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TRANSDERMAL DRUG    DELIVERY               Arya Soman         first year M.Pharm
Content•   Anatomy of skin•   Mechanism of skin permeation•   TDDS•   Advantages & disadvantages•   Factors affecting skin...
ANATOMY OF SKIN• Skin is a multilayered organ• It is composed of three tissue layers mainly   The epidermis    The dermi...
Basic diagram of skin structure.                                   4
• Outer layer of the skin• Composed of stratified squamous epithelial cells. These are held    together mainly by highly c...
DERMIS• It is composed of network of collagen & elastic fibers  embedded in a mucopolysaccharide matrix, which  contain bl...
SUBCUTANEOUS TISSUE• This is a sheet of fat containing areolar tissue, known as superficial fascia, attaching the dermis t...
MECHANISM OF SKIN                   PERMEATION• It consist of series of step in sequence…            Sorption of a parente...
Process of transdermal permeation.                                     9
TRANSDERMAL DRUG DELIVERY         SYSTEM• Transdermal drug delivery is defined as self contained, discrete dosage forms wh...
ADVANTAGES OF TDDS1.   Avoidance of significant presystemic metabolism & the need     therefore a lower daily dose.2.   Re...
DISADVANTAGES1. It is limited only to potent drug molecule.2. Pharmacokinetic & pharmacodynamic characteristics of    the ...
FACTORS AFFECTING SKIN PERMEATION– Age– Physicochemical properties of penetrant (pKa, molecular size,   stability, binding...
DESIGN OF TRANSDERMAL           SYSTEM The components are :1. Polymer matrix2. The drug3. Enhancers4. Excipients          ...
15
1.POLYMER MATRIX• They are film or membrane with or without micro pores & consist of     gelatin, gum acacia, ethyl cellul...
• The selection of polymer depends oni.    Proper diffusion & release of drug.ii.   Compatibilityiii. Non toxiciv.   Stabi...
2. DRUG•    Judicious choice of drug.•    The important drug properties that affect its diffusion     from devices as well...
It is generally accepted that the best drug candidates for  transdermal patches must be :• Non ionic• Low molecular weight...
• The drug should be non irritating & non allergic to human     skin.• The main factors that control drug absorption are1....
3. EXCIPIENTS & ENHANCERS•    It is an integral part of most of the transdermal formulation     because of the barrier pro...
3. Surface-active agents :enhance the permeation of hydrophilic  drugs• In commercially available transdermal products, us...
4. ADHESIVES & PACKAGING• pressure sensitive polymeric adhesive .• The adhesive system should posses following characteris...
5.BACKING MEMBRANE It is an impermeable membrane that protect the  product during the use on the skin & prevent the drug ...
6.RELEASE LINER• During storage the patch is covered by a  protective liner that is removed & discharged  immediately befo...
TECHNOLOGIES FOR DEVELOPING    TRANSDERMAL DELIVERY• Based on the components the delivery systems could be  essentially be...
1.MEMBRANE MODERATED TDDS     [RESERVOIR TYPE]• The drug reservoir is encapsulated in a shallow  compartment moulded from ...
Drug mixed with polymer       solution    Drug suspended in    polymer solution    Volume controlled  injection pump syste...
• The rate of drug release from this type of  TDDS can be tailored by varying the polymer  composition, permeability coeff...
30
• The intrinsic rate of drug release from this type  of systems is defined as following:                                  ...
2.ADHESIVE DISPERSION TYPE               TDDS•   It is the simplified form of membrane moderated drug delivery system•   I...
33
• The drug reservoir layer is then covered by a  non medicated rate controlling adhesive  polymer of constant thickness to...
3.MATRIX DIFFUSION CONTROLLED TDDS           [MONOLITHIC DEVICE]• It is formed by homogenously dispersing the drug in a mi...
36
• The adhesive polymer is applied along the  circumference to form an adhesive rim around  the medicated disc.• The rate o...
MICRORESERVOIR TYPE TDDS• It has features of both reservoir & matrix dispersion  type drug delivery system.• The drug rese...
39
40
EVALUTION OF TDDS• It is evaluated by using a 2 – compartment diffusion cell  assembly under identical conditions.• It is ...
• Franz – diffusion cell is being commercialized & widely employed  for studying the skin permeation profile by finite dos...
• The drug delivery systems are then applied with their drug releasing   surface being in intimate contact with the stratu...
OPTIMIZATION OF TDDS• To formulate a TDDS one should take into consider:        The rate of drug delivery to the skin sur...
• A TDDS should ideally be designed to have a skin  permeation rate determined the rate of drug  delivery from the TDDS , ...
• The rate of transdermal permeation of a  drug at steady state (Rp)ss is  mathematically related both i.e..., the  actual...
ADVANCES IN TRANSDERMAL CONTROLLED DRUG DELIVERY RESEARCH• Transdermal rate controlled drug delivery offers  the following...
3. Permit continuous drug administration & the use of   drugs with a short biological half lifes.4. Increase the bioavaila...
5.   Provide a simplified therapeutic regime leading to better patient     compliance.6.   Permit a rapid termination of t...
50
Table 1 Transdermal Controlled-        Release Products and DevicesDrug             Trade Name      Type of Devices Indica...
Table 2 transdermal products under              developmentDrug            Trade name   Producer-MarketerMinocycline     S...
REFERRENCE• Controlled drug delivery by Lee, 2nd edition  revised & expanded.• Textbook of pharmaceutics by Aulton 2nd  ed...
THANK        YOU              54
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Transcript of "Transdermal drug delivery"

  1. 1. TRANSDERMAL DRUG DELIVERY Arya Soman first year M.Pharm
  2. 2. Content• Anatomy of skin• Mechanism of skin permeation• TDDS• Advantages & disadvantages• Factors affecting skin permeation• Design of TDDS• Technologies for developing TDDS• Kinetic evaluation of TDDS• Optimization of TDDS• Advance in TDDS researches. 2
  3. 3. ANATOMY OF SKIN• Skin is a multilayered organ• It is composed of three tissue layers mainly The epidermis The dermis Subcutaneous fat tissue 3
  4. 4. Basic diagram of skin structure. 4
  5. 5. • Outer layer of the skin• Composed of stratified squamous epithelial cells. These are held together mainly by highly convoluted interlocking bridges which are responsible for the unique integrity of skin . Microscopic section of epidermis shows two main parts mainly 1.Stratum corneum 2.Stratum germinativum 5
  6. 6. DERMIS• It is composed of network of collagen & elastic fibers embedded in a mucopolysaccharide matrix, which contain blood vessels, lymphatic & nerve endings, there by providing physiological support for epidermis 6
  7. 7. SUBCUTANEOUS TISSUE• This is a sheet of fat containing areolar tissue, known as superficial fascia, attaching the dermis to underlying structure. 7
  8. 8. MECHANISM OF SKIN PERMEATION• It consist of series of step in sequence… Sorption of a parenteral molecule on to the surface layers of stratum corneum Diffusion through it & viable epidermis & finally at the papillary layers of dermis The molecule is taken up into the microcirculation for subsequent systemic distribution The viable tissue layers & the capillaries are relatively permeable & the peripheral circulation is sufficiently rapid so that for the great majority of penetrant, diffusion through the stratum corneum is often the rate limiting step 8
  9. 9. Process of transdermal permeation. 9
  10. 10. TRANSDERMAL DRUG DELIVERY SYSTEM• Transdermal drug delivery is defined as self contained, discrete dosage forms which, when applied to the intact skin, deliver the drug, through the skin at controlled rate to the systemic circulation. Transdermal drug delivery system (TDDS) established itself as an integral part of novel drug delivery systems. 10
  11. 11. ADVANTAGES OF TDDS1. Avoidance of significant presystemic metabolism & the need therefore a lower daily dose.2. Recent inter & intra patient variability.3. Drug input can be terminated simply by removal of patch.4. Drug levels can be maintained in the systemic circulation, with in the therapeutic window for a prolonged period of time.5. Thus the duration of drug action can be extended & frequency of dosing is decreased.6. Improved patient compliance & acceptability of the drug therapy. 11
  12. 12. DISADVANTAGES1. It is limited only to potent drug molecule.2. Pharmacokinetic & pharmacodynamic characteristics of the drug must be such that relatively sustained & slow input provided by transdermal delivery produces desirable therapeutic effect.3. Drugs with short biological half lifes that are subject to large first pass metabolism.4. Drugs must not be locally irritating or sensitizing. 12
  13. 13. FACTORS AFFECTING SKIN PERMEATION– Age– Physicochemical properties of penetrant (pKa, molecular size, stability, binding affinity, solubility, partition coefficient)– Integrity and thickness of stratum corneum– Density of sweat glands and follicles– Skin hydration– Metabolism– Vehicle effects 13
  14. 14. DESIGN OF TRANSDERMAL SYSTEM The components are :1. Polymer matrix2. The drug3. Enhancers4. Excipients 145. Adhesive
  15. 15. 15
  16. 16. 1.POLYMER MATRIX• They are film or membrane with or without micro pores & consist of gelatin, gum acacia, ethyl cellulose, starch, shellac, natural rubber, neoprene, polystyrene, pvp…….• The polymer must fulfill the following requirements.1. It must allow the diffusion of drug substance at desirable rates.2. It should be an inert drug carrier.3. It must not decompose on storage or during the life of the device.4. The polymer and its decomposed products should not be toxic5. The cost of polymer should not be excessively high6. The polymer must be easy to manufacture & fabricate into the desired 16 products.
  17. 17. • The selection of polymer depends oni. Proper diffusion & release of drug.ii. Compatibilityiii. Non toxiciv. Stability on storagev. Cost of storage• The polymer which are most widely used in TDDS :a. Polypropylene. f. Polyethylene terphthalateb. Poly vinyl carbonate g. Hydroxypropyl cellulosec. Cellulose acetate nitrate h. polyesterd. Polyacrylonitrile i. EVA poymere. Ethylene vinyl acetate {EVAc} copolymer 17
  18. 18. 2. DRUG• Judicious choice of drug.• The important drug properties that affect its diffusion from devices as well as across the skin include:a. Molecular weightb. Chemical functionalityc. Physical properties 18
  19. 19. It is generally accepted that the best drug candidates for transdermal patches must be :• Non ionic• Low molecular weight{less than 500 Dalton}• Adequate solubility in oil & water• Low melting point{less than 200ºc}• Potent{dose is less than 50 mg per day &ideally less than 10 mg per day} 19
  20. 20. • The drug should be non irritating & non allergic to human skin.• The main factors that control drug absorption are1. Solubility2. Partition coefficient3. Particle size4. Diffusion coefficient5. Ionized or unionized form 20
  21. 21. 3. EXCIPIENTS & ENHANCERS• It is an integral part of most of the transdermal formulation because of the barrier properties of stratum corneum.• The penetration enhancers have been classified broadly into 3 main categories:1. Lipophilic solvent : increases the permeation of lipophilic drugs eg. Dimethyl sulfoxide2. Two component system : mainly composed of oleic acid & propylene glycol. The system affect the multilaminate 21 hydrophilic layers as well as the continuous path of skin.
  22. 22. 3. Surface-active agents :enhance the permeation of hydrophilic drugs• In commercially available transdermal products, use of enhancers is not indicated, however many excipients may be additionally incorporated which could facilitate & support the permeation. They include : Propylene glycol Glycerol Ethanol Silicone fluids Isopropyl palmitate 22
  23. 23. 4. ADHESIVES & PACKAGING• pressure sensitive polymeric adhesive .• The adhesive system should posses following characteristics:1. It should not cause an irritation, sensitization or imbalance in the normal skin flora.2. It should adhere to the skin strongly & should be easily removable without leaving any unwashable remains.3. It should have intimate contact with the skin at both macroscopic & microscopic levels. 23
  24. 24. 5.BACKING MEMBRANE It is an impermeable membrane that protect the product during the use on the skin & prevent the drug from leaving the dosage form through the top. It contain formulation through out the shelf life & during wear period. Must be compatible with formulation. eg: metallic plastic laminate, plastic backing with adsorbent pad adhesive foam pad. 24
  25. 25. 6.RELEASE LINER• During storage the patch is covered by a protective liner that is removed & discharged immediately before the application of the patch to the skin.• It is there fore regarded as a part of primary packing material rather than a part of dosage form for delivering the drug. 25
  26. 26. TECHNOLOGIES FOR DEVELOPING TRANSDERMAL DELIVERY• Based on the components the delivery systems could be essentially be classified as :a) Membrane moderatedb) Adhesive diffusion controlledc) Matrix dispersion typed) Micro reservoir type 26
  27. 27. 1.MEMBRANE MODERATED TDDS [RESERVOIR TYPE]• The drug reservoir is encapsulated in a shallow compartment moulded from a drug impermeable metallic – plastic lamination whilst the drug delivery side is covered by controlling polymeric membrane.• The drug molecules are released only through the rate controlling membrane. 27
  28. 28. Drug mixed with polymer solution Drug suspended in polymer solution Volume controlled injection pump system Molding as TDDS using primary packing material Packing machinery usingsecondary packing material Transdermal therapeutic system 28
  29. 29. • The rate of drug release from this type of TDDS can be tailored by varying the polymer composition, permeability coefficient & thickness of the rate controlling membrane. 29
  30. 30. 30
  31. 31. • The intrinsic rate of drug release from this type of systems is defined as following: 31
  32. 32. 2.ADHESIVE DISPERSION TYPE TDDS• It is the simplified form of membrane moderated drug delivery system• It is prepared by directly dispensing the drug in an adhesive polymer & then spreading the medicated adhesive by solvent film casting method over a flat sheet of drug impermeable metallic or plastic backing membrane, this forms a thin drug reservoir layer. 32
  33. 33. 33
  34. 34. • The drug reservoir layer is then covered by a non medicated rate controlling adhesive polymer of constant thickness to produce an adhesion diffusion controlling drug delivery system.• The rate of drug release is defined by: 34
  35. 35. 3.MATRIX DIFFUSION CONTROLLED TDDS [MONOLITHIC DEVICE]• It is formed by homogenously dispersing the drug in a mixture of hydrophilic – Lipophilic polymer{matrix} & the medicated polymer is moulded on the medicated disc of defined surface area & thickness .• It is then glued over an occlusive base plate consisted of compartment fabricated using an impermeable plastic backing. 35
  36. 36. 36
  37. 37. • The adhesive polymer is applied along the circumference to form an adhesive rim around the medicated disc.• The rate of drug release from this type of TDDS is defined as follows: 37
  38. 38. MICRORESERVOIR TYPE TDDS• It has features of both reservoir & matrix dispersion type drug delivery system.• The drug reservoir is formed by suspending the drug solid in an aq. Solution of water soluble polymer.• The drug suspension is dispersed homogenously in a Lipophilic polymer, by high shear mechanical agitation to form thousands of unleachable microspheres of drug. 38
  39. 39. 39
  40. 40. 40
  41. 41. EVALUTION OF TDDS• It is evaluated by using a 2 – compartment diffusion cell assembly under identical conditions.• It is carried out by mounting the freshly excised skin from either human or hairless mouse on diffusion cell assembly. 41
  42. 42. • Franz – diffusion cell is being commercialized & widely employed for studying the skin permeation profile by finite dosing technique.• The full thickness abdominal skin freshly excised from either human cadaver or hairless mouse is mounted between the donor & receptor compartment . 42
  43. 43. • The drug delivery systems are then applied with their drug releasing surface being in intimate contact with the stratum corneum surface of the skin.• The permeation profile of the drug is assessed by sampling the receptor solution at predetermined intervals for definite duration & assessing the drug concentration in the sample using a sensitive analytical method.• The release profile can also be investigated by using the same experimental setup with out skin. 43
  44. 44. OPTIMIZATION OF TDDS• To formulate a TDDS one should take into consider: The rate of drug delivery to the skin surface Rate of skin absorption of the drug.• This is particularly important because of stratum corneum is known to be highly permeable to most drugs. 44
  45. 45. • A TDDS should ideally be designed to have a skin permeation rate determined the rate of drug delivery from the TDDS , not by the skin permeability to the drug to be delivered.• In such a case, transdermal bioavailability of a drug become less dependent upon the intra & or inter – patient variability in the skin permeation. 45
  46. 46. • The rate of transdermal permeation of a drug at steady state (Rp)ss is mathematically related both i.e..., the actual rate of drug delivery from a TDDS (Rd)a to the skin surface & to maximum achievable rate of skin absorption (Ra)m by the following equation 46
  47. 47. ADVANCES IN TRANSDERMAL CONTROLLED DRUG DELIVERY RESEARCH• Transdermal rate controlled drug delivery offers the following potential biomedical benefits :1. Avoid the risks & inconveniences of i.v therapy.2. Bypass the variation in the absorption & metabolism associated with oral administration. 47
  48. 48. 3. Permit continuous drug administration & the use of drugs with a short biological half lifes.4. Increase the bioavailability & efficacy of drugs through the bypass of hepatic first pass elimination.5. Decrease the chance of over or under dosing through the prolonged, preprogrammed delivery of drug at the required therapeutic rate. 48
  49. 49. 5. Provide a simplified therapeutic regime leading to better patient compliance.6. Permit a rapid termination of the medication, if needed , by simply removing the TDDS from the skin surface.7. The intensity of interest in the potential biomedical applications of rate controlled transdermal drug administration has been demonstrated by a substantial increase in the R & D activities in many health care institutions aiming to develop viable TDDS for the prolonged continuous transdermal infusion of therapeutic agent 49
  50. 50. 50
  51. 51. Table 1 Transdermal Controlled- Release Products and DevicesDrug Trade Name Type of Devices IndicationScopolamine Transderm-Scop Reservoir Motion sicknessNitroglycerine Transderm-Nitro Reservoir Angina Nitro-Dur Monolithic Nitrodisc MonolithicEstradiol Estraderm Reservoir and Hormone ethanol treatment enhancer 51
  52. 52. Table 2 transdermal products under developmentDrug Trade name Producer-MarketerMinocycline Sunstar American Cyanamide, TakedaEstradiol+Noret Estracombi Ciba-Geigy, Alzahisterone TISDHEA PharmedicFentanylTriamcinolone Whitby Pharm.acetonide 52
  53. 53. REFERRENCE• Controlled drug delivery by Lee, 2nd edition revised & expanded.• Textbook of pharmaceutics by Aulton 2nd edition.• Novel drug delivery by Y.M.Chein, 2nd edition.• www.google.com 53
  54. 54. THANK YOU 54
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