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• the rate of drug release from this sytem is defined as
A Cp Dp
Dq/dt = [ ---------------------] 1/2
2t
where
A initial drug loading dose
Cp and Dp are solubility and diffusivity of drug in poymer matrix
the rate of drug release from this system at steady state is defined as
Q/t1/2= [(2A-Cp) Cp Dp] 1/2](https://image.slidesharecdn.com/mpharmtdds-140930003508-phpapp02/85/M-pharm-tdds-25-320.jpg)
Uploaded byMalla Reddy College of Pharmacy
M pharm tdds
The document discusses transdermal drug delivery systems (TDDS), outlining their advantages such as elimination of oral absorption variables and the ability to self-administer. It also details limitations, design factors, and the essential components involved in TDDS including polymers, drug candidates, permeation enhancers, and adhesives. Furthermore, various types of transdermal systems, market products, and evaluation parameters are presented, emphasizing the mechanisms of drug release and application methods.
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M pharm tdds
- 1.
- 2. 2 Transdermal Therapeutic Systems Diffusion of the medication (drug) through skin into the systemic circulation for distribution and therapeutic effect Most TDD systems use passive delivery
- 3. 3 13.1 13.1AAddvvaannttaaggeess ooff TTTTSS’’ss 1. Eliminates oral absorption variables. 2. Eliminates first-pass metabolism 3. Provides controlled constant drug. 4. Can accommodate potent drugs 5. Permits self-administration 6. Non-invasive (no needles or injections) 7. Improves patient compliance 8. Easy treatment termination
- 4. 4 Limitations ofTDD Systems • Poor diffusion of large molecules • Skin irritation
- 5. 5 TDD SystemDesign Factors • Therapeutic indication • Desired drug delivery profile - Dose level, duration, etc. • Skin adhesion profile • Application site • Ease of application • Patch size, shape, appearance, comfort • Wear period • Packaging • Patch disposal • Patch cost
- 6. 6 Process oftransdermal permeation.
- 7. 7 BASIC COMPONENTSOF TDDS 1.Polymer matrix 2.The drug 3.Permeation enhancers 4.Other excipients 1.Polymer matrix Ideal polymer ٠MWT,and chemical functionality of the polymer should not affect the diffusivity of drug and its release ٠stable ٠non reactive ٠easily manufactured ٠easily fabricated into desired product ٠inexpensive ٠degaradation product must be non toxic or non antagonistic to the host ٠ should retain its mechanical properties when the large amount of drug is loaded in to it
- 8. 8 Polymers usedin TDDS • Natural polymers – Cellulose derivatives – Zein – Gelatin – Shellac – Waxes – Proteins – Gums – Natural rubbers – starch • Synthetic elastomers --polybutadiene --hydrin rubber --polysiloxone --silicone rubber --nitrile --acrylonitrile --butyl rubber --styrene butadiene rubber --neoprine etc. • Synthetic polymers PVA,PVC,PE,PP,Poly amide,Poly acrylate,Polyurea,PVP,PMMA,Epoxy etc.
- 9. 9 2. Suitabledrug candidate • Physico chemical properties of drug – Should have MW less than 1000 daltons(800-1000) – Should have affinity for both lipophilic and hydrophilic phases – Should have low melting pont • Biological properties of drug – Should be potent(less than 20mg) – Half life should be short – Must not induce a cutaneous irritant or allergic response – Drugs which degrade in the GI tract or inactivated by hepatic first pass effect are suitable candidate – Tolerance to the drug must not develop – Drugs which has to be administered for a longer period of time can be formulated – Drugs which cause adverse effects to non target tissues can also be formulated
- 10. 10 3.PERMEATION ENHANCERS (to enhance stratum corneum permeability) • Solvents Increases penetration by swelling the polar pathway transport or fluidising lipids Eg.water,ethanol,methanol,DMS,homologs of methyl sulphoxide,dimethyl acetamide,and DMF,2-pyrrolidone,N-methyl,2- pyrrolidone,laurocapram,PG,glycerol,silicone fluids,isopropyl palmitate. • Surfactants Enhances the polar pathway transport of hydrophilic drugs • Anionic surfactants Dioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc. • Non ionic surfactants Pluronic F127,Pluronic F68,etc. • Bile salts Sodium taurocholate,sodium deoxy cholate,sodium tauroglycocholate. • Binary systems Propylene glucol-oleic acid and 1,4-butane diol-linoleic acid • Miscellaneous Urea-hydrating and keratolytic agent,N,N-dimethyl-m-toluamide,calcium thioglycolate,anti cholinergic agents • Potential permetion enhancers Euclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein
- 11. 11 Permeability CoefficientIs the Critical Predictor of Transdermal Delivery Transport = Flux = (mg/cm2/sec) = P x A x (Cd – Cr) Permeability Coefficient = P = D x K (cm/sec) h Where A = Surface area of patch D = Diffusivity of drug in membrane (skin) K = Partition coefficient (patch/skin) C = Concentration in donor or receptor (patch or skin) h = Thickness of membrane (skin)
- 12. 12 4.OTHER EXCIPIENTS • Adhesives Ideal properties • Should not irritate or sensitize the skin or affect normal functions of the skin • Should adhere to the skin aggressively • Should be easily removed • Should not leave an un washable residue on the skin • Should have an intimate contact with the skin • Should be compatible with the drug,excipients and permeation enhancers • Permeation of drug should not be affected • Backing membrane Ideal properties • Flexible and provide good bond to the drug reservoir • Prevent drug from leaving the dosage form • Should be impermeable • E.g.metallic plastic laminate,plastic backing with absorbent pad and occlusive base plate,adhesive foam pad with occlusive base plate.
- 13. • Liner: Protectsthe drug during storage and is removed prior to use • Drug • Adhesive: Serves to bind the components of the patch to the skin • Membrane: Controls the release of the drug from the reservoir in certain types of patches • Backing: Protects the patch from the outer environment. 13
- 14. 14 Formulation ofTDDS 1.Membrane-moderated or permeation controlled TDDS • Drug reservoir(homogenous dispersion of drug with polymeric matrix or suspension of drug in un leachable viscous liquid medium such as silicone fluid) is encapsulated within drug impermeable metallic plastic laminate and a rate controlling polymeric membrane(ethylene vinyl acetate co polymer) • The cross sectional view of this system is shown in the following Fig.1
- 15. 15 Reservoir Patches • The reservoir system has a drug layer that is separate from the adhesive.
- 16. 16 Schematic Drawingof the Reservoir type of patch. Film Backing Drug Layer Rate-controlling Membrane Contact Adhesive Protective Peel Strip (removed prior to use) skin
- 17. 17 • Drugmolecule are permitted to release through this rate controlling membrane • A thin layer of silicone or poly acrylate adhesive may be applied to the external surface of the rate controlling membrane to achieve intimate contact of the TDDS and the skin surface • Release rate of this TDDS depends upon the polymer composition,permeability co efficient and thickness of the rate cotrolling membrane and adhesive • The intrinsic rate of drug release from this TDDS is calculated by the following formula.1 CR dQ/dt= -------------------- 1/Pm+1/Pa
- 18. 18 Where CR-con.ofdrug in the reservoir compartment Pm-permeability co efficient of rate controlling polymeric membrane Pa- permeability co efficient of adhesive For microporous membrane Km/r. Dm Pm = -------------------- hm Ka/m. Da Pa = -------------------- ha Substituting these values in formula.1, it becomes Km/r .Ka/m .Dm.Da dQ/dt= ---------------------------------------------CR Km/r. Dm.ha + Ka/m. Da. hm
- 19. 19 Where •Km/r --partition co-efficient of drug between membrane and reservoir • Ka/m --partition co-efficient of drug between adhesive and membrane • Dm --diffusion co-efficient of drug in the membrane • Da -- diffusion co-efficient of drug in the adhesive Example of this system are 1.Nitro glycerin releasing TDDS (Transderm-Nitro/ciba,USA)for once a day medication in angina pectoris 2.Scopolamine releasing TDDS (Transderm-Scop/ciba,USA)for 72 hrs.prophylaxis of motion sickness 3. Estradiol releasing TDDS (Estraderm/ciba)for treatment of menopausal syndrome 4. Clonidine releasing TDDS (Catapres/Boehringer Ingelheim)for 7 day therapy of hyper tension 5. Prostaglandin-derivatives TDDS
- 20. 20 2.Adhesive diffusion/dispersion-controlled TDDS Drug reservoir • homogenous dispersion of drug with adhesive polymer(poly(isobutylene) or poly acrylate) • Then spreading of this medicated adhesive polymer on flat sheet of drug impermeable metallic plastic backing to form thin drug reservoir layer • On top of the drug reservoir layer,thin layers of rate controlling adhesive polymer of specific permeability and constant thickness are applied to produce an adhesive diffusion/dispersion-controlled TDDS • The cross sectional view of this system is shown in the following Fig.2
- 21. 21 Drug inAdhesive Patches • A system in which the drug is incorporated directly into the adhesive, rather than into a separate layer. Usually used for smaller molecular weight compounds. • These can be either a single layer or multi-layer. • Sometimes referred to as the “matrix type patch”
- 22. 22 Schematic Drawingof the Matrix (Drug-in-Adhesive) type of patch. Film Backing Drug/Adhesive Layer Protective Liner (removed prior to use) skin
- 23. 23 • Therate of drug release in this system is defined by Ka/r.Da dQ/dt= -----------------CR ha Where Ka/r-partition co-efficient of drug bw adhesive layer and reservoir layer Da-diffusion co-efficient of drug in the adhesive layer ha-thickness of adhesive layer Examples for this system 1.Iso sorbide dinitrate-releasing TDDS 2.Verapamil releasing TDDS
- 24. 24 • 3.Matrixdiffusion-controlled TDDS Drug reservoir • homogenous dispersion of drug with hydrophilic or lipophilic polymer matrix by any one of the following methods • Homogenous dispersion of finely ground drug particles with liquid polymer or highly viscous base polymer followed by cross linking of polymer chains • Homogenous mixing of drug solid with rubbery polymer at an elevated temperature • Dissolving the drug and polymer in a common solvent follwed by solvent evaporation in a mould at an elevated temperature or under vaccum. • Medicated polymer is moulded in to desired surface area and controlled thickness • This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing • Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc
- 25. 25 • therate of drug release from this sytem is defined as A Cp Dp Dq/dt = [ ---------------------] 1/2 2t where A initial drug loading dose Cp and Dp are solubility and diffusivity of drug in poymer matrix the rate of drug release from this system at steady state is defined as Q/t1/2= [(2A-Cp) Cp Dp] 1/2
- 26. 26 Example ofthis system are 1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key pharmaceuticals,USA) 2. Estradiol di acetate releasing TDDS 3. Verapamil releasing TDDS The cross sectional view of this system is shown in the following Fig.3
- 27. 27 4.Micro reservoirtype/micro sealed dissolution-controlled TDDS Combination of the reservoir and matrix diffusion Drug reservoir •suspension of drug with aqueous solution of water soluble liquid polymer •Homogenous dispersion of drug suspension in a lipophilic polymer(silicone elastomer) •As a result discrete un leachable microscopic spheres of drug reservoir is formed which is stabilized by cross linking •Medicated polymer is moulded in to desired surface area and controlled thickness and it is coated with a layer of bio compatible polymer to modify mechanism and rate of drug release •This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing •Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc Example of this system are 1.Nitro glycerin releasing TDDS (Nitrodisc /searle,USA) The cross sectional view of this system is shown in the following Fig.4
- 28.
- 29. Products on themarket, or in development include: • Clonidine • Works as an agonist of adrenaline at the presynaptic a2 adrenergic • Product name = Catapres-TTS® • used to treat hypertension 29
- 30. 30 • Ethinylestradiol(EO) and norelgestromin (N) • Product name = Ortho-Evra® • Used for Contraception • Type of patch = Drug-in-Adhesive • Frequency of application = weekly
- 31. 31 • Fentanyl • Product Name = Duragesic® • Used for: Analgesia • Type of Patch = Drug-in-Adhesive • Frequency of Application = Weekly
- 32. 32 • Lidocaine • Product Name = Lidoderm® • Used for: analgesia of postheretic neuralgia (PHN), a painful condition caused by the varicella zoster virus (herpes zoster = shingles) • Type of Patch = Reservoir • Frequency of Application = Daily
- 33. 33 • Nicotine • Product name = Habitrol®, Nicoderm – CQ®, Nicotrol®, Prostep® • Used for: Smoking cessation • Frequency of administration = Daily
- 34. • Nitroglycerin •Works by producing nitric oxide (NO), which then acts as a vasodilator • Product Names = Nitro-Dur®, Transderm-Nitro® • Used for: Angina • Type of Patch = Nitro-Dur is Drug-in-adhesive 34 Nitrodisc is reservoir • Frequency of administration = Daily
- 35. 35 • Estradiol • Product Name = Alora®, Climara®, Esclim®, Estraderm®, FemPatch®, Vivelle®, Vivelle-DOT® • Used for: Hormone replacement • Type of Patch: Drug-in-adhesive • Frequency of application = weekly
- 36. 36 • Estradiol+ Norethindrone • Product name = CombiPatch® • Used for: Hormone Replacement
- 37. 37 • Oxybutynin • Works as competitive antagonist of the muscarinic acetycholine receptor • Product name = Oxytrol® • Used for: Overactive bladder (antispasmodic) • Type of Patch: Drug-in-adhesive • Frequency of application = twice a week
- 38. • Scopolamine •Works as competitive antagonist of acetylcholine at the muscarinic receptor • Product Name = Transderm Scop® • Used for: Motion Sickness 38
- 39. 39 • Testosterone • Product Names = Androderm®, Testoderm TTS®, Testoderm® • Used for: Hypogonadism
- 40. • Lidocaine +Epinephrine • Product name = Lidosite • Used for: Dermal anesthesia • Type of Patch = Reservoir, iontophoretic. Epinephrine acts as vasoconstrictor, thus prolonging the duration of action of lidocaine (by delaying resorption) at the site 40
- 41. Manufacturer Trade nameDrug Strength available 41 Ciba Estraderm Estradiol 25 μg, 50 μg, 100 μg Transderm-Scop Scopolamine 1.5 mg Transderm-Nitro Nitroglycerin 0.1 mg, 0.2 mg Janssen Duragesic Fentanyl 25 μg, 50 μg, 100 μg Basel Habritol Nicotine 21 μg Parke-Davis Nicotrol Nicotine 21 μg Lederle Prostep Nicotine 21 μg
- 42. 42 TTS Availablein market Large scale mfg of TTS
- 43. 43 Evaluation Parameters Physical parameters Evaluation of adhesive In-vitro testing In-vivo assessment Cutaneous metabolism Stability studies Evaluation of skin reactions. 09/30/14 43
- 44.
- 45. 45 Weight variation 09/30/14 45
- 46. 46 Folding endurance 09/30/14 46
- 47. 47 Moisture content % Moisture content = Initial weight – Final weight X 100 Final weight 09/30/14 47
- 48. 48 Moisture uptake % moisture uptake = Final weight – Initial weight X 100 Initial weight 09/30/14 48
- 49. 49 Flatness %constriction = I1 – I2 X 100 I1 I2 = Final length of each strip I1 = Initial length of each strip 09/30/14 49
- 50. 50 Drug content 09/30/14 50
- 51. 51 Water VaporTransmission studies 09/30/14 51
- 52. 52 Evaluation ofadhesive 1} Peel adhesion properties It is the force required to remove adhesive from test substrate. 09/30/14 52
- 53. 53 2} Tackproperties It is the ability of the polymer to adhere to substrate with little contact pressure. 2.1} Thumb tack test 2.2} Rolling ball tack test 09/30/14 53
- 54. 54 2.3}Quick-stick (orpeel-tack) test 09/30/14 54
- 55. 55 2.4} Probetack test 09/30/14 55
- 56. Shear strength isthe measurement of the cohesive strength of adhesive polymer. 56 3} Shear strength properties 09/30/14 56
- 57. 57 Tensile strength Tensile strength= F/a.b (1+L/l) F - the force required to break a - width of film b - thickness of film L - length of film l - elongation of film at break point 09/30/14 57
- 58. 58 In-vitro testing The Paddle over Disc The Cylinder modified USP Basket The reciprocating disc Diffusion Cells e.g. Franz Diffusion Cell and its modification Keshary- Chien Cell 09/30/14 58
- 59. 59 In-vitro testing Importance (1)Defining skin permeation kinetic studies using a diffusion cell system and cadaver skin during the drug development process. (2) in vitro drug release kinetics, to be used for batch-to- batch release and as a compendial test. 09/30/14 59
- 60. Preparation of skinfor permeation studies • Intact Full thickness skin • Separation of epidermis from full thickness skin: 60
- 61. 61 K-C cellfor permeation studies 09/30/14 61
- 62.
- 63. Effect of skinuptake metabolism 63
- 64. 64 In-vivo assessment 1} Animal model Mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig 09/30/14 64
- 65. 65 In-vivo assessment 2} Human model . Phase I clinical trials are conducted to determine mainly safety in volunteers. Phase II clinical trials determine short term safety and mainly effectiveness in patients. Phase III trials indicate the safety and effectiveness in large number of patient population. Phase IV trials at post marketing surveillance are done for marketed patches to detect adverse drug reactions. 09/30/14 65
- 66. Skin irritation studies • Group I was served as normal, without any treatment. • Group II, control, was applied with marketed adhesive tape. • Group III Transdermal systems (blank) • Group IV Transdermal systems (drug loaded) • Group V standard irritant . 66 Contact dermatitis
- 67. 67 Evaluation ofskin reactions. 09/30/14 67
- 68. 68 Stability studies 09/30/14 68
- 69. Study Storage conditionsTime period Temperature Relative humidity Long Term 25°C± 2°C OR 30°C± 2°C 60%± 5% OR 65%± 5% 12 months Intermediate 30°C± 2°C 65%± 5% 6 months Accelerated 40°C± 2°C 75%± 5% 6 months 69
- 70.
- 71. 71 The Past • 3000 BC--Pharmaceuticals and plasters first recorded in Babylonia. • 1500 BC--Plasters recorded in the Ebers Papyrus (Egypt). • Plasters made by physicians or pharmacists at the time of dispensing 09/30/14 71
- 72. 72 The Past P Plasters, Poouullttiicceess aanndd CCeerraatteess • Used for topical and deep tissues • Counterirritants, protective dressings, belladonna, salicylic acid, flaxseed, mustard, • Adhered to skin with stiff ointments, waxes, melted waxes and rubber resins, kaolin • Applied hot, could absorb water • Backings made of cloth or animal skin 09/30/14 72
- 73. 73 The Past:Adhesives Example of plaster formula (1909) Rubber 20 grams Petrolatum 20 grams Lead Plaster 960 grams To make, 1000 grams Add any one of the following Belladonna Leaves, Oleoresin of Capsicum, Mercury, Opium, Soap 09/30/14 73
- 74. The Past Thelast 150 years: • Electrically assisted applications first occurred in late 1800s and in early 1900s. • Rubber became available in the 1800s • Nitroglycerin was applied topically as an ointment for delivery to the bloodstream in the 1950 to present. • Belladonna, capsicum, mustard and salicylic acid plasters 74 09/30/14 74
- 75. 75 The PresentDay • 1970-- Alza Research (US) began first development of the modern transdermal • 1980-- Scopolamine first transdermal reached US • 2002– Many Rx and non-RX products in US market. • Transdermals deliver drugs from a few hours up to 7 days. 09/30/14 75