhancers Pressure sensitive adhesive (PSA) Backing laminate Liner

36. POLYMERS Following criteria to be considered in selection a polymer: Molecular weight, physical nature of polymer must allow diffusion of drug at desired rate. Polymer must be non-reactive, inert, non-toxic, easy to manufacture, inexpensive. It should not decompose on storage of the device & not deteriorate when large amount of active ingredient is incorporated into it.

37. LIST OF POLYMER USED

38. DRUG

39. PERMEATION ENHANCER These are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrant. Flux J across the skin can be given by J= D. dc/dx D= diffusion coefficient C= concentration x=Spatial coordinate D is function of size, shape, flexibility of diffusing drug molecule

40. Activity of penetration enhancers Interaction with the polar head groups of lipid via hydrogen and ionic bonding. Change in hydration sphere of lipids and affect the packing at the head region. Increase volume of the aqueous layer,swelling and hydration. Protein modification- open up the dense keratin structure and make it more permeable.

41. Ideal Characteristic Of Penetration Enhancers IT SHOULD BE INERT NON-TOXIC, NON- IRRITATING ACTION SHOULD BE IMMEDIATE& PREDICTABLE SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS COSMETICALLY ACCEPTABLE ODORLESS, TASTELESS, COLORLESS & CHEAP

42. CLASSIFICATION OF PEMEATION ENHANCER SOLVENTS SURAFACTANTS 1)Anionic surfactant 2)Non-ionic surfactant 3)Bile Salts Binary Systems Miscellaneous Chemicals

43. SOLVENTS The compounds increase penetration possibly by swelling the polar pathway and fluidizing the lipid e.g.. Methanol, ethanol, DMSO, DMA, DMF, propylene glycol, glycerol etc.

44. SURFACTANTS They enhance polar pathway transport of hydrophilic drugs ANIONIC SURFACTANTS Dioctyl sulpho succinate, SLS, Decode methyl sulphoxide CATIONIC SURFACTANTS Pluronic F127 , Pluronic F58 BILE SALTS Sodium tourocholate,Sodium deoxycholate

45. Miscellaneous chemicals Urea, Calcium Thioglycolate

46. Pressure Sensitive Adhesives A PSA is a material that helps in maintaining an intimate contact between transdermal system and the skin surface. Some widely used pressure sensitive adhesives are- Eg - Polyisobutylenes , Polyacrylates , Silicones.

47. Backing Laminate Hold and protect the drug reservoir from exposure to atmosphere. Avoid loss of drug Accept printing High flexibility Eg -polyethylene and polyester films, Aluminium foil, foam pad, Metallic plastic laminate.

48. LINER Protects the patch during storage. The liner is removed prior to use. Drug – Drug solution in direct contact with release liner.

49. FORMULATION OF TDDS Polymer Membrane Permeation Controlled TDDS. Polymer Matrix Diffusion Controlled TDDS. Drug Reservoir Gradient Controlled TDDS. Micro reservoir Dissolution Controlled TDDS.

50. Polymer Membrane Permeation Controlled TDDS Drug formulation is totally or partially encapsulated within drug reservoir compartment, which may exist as solid, suspension or solution form. Drug release surface is covered by a rate-controlling polymeric membrane having a specific permeability. Rate-controlling polymeric membrane can be fabricated from a nonporous (homo/ hetero- genous ) polymeric material or a microporous (or semipermeable) membrane.

51. The encapsulation of drug formulation inside the reservoir compartment is done by 1. Injection molding 2. Spray coating 3. Capsulation 4. Microencapsulation, & other techniques at Different sizes & shapes

52. The rate of drug release Q/t is given by where K m/r & K a /m are the partition coefficients for interfacial partitioning of drug molecules from the reservoir to the rate controlling membrane & from the rate controlling membrane to the surrounding aqueous diffusion layer respectively. D m D d are diffusion co-efficient in the rate controlling membrane (with thickness h m ) & in the aqueous diffusion layer (thickness h d )

53. For a micro-porous or semi-permeable membrane the porosity & tortuosity of the pores should be included in the determination of D m h m C R is the drug concentration in the reservoir compartment . Release is controlled by Partition co-efficient & diffusivity of the drug The thickness of the rate controlling membrane h m Example 1. Progestasert IUD 2. Norplant subdermal implant 3. Ocusert system 4. Transderm -nitro

54. Polymer Matrix Diffusion Controlled TDDS Preparation of DR: drug is dispersed homogenously in a rate-controlling polymer matrix (lipophilic or a hydrophilic polymer ). The drug is dispersed in the polymer matrix by Blending: a therapeutic dose of finely powdered drug particles are blended with a liquid polymer or a highly viscous base polymer , followed by cross linking of the polymer chains. Mixing: drug solids are mixed with a rubbery polymer at an elevated temperature.

55. Resultant drug polymer dispersion is then molded or extruded to form a drug delivery device of various shapes & sizes. Also be fabricated by dissolving the drug & the polymer in a common solvent, followed by solvent evaporation at an elevated temperature or under a vacuum.

56. The rate of drug release is time dependent & is defined at steady state by Where, A is the loading dose in the polymer matrix. C R is the drug solubility in the polymer. D P is the diffusivity of the drug in the polymer matrix.

57. Release rate is controlled by Loading dose Polymer solubility of the drug Drug diffusivity in the polymer matrix Example: 1.Nitro-Dur 2.Compudose subdermal implant

58. Drug Reservoir Gradient Controlled TDDS Drug – impermeable metallic plastic laminate

59. Microreservoir Dissolution Controlled TDDS DR is fabricated by microdispersion of an aqueous suspension of drug using a high-energy dispersion technique in a biocompatible polymer , such as silicone elastomers , to form a homogenous dispersion of many discrete, unleachable , microscopic DRs. Method: molding or extrusion (at different shapes & sizes)

60. The rate of release of drugs of the micro reservoir system is defined by

61. D l , D p and D d and h l , h p and h d ; are diffusivities and thickness of liquid layer surrounding the drug particle, polymer coating membrane surrounding the polymer matrix and the hydrodynamic diffusion layer surrounding the polymer coating . K l , k m and k p are the partition coefficient for the interfacial partitioning of the drug from the liquid compartment to the polymer matrix, from the polymer matrix to the polymer coating membrane and from the polymer coating membrane to the elution solution respectively.

62. S l and S P are the solubility of the drug in the liquid compartment and in the polymer matrix respectively. The release of drug from this system can follow either a partition control or matrix diffusion control process depending upon the relative magnitudes of S l and S P.

63. Example, 1. Nitro – disc system 2. Transdermal contraceptive device 3. Subdermal syncro -mate-c implant

64. EVALUATION OF TDDS A) Physicochemical Evaluation : Thickness Uniformity of weight Drug content determination Moisture content Flatness Folding Endurance Tensile Strength Water vapour transmission studies (WVT) Microscopic studies

65. EVALUATION OF TDDS B) Adhesion 1) Peel adhesion properties 2) Tack properties Rolling ball test Quick stick test Probe tack test 3) Shear strength C) In-vitro drug release D) Effect of skin uptake and metabolism

66. Thickness of the patch 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 .

67. 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

68. 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.

69. 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. % Moisture content = Initial weight – Final weight X100 Final weight

70. Moisture Uptake: Weighed film 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. % moisture uptake = Final weight – Initial weight X100 Initial weight 

71. 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 

72. 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.

73. 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 . 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.

74. B)EVALUATION OF ADHESIVE Peel adhesion properties Peel adhesion is the force required to remove an adhesive coating from a test substrate. This properties are affected by the molecular wt. of the adhesive polymer, the type and amount of additives, and polymer composition

75. It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at a 180 o angle

76. 2 . Tack properties: Tack is ability of the polymer to adhere to substrate with little contact pressure. It is dependent on the molecular weight and composition of polymer as well as the use of tackifying resin in the polymer. Tests for tack include....

77. 2 A)Rolling ball test: This test involves measurement of the distance that a stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the farther the ball will travel.

78. 2B) Quick-stick (or peel-tack) test: The peel force require to break the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90 o at a speed at 12 inch/min. The force is recorded as the tack value and is expressed in ounce or grams per inch width with higher values indicating increasing tack.

79. 2C) Probe tack test: Here, the force required to pull a probe away from an adhesive at a fixed rate is recorded as tack (in grams) Adhesive film Annular weight Dial Probe

80. C. Shear strength properties: Shear strength is the measurement of the cohesive strength of an adhesive polymer. It is affected by molecular weight as well as the type and amount of tackifier added. Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the tape which pulls the tape in a direction parallel to the plate

81. Stainless steel plate Adhesive coated tape Weight

82. 2. IN-VITRO DRUG RELEASE EVALUATION In these studies, excised skin is mounted on skin permeation cells. Skin of hairless mouse is used rather than human cadaver skin. In-vitro system should be designed in such way that the intrinsic rate of release or permeation which is theoretically independent of the in-vitro design can be accurately determined.

83. Several designs of the in-vitro membrane permeation cell, the Jhawer -Lord (J-L), Valia-Chien (V-C) Cell, Ghannam-Chein (G-C) membrane permeation enhancer, Franz Diffusion Cell and the Keshry-Chien (K-C) Cell. K-C Cell has an effective receptor volume 12ml, skin surface area of 3.14cm 2 . the receptor solution is stirred by star-head magnet rotating at a constant speed of 600rpm driven by 3W synchronous motor.

84. EFFECT OF SKIN UPTAKE AND METABOLISM In this study, a piece (3cm by 3cm) of full thickness skin (human cadaver skin) or stripped skin freshly excised from a hair less mouse, 5-7 week old, was mounted between the two compartments of each V-C permeation cell. It was mounted in such a way that either the stratum corneum or the dermis faced the drug solution and the other side of the skin was protected with impermeable aluminum foil.

85. 3. EFFECT OF SKIN UPTAKE AND METABOLISM The compartment with the skin surface uncovered was filled with a saturated solution of drug in normal saline and the compartment with the skin surface covered with aluminum foil remained empty. Both the compartment were maintained isothermally at 37 o C. Samples were withdrawn from solution compartment at predetermined times and assayed for drug and any possible metabolite.

86. ADVANTAGES It can help in investigating the mechanism of skin permeation of the drug before it can be developed in TDDS. Time needed to attain steady state permeation and the permeation flux at steady state can be obtained. It is use to optimize the formulation before more expensive in vivo studies are performed.

87. Franz Diffusion Cell

88. REFERENCES Novel drug delivery systems, 2 nd edition, by Y.W. Chein page no.: 338 – 380. http://www.google.com

89. THANK YOU