Transdermal drug delivery system

TRANSDERMAL DRUG DELIVERY SYSTEM : 

TRANSDERMAL DRUG DELIVERY SYSTEM PRESENTED BY Parmar Krutin D. M. PHARM, 3 rd SEM.(PHARMACEUTICS) N.D.D.S.-II C.C.P.R. 1

CONTENT Introduction Trasdemal permeation Advantages of TDDS Limitations of TDDS Basic components of TDDS Different approches of TTDS Evaluations Marketed products Conclusion : 

CONTENT Introduction Trasdemal permeation Advantages of TDDS Limitations of TDDS Basic components of TDDS Different approches of TTDS Evaluations Marketed products Conclusion 2

Slide 3: 

INTRODUCTION Transdermal drug delivery systems (TDDS), also known as ‘‘patches,’’ are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin . An ideal dosage form would be maintaining the drug concentration in the blood at a constant level nearly coinciding with the Minimum Effective Concentration (MEC) of drug throughout the treatment period. This leads to the concept of the controlled drug delivery. The primary objective of controlled drug delivery is to ensure safety and efficacy of the drugs as well as patients compliance. 3

Slide 4: 

To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and polymer are required. TDDS a realistic practical application as the next generation of drug delivery The future of transdermal drug delivery is the development of skin pretreatment methods & combination devices . 4

Slide 5: 

ADVANTAGES Avoid the risk and inconvenience of intravenous therapy No gastrointenstinal degradation Substitute for oral administration of medication when that route is unsuitable as with vomiting and diarrhea. Extended therapy avoiding frequent dose administration. Controlled drug delivery for a longer time. Reduces the chance of over and under dosing through the prolonged preprogrammed delivery of drug at the required therapeutic rate. Better patient compliance 5

Slide 6: 

Rapidly termination possible when needed simply by removing the patch from the skin surface. Ability to modify the properties of the biological barrier to absorption (Penetration Enhancement). Relatively large area (1-2m 2 ) of application in comparison with the buccal or nasal cavity. Easily and rapidly identified in emergencies 6

Slide 7: 

LIMITATIONS Limited skin permeability Restricted to potent drug Cannot use for large molecule (>500 Dalton) Significant lag time Skin irritation and allergic response Tolerance inducing drugs or those (e.g., hormones) requiring chronopharmacological management are not suitable candidates 7

Slide 8: 

Transdermal Permeation Skin is the most intensive and readily accessible organ of the body as only a fraction of millimeter of tissue separates its surface from the underlying capillary network. The various steps involved in transport of drug from patch to systemic circulation are as follows: Diffusion of drug from drug reservoir to the rate controlling membrane. Diffusion of drug from rate limiting membrane to stratum corneum . Sorption by stratum corneum and penetration through viable epidermis. Uptake of drug by capillary network in the dermal papillary layer. 8

Slide 9: 

9

Slide 10: 

ROUTES FOR DRUG PENETRATION THROUGH SKIN (A) MACROROUTE SWEAT DUCT ACROSS STRATUM CORNEUM HAIR FOLLICLES 10

Slide 11: 

(B) MICROROUTE INTERCELLULAR (TORTOUS PATHWAY) TRANSCELLULAR 11

Slide 12: 

12

Slide 13: 

IDEAL DRUG CANDIDATE FOR TDD : Must be non-ionic Low molecular weight (less than 500 Daltons) Have adequate solubility in oil and water (log P: 1-3) Low melting point (less than 200 degree C) Dose is less than 50 mg per day, and ideally less than 10 mg per day. 13

Slide 14: 

CLASSIFICATION OF TDDS : DRUG IN ADHESIVE SYSTEM MATRIX DISPERSION SYSTEM 14

Slide 15: 

RESERVOIR SYSTEM ( MEMBRANE MODERATED TDDS ) : Figure: 1 Polymer membrane permeation-controlled TDDS TransdermScop (Scopolamine) for 3 days protection of motion sickness and TransdermNitr( Nitroglycerine ) for once a day medication of angina pectoris . 15

Slide 16: 

MATRIX SYSTEM --- DRUG IN ADHESIVE SYSTEM (ADHESIVE DIFFUSION CONTROLLED TDDS) Figure: 2 Adhesive diffusion controlled TDDS Deponit (Nitroglycerine) for once a day medication of angina pectoris. 16

Slide 17: 

MATRIX SYSTEM --- MATRIX DISPERSION SYSTEM (MATRIX DIFFUSION CONTROLLED SYSTEM) Figure: 3 Matrix diffusion controlled TDDS Nitro Dur (Nitroglycerine) used for once a day medication of angina pectoris. 17

Slide 18: 

MICRORESERVOIR SYSTEM : Figure 4: Microreservoir controlled TDDS Nitro- dur ® System (Nitroglycerin) for once a day treatment of angina pectoris. 18

Slide 19: 

Basic Components of TDDS • a) Backing films b) Release liners c) Pressure-sensitive adhesives d) Active ingredient(s) e) Permeation enhancers f) Other additives g) Microporous or semi-permeable membranes h) Pouching materials 19

Slide 20: 

20 The role and characteristics of film is: To protect the active layer and safeguard the stability of the system, and To affect skin permeation and tolerance, depending on occlusion or breathability. It must also be flexible, comfortable and must present good affinity with the adhesive, as well as excellent printability. The most common materials used polypropylene, polyethylene (both high and low density), polyesters, PVC Nylon, etc. Backing Films

Slide 21: 

21 Release liners A release liner is a film covered with an anti-adherent coating. The role of the release liner is: To protect the system as long as it is in the package, and it is removed just before the adhesion of the TDDS to the skin. Release liners play a crucial role in the stability of the product and in its safe and functional use. An incorrect release liner does not permit the easy release of the patch, and can interfere with the active or other components, thereby reducing its shelf life.

Slide 22: 

22 There are several combinations of film and anti-adherent coating that are suitable, and the choice made depends on the ingredients of the system. The most common films used as release liners are paper-based, plastic film-based and composite films. The two major classes of coating are silicones and fluoro -polymers.

Slide 23: 

23 Pressure-Sensitive Adhesives (PSA) The PSA must stick to the skin immediately and stay there for as long as it is needed. The correct choice of PSA has a critical effect on the stability of the system, the release of the active drug, the dermatotoxicity potential, and the accurate administration of the drug. There are three major families of PSAs: Rubber-based PSAs, Acrylic PSAs in the form of acrylic solutions, Emulsion polymers or hot melts, and silicon PSAs.

Slide 24: 

24 Chemical Enhancers / Accelerants / Absorption Promoters Lipid Action Protein Modification Partitioning Promotion three possible mechanism for enhancing the permeation of drug through skin. Cont…..

Slide 25: 

25 CHEMICAL CLASS EXAMPLE(s) Fatty acids Oleic acid, Undecanoid acid Fatty alcohols Octanol, Nonanol Terpenes Menthol, Thymol, Limonene Sulfoxides Dimethyl sulfoxide, Dodecyl methyl sulfoxide Anionic surfactants Sodium lauryl sulfate Cationic surfactants N,N-bis (2 hydroxy ethyl) oleylamine Nonionic surfactants Polyoxyethylene(20) sorbitan mono oleate Zwitterionic surfactants Dodecyl dimethyl ammoniopropane sulfate Polyols Propylene glycol, Polyethylene glycol Amides n,n-dimethyl-m-toluamide Ureas Urea Lactam Laurocaparan ( Azone ®) Chemical classes of penetration enhancers

Slide 26: 

26 Microporous or Semi-Permeable Membranes There are two types of porous membranes . I Ethylene Vinyl Acetate Membranes (EVA) II Microporous Polyethylene Membranes

Slide 27: 

27 Pouching Materials: There are three main layers in the composite materials used for pouches: the internal plastic heat sealable layer, the aluminium foil layer and the external printable layer. Most patches for use in a TDDS are packaged as unit doses in sealed pouches. The pouching material is therefore critical to the stability and integrity of the product . This packaging component compensates for the stability or the instability of the system.

Slide 28: 

PREPARATION OF TRANSDERMAL PATCH FROM INDUSTRIAL POINT OF VIEW. 28

Slide 29: 

These studies are predictive of transdermal dosage forms and can be classified into following types: • Physicochemical evaluation • In vitro evaluation • In vivo evaluation EVALUATION PARAMETER 29

Slide 30: 

Physicochemical Evaluation : Thickness : Uniformity of weight Drug content determination : Moisture content : Flatness: Folding Endurance: Tensile Strength: Water vapour transmission studies (WVT): Microscopic studies: 30

Slide 31: 

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 31

Slide 32: 

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 32

Slide 33: 

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 33

Slide 34: 

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. Initial weight – Final weight % Moisture content = ---------------------------------X100 Final weight 34

Slide 35: 

Moisture Uptake: Weighed film sare 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. Final weight – Initial weight % moisture uptake =---------------------------------- X 100 Initial weight 35

Slide 36: 

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 flatness. 36

Slide 37: 

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. 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 a pulley. The weights are added gradually to the pan attached with the hanging end of the thread. 37

Slide 38: 

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. 38

Slide 39: 

Peel Adhesion properties Tack properties Thumb tack test Rolling ball test Quick stick (Peel tack) test Probe tack test Shear strength properties or creep resistance Adhesive studies : 39

Slide 40: 

In this test, the force required to remove an adhesive coating form a test substrate is referred to as peel adhesion. Molecular weight of adhesive polymer, the type and amount of additives are the variables that determined the peel adhesion properties. A single tape is applied to a stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180°C angle, and the force required for tape removed is measured Peel Adhesion test: Figure: 1 Peel Adhesion test 40

Slide 41: 

Tack properties : It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is dependent on molecular weight and composition of polymer as well as on the use of tackifying resins in polymer Thumb tack test The force required to remove thumb from adhesive is a measure of tack. Rolling ball tack test This test measures the softness of a polymer 41

Slide 42: 

In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so that it rolls down and comes into contact with horizontal, upward facing adhesive (Figure-2). The distance the ball travels along the adhesive provides the measurement of tack, which is expressed in inch Figure: 2 Rolling ball tack test 42

Slide 43: 

Quick stick (peel-tack) test In this test, the tape is pulled away from the substrate at 90ºC at a speed of 12 inches/min. The peel force required breaking the bond between adhesive and substrate is measured (Figure-3) and recorded as tack value, which is expressed in ounces or grams per inch width . Figure: 3 Quick stick (peel-tack) test 43

Slide 44: 

Shear strength properties or creep resistance Shear strength is the measurement of the cohesive strength of an adhesive polymer i.e., device should not slip on application determined by measuring the time it takes to pull an adhesive coated tape off a stainless plate Figure: Shear strength properties or creep resistance 44

Slide 45: 

Probe Tack test In this test, the tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it (Figure-4). The force required to pull the probe away from the adhesive at fixed rate is recorded as tack and it is expressed in grams Figure: 4 Probe Tack test 45

Slide 46: 

In vitro studies INVITRO TESTING SKIN PREPARATION CELL DESIGN SELECTION OF SKIN SEPARATION Human Animal Artificial Heat Chemical Physical One chambered (Vertical type) Two chambered 46

Slide 47: 

In vivo Studies Animal models Human volunteers 47

Slide 48: 

Innovations Transdermal Drug Delivery 48

Slide 49: 

I. Iontophoresis : Iontophoresis is an effective and painless method of delivering medication to a localized tissue area by applying electrical current to a solution of the medication. 49

Slide 50: 

v Anode + Cathode - Analyte – Cl - Neutral analyte Analyte + Na + Drug + Na + Drug – Cl - Neutral drug BLOOD VESSEL 50

Slide 51: 

Iontophoretic Patches 51

Slide 52: 

Reverse iontophoresis : Iontophoresis can be used in reverse to remove molecules from the circulation. One example, the GlucoWatch , a needleless means of monitoring blood glucose levels in diabetic patients, uses an electrical signal that is proportional to the amount of glucose in the extracellular fluid. 52

Slide 53: 

Merits of Iontophoresis : - Efficient degree of enhancement achieved - Iontophoresis enlarges the range of drug candidates for transdermal administration (polar and/or charged drugs whose passive skin permeation is severely restricted) - Fast skin recovery - Minor irritation - Less sensitive to the condition of the skin at the application site 53

Slide 54: 

2. ULTRASOUND / SONOPHORESIS / PHONOPHORESIS : - The use of ultrasound of a suitable frequency to enhance skin permeability seems to be a useful alternative technique for delivering drugs through the skin and can be applied to vaccination and gene therapy. 54

Slide 55: 

TYPE FREQUENCY MECHANISM DRUG Low frequency sonophoresis 20 KHz - 1 MHz Cavitational Formation of aqueous channel into lipid of SC Hydrophilic drug Protein Moderate frequency sonophoresis (Therapeutic ultrasound) 1 - 3 MHz Structural disorder of SC in lipid due to collapse of cavitational bubble Corticosteroid Dexamathasone Estradiol Hydrocortisone Progesterone High frequency Sonophoresis 3 MHz - 16MHz Enhance skin permeation due to oscillation of bubble Salicylic acid Lanthanum tracers Types of sonophorosis 55

Slide 56: 

Mechanism of action of phonophoresis: 56

Slide 57: 

57

Slide 58: 

Phonophoresis (sonophoresis) 58

Slide 59: 

3. ELECTROPORATION : This process, in which brief, intense electric charges create small pores in the phospholipid bilayer of cell membranes, can assist in the transdermal delivery of drugs. Electroporation appears to reversibly disrupt the lipid bilayers in the stratum corneum , and the channels it creates are said to promote the passage of hydrophilic drugs through the skin. 59

Slide 60: 

Before field application ii) When the electric field is applied, the ions move according to their charge. iii) Pathways are formed across the cell membrane allowing DNA to enter. iv) When the electric field is deactivated,the membrane heals. 60

Slide 61: 

FACTOR IONTOPHORESIS ELECTROPORATION Electric input Constant current; low voltage Current intensity (<0.5mA/cm2) High voltage pulse up to 100 V Electrode It must avoid electrolysis of water (Ag-AgCl electrode) It also withstand high instantaneous current (platinum electrode) Drug property Charge of drug - high Size of drug- small Structure of drug- compact Lipophilicity- water soluble M.Wt.- max.12000 Charge of drug - no significant effect M.Wt. – no upper limit Formulation factor Concentration of drug pH of solution Ionic strength Concentration of the drug Electroosmosis Significant electroosmotic flow Insignificant Reversibility At low current density At low pulse voltage Comparison of Iontophoresis and Electroporation : 61

Slide 62: 

4. MINIMALLY INVASIVE SYSTEM : (A) MICROFABRICATED MICRONEEDLES (B) ENERGY INDUCED I Laser Assisted TDD II Direct Heat Induced Microporation 62

Slide 63: 

(A) MICROFABRICATED MICRONEEDLES : Poke with patch 63

Slide 64: 

Microneedles An array of stainless steel microneedles An array of stainless silicon microneedles 64

Slide 65: 

(B) (I) LASER ASSISTED DELIVERY (LAD) : Two mechanisms possible: Ablative and Laser induced stress waves (photomechanical waves). In Ablation: The high energy of laser is imparted into the skin to form pores that permit the transit of drug through Stratum Corneum . In Laser induced stress waves : There is transient permeabilisation effect of macromolecules through SC due to changes in lacunar system 65

Slide 66: 

Laser source Reservoir 66

Slide 67: 

(B) II DIRECT HEAT INDUCED MICROPORATION : The system of interest comprises a wire mesh through which current is applied and which, through the resistance, produces heat. Resulting, small holes are burned into the SC that are stated to allow the ingress of drugs into the dermis MicroPor (Thermal Creation of Micropores ) is one such product based on direct heat induced micropo 67

Slide 68: 

5. RADIOFREQUENCY-DRIVEN SKIN MICROCHANNELING : The high frequency electrical current conducted through the aqueous medium of the stratum corneum generates heat that brings about an instant removal of cells beneath the electrode. 68

Slide 69: 

6. TRANSFEROSOMES Transferosomes are modified liposomes with edge activator(sodium cholate ). When transferosomes vesicles in suspension form is applied to skin surface, water evaporates from the surface and vesicles dry out. Because of strong polarity vesicles gets attracted towards area of higher water content in the narrow gaps of the skin. This process plus vesicles deformability enables transferosomes to open the tiny pores resulting into activated intercellular channels. 69

Slide 70: 

Advantages of Transferosomes : 1. Higher entrapment efficiency protecting encapsulated drug from degradation 2. Carrier for low and high molecular weight drugs 3. Acts as depot releasing the content slowly 4. More stable 5. High penetration efficiency because of deformability 6. Biodegradable and Biocompatible 7. Preparation and scale-up preparation is simple 8. Site specific local therapy possible 9. Minimizes adverse systemic effect 70

Slide 71: 

7. SUPERSATURATED SYSTEMS/ CRYSTAL RESERVOIR TECHNOLOGY Smaller patches with a more controlled and sustained drug release. By modifying the concentration of crystals to solute, various patterns of drug release are achieved Sustained release Burst Chrono -controlled release 71

Slide 72: 

1 . Sustained release 2. Burst release 72 Isosorbide dinitrate Lidocaine transdermal patch

Slide 73: 

3. Chrono -controlled release 73 Tulobuterol transdermal patch

Slide 74: 

8. ALZA TRANSDERMAL PRODUCTS : D-TRANS : It is a conventional transdermal patch. (Passive transdermal drug delivery) E-TRANS : It is a electrotransport technology. E-TRANS can deliver drugs both locally and systemically by using low-level electrical energy to actively transport drugs through intact skin. Macroflux : Macroflux systems can be drug-coated for direct administration or can be used in combination with passive transdermal or electrotransport systems to significantly expand the delivery opportunities for synthetic drugs, therapeutic proteins and vaccines. 74

Slide 75: 

9. THE VIADERM DRUG DELIVERY SYSTEM : Array Dimensions: 5.0 cm 2 2.5 cm 2 1.0 cm 2 Array Dimensions 5.0 cm2 2.5 cm2 1.0 cm2 75 Reusable battery Disposable microelectrode Patch containing the drug

Slide 76: 

Product name Drug Manufacturer Indication Alora Estradiol TheraTech/ Proctol and Gamble Postmenstrual syndrome Androderm Testosterone TheraTech/GlaxoSmithKline Hypogonadism in males Catapres-TTS Clonidine Alza/ Boehinger Ingelheim Hypertension Climaderm Estradiol Ethical Holdings/ Wyeth- Ayerest Postmenstrual syndrome Climara Estradiol 3M Pharmaceuticals/ Berlex Labs Postmenstrual syndrome CombiPatch Estradiol/ Norethindrone Noven , Inc./Aventis Hormone replacement therapy Deponit Nitroglycerin Angina pectoris Duragesic Fentanyl Alza / Janssen Pharmaceutica TDDS products 76

Slide 77: 

CONCLUSION Due to the recent advances in technology and the incorporation of the drug to the site of action without rupturing the skin membrane transdermal route is becoming the most widely accepted route of drug administration. The foregoing shows that TDDS have great potentials, being able to use for both hydrophobic and hydrophilic active substance into promising deliverable drugs. To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and polymer are required. 77

Slide 78: 

Research Article IN VITRO CHARACTERZATIOAN AND EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEM FOR METOPROLOL TARTARATE Dr.B.Anilreddy , M.Pharm , Ph.D MCPP, Hyderabad. JPRHC, Volume-2, Issue-4, 325-329 78

Slide 79: 

Abstract Transdermal films of metoprolol tartarate were prepared using polymers such as ethyl cellulose, poly vinyl alcohol, eudragit RL100, eudragit L100. Di-n- butylphlthalate was used as plasticizer. The study was undertaken to report the film forming properties of polymers used and in vitro drug release from the prepared monolithic matrices. Effect of drug loading on the drug release rate was also studied. The transdermal films were prepared using solvent casting method. These films were evaluated for Thickness, Percent moisture loss, Percent moisture absorption, Drug content, Weight variation and folding endurance. In-vitro drug release kinetics was studied using Franz-diffusion cell. Drug release followed zero order kinetics. 79

Slide 80: 

80

Slide 81: 

RESULTS AND DISCUSSION 81

Slide 82: 

82

Slide 83: 

REFERENCES Controlled Drug Delivery : Concepts and Advances : S.P.Vyas & Roop K Khar : Chapter 10 : “ Transdermal Drug Delivery” : Pg No. 411 – 476 Encyclopedia of Pharmaceutical Technology : James Swarbrick and James Boylan : Volume 18 : “ Transdermal Drug Delivery Devices : System Design and Composition” : Pg No. 309 – 337 Loyd V.Allen,Jr ., Nicholas G. Popovich & Howard C. Ansel , Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Chapter 11 : Transdermal Drug Delivery Systems, Pg No. 298 – 315. Richard H Guy & Jonathan Hadgraft , Drugs and The Pharmaceutical Sciences, Marcel Dekker, Volume 123, Transdermal Drug Delivery, Chapter 5 : “ Iontophoresis ” Pg No. 199 – 226, Chapter 6 : “Skin Electroporation for Transdermal and Topical Drug Delivery” Pg No. 227 – 254, Chapter 7 : “ Sonophoresis ” Pg No. 255 – 284, Chapter 10 : “Minimally Invasive Systems for Transdermal Drug Delivery” Pg No. 327 - 360 Nakano Yoshihisa et al., “Dosage and Design of Transdermal Patch”, Natto journal, Vol. 39, (2001), 60 – 64 83

Slide 84: 

Sateesh Kandavilli , Vinod Nair, and Ramesh Panchagnula Pharmaceutical Technology : May 2002 : “Polymers in Transdermal Drug Delivery Systems” : Page No. 62 – 80 M.E.Aulton , Pharmaceutics : The Science of Dosage Form Design, Second Edition, Part Four, Dosage Form Design and Manufacture, Chapter 33, “ Transdermal Drug Delivery”, Pg No. 499 - 533 H.M.Wolff , “Optimal Process Design for the Manufacture of Transdermal Drug Delivery Systems”, PSTT, Vol.3, No.5, May 2000,Pg No.173 – 181 S.E.Cross & M.S.Roberts , “Physical enhancement of Transdermal Drug Application : Is Delivery Technology Keeping up with Pharmaceutical Development?”, Current Drug Delivery, 2004, 1, Pg No. 81 – 92 B.W. Barry, “Novel mechanisms and devices to enable successful transdermal drug delivery”, European Journal of Pharmaceutical Sciences, Vol. 14, (2001), 101–114 84

THANK YOU: 

THANK YOU 85