Transdermal drug delivery system

1. RATE CONTROLLED
TRANSDERMAL DRUG DELIVERY
SYSTEM (TDDS)
By
Ms. Priyanka Dattatray Mundale.
M. Pharmacy First Year (Sem. 2)
Department of Pharmaceutics
C. U. Shah College of Pharmacy
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2. Contents:
Introduction
Merits and Demerits of TDDS
Ideal Properties
Factors Affecting Transdermal Permeability
Basic Components of Transdermal Devices
Various Approaches for TDDS
Advancements in TDDS
Future Prospects of TDDS
References
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3. Introduction
 Today about one third of drugs are taken orally and are found not to be
as effective. To improve such characters, transdermal drug delivery
system was emerged.
 After tedious research, it found that skin can be explored as a site for
drug delivery which led to the development of transdermal drug delivery
system.
 Transport of drug across the skin is best route of drug delivery
 In 1944, the term ‘transdermal’ was coined by Merrium Webster.
 In 1979, FDA approved the first transdermal patch (TDP) namely
Transderm-Scop® for the treatment of motion sickness.
 Till date, we have around 35 transdermal patches for various diseases.
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4.  It can be defined as a system that can deliver the drugs through the skin
to systemic circulation at predetermined rate and maintain clinically the
required effective concentration over a prolonged period of time.
 It is a better and effective substitute to oral drug delivery because able to
provide drug at a controlled rate and minimizes the fluctuations in serum
drug concentration.
 In general topical and transdermal terms are used synonymously. But
there is a major difference between them.
 The drugs which can be delivered by transdermal route are Fentanyl,
Scopolamine, Nitroglycerine, Clonidine, Diclofenac, Indomethacin,
Nicotine, Estradiol etc.
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5. Merits And Demerits of TDDS5
Suitable for drug
candidates with short
half life & low
therapeutic index
Minimization of
side effects
Reduction in
dosing frequency
Reduction of fluctuations
in plasma drug
concentration
Improves patient
complience
Minimization of
daily intake of drug
Simple & non-
invasive
No first pass
effect

6. 6
Possibility of local
irritation at the site of
application
Chances of drug
degradation on
exposure to
atmosphere
A constant conc.
Gradient is difficult
to maintain
Damage to drug
reservoir may
possible
The skin’s low
permeability to
some drugs
High plasma
levels of drug
Barrier nature
of the skin
Drugs
undergoing
metabolism
across skin

7. 7
Molecular weight
< 500 Dalton
Compatible with
skin secretions &
skin pH
Low oral
bioavailability and
Short half life
Partition
coefficient
1-4
Good stability
profile &
toxicity profile
Ease of
removal
Low dose of
drug
Narrow
therapeutic
index

8. Factors Affecting Transdermal Permeability of Drug:
Physicochemical
properties of drug
• Diffusion
• Partition coefficient
• pH conditions
• Conc. Of drug
Physicochemical
properties of DDS
• Vehicle
• Composition of drug
delivery system
Physiological and
pathological conditions
of skin
• Lipid film
• Skin hydration
• Skin temperature
• Region variation
• Injuries to skin
• Cutaneous drug metabolism
• Drug metabolism by microbes
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9. Basic Components of Transdermal Devices
 Drug Reservoir System:
 reservoir can be prepared by dispersion of drug in liquid and solid state
synthetic polymer base.
 Polymers used in TDDS should have good compatibility and stability with
the drug and other components of the system
 They should provide effective release of drug throughout the device with
safe status.
 Decomposed products of the polymer should be non-toxic.
 E.g. polypropylene, polyvinyl carbonate, cellulose acetate nitrate,
polyacrylonitrile, ethylene vinyl acetate copolymer, polyethylene
terephthalate, etc.
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10.  Drug:
 E.g. Scopolamine, Fentanyl, Nitroglycerine, Naproxen, Ketoprofen, Clonidine,
Hormones releasing drugs etc.
 Pressure Sensitive Adhesives:
 They are used for adherence of transdermal patch to the skin.
 When pressure is applied, they firmly attached to skin and allow the drug to
diffuse out slowly.
 Non-toxic, non-irritant and non-sensitizing in nature.
 They should be easily removable and should not leave any kind of patch.
 Broadly classified into 3 groups i.e. Acrylates, Polyisobutylenes and
Polysiloxanes.
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11.  Permeation Enhancer:
 Chemical substances which plays a crucial role in drug diffusion across the
skin.
 These compounds interact with structural components of stratum cornium.
 E.g. Dimethyl sulphoxide, propylene glycol, 2-pyrollidone, isopropyl
myristate, SLS, pluronic, cardamom oil, caraway oil, menthol etc.
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12.  Backing Laminate:
 They are used to maintain the physical and chemical properties of patch
during its shelf life and therapy periods.
 It acts as shelter for drug reservoir and protects it from harmful effects of
external environment.
 It must be flexible and should have high tensile strength.
 E. g. polyethylene resins, polypropylene resins, polyester films etc.
 Release Liner:
 The patch is covered by a protective liner which is removed and
discharged before the application of the patch to the skin.
 It may be regarded as a primary packaging material rather than a part of
dosage form.
 E.g. Polyvinyl chloride, polyethylene, polyester foils, etc.
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13. Various Approaches to Transdermal Devices
Approaches
to TDDS
Adhesive
Dispersion
Type TDDS
Membreane
Permeation
Controlled
TDDS
Polymer Matrix
Diffusion
Controlled TDDS
Microreservoir
Type TDDS
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14. Membrane Permeation controlled TDDS
 In this type of TDDS, drug reservoir is sandwiched between drug
impermeable backing membrane and rate controlling membrane.
 The drug releases only through the rate controlling membrane. It can be
microporous or non-porous.
 Drug can be in the form of solution, suspension, gel or dispersion in
polymer matrix in the reservoir compartment.
 The release rate of drug from this type of system can be controlled by
varying polymer composition, permeability coefficient or thickness of rate
controlling membrane.
 On the outer surface of polymeric membrane, a thin layer of adhesive
polymer is applied.
 A constant release rate of drug.
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15.  The intrinsic rate of drug release is given by:
Where, dQ/dT = Rate of drug diffusion
CR = Conc. Of drug in reservoir
Ka/m = Partition coefficient of drug from membrane to adhesive
Km/r = Partition coefficient of drug from reservoir to membrane
Da = Diffusion coefficient in adhesive layer
Dm = Diffusion coefficient in membrane
ha = Thickness in adhesive layer
hm = Thickness of membrane
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16. 16

17. Adhesive Dispersion Type TDDS:
 In this type, the drug reservoir is prepared by directly dispersing the drug in an
adhesive polymer.
 Then this medicated adhesive polymer is spread over a flat sheet of drug
impermeable backing membrane.
 The drug reservoir layer is then covered by a non-medicated rate controlling
polymer of constant thickness to produce an adhesive diffusion controlling DDS.
 The rate of drug release is given as:
where, Ka/r = Interfacial partitioning of the drug from reservoir layer to adhesive
layer
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18. 18

19. Polymer Matrix Diffusion Controlled TDDS
 Drug reservoir is prepared by dispersing the drug homogenously in a hydrophilic
and lipophilic polymer matrix.
 The resultant medicated polymer is then moulded on a medicated disc of defined
surface area and thickness.
 The drug reservoir can also be formed by dissolving the drug and polymer in a
common solvent and then evaporation of solvent at an elevated temperature.
 This drug reservoir containing polymer disc is then is then pasted over a base plate
containing drug impermeable backing membrane.
 The rate of drug release is given by:
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20. 20

21. Microreservoir Type TDDS
 A combination of reservoir and matrix diffusion type drug delivery system.
 A drug reservoir is formed by first suspending the solid drug in an
aqueous solution of water soluble polymer. This drug suspension is
homogenously dispersed in a lipophilic polymer by high energy
dispersion technique.
 This forms the microscopic spores of drug reservoir which are supported
over an occlusive pad and are thermodynamically unstable.
 Stabilization by cross linking the polymer chain in-situ using cross linking
agent.
 It can be further coated with a layer of biocompatible polymer to improve
the drug release.
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22. 22

23. Some Marketed Formulations:
Type of TDDS Example
Membrane Permeation Controlled TDDS • TransderScop® (Motion sickness)
• TransNitro® (Angina pectoris)
• Cetapres-TTS® (Hypertension)
• Delivery of Estradiol, Prostaglandin
Adhesive Dispersion Type TDDS • Deponit® (Angina pectoris)
• Frandol® (Angina pectoris)
• Controlled administration of Verapamil
Polymer Matrix Diffusion Controlled TDDS • Nitro-Dur® (Angina pectoris)
• Estradiol
• Verapamil
Microreservoir Type TDDS • Nitro-Disc® (Angina pectoris)
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24. Current Limitations of TDDS
 Restricted to only small population of drug candidates.
 No guarantee that the proposed TDDS can deliver 100% dose of the drug.
 Cannot optimize the ‘inter and intra’ subject variability, hence may leads to
fluctuations in result.
 The performance of TDDS is totally depend upon adhesive.
 Small damage to the drug reservoir may lead to dose dumping.
 Drug after passing through the skin may either precipitate due to pH of
the skin or metabolize due to enzymes.
 These limitations leads to the advancements in some effective techniques
in TDDS.
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25. Advancements in TDDS:
Iontophoresis
 It utilizes the small amount of current to deliver the charged molecules across the
skin.
 It was first used experimentally to deliver strychnine and cyanide to rabbits.
 Iontophoresis simply defined is the application of an electrical potential that
maintains a constant electric current across the skin and enhances the delivery of
ionized as well as unionized moieties.
 Offering better control over the amount of drug delivered.
 Improving the delivery of polar molecules as well as high molecular weight
compounds.
 Reducing considerably inter and/ or intra subject variability
 Better absorption of poorly absorbed ionic drugs.
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26. Continued….
 The iontophoretic technique is based on the general principle that like
charges repel each other.
 Thus during iontophoresis, a positively charged drug is delivered at the
anode.
 Similarly negatively charged ions are delivered at the cathode.
 The intensity of current should be taken into consideration.
 Drawbacks are possibility of electric shock, skin irritation, burns.
 Cost of treatment.
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27. 27

28. Electroporation
 In this technique, the high voltage is applied across the skin which generates
the pores and facilitates drug transport across the skin.
 High voltage ~100V and short treatment duration is applied.
 Drug is encapsulated in vesicles or particles.
 E.g. Fentanyl, Mannitol, Methotrexate, Ascorbic acid, Timolol, etc.
 DNA delivery in mice.
 It causes rapid dissociation of stratum corneum through which large and small
peptides, oligonucleotides, and such other drugs can be penetrated.
 The degree of enhancement is related to the applied voltage, number and
duration of the pulse.
 More clinical experimentation is needed for commercialization of this therapy.
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29. 29

30. Sonophoresis/ Phonophoresis
 It was firstly suggested for absorption of analgesics and anti-inflammatory
agents.
 A technique which utilizes the ultrasonic sound energy for the delivery of
drug via skin.
 Application of ultra sound increases the permeability of skin.
 Ultrasonic sound- 0.02 MHz frequency- not audible to human.
 Short duration of treatment
 Ultrasonic waves are mainly created by transducer which converts
electricity to sound energy.
 It basically works on cavitation phenomenon
 E.g. Interferon, Insulin, Erythropoietin etc.
 Also can be applied to vaccines and gene delivery.
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31. 31

32. Microneedles:
 It was first used during 1900’s.
 But the concept was floored up and patented by ALZA Corp.
 Microneedles are 100 to 200 µm in length. It is provided with drug
reservoir and acts as a mean to increase drug permeation across the skin.
 Microneedles, when applied to the skin, painlessly create micropores in
the stratum corneum without causing bleeding.
 These micropores offer lower resistance to drug diffusion.
 Omits the SC.
 It can be made from various materials like silicon, glass, titanium or any
other material.
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33. 33

34. Vesicular Systems:
 these are like liposomes.
 Two vesicular novel DDS have been emerged – Transferosomes and ethosomes.
 These have some favorable characteristics due to which they have gather the
attention of researchers.
 Vesicular systems show importance because of their ability to give sustained
release action of drugs.
 These systems exhibit several advantages which include:
1. They can encapsulate both hydrophilic and lipophilic moieties.
2. Prolong half lives of drugs by increasing duration in systemic circulation due to
encapsulation.
3. Ability to target organs for drug delivery.
4. Biodegradability and lack of toxicity.
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35. Transferosomes: features
 Nanosized lipid vesicles (200-300 nm) composed of drug, lipid and surfactant.
 Also known as ‘ultra-deformable vesicles’
 Consists of central aqueous cavity.
 Minimum chances of immunogenic reactions.
 Can act as depot forming tool.
 Limitations are- 1. they are expensive
2.not stable under normal conditions, hence requires special
conditions for manufacturing, transport and storage etc.
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36. Composition of Transferosomes
Sr.
No
Class Example Use
1 Phospholipids Soya phosphatidyl choline, egg
phosphatidylcholine etc.
Vesicles forming
component
2 Surfactants Sod.cholate, Sod.deoxycholate,
Tween-80, Span-80, Tween 20
Vesicles forming
component
3 solvents Ethanol, methanol, isopropyl
alcohol, chloroform
As a vehicle
4 Buffering agent Saline phosphate buffer (pH 6.4),
phosphate buffer (pH 7.4)
As a hydrating
medium
5 Dye Rhodamine For CSLM study
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37. Method of preparation: Thin film hydration
method
Phospholipid +
surfactant dissolved in
volatile organic
solvent (lipophilic
drug)
Evaporation at 40-
50ºc to form a thin
film
Thin film hydrated
with buffer (pH 6.8) at
60 rpm with rotation
for some time
(hydrophilic drug)
Prepared vesicles
allowed to swell at
room temperature
for 2 hrs.
Sonication of
formulation to get
the vesicles of
uniform shape and
size
Sonicated vesicles
are dried in vacuum
to remove traces of
solvent
Transferosomes
will form
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38. Lipid Film Hydration Technique
Drug+phospholipid+et
hanol are dissolved in
the mixture of ethanol:
chloroform(1:1)
Evaporation of solvent
while hand shaking
above lipid transition
temp.(43°C).
A thin film is formed at the
wall of flask with rotation
A thin film kept overnight
to remove traces of
solvents
Film is hydrated with
phosphate buffer of
pH 7.4 with gentle
shaking for 15 minutes
Transferosomes will form
Further shake the
Transferosome suspension
for 15-20 minutes
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39. Mechanism of drug delivery via skin39
 TFS when applied under suitable conditions, can transfer 0.1 mg of drug
across the intact skin.
 The drug delivery across the skin depends on either the pore size or its
capacity to deform itself.
 When applied topically, they fairly interact with skin and finally squeeze
themselves through the pores of skin to cross the major barrier presented
by SC.
 The mechanism for penetration is the generation of osmotic gradient due
to evaporation of water while applying the Transferosome on the skin
surface.
 The transport of these elastic vesicles is thus independent of
concentration.

40.  The two mechanisms of action have been proposed:
1. TFS act as drug vectors, remaining intact after entering the skin
2. TFS act as penetration enhancers, disrupting the highly organized
intercellular lipids from stratum corneum, and hence facilitating the drug
penetration in and across the stratum corneum.
 The recent study proposed that the penetration and permeation of the
vesicles across the skin are due to the combination of the two mechanism.
 Depending on the nature of the active substance and composition of
Transferosomes, one of the two mechanism will work..
 The magnitude of the driving force of transport also plays an important
role.
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41. Applications of TFS:41
 Transferosomes as a carrier for proteins:
 The Transferosomes-mediated bioavailability of serum albumin is very
effective.
 The transferosomal preparation of this protein induces a strong response
after a repeated cutaneous applications.
 Transferosomes as a carrier for insulin:
 Transferosome associated insulin has an efficiency of >80% if optimized
properly.
 Transfersulin™ - The first sign of systemic hypoglycemia is observed after
90 to 180 min.

42.  Transferosomes as a carrier for interferon:
 INF-α is chemically protein, so its delivery is very difficult.
 TFS as drug delivery system have potential for providing controlled release of
 Transferosomes for transdermal immunization:
 TFS can be loaded with soluble and immunologically active proteins like integral
membrane protein, human serum albumin.
 Advantage is that they can be applied without injection.
 Transferosomes as a carrier for corticosteroids:
 Corticosteroids are used topically for many dermatological conditions.
 Available corticosteroid formulations for topical use fulfill only a few of the
therapeutic goals.
 Corticosteroids TFS can adapt their shape and size to the surrounding stress and
thus penetrate the drug through the skin barrier.
 TFS loaded corticosteroids are active at low dose than currently available topical
formulations.
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43.  TFS as a carrier for topical analgesics and anesthetic agents:
 Transdermal analgesics hardly respond due to their high water solubility and do
not adequately permeate through the skin.
 Lipophilic analgesics have a somewhat higher chances of achieving desired
therapeutic effect if they are applied under appropriate conditions.
 But analgesic loaded TFS can penetrate rapidly through the intact dermis and can
also bring appropriate amount of drug into the skin
 Application of anesthetic in Transferosome suspension induces a local anesthesia
within less than 10 minutes.
 But the effect of transferosomal anesthesia lasts longer i.e. up to 3 hours.
induced local anesthesia lasts for less than 30 minutes.
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44.  TSF as a carrier for anticancer drugs:
 Tamoxifen loaded Transferosomes were studied in animals.
 Experiments with the radioactively labelled tamoxifen in TFS
mice reveal significantly higher concentration and better
specificity when compared with oral administration.
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45. Marketed Formulations of TFS:
Drug Marketed Formulation
Ketoprofen:
NSAID
Diractin (Transferosome gel) developed by
IDEA AG
Diclofenac:
NSAID
Transfenac Lotion
45

46. Ethosomes:
 Another vesicular system resembling liposomes, but differ in composition.
 Liposome chiefly consists of phosphatidyl choline and cholesterol.
 In ethosomes, cholesterol is replaced with large quantity of ethanol (25-40%).
 Silent features of ethosomes:
 These ethanolic vesicles can be used for delivery of hydrophilic, lipophilic and
ampiphilic drugs.
 They can act as a carrier for low as well as high molecular weight substances. E.g.
analgesics, corticosteroids, sex hormones, insulin.
 Biocompatible and biodegradable
 Entrapment efficiency is high due to high amount of ethanol.
 May act as depot formulation.
 They can be applicable as topical as well as systemic delivery
46

47. Mechanism of drug delivery by ES:
 Increased penetration of drug with ethosomal formulations could be due
to combined effect of ethanol and lipid vesicles.
 Skin has densely packed structure where lipids are systemically arranged.
 Alcohol is known as penetration enhancer. It might interact and disturb
the configuration of skin lipids and penetrate through the SC.
 E.g. Minoxidil, Testosterone, Zidovudine, Lamivudine, Acyclovir etc.
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48. Future Prospects of TDDS:
 Now a days TDDS is achieved not only with conventional formulations but with
some novel approaches such as transdermal films, transdermal patches,
transdermal vesicular systems.
 There are various hidden shades that are still to be explored and can be used for
the benefits of the patients.
 Among all the novel forms of TDDS Transferosomes and ethosome are looking
promising as they can provide excellent transdermal permeability and entrapment
efficiency.
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49. References:
 Manish k. Chaurasia, Mohini Chaurasia, Nitin K. Jain; Novel Carriers for
Drug Delivery; PharmaMed Press; Second Edition; Reprint 2016; 217-254.
 N. K. Jain; Controlled and Novel Drug Delivery; CBS Publishers and
Distributors; First Edition; Reprint 2005; 100-129.
 International Journal of Pharmaceutical Sciences Review and Research;
Available online at www.globalresearchonline.net; Volume 3, Issue 2, July –
August 2010; Article 009; ISSN 0976 – 044X.
 International Journal of Research and Development in Pharmacy and Life
Sciences: Available online at http//www.ijrdpl.com; February - March, 2013,
Vol. 2, No.2, pp 309-316; ISSN: 2278-0238
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50. THANK YOU
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