Transdermal drug delivery system


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Transdermal drug delivery system

  1. 1. Seminar on….. TRANSDERMAL DRUG DELIVERY SYSTEMS Presented by….. P.CHAKRADHAR M. Pharm 1st Year Dept. of Pharmaceutics K.L.E. University, 1
  2. 2. Contents Introduction. Advantages & Disadvantages Structure of the skin. Permeation through skin. Factors affecting permeation. Basic components of TDDS Formulation approaches used in the development of TDDS Evaluation of TDDS Advances in TDDS References. 2
  3. 3. Introduction Definition – Transdermal therapeutic systems are defined as self contained ,self discrete dosage forms ,which when applied to the intact skin deliver the drug at a controlled rate to the systemic circulation. A simple patch that you stick onto your skin like an adhesive bandage, which utilize passive diffusion of drugs across the skin as the delivery mechanism. 3
  4. 4. Advantages1. It delivers a steady infusion of the drug over an extended period of time .Adverse effects and therapeutic failures can be avoided .3. It increases the therapeutic value of many drugs by avoiding specific problems associated with the drug .5. The simplified medication regimen leads to an improved patient compliance and reduce inter patient and intra patient variability.7. Self medication is possible with this type of system.9. The drug input can be terminated at any point of time by removing the patch. 4
  5. 5.  Transdermal Drug Delivery Offers the Best of IVand Oral Administration IV Oral TDD Reduced first-pass effects Yes No Yes Constant drug levels Yes No* Yes Self-administration No Yes Yes Unrestricted patient activity No Yes Yes 5
  6. 6. 1. The drug must have desired physicochemical properties for penetration through the stratum corneum.3. Skin irritation or contact dermatitis due to excipient and enhancers of the drug used to increase the percutaneous absorption, is the other limitation.5. The barrier function of the skin changes from one site to the another on the same person , from person to person and with age .7. 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.9. The patches fall off during bathing and sleeping. … has resorted to using medical tape to help secure patches.11. Patches fall off completely during bathing or swimming; patches sometimes fall off during walking.13. Slight movement and sweating will cause patches not to stick. 6
  7. 7. History The first Transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness. The FDA has approved, till 2003, more than 35 Transdermal patch products, spanning 13 molecules ( In USA). The US Transdermal market approached $1.2 billion in 2001 It was based on 11 drug molecules: fentanyl, nitroglycerin, estradiol, ethinylestradiol, norethindroneacetate, testosterone, clonidine, nicotine, lidocaine, prilocaine, and scopolamine. Two new, recently approved Transdermal patch products (a contraceptive patch containing ethinylestradiol and nor elgestromin ,and a patch to treat overactive bladder, containing oxybutynin. 7
  8. 8. More than 35 TDD products have now beenapproved for sale in the US 。And approximately 16 active ingredients areapproved for use in TDD products globally
  9. 9. Where as 13 compoundscurrently exist in approvedTransdermal products in theUSSix new (i.e., new to theTransdermal market) lowmolecular weight moleculesare currently in eitherpreclinical or clinicaldevelopment.Another noteworthy elementof Table 1is that several of thecompounds (macromoleculesand vaccines) in developmentare outside of the normalniche for TDD
  10. 10. Structure of the skin Anatomically the skin has many histological layers, but it is divided into three layers –2. Epidermis .4. Dermis .6. Subcutaneous tissue. 10
  11. 11. 11Structure of Skin
  12. 12. Epidermis The epidermis is divided into following parts The stratum corneum and stratum germinativum. The stratum corneum forms the outer most layer of the epidermis and consists many layers of compacted , flattened, dehydrated keratinized cells in the stratified layer . Water content of stratum corneum is around 20%. The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness. 14
  13. 13.  The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption. It is made up of three layers in thicker parts – stratum granulosum ,stratum lucidum ,stratum spinosum. Removal of these layers results in increased permeability and water loss. 15
  14. 14. 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. Below the dermis there is a fat containing subcutaneous tissue . Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings. 16
  15. 15. Subcutaneous This is a sheet of the fat containing areolar tissue known as the superficial fascia. attaching the dermis to the underlying structures . 17
  16. 16.  BIOCHEMISTRY OF THE SKINEpidermis –4. The main source of energy for the lower portions of the epidermis is the glucose and the end product is the lactic acid.6. Fatty acids are required for the cellular functions of the skin and cells derives their energy from the degradation of the phospholipids .8. The energy derived is used for the synthesis of proteins and construction of the stratum corneum.10. Proteolytic enzymes are present in the stratum corneum and epidermis consists of specialized organelles like lysosymes . 18
  17. 17.  Dermis-2. Protein synthesis is the key factor in the dermal metabolism.3. Fibroblast extracellularly deposit large quantities of collagen and elastin.4. Protein synthesis occurs in the hair follicles .5. The sebaceous gland produce large quantities of lipids and the energy is derived from the intracellular aerobic carbohydrate metabolism is used for cellular synthetic process. 19
  18. 18.  Skin surface –2. The skin surface has a population of micro organisms and can contribute to enzymology.4. The diversity and abundance varies from individual to individual.6. The microorganism alter the skin surface lipid composition via hydrolysis of secreted sebum 20
  19. 19. Permeation through skin The permeation through the skin occurs by the following routes- Transepidermal absorption. Transfollicular (shunt pathway absorption). Clearance by local circulation . 21
  20. 20. Pathways of permeationthrough skin 22
  21. 21. Transepidermal Absorption 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 . 23
  22. 22. Transfollicular Absorption The skin appendages (sebaceous and eccrine glands ) are considered as shunts for by passing the stratum corneum. Follicular route is important for permeation because the opening of the follicular pore is relatively large and sebum aids in the diffusion of the penetrant. Partitioning into the sebum followed by the diffusion to the depths of the epidermis is the mechanism 24
  23. 23. Clearance by local circulation The earliest point of entry of drugs into the systemic circulation is within the papillary plexus in the upper epidermis The process is thus regarded as the end point. 25
  24. 24. Factors affecting permeationthrough skin Age has an effect on the permeation of drugs through the skin. Blood flow (dermal clearance of the molecule transversing the tissue ) tends to decrease with age and could reduce transdermal flux. 26
  25. 25.  The other factors that affect the permeation of the drug through the skin are – The stratum corneum thickness . Presence of hair follicles . Injury or trauma to the skin . Hydration of the skin. Effect of humidity and temperature . Chemical exposure. Chronic use of certain drugs . 27
  26. 26. Basic Components of TDDS The components of the transdermal drug delivery system include – Polymer matrix or matrices The drug The permeation enhancers Other excipients 28
  27. 27. Basic components of Transdermaldrug delivery 29
  28. 28. Polymer matrix It releases the drug from the device and should satisfy the following criteria-ii. Molecular weight , chemical functionality of the polymer should be such that specific drug diffuses properly and gets released through it .iii. It should be stable , non reactive with the drug, easily manufactured and fabricated into the desired productiv. The polymer and its degradation products must be non toxic or non antagonistic to the host . 30
  29. 29.  The mechanical properties of the polymer should not deteriorate excessively when the large amount of the active agents are incorporated into it. The polymers used in the transdermal drug delivery systems are – Natural polymers – cellulose derivatives ,zein , gelatin , shellac ,waxes , proteins , gums and their derivatives , natural rubber starch etc . 31
  30. 30.  Synthetic elastomers- poly butadiene , hydrin rubber , poly siloxane silicone rubber , nitrile , acrylonitrile ,butyl rubber, butadiene Neoprene etc . Synthetic polymers-polyvinyl chloride, polyethylene, poly propylene, polyacrylate ,polyamide ,polyurea, polyvinyl pyrrolidone, poly methyl methaacrylate 32
  31. 31. Drug For successful development of a transdermal drug delivery, the following are the desirable properties of a drug for transdermal drug delivery. Physicochemical properties . Biological properties . 33
  32. 32.  Physicochemical properties.- It is generally accepted that the best drug candidates for passive adhesive Transdermal patches must be : Non-ionic. Low molecular weight (less than 500 Daltons), Adequate solubility in oil and water . Low melting point (less than 200℃ ) Potent (dose is less than 50 mg per day, and ideally less than 10 mg per day) . 34
  33. 33.  Biological properties –3. The drug should be potent with a daily dose of order of a few mg/ day.4. The half life of the drug should be short.5. The drug must not induce a cutaneous irritant or allergic response.6. Drugs degraded in the GIT or inactivated by the hepatic first pass are suitable candidates for transdermal drug delivery. 35
  34. 34. Permeation enhancers These are compounds which promote skin permeability by altering the skin as a barrier to the flux of the desired penetrant . The flux of the drug (J) is given by- dc J D dx D= diffusion coefficient C = conc. of the diffusing species . X= spatial coordinate 36
  35. 35.  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, Calcium thioglycholate. 37
  36. 36. Other excipients Adhesives –The fastening of the transdermal device is usually done by the adhesive .The adhesive should satisfy the following criteria . Do not irritate or sensitize the skin. Adhere to the skin during the dosing interval. It should be easily removed . It should not leave any unwashable residue. 38
  37. 37.  The face adhesive system should satisfy the following criteria . It should be physically and chemically compatible with the drug, excipients and the enhancers. Permeation of the drug should not be affected . The delivery of the permeation enhancers should not be affected. Polymers used in the adhesives are polyisobutylenes , acrylic and silicones . 39
  38. 38. Backing membrane They are flexible and provide a good bond to the drug reservoir , prevent the drug from leaving the dosage form through top. It is an impermeable membrane that protects the product during the use on the skin.• Contains formulation throughout shelf-life and during wear period• Must be compatible with formulation (nonadsorptive)• Printable Eg: metallic plastic laminate , plastic backing with adsorbent pad adhesive foam pad . 40
  39. 39. Schematic Skin absorption ofdrug 41
  40. 40.  Transdermal Drug Delivery mechanism Passive Matrix (Oxytrol,) Reservoir ( Duragesic) Active Iontophoresis Electroporation Sonophoresis Heat or thermal energy Micro needles
  41. 41. Formulation Approaches used in thedevelopment of TDDS1. Membrane permeation – controlled systems.3. Adhesive dispersion – type systems.5. Matrix diffusion – controlled systems.7. Microreservoir type or Microsealed dissolution – controlled systems.9. Poroplastic – type systems.11. Transdermal delivery of Macromolecules. 43
  42. 42. 1. Membrane permeation – controlled systems The drug reservoir is totally encapsulated in a shallow compartment moulded from a drug – impermeable metallic plastic laminate & a rate controlling polymeric membrane which may be microporous or non-porous. The rate of drug release from this type of TDDS can be tailored by varying the composition of polymer, permeability coefficient, thickness of the rate limiting membrane & adhesive. Example:- i) Nitroglycerine-releasing Transdermal system (Transderm-nitro) for once a day medication in angina pectoris. ii) Scopolamine-releasing Transdermal system (Transderm- scop) for 72 hrs. prophylaxis of motion sickness. 44
  43. 43. Fig. Membrane moderated Transdermal drug delivery system 45
  44. 44. Continued… The intrinsic rate of drug release from this type is… dQ CR dt 1 1 Pm Pa ……………………(1) Where, CR = Drug conc. In the reservoir compartment. Pa & Pm = permeability coefficients of Adhesive & the rate controlling membrane respectively. 46
  45. 45. Continued… For microporous membrane, Pm is the sum of permeability coefficients for simultaneous penetration across the pores & polymeric material, hence… Km/r Dm Ka/m Da Pm & Pa hm …….(2) ha …….(3) 47
  46. 46. Continued… In case of micro porous membrane, the porosity of the membrane should be taken in to the calculation of Dm & hm values, Substituting eq. (2) & (3) in eq. (1)… dQ Km/r Ka/m Dm Da CR dt Km/r Dm ha Ka/m Da ha …………...(4) 48
  47. 47. 2. Adhesive dispersion – type systems The drug reservoir is formulated by directly dispersing the drug in an adhesive polymer & then spreading the medicated adhesive by hot melt, on to a flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer. Example: Isosorbide dinitrate-releasing Transdermal therapeutic system (Frandol tape) for once a day medication of angina pectoris. 49
  48. 48. Fig. Adhesive dispersion type Transdermal drug delivery system 50
  49. 49. Continued… The rate of drug release in this system is defined by… dQ Ka/r Da CR dt ha Where, Ka/r = Partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer. 51
  50. 50. 3. Matrix diffusion – controlled systemsi) It is prepared by homogeneously dispersing the drug particles with a liquid polymer or a highly viscous base polymer followed by cross linking of the polymer chains or homogeneously blending the drug solids with a rubbery polymer at an elevated temp.ii) It can also be prepared by dissolving the drug & polymer in a common solvent followed by solvent evaporation in a mould at an elevated temp. or in a vaccum. It is then pasted on to an occlusive base plate in a compartment fabricated from a drug impermeable plastic backing, the adhesive polymer is then spread along the circumference to form a strip of adhesive rim around the medicated disc. 52
  51. 51. Fig. Matrix diffusion controlled Transdermal drug delivery system 53
  52. 52. Continued… Example: Nitroglycerine-releasing Transdermal system (Nitro- Dur & Nitro- Dur II ) at a daily dose of 0.5 g/cm2 for therapy of angina pectoris. The rate of drug release from this type is given by… dQ ACp Dp 1/2 dt 2t Where, A = Initial drug loading dose dispersed in the polymer matrix. Cp & Dp = Solubility & diffusivity of the drug in the polymer respectively. 54
  53. 53. 4. Microreservoir type or Microsealeddissolution – controlled systems This is the combination of reservoir & 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 & then dispersing the drug suspension homogeneously in a lipophilic polymer such as silicone elastomers by high dispersion technique. Example: Nitroglycerine-releasing Transdermal system (Nitro disc) for once a day therapy of angina pectoris. 55
  54. 54. rimFig. Micro reservoir dissolution-controlled transdermal drug delivery system 56
  55. 55. 5. Poroplastic– type systems It is made utilizing the concept of the water coagulation of cellulose triacetate solution in organic acids at low temp. The coagulation is performed under controlled condition. The water may be exchanged subsequently for another vehicle by a diffusional exchange process, & hence it is also known as “solid composed mostly of liquid.” 57
  56. 56. 6. Transdermal delivery of Macromolecules Macromolecules such as Hormones, interferons, bioactive peptides can be deliver by Transdermal delivery system. The devices used for this purpose are divided in to two categories…. a. Devices based on ethylene vinyl acetate copolymers (EVAc). b. Devices based on silicone elastomers. This both the systems utilize one common concept i.e. matrix must have channels to facilitate the release of macromolecules. These devices are used as implants. 58
  57. 57. Transdermal patch designs Matrix Reservoir Multilaminate Drug in adhesiveBacking Drug Membrane Adhesive Liner / skin
  58. 58. Evaluation of TDDS1. Evaluation of Adhesive :A. Peel adhesion properties:-i) It is the force required to remove an adhesive coating from a test substrate.ii) It is affected by molecular wt. of the adhesive polymer, the type & amount of additives & polymer composition.iii) It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at an angle of 1800, no residue on the substrate indicates ‘Adhesive failure’ signifying a deficit of cohesive Fig. Peel adhesion test for strength in the coating. adhesive evaluation 61
  59. 59. B. Tack properties:- i) It is the ability of polymer to adhere to a substrate with little contact pressure. ii) It is dependent on the molecular wt. & composition of the polymer as well as the use of tackifying resins in the polymer. iii) It includes….a. Rolling ball tack test : It involves the measurement of the distance that a stainless steel ball travels along an upward-facing adhesive, less tacky the adhesive, the further Fig. Rolling ball tack test for the ball will travel. adhesive evaluation 62
  60. 60. b. Quick- stick (peel tack) test : The peel force required tobreak the bond between anadhesive & substrate at 900 ata speed of 12 inch/min. Theforce recorded as the tackvalue & is expressed in ounces(or grams) per inch width withhigher values indicatingincreasing tack. Fig. Quick stick test for adhesive evaluation 63
  61. 61. c. Probe tack test : The force required to pull a probe away from an adhesive at a fixed rate is recorded as tack. (expressed in grams) Probe Force gauge Fig. Probe tack test for adhesive evaluation 64
  62. 62. C. Shear strength properties i) It is affected by molecular wt. as well as the type & amount of tackifieradded. ii) Shear strength is determined bymeasuring the time it takes to pull anadhesive coated tape of stainless steelplate when a specified wt. is hung fromthe tape which pulls the tape in adirection parallel to the plate. Fig. Shear strength test for adhesive evaluation 65
  63. 63. 2. In-vitro drug release evaluation : i) In these studies, excised skin is mounted on skin permeation cells. ii) Skin of hairless mouse is used rather than human cadaver skin. iii) In-vitro system should be designed in such a way that the intrinsic rate of release or permeation which is theoretically independent of the in-vitro design can be accurately determined. iv) Several designs of the in-vitro membrane permeation apparatus are in existence. E.g. Valia-Chien (V-C) cell, Ghannam-Chien (G-C) membrane permeation cell, Jhawer-Lord (J-L) rotating disc cell, Franz diffusion cell & Keshary-Chien (K-C) cell. 66
  64. 64.  Keshary-Chien (K-C) cell : It has an effective receptor volume 12 ml & a skin surface area of 3.14 cm2. The receptor solution is stirred by a star-head magnet rotating at a constant speed of 600 rpm driven by 3 W Synchronous motor. Fig. K-C cell for permeation study 67
  65. 65. 3. In-vivo evaluation :A. Animal models:- The species used for this are mouse, rat, guinea pig, rabbit, hairless mouse, hairless cat, hairless dog, cat, dog, pig, goat, squirrel, monkey, rhesus monkey, chimpanzee. The rhesus monkey is the most reliable model for in-vivo evaluation of TDDS. Standard radio tracer methodology is used . The application site is generally the forearm or abdomen which are less hairy sites on the animals body. The compound is applied after light clipper shaving of the site. 68
  66. 66. B. Human volunteers:-  Procedures for in-vivo evaluation in humans were first described by Feldmann & Mailbach in 1974.  They involve the determination of cutaneous absorption by an indirect method of measuring radioactivity in excreta following topical application of the labelled drug.  This method is used since plasma level following Transdermal administration of a drug are too low to use chemical assay procedure.  The % of dose absorbed transdermally is calculated by… Total radioactivity excreted after topical administration% of dose absorbed = x 100 Total radioactivity excreted after I. V. administration 69
  67. 67.  Various modifications have been made for above method…“Reservoir” technique:- It involves a simple, short exposure of the skin to the compound (radio labelled) under study followed by removal of the striatum corneum by tape striping & analysis of the content of the compound in the striatum corneum. From this it is possible to predict amount of drug that will penetrate over a long period of time. Limitations: i) Invasive nature of the technique due to the tape striping required. ii) The single measurement obtained which does not allow detailed kinetic analysis & the administration of large dose of radioactive material is required. 70
  68. 68. OTHER EVALUATION PARAMETERS2) Thickness .3) Moisture content.4) Folding endurance.5) Tensile strength . Break force ∆L T.S = 1+ L a.b. 71
  69. 69. Advances in TDDS Active Transdermal Systems:- Micro structured Transdermal System (MTS) is a state-of- the-art micro needle system for transcutaneous drug delivery that has potential for providing a drug delivery solution for a wide variety of molecules, including vaccines, proteins and peptides. MTS provides targeted delivery to the dermal/epidermal layers of the skin. Further, MTS has the potential to enhance the efficacy of vaccines while improving the overall delivery efficiency for vaccines, proteins, or peptides. Finally, MTS is an easy-to-use system with the potential to improve health care providers vaccine regimen. 72
  70. 70. 73
  71. 71. Find an appropriate place to put the patch. Choose a dry, unbroken, non-hairy part of your skin. The buttocks, lower abdomen, lower back, and upper arm (outer part) are good choices. If the area you choose has body hair, clip (do not shave) the hair close to the skin with scissors. Make sure that the area is clean. If there is any oil or powder (from bath products, for example), the patch may not stick properly . • A stiff protective liner covers the sticky side of the patch - the side that will be put on your skin. Hold the liner at the edge and pull the patch from the liner. Try not to touch the adhesive side of the patch. Throw away the liner. • Attach the adhesive side of the patch to your skin in the chosen area.
  72. 72. • Press the patch firmly on your skin with the palm of your hand for about 30 seconds. Make sure the patch sticks well to your skin, especially around the edges. If the patch does not stick well, or loosens after you put it on, tape the edges down with first aid tape.• Wash your hands after applying the patch.
  73. 73. References Y. W. Chien, Novel drug delivery systems, 2nd edition, Revised & expanded, Marcel Dekker, Inc., New York, 1992. N. K. Jain, Controlled & Novel drug delivery, CBS Publishers & Distributors, New Delhi, First edition, 1997. Controlled drug delivery devices by Pravin Tyle, Marcel Dekker, Inc., New York, 1992, pg. no. 406 – 408. Mechanisms of Transdermal drug delivery system by Y. W. Chien, Marcel Dekker, Inc., New York. 77
  74. 74. THANK YOU FOR.. 78