1. TRANSDERMAL DRUG DELIVERY SYSTEM
Dr. Basavaraj K. Nanjwade M. Pharm., PhD
KLE University College of Pharmacy
BELGAUM , Karnataka, India.
Cell No:
14th December 2012
KLE College of Pharmacy, Nipani.

2. KLE College of Pharmacy, Nipani.
CONTENTS
Introduction
Objectives of TDDS
Advantages & disadvantages
Mechanism of percutenious absorption
Permeation through skin
Kinetics of transdermal drug delivery system
Factors affecting permeation
Basic components of TDDS
Formulation approaches used in development of TDDS and their evaluation
Permeation enhancer.
References
14th December 2012
KLE College of Pharmacy, Nipani.

3. TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS)
When one hears the words transdermal drug delivery, what comes to mind? More than likely one thinks about a simple patch that one stick onto skin like an adhesive bandage such as nicotine patch.
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KLE College of Pharmacy, Nipani.

4. KLE College of Pharmacy, Nipani.
Brief History of TDDS
The NDDS may involve a new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of injections.
Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms.
Because transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms
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5. KLE College of Pharmacy, Nipani.
Brief History of TDDS
Transdermal drug delivery system was first introduced more than 20 years ago.
The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s.
First transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness, the FDA has approved, throughout the past 22 years, more than 35 transdermal patch products, spanning 13 molecules.
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KLE College of Pharmacy, Nipani.

6. KLE College of Pharmacy, Nipani.
INTRODUCTION
Definition:
Transdermal drug delivery is defined as a self contained discrete dosage form, which when applied to the intact skin, will deliver the drug at a controlled rate to the systemic circulation.
14th December 2012
KLE College of Pharmacy, Nipani.

7. POTENTIAL BENEFITS OF TRANSDERMAL DRUG DELIVERY (ADVANTAGES)
Easy to use.
Avoid GIT absorption problems for drugs.
Avoids FP hepatic metabolism of drugs.
More improved and convenient patient compliance.
Rapid termination in case of toxicity is possible.
Self medication is possible.
Reduces frequency of dosing.
Maintains therapeutic level for 1 to 7 days.
Controlled delivery resulting in more reliable and predictable blood levels.
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8. KLE College of Pharmacy, Nipani.
DISADVANTAGES
Daily dose of more than 10mg is not possible.
Local irritation is a major problem.
Drug requiring high blood levels are unsuitable.
Drug with long half life can not be formulated in TDDS.
Uncomfortable to wear.
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.
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9. KLE College of Pharmacy, Nipani.
STRUCTURE OF SKIN
Epidermis:
Stratum corneum (Horny cell layer)
Stratum lucidum (Clear layer)
Stratum granulosum ( Granular Layer)
Stratum spinosum (Prickly layer)
Stratum germinativum
Dermis:
Hypodermis or Subcutaneous layer:
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10. KLE College of Pharmacy, Nipani.
STRUCTURE OF SKIN
Epidermis:
The outer layer of skin is made up of Stratified Squamous epithelial cells.
Epidermis is thickest in palms and soles.
The stratum corneum forms the outer most layer (10-15µm thick ) which consists of many layers of compacted , flattened, dehydrated keratinized cells.
Keratin contains cells called as Corneosites.
Stratum corneum layer forms permeability barrier for external environment.
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11. KLE College of Pharmacy, Nipani.
STRUCTURE OF SKIN
Water content of stratum corneum is around 20%.
The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness.
It consists of Cermides and neutral lipids such as Sterols, free fatty acids and triglycerides.
The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption.
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12. KLE College of Pharmacy, Nipani.
STRUCTURE OF SKIN
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.
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STRUCTURE OF SKIN
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.
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14. KLE College of Pharmacy, Nipani.
STRUCTURE OF SKIN
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 & 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.
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KLE College of Pharmacy, Nipani.

15. Mechanism of absorption through skin
Mechanism involved is passive diffusion
This can be expressed by FICK’s LAW of DIFFUSION
dq = D K A ( 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
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KLE College of Pharmacy, Nipani.

16. Routes of drug absorption through skin
Trans follicular route
Trans epidermal route
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KLE College of Pharmacy, Nipani.

17. Routes of drug absorption through skin
Trans follicular route:
Fractional area available through this route is 0.1 %
Human skin contains hair follicles, 200 to 250 sweat glands on every sq.cm. of skin area.
Mainly water soluble substance are diffused faster through appendages than that of other layers.
Sweat glands and hair follicles act as a shunt i.e. easy pathway for diffusion through rate limiting ST corneum.
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KLE College of Pharmacy, Nipani.

18. Routes of drug absorption through skin
Trans Epidermal route
Epidermal barrier function mainly resides in horny layer
The viable layer may metabolize, inactivate or activate a prodrug.
Dermal capillary contains many capillaries so residence time of drug is only one minute.
Within stratum corneum molecule may penetrate either transcellularly or intercellular.
Intracellular region is filled with lipid rich amorphous material.
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KLE College of Pharmacy, Nipani.

19. Routes of drug absorption through skin
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KLE College of Pharmacy, Nipani.

20. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
Physico chemical properties of parent molecule
Solubility and partition co- efficient
pH condition
Penetrant concentration
Physico chemical properties of drug delivery system
Release characteristic
Composition of drug delivery system
Permeation enhancer used
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21. KLE College of Pharmacy, Nipani.
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
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22. KLE College of Pharmacy, Nipani.
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.
Drug solubility determines concentration presented to absorption site which will effect rate and extent of absorption.
Skin permeation can be enhanced by increasing lipophilic character of drug, so that drug penetrates through STC but not through epidermis due to decreased water solubility.
Drug which is lipid & water soluble is favored.
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23. KLE College of Pharmacy, Nipani.
pH & penetration concentration:
Moderate pH is favorable because if solutions with high or low pH will result in destruction to the skin.
Higher the concentration of the drug in vehicle faster the absorption.
At higher concentrations than solubility the excess solid drug will function as a reservoir and helps to maintain a constant drug constitution for prolonged period of time.
14th December 2012
KLE College of Pharmacy, Nipani.

24. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
Physico-chemical properties of drug delivery system
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.
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KLE College of Pharmacy, Nipani.

25. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
Physiological and pathological condition of skin
Lipid film:
It acts as protective layer to prevent removal of moisture from skin. Defeating 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.
14th December 2012
KLE College of Pharmacy, Nipani.

26. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
Effect of vehicle:
A vehicle can influence absorption by its effect on physical state of drug and skin. Example greases, paraffin bases are more occlusive while water in oil bases are less. Humectants in bases will dehydrate the skin and decrease percutaneous absorption.
14th December 2012
KLE College of Pharmacy, Nipani.

27. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
Biological factors:
Skin age:
Skin of foetus, young ones and elders is more permeable than adult tissue.
Skin metabolism:
Viable epidermis is metabolically active than dermis. If topically applied drug is subjected to biotransformation during permeation local and systemic bioavailability is affected.
14th December 2012
KLE College of Pharmacy, Nipani.

28. BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY SYSTEM
COMPONENT OF TRANSDERMAL DEVICE INCLUDE:
1) POLYMER MATRIX
2) THE DRUG
3) PERMEATION ENHANCER
4) OTHER EXCEPIENTS
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KLE College of Pharmacy, Nipani.

29. Basic components of Transdermal drug delivery
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30. KLE College of Pharmacy, Nipani.
POLYMER MATRIX
Following criteria to be considered in selection a polymer:
Molecular weight, physical 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 in corporated into it.
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31. KLE College of Pharmacy, Nipani.
LIST OF POLYMERS USED
NATURAL POLYMERS:
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Gums & Natural rubber
SYNTHETIC ELASTOMER POLYBUTADIENE: Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle, Butyl rubber, Styrene butadiene rubber.
SYNTHETIC POLYMER
Poly vinyl alcohol, Poly vinyl chloride, Polyethylene, Poly propylene, Poly urea, PVP, Polymethacrylate
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32. KLE College of Pharmacy, Nipani.
DRUG
For successful developing transdermal delivery, drug should be chosen with great care physicochemical properties
1. Mol. wt. less than 1000 Daltons
2. Affinity for both lipophilic & hydrophilic phase
3. Drug should have low melting point
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KLE College of Pharmacy, Nipani.

33. BIOLOGICAL PROPERTIES
It should be potent with daily dose of few mg/ day.
Half life of drug should be short.
Non irritant to skin.
Drug prone to ‘first pass effect’ and which degrade in GIT are ideal candidate.
14th December 2012
KLE College of Pharmacy, Nipani.

34. Ideal properties of drug candidate
PARAMETER
PROPERTIES
Dose
Sh’d be low( < 20mg/day)
Half life
10 or less
Molecular weight
< 400
Skin permeability co- efficient
> 0.5 X cm/ hr
Skin reaction
Non irritating & non sensitizing
Oral Bioavailability
low
Therapeutic index
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35. KLE College of Pharmacy, Nipani.
PERMEATION ENHANCERS
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
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KLE College of Pharmacy, Nipani.

36. 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
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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 (non adsorptive)
Printable
E.g.: Metallic plastic laminate , plastic backing with adsorbent pad adhesive foam pad.
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38. Schematic Skin absorption of drug
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39. Topical application-absorption & action of drugs
DRUG IN TARGET TISSUE
DRUG IN BLOOD CIRCULATION
DISTRIBUTION
ELIMINATION
PHARMACOLOGICAL
RESPONSE
TOPICAL
ABSORPTION
DRUG IN DELIVERY
SYSTEM
DRUG IN SKIN SECRETION
FLUIDS, SWEAT, SEBUM, pH
TRANSDERMAL
LOCALIZED
RELEASE
SYSTEMIC
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40. KLE College of Pharmacy, Nipani.
FORMULATION APPROACHES FOR DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY SYSTEM
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TYPES OF FORMULATION
PLATFORM FOR THE DRUG:
Liquids
Semisolids : ointments and gels
Non flowing material
That is …
Polymeric film or rubbery gels and
Solid-state platform
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42. KLE College of Pharmacy, Nipani.
TYPES OF PLATFORM
MONOLITH : slabs, reservoir, vehicle, film, polymer matrix
FILMS :
Natural or synthetic
Porous and non porous
ADHESIVES: viscoelastic materials which remains permanently tacky
E.g. Natural or synthetic rubber, polyacrylates and silicon elastomer
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KLE College of Pharmacy, Nipani.

43. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
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KLE College of Pharmacy, Nipani.

44. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
RCM made up of EVA copolymer
A thin layer of drug compatible, hypoallergenic adhesive polymer e.g. Silicon or polyacrylet adhesive may be applied to the external surface.
Rate of drug release affect by varying the polymer composition, permeability coefficient and thickness of rate limiting membrane and adhesive.
14th December 2012
KLE College of Pharmacy, Nipani.

45. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
Accidental breakage of the rate controlling membrane can result in dose dumping or a rapid release of the entire drug content.
E.g.
Nitroglycerine releasing trans dermal system for once a day medication for angina
14th December 2012
KLE College of Pharmacy, Nipani.

46. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
Scopolamine-releasing transdermal system for 72 hr. prophylaxis of motion sickness.
Clonidine releasing transdermal system for 7 day therapy of hypertension.
Estradiol-releasing transdermal system for treatment of menopausal syndrome for 3-4 days.
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KLE College of Pharmacy, Nipani.

47. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
The intrinsic rate of the drug release from this type of drug delivery system is defined by
dq CR
dt /pm + 1/pa =
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KLE College of Pharmacy, Nipani.

48. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
Pm and pa respectively defined as….
pm km/r . Da hm
ka/m . Da ha = pa =
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KLE College of Pharmacy, Nipani.

49. 1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
Where,
Km/r and ka/m are the partition coefficient for the interfacial partitioning of the drug from reservoir to the membrane and from the membrane to adhesive layer respectively.
Dm and Da are diffusion coefficient and
hm and ha are the thickness
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KLE College of Pharmacy, Nipani.

50. 1.POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM
Substituting the pm and pa equation in equation 1
dq km/r . Ka/m . Dm . Da
dt km/r. Dm. ha + ka/m . Da . hm
Which define the intrinsic rate of drug release from a membrane moderated drug delivery system. = cr
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KLE College of Pharmacy, Nipani.

51. 2. ADHESIVE DISPERSION-TYPE SYSTEM
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KLE College of Pharmacy, Nipani.

52. 2. ADHESIVE DISPERSION-TYPE SYSTEM
e.g. of adhesive polymer is poly(isobutylene) or poly(Acrylet) adhesive
E.g. of this type of system is isosorbide dinitrate releasing transdermal therapeutic system for once a day medication of angina pectoris.
It is used for the administration of verapamil.
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KLE College of Pharmacy, Nipani.

53. 2. ADHESIVE DISPERSION-TYPE SYSTEM
The rate of drug release in this system is defined by:
dq ka/r . Da
dt ha
where,
Ka/r is partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer. cr =
14th December 2012
KLE College of Pharmacy, Nipani.

54. 3. GRADIENT CONTROLLED TDDS
Drug – impermeable metallic plastic laminate R1 R2 R3 }
Drug reservoir gradient layers
R1>R2>R3
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KLE College of Pharmacy, Nipani.

55. 3. GRADIENT CONTROLLED TDDS
The rate of drug release from this drug reservoir gradient controlled system is given by:
dq ka/r . Ds
dt ha (t)
Thickness of the adhesive layer for drug molecules to diffuse through increases with time h(t)
E.g. Nitroglycerine TDD patch
A (ha) =
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KLE College of Pharmacy, Nipani.

56. 4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM
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57. 4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM
E.g. of this type of system is nitro-dur I and nitro-dur II. for continuous transdermal fusion of nitroglycerine at a daily dose of 0.5 mg/cm2 for therapy of angina pectoris.
Nitro dur II is modified version of I in which the drug is dispersed in acrylic based polymer adhesive with a resinous cross linking agent which result in much thinner and more elegant patch.
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KLE College of Pharmacy, Nipani.

58. 4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM
The rate of drug release from this type of system is defined as:
A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are the solubility and diffusivity of the drug polymer respectively.
Since only the drug species dissolved in the polymer can release .
1/2
dq ACp Dp
dt t =
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KLE College of Pharmacy, Nipani.

59. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
rim
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KLE College of Pharmacy, Nipani.

60. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
Silicon elastomer the lipophillic polymer is used for dispersion technique to form unleachable microscopic sphere of drug reservoir.
The quick stabilization occur by cross linking of the polymer chain which produced medicated polymer disc with a constant surface area and fixed thickness according to requirement of drug release.
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KLE College of Pharmacy, Nipani.

61. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
Extra coating is available as a biocompatible polymer to modify the mechanism and rate of drug release.
A trans dermal therapeutic system is produced by positioning the medicated disc at the centrally and surrounded bit with an adhesive rim.
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KLE College of Pharmacy, Nipani.

62. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
It is successfully utilized in the preparation of nitro-disc, a nitroglycerine releasing trans dermal therapeutic system used in angina pectoris.
This system followed zero order release of drug without the danger of dose dumping.
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KLE College of Pharmacy, Nipani.

63. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
The rate of release of drugs of the micro reservoir system is defined by,
dq Dp .Dd .m .kp
dt Dphd+Ddhpmkp
DISl (1-n)
n.Sp hI 1 kI = + km
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KLE College of Pharmacy, Nipani.

64. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
Where, m=a/b is the ratio of the bulk of the elution medium over drug solubility of the same medium and b is the ratio of drug concentration at the outer edge of the polymer coating for the drug solubility in the same polymer composition.
n is the ratio of the drug concentration at the inner layer of the interfacial barrier over drug solubility in the polymer matrix.
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KLE College of Pharmacy, Nipani.

65. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
Dl, Dp and Dd and hl, hp and hd; 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 .
Kl, km and kp 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.
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KLE College of Pharmacy, Nipani.

66. 5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED SYSTEM
Sl and SP 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 Sl and SP
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KLE College of Pharmacy, Nipani.

67. 6. POROPLASTIC TYPE SYSTEM
Poroplastic film consists of ultra micro porous membranes which are not sensitizing to skin and are fairly stable at higher than normal temperature and at biological pH.
It is made utilizing the concept of water coagulation of cellulose triacetate solution in organic acid at low temperature.
The coagulation is performed under controlled condition.
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KLE College of Pharmacy, Nipani.

68. 7. TRANSDERMAL DELIVERY OF THE MACROMOLECULE
Macromolecules such as Hormones, interferons, bioactive peptides can be delivered by Trans dermal delivery system.
The devices used for this purpose are divided in to two categories….
1. Devices based on ethylene vinyl acetate copolymers (EVAc).
2. Devices based on silicone elastomer.
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KLE College of Pharmacy, Nipani.

69. 7. TRANSDERMAL DELIVERY OF THE MACROMOLECULE
This both the system utilize one common concept i.e.
Matrix must have channel to facilitate the release of macro molecule
This device is used as implants
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70. KLE College of Pharmacy, Nipani.
8. OTHER TDDS
IONTOPHORESIS
Built-in battery layer
Comparable in size to a normal transdermal patch
The Lectro Patch, General Medical Co.
Treatment time : 20 min
Recommended maximum current : 4mA
Lidocaine (local anesthesia), dexamethasone (arthritis), hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc.
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KLE College of Pharmacy, Nipani.

71. KLE College of Pharmacy, Nipani.
IONTOPHORESIS
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72. KLE College of Pharmacy, Nipani.
8. OTHER TDDS
Sonophoresis:
The application of high frequency ultrasound to enhance drug penetration.
Examples:. Lidocaine, hydrocortisone, salicylic acid.
Electroporation:
Transient high-voltage electrical pulses, to cause rapid permeabilization of the stratum corneum through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts.
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KLE College of Pharmacy, Nipani.

73. KLE College of Pharmacy, Nipani.
8. OTHER TDDS
Reverse iontophoresis:
Current passage causes ions and other molecules to move in both directions under both electrodes. Hence it is possible to sample an analyte in the body, and to provide a drug in response to the analyte level, e.g., sugar, glucose.
14th December 2012
KLE College of Pharmacy, Nipani.

74. Trandermal Matrix patch designs
Reservoir
Drug in adhesive
Multilaminate
Backing
Drug
Membrane
Liner / skin
Adhesive
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KLE College of Pharmacy, Nipani.

75. Transdermal Production Process
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76. Transdermal Controlled-Release Products and Devices
Drug
Trade Name
Type of Devices
Indication
Scopolamine
Transderm-Scop
Reservoir
Motion sickness
Nitroglycerine
Transderm-Nitro
Angina
Nitro-Dur
Monolithic
Nitrodisc
Estradiol
Estraderm
Reservoir and ethanol enhancer
Hormone treatment
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KLE College of Pharmacy, Nipani.

77. Transdermal Products under Development
Drug
Trade name
Producer-Marketer
Minocycline
Sunstar
American Cyanamide, Takeda
Estradiol+Norethisterone
Estracombi TIS
Ciba-Geigy, Alza
DHEA
Pharmedic
Fentanyl
Triamcinolone acetonide
Whitby Pharm.
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KLE College of Pharmacy, Nipani.

78. Recently approved transdermal contraceptive
Recently approved by FDA (Ortho-McNeil)
Once a week for three weeks, fourth week patch free
99 percent effective when used as directed
Combination estrogen and progestin
One-and-three-quarter inch square applied to the lower abdomen, buttocks or upper body.
Skin irritation or detachment reported in 2-5% of patients
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79. KLE College of Pharmacy, Nipani.
EVALUATION
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80. 1.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.
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81. 1.EVALUATION OF ADHESIVE
It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at a 180o angle.
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KLE College of Pharmacy, Nipani.

82. 1.EVALUATION OF ADHESIVE
B. 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....
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KLE College of Pharmacy, Nipani.

83. KLE College of Pharmacy, Nipani.
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.
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KLE College of Pharmacy, Nipani.

84. b. 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 90o 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.
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KLE College of Pharmacy, Nipani.

85. 1.EVALUATION OF ADHESIVE
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KLE College of Pharmacy, Nipani.

86. KLE College of Pharmacy, Nipani.
c. 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
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KLE College of Pharmacy, Nipani.

87. 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
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KLE College of Pharmacy, Nipani.

88. 1.EVALUATION OF ADHESIVE
Stainless steel plate
Adhesive coated tape
Weight
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KLE College of Pharmacy, Nipani.

89. 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.
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KLE College of Pharmacy, Nipani.

90. 2. IN-VITRO DRUG RELEASE EVALUATION
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 3.14cm2. the receptor solution is stirred by star-head magnet rotating at a constant speed of 600rpm driven by 3W synchronous motor.
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KLE College of Pharmacy, Nipani.

91. KLE College of Pharmacy, Nipani.
Franz Diffusion Cell
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KLE College of Pharmacy, Nipani.

92. KLE College of Pharmacy, Nipani.
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.
Studies on skin metabolism can also be performed.
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KLE College of Pharmacy, Nipani.

93. KLE College of Pharmacy, Nipani.
ADVANTAGES
It includes also ease of methodology, analytical assay since there are no complication arising from the disposition of the drug in the body and better control over experimental condition than is possible in vivo.
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KLE College of Pharmacy, Nipani.

94. 3. 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.
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KLE College of Pharmacy, Nipani.

95. 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 37oC. Samples were withdrawn from solution compartment at predetermined times and assayed for drug and any possible metabolite.
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KLE College of Pharmacy, Nipani.

96. KLE College of Pharmacy, Nipani.
4.IN-VIVO EVALUATION
a. Animal models:
The rhesus monkey is the most reliable model for in vivo evaluation of transdermal drug in man.
Standard radiotracer methodology is used.
The application site is generally the forearm or abdomen which are the least hairy sites on the animal’s body.
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KLE College of Pharmacy, Nipani.

97. KLE College of Pharmacy, Nipani.
4. IN-VIVO EVALUATION
Limitation of using this animal include cost and handling capabilities required.
Ethical consideration also limit the use of rhesus monkey.
Other animals are weanling pig and human skin grafted nude mouse.
Difficulties in using these animals are their non availability and the facilities and skill required for their handling.
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KLE College of Pharmacy, Nipani.

98. KLE College of Pharmacy, Nipani.
4. IN-VIVO EVALUATION
b. Human models:
Procedure for in vivo evaluation in humans were first described by feldmann and maibach in 1974.
They involve the determination of cutaneous absorption by an indirect method of measuring radio activity in excreta following topical application of the labelled drug.
This method is used since plasma level following trans dermal administration of a drug are too low to use chemical assay procedure.
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KLE College of Pharmacy, Nipani.

99. KLE College of Pharmacy, Nipani.
4. IN-VIVO EVALUATION
The % of dose absorbed transdermally is calculated by
Total radioactivity excreted after topical adm.
Total radioactivity excreted after i.v. adm.
Various modification have been made for this method, it is given below.
% Drug absorbed =
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KLE College of Pharmacy, Nipani.

100. KLE College of Pharmacy, Nipani.
RESERVOIR TECHNIQUE
It is simple technique, short exposure of the skin to the compound (radio-labelled) under study followed by removal of the stratum corneum.
From this analysis, it is possible to predict the amount of drug that will penetrate over a longer period of time.
LIMITATION:
Invasive nature of the technique due to the tape stripping required.
The single measurement obtained which does not allow detailed kinetic analysis & adm. of large dose of radio active material is required.
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KLE College of Pharmacy, Nipani.

101. 5. CUTANEOUS TOXICOLOGICAL EVALUATION
CONTACT DERMATITIS:
It can be either
Contact irritant dermatitis or
Contact allergic dermatitis
Contact irritant dermatitis:
It results from direct toxic injury to cell membrane, cytoplasm or nuclei.
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KLE College of Pharmacy, Nipani.

102. 5. CUTANEOUS TOXICOLOGICAL EVALUATION
Two types of protocols are used
Ten days primary irritation test &
Twenty one days irritation test
Contact allergic dermatitis:
It involves a host immunological reaction to an antigen.
It can be screened by the guinea pig maximization test.
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KLE College of Pharmacy, Nipani.

103. KLE College of Pharmacy, Nipani.
ADVANCED RESEARCHES
MICROARRAY NEEDLE
Advanced micro-needle Patch transdermal system allowing continuous delivery through the skin of proteins and water-soluble drugs.
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KLE College of Pharmacy, Nipani.

104. KLE College of Pharmacy, Nipani.
ADVANCED RESEARCHES
The device create painlessly micropores in the S.C. known as microstructered arrays or microneedles.
These devices have about 400 microneedles.
The solid silicone needles (coated with drug) or hollow metal needles (filled with drug solution) penetrate the horny layer without breaking it or stimulating nerves in deeper tissues.
Flux increase up to 1,00,000 fold are reported.
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KLE College of Pharmacy, Nipani.

105. KLE College of Pharmacy, Nipani.
MICRONEEDLE ARRAY
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KLE College of Pharmacy, Nipani.

106. Multidose Transdermal Drug Delivery System
It is comprises a laminate composite with a plurality of compartments.
Each compartment is a reservoir for a unit dose of a drug active to be transdermally administered.
Individual seals are provided for resealably enclosing the drug active in each of the reservoirs.
The individual enclosing seals are removable to release the unit dose into contact with the skin of the patient and are actuable to control the transdermal absorption of the drug actives.
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KLE College of Pharmacy, Nipani.

107. KLE College of Pharmacy, Nipani.
MICRO TRANS
Applications :
Delivery of large proteins, fragile antibodies, and hormones.
Delivery of small molecules, particularly those
with difficulty diffusing through skin layers.
Delivery of vaccines, both conventional and DNA- based.
Fluid sensing of glucose, hormones, blood gases, and therapeutic drug levels.
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KLE College of Pharmacy, Nipani.

108. Crystal reservoir technology
This system makes oversaturation of adhesive polymer with drug forcing partial crystallization.
Presence of both molecular and solid state, allow higher conc. & consistent supply of drug.
As skin absorbs dissolved drug, crystals re-dissolve to maintain drug at solubility limit (max. thermodynamic activity) at the site of contact.
This results in smaller thinner patches with better patient acceptability. Clinical trials with this technology with β2 adrenergic agonist tulobutarol confirmed superiority of TDDS formulation over oral formulation
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KLE College of Pharmacy, Nipani.

109. KLE College of Pharmacy, Nipani.
PERMEATION ENHANCERS
These are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrate
Flux J across the skin can be given by J = D dc dx D = diffusion coefficient C = concentration
D is function of size, shape, flexibility of diffusing drug molecule
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KLE College of Pharmacy, Nipani.

110. 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.
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KLE College of Pharmacy, Nipani.

111. IDEAL CHARACTERISTIC OF PENETRATION ENHANCERS
IT SHOULD BE INERT
NON-TOXIC, NON- IRRITATING
ACTION SHOULD BE IMMEDIATE& PREDICTABLE
SHOULD NOT CAUSE REMOVAL OF BODY FLUID
SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS
COSMETICALLY ACCEPTABLE
ODORLESS, TASTELESS, COLORLESS & CHEAP
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KLE College of Pharmacy, Nipani.

112. KLE College of Pharmacy, Nipani.
SOLVENTS
The compounds increase penetration possibly by swelling the polar pathway and fluidizing the lipid
e.g.. Methanol, ethanol, DMSO, DMA, DMF, pyrolidiones, propylene glycol, glycerol etc..
SURFACTANTS
They enhance polar pathway transport of hydrophillic drugs
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KLE College of Pharmacy, Nipani.

113. KLE College of Pharmacy, Nipani.
ANIONIC SURFACTANTS -
Dioctyl sulpho succinate, SLS, decodemethyl sulphoxide
CATIONIC SURFACTANTS -
Pluronic F127, pluronic F58
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KLE College of Pharmacy, Nipani.

114. KLE College of Pharmacy, Nipani.
BINARY SYSTEMS
These systems open up the multilaminate path way as well as the continuous path way
e.g. Propylene glycol-oleic acid.
1,4, butane diol- linoleic acid.
MISCELLANIOUS CHEMICALS
e.g. Urea, N,N- dimethyl m- toluamide
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KLE College of Pharmacy, Nipani.

115. KLE College of Pharmacy, Nipani.
Key Features
Simple for patient to use, and fully disposable.
Unique manufacturing techniques result in very low cost.
Accurate, reliable delivery of drug to epidermis or dermis, circumventing the stratum corneum.
Passive or active drug delivery profiles.
Can be used with Valeritas' e-Patch and h-Patch™ device to deliver a wide range of drug volumes under various extended or time-release profiles
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KLE College of Pharmacy, Nipani.

116. 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.
Attach the adhesive side of the patch to your skin in the chosen area.
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KLE College of Pharmacy, Nipani.

117. Find an appropriate place to put the patch
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.
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.
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KLE College of Pharmacy, Nipani.

118. Find an appropriate place to put the patch
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KLE College of Pharmacy, Nipani.

119. Product Development Challenges
Flux sufficient but manageable size
Adequate skin adhesion
Adequate shelf life stability
Non-irritating
Aesthetically pleasing
Easy to handle and use
Comfortable
Unobtrusive
Product cost
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KLE College of Pharmacy, Nipani.

120. KLE College of Pharmacy, Nipani.
REFERENCES
Transdermal controlled systems medication by Y.W. Chein.
Controlled drug delivery – Fundamental and Application, 2nd edition, by Joseph R. Vincent, H.C. Lee page no.: 524 – 589.
Controlled drug delivery – Concepts and Advances, by S.P. Vyas and Roop K. Khar page no.: 411 – 447.
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KLE College of Pharmacy, Nipani.

121. KLE College of Pharmacy, Nipani.
REFERENCES
Novel drug delivery systems, 2nd edition, by Y.W. Chein page no.: 338 – 380.
The Eastern Pharmacist - “Transdermal drug delivery system”, vol.34,1991
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KLE College of Pharmacy, Nipani.

122. E-mail: nanjwadebk@gmail.com
THANKING YOU
Cell No:
14th December 2012
KLE College of Pharmacy, Nipani.